RNA SEQUENCING TO DIAGNOSE SEPSIS

Deep RNA sequencing is a technology that provides an initial diagnostic for sepsis that can also monitor the indicia of treatment and recovery (bacterial counts reduce, physiology returns to steady-state). The invention can be used for many other hospital conditions, particularly those needing an intensive care unit stay with the attendant risk of bacterial infection, such as trauma, stroke, myocardial infarction, or major surgery.

FIELD OF THE INVENTION

This invention generally relates to chemical analysis of biological material, using nucleic acid products used in the analysis of nucleic acids, e.g., primers or probes for diseases caused by alterations of genetic material.

REFERENCE TO RELATED APPLICATIONS

This patent matter claims priority to provisional patent application U.S. Ser. No. 62/976,873, filed Feb. 14, 2020.

BACKGROUND OF THE INVENTION

Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection. Despite declining age-standardized incidence and mortality, sepsis remains a significant cause of health loss worldwide. Rudd et al., The Lancet, 395(10219), 200-211 (Jan. 18, 2020). Sepsis is treatable, and timely implementation of targeted interventions improves outcomes.

Sepsis is diagnosed clinically by the presence of acute infection and new organ dysfunction. Singer et al., JAMA, 315, 801-810 (February 2016). Unlike the previous concepts of septicemia or blood poisoning, the current definition of sepsis extends across bacterial, fungal, viral, and parasitic pathogens. The definition focuses on the host response as the major source of morbidity and mortality. Bone et al., Chest, 101, 1644-1655 (1992). Globally, there were about 48.9 million cases of sepsis in 2017, with about 11.0 million total sepsis-related deaths worldwide, representing 19.7% (18-2-21-4). This number may be a substantial undercount. Rudd et al., The Lancet, 395(10219), 200-211 (Jan. 18, 2020). Sepsis results from an underlying infection, so sepsis is an intermediate cause of health loss. Because, according to the principles of the International Classification of Diseases (ICD), causes of death are assigned based on the underlying disorder that triggers the chain of events leading to death rather than intermediate causes, sepsis, when reported as the cause of death, are considered miscoded.

Thus, the global burden of sepsis is more significant than previously appreciated. There is substantial variation in sepsis incidence and mortality according to Healthcare Access and Quality Index (HAQ Index), Lancet, 390, 231-266 (2017)), with the highest burden in places that cannot prevent, identify, or treat sepsis. Further research is needed to understand these disparities and developing policies and practices targeting their amelioration. More robust infection-prevention measures should be assessed and implemented in areas with the highest incidence of sepsis and among populations on which sepsis has the most significant impact. The impact of sepsis is especially severe among children, so more than half of all sepsis cases worldwide in 2017 occurred among children, many of them neonates.

Physicians diagnose sepsis using clinical judgment under one or more clinical scores. The systemic inflammatory response syndrome (SIRS) approach assesses an inflammatory state affecting the whole body, which is the body's response to an infectious or non-infectious challenge. Jui et al. (American College of Emergency Physicians), Ch. 146: Septic Shock. in Tintinalli et al. (eds.). Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 7th edition, (New York: McGraw-Hill, 2011). pp. 1003-14. Sepsis has both pro-inflammatory and anti-inflammatory components. The qSOFA approach simplifies the SOFA score by including only its three clinical criteria and by including any altered mentation. Singer et al., JAMA, 315, 801-810 (February 2016). qSOFA can easily and quickly be repeated serially on patients.

A culture of the bacterial infection confirms a diagnosis of sepsis. A culture diagnosis can be delayed by forty-eight hours and sometimes cannot be performed successfully. Clinical judgment sometimes misses sepsis.

Biomarkers are being developed for sepsis, but no reliable biomarkers exist. A 2013 review concluded moderate-quality evidence exists to support the use of the procalcitonin level as a method to distinguish sepsis from non-infectious causes of SIRS. Still, he level alone could not definitively make the diagnosis. Wacker et al., The Lancet Infectious Diseases. 13(5), 426-35 (May 2013). A 2012 systematic review found that soluble urokinase-type plasminogen activator receptor (SuPAR) is a nonspecific marker of inflammation and does not accurately diagnose sepsis. Backes et al. Intensive Care Medicine, 38(9): 1418-28 (September 2012).

There remains a need in the medical art for a better diagnosis of sepsis.

SUMMARY OF THE INVENTION

The concept of diagnostics is analogous to using a fishing lure to find a single protein, gene, or RNA sequence. The invention provides an improved concept, using a fishing net to obtain all the RNA data in a sample, and use computational biology to better sort through all the data (fish) to identify patients with sepsis and the bacteria causing the immune response. The invention provides an initial diagnostic for sepsis that can also monitor the indicia of treatment and recovery (bacterial counts reduce, physiology returns to steady-state). The invention can be used for many other hospital conditions, particularly those needing an intensive care unit stay with the attendant risk of bacterial infection, such as trauma, stroke, myocardial infarction, or major surgery.

In the first embodiment, the invention provides unmapped bacterial RNA reads to identify bacteria that cause sepsis. In the second embodiment, the invention provides unmapped viral reads to identify sepsis or viral reactivation. In the third embodiment, the invention provides the use of unmapped B/T V(D)J to identify sepsis. In the fourth embodiment, the invention provides Principal Component Analysis of RNA splicing entropy to identify sepsis. In the fifth embodiment, the invention provides RNA lariats to identify sepsis. In the sixth embodiment, the invention provides a Principal Component Analysis of gene expression, alternative RNA splicing, or alternative transcription start and end to identify sepsis.

In producing the listed embodiments, one of ordinary skill in the molecular biological art uses one or more of the following steps.

The first step is for one of ordinary skill in the molecular biological art to obtain RNA sequencing from a body sample. In the seventh embodiment, the body sample is a bodily fluid sample. In the eighth embodiment, the bodily fluid sample is blood. In the ninth embodiment, the target is 100,000,000 reads/sample.

The second step is for one to align the RNA sequencing data (reads) to the genome of interest. In the tenth embodiment, the reads from a human sample are aligned to a human genome. In the eleventh embodiment, the reads from a mouse sample are aligned to a mouse genome.

The third step is to select the un-mapped reads and analyze the reads using a Read Origin Protocol (ROP).

In the first embodiment (above), the next step is to identify bacteria that are present in the sample. From the ROP, one of ordinary skill in the molecular biological art identifies bacteria that are present in the sample. In the twelfth embodiment, one of ordinary skill in the molecular biological art or medical art uses the identified bacteria to list potential causative organisms of sepsis (product).

In the second embodiment (above), from the ROP, the next step is to identify the viruses present in the sample. In the thirteenth embodiment, one uses the virus identified with PCA to identify likely sepsis samples.

In the third embodiment (above), from the ROP, the next step is to identify the T/B cell epitopes present in the samples. In the fourteenth embodiment, one uses the T/B cell epitopes identified with PCA to identify likely sepsis samples.

Alternatively (or in combination), in the third step, one selects the mapped reads and then uses a program that enables detection and quantification of alternative RNA splicing events to identity gene expression, RNA splicing events, alternative transcription start/end, or RNA splicing entropy. In a fifteenth embodiment, the program that enables detection and quantification of alternative RNA splicing events is Whippet. In the sixteenth embodiment, one uses the gene expression changes, RNA splicing events, and alternative transcription start/end with PCA to identify likely sepsis samples. In the seventeenth embodiment, one uses the RNA splicing entropy identified with PCA to identify likely sepsis samples.

In the fifth embodiment, from the gene expression, RNA splicing events, alternative transcription start/end, or RNA splicing entropy, the next step is for one to identify RNA lariats from the mapped reads. In the eighteenth embodiment, one uses the RNA lariats with PCA to identify likely sepsis samples.

In the nineteenth embodiment, the invention provides an output product with five plots comprising bacterial RNA reads, viral reads, B/T V(D)J epitopes, RNA splicing entropy, and RNA lariat embodiments described above and a list of likely bacteria causing the infection.

RNA sequencing data be used in several ways. (1) Identification of biomarkers. Rather than need to pick a subset to test for, RNA sequencing data can identify genes with increased expression that would correlate to biomarkers of interest. (2) Identification of new biomarkers. RNA sequencing data allows for analysis of processes such as RNA splicing. The method of RNA splicing entropy can be quantified and grouped according to a Principal Component Analysis into sick or not sick. RNA lariats can also be identified in sequencing data and used as a potential biomarker. All biomarkers can be followed over time to assess for resolution of the sepsis. (3) Use of un-mapped reads in sepsis. RNA sequencing typically aligns with the genome of reference (i.e., the human genome). Reads that are not aligned to the human genome are discarded (the percentage of un-mapped reads could itself be a biomarker). These un-mapped reads could be of two major potential interests. (4) Identification of the microbe causing the infection. The unmapped reads can be referenced to the genome of disease-causing microbes (bacteria, viruses, fungi, etc.) to identify the causative organism and start treatment earlier. Serial measurements can also assess the effectiveness of treatment.

The results presented show that mice exposed to trauma separated from controls using PCA. Similarly, mice that did not survive fourteen days post exposure clustered closely together on PCA. These results show a substantial difference in global pre-mRNA processing entropy in mice exposed to trauma vs. controls, and that pre-mRNA processing entropy is useful in predicting mortality.

DETAILED DESCRIPTION OF THE INVENTION

Industrial Applicability

Despite being the cause of death in 1 out of 5 people in the world, there is not a single standard test to diagnose sepsis. Despite declining age-standardized incidence and mortality, sepsis remains a significant cause of health loss worldwide. Rudd et al., The Lancet, 395(10219), 200-211 (Jan. 18, 2020). Sepsis patients undergo the physiology common to patients in the intensive care unit: hypotension, tachycardia, hyperthermia, and hypoxia.

Delays in treatment for sepsis is known to impact mortality. Early identification of the differences between clinically similar patients would allow for earlier interventions (surgery, antibiotics). Using RNA sequencing technology combined with computation biology techniques to understand RNA biology the differences in these two patients could be identified. Earlier prediction of complications would also allow for triage of patients to facilities equipped to deal with them and allow for better discussions regarding expected mortality and morbidity.

Currently it takes days to get a final diagnosis for bacterial pathogen, since culturing of the bacteria is needed. Confirming bacteremia is currently done microbial blood culture, but the turnaround time can lead to a delay in diagnosis. Biron et al., Biomarker Insights, 10(Suppl 4), 7-17 (Sep. 15, 2015). Procalcitonin (PCT) has been shown to correlate more closely to onset and treatment of sepsis than C-reactive protein (CRP). Vijayan et al., J. Intensive Care (Aug. 3, 2017). Much work has been done with PCT as a predictor of sepsis before symptom onset. Dolin et al., Shock, 49(4), 364-70 (April 2018). PCT has low specificity for sepsis, and is elevated in cancers, autoimmune diseases, and other physiological stressors. Bloos & Reinhart, Virulence, 5(1), 154-60 (Jan. 1, 2014).

RNA sequencing data can identify the bacteria more quickly than culture. The drop in the cost of sequencing has refocused genetic analyses from DNA to RNA sequencing. Methods to analyze this data have improved. Stark et al., Nature Reviews Genetics (2019). Compared to DNA, RNA undergoes dynamic changes by transcription and post-transcriptional processing, providing unique insight into cellular activity. RNA reflects a broader source of infectious etiologies, given that both DNA and RNA viruses have RNA genetic material, whether in the genome or by transcription of mRNA. Patients with trauma who die or have complications are expected to have different changes in expression, alternative RNA splicing, and alternative transcription start/end compared to patients who survive and do not have a complication. The differences seen in RNA biology may correlate with injury severity or predict outcomes. This invention should help direct care in trauma patients when RNA sequencing speeds increase to allow for results that are available when needed for patients in the ICU (within one hour).

RNA sequencing data related to other processes (RNA splicing entropy, gene expression, viral counts, lariat counts, etc.) will provide a signature that can identify patients with sepsis. A better understanding of RNA biology in the clinical scenario of critically ill sepsis patients can have a broad impact on biomedical science. When the information in RNA sequencing data can identify patients who have not resolved the immune response to the initial sepsis, outcomes can improve.

The number of unmapped reads aligning to viral pathogenic genomes can be a biomarker of critical illness. Patients with late death should have different gene expression, alternative RNA splicing (including RNA splicing entropy), and alternative transcription start/end as compared to patients with an early death. the genes with increased alternative RNA splicing (including RNA splicing entropy), and alternative transcription start/end are expected to be different in the patients who died late compared to those who died early. These identified genes provide insight into proteins not considered in trauma patients as potential biomarkers or targets of therapeutic intervention, but point to pathological mechanism not appreciated or unclear.

Moreover, RNA biology before the trauma should be able to predict survivors. Mice that survive to fourteen days should have less RNA biology changes compared to mice at the early time point. This are done across three distinct background mice to account for the heterogeneity of humans and the comparability of the two most common immunological/genetic mouse model strains used. As it relates to comparing samples across mouse strains, since gene expression, RNA splicing, and alternative transcription start/end are all basic molecular functions, the results remain similar across the multiple strains.

Identification of B and T cell epitopes from the unmapped reads could be a biomarker for sepsis. Critical illness decreases the diversity of these epitopes. A resolution could signal an improvement in clinical status. Losing some epitopes could indicate immune suppression seen in critical illness.

Alternative transcription start and end is another biological process potentially influenced by sepsis. Current technology now allows us to identify changes in transcription with RNA sequencing data. Hardwick et al., Frontiers in Genetics, 10, 709 (2019); Cass & Xiao X, Cell Systems, 9(4), 23, 393-400.e6 (October 2019). The genes that have increased difference in alternative transcription start/end could be disease treatment targets. A change to the start or end of the RNA is likely to change the ultimate endpoint of that transcript. Understanding the changes in transcription start and end would better describe the ultimate result of proteins since that were thought to be transcribed and translated could have been transcribed (with changes in the start or end) which lead to nonsense mediated decay or the translation of an alternative isoform.

Genes with significant alternative splicing and high entropy in the mouse after trauma may be target for intervention. This invention can better diagnose sepsis and the microbe causing the disease. Emergency room and critical care physicians can use the invention.

Solution: RNAs as Biomarkers of Critical Illness

While proteins have traditionally been used to reflect inflammatory load, RNAs are more specific to certain etiologies and clinical outcomes.

High through-put sequencing technologies allows for coding and non-coding RNAs (ncRNA) as markers of disease risk and progression. Next-generation sequencing (NGS) quantifies RNAs by sequencing of complementary DNA (cDNA), allowing transcriptomic analysis of mRNAs, ribosomal RNAs (rRNA), and ncRNAs. Kukurba & Montgomery, Cold Spring Harb. Protoc., 2015(11), 951-69 (Apr. 13, 2015).

Coding and non-coding RNAs have been studied as biomarkers. Less attention has been on the portion of data produced (9-20%) via RNA-sequencing that is consistently discarded when it cannot be mapped to a reference genome. Mangul et al., ROP: Dumpster diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues. Genome Biol., 19 (Feb. 15, 2018).

Physiologic stress induces viral reactivation by impairing the immune response and upregulating cell cycle progression pathways such as MAPK and NF-κB. Walton et al., PLoS One, 9(6), e98819 (Jun. 11, 2014); Traylen et al., Future Virol., 6(4), 451-63 (April 2011). Secretion of pro-inflammatory cytokines, such as TNF-α, has been shown to play a role in reactivating latent cytomegalovirus (CMV) in patients that had undergone recent stress even absent systemic inflammation. Prosch et al., Virology, 272(2), 357-65 (Jul. 5, 2000). A combination of inflammatory challenges and immune cell dysregulation has been shown to contribute to an environment that both promotes viral reactivation and maintains viremia. Walton et al., PLoS One, 9(6), e98819 (Jun. 11, 2014).

In a traumatic shock EXAMPLE, C57BL6 mice were treated by sequential hemorrhagic shock followed by cecal ligation and puncture, which induces sepsis. RNA was extracted from cellular component of lung and immune cells in blood after discarding plasma and serum. Samples were collected from both healthy and critically ill mice and sequenced via NGS at Gene Wiz in South Plainfield, N.J., USA. Reads were aligned to mm9 genome using STAR and then unmapped reads were mapped to viral genomes via ROP. Dobin et al., Bioinformatics, 29(1), 15-21 (January 2013). Mangul et al., Genome Biol., 19 (Feb. 15, 2018). Two-sample t tests were conducted to compare number of viral reads in healthy versus critically ill mouse lung and blood.

Definitions

For convenience, the meaning of some terms and phrases used in the specification, examples, and appended claims, are listed below. Unless stated otherwise or implicit from context, these terms and phrases have the meanings below. These definitions are to aid in describing particular embodiments and are not intended to limit the claimed invention. Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For any apparent discrepancy between the meaning of a term in the art and a definition provided in this specification, the meaning provided in this specification shall prevail.

“Acute respiratory distress syndrome (ARDS)” has the medical art-defined meaning. ARDS is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Symptoms include shortness of breath, rapid breathing, and bluish skin coloration. Causes may include sepsis, pancreatitis, trauma, pneumonia, and aspiration.

“Alternative splicing (AS)” has the molecular biological art-defined meaning. RNA splicing is a basic molecular function that occurs in all cells directly after RNA transcription, but before protein translation, in which introns are removed and exons are joined. Alternative splicing or alternative RNA splicing, or differential splicing, is a regulated process during gene expression that results in a single gene coding for multiple proteins. Exons of a gene can be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. The proteins translated from alternatively spliced mRNAs can contain differences in their amino acid sequence and, often, in their biological functions.

“Mann Whitney U tests” has the statistical art-defined meaning. The Mann-Whitney U test (also called the Mann-Whitney-Wilcoxon (MWW), Wilcoxon rank-sum test, or Wilcoxon-Mann-Whitney test) is a nonparametric test of the null hypothesis that it is equally likely that a randomly selected value from one population is less than or greater than a randomly selected value from a second population. This test can be used to investigate whether two independent samples were selected from populations having the same distribution.

“mountainClimber” is a cumulative-sum-based approach to identify alternative transcription start (ATS) and alternative polyadenylation (APA) as change points. Unlike many existing methods, mountainClimber runs on a single sample and identifies multiple ATS or APA sites anywhere in the transcript. Cass & Xiao X, “mountainClimber identifies alternative transcription start and polyadenylation sites in RNA-Seq.” Cell Systems, 9(4), 23, 393-400.e6 (October 2019).

“Next Generation Sequencing (NGS)” has the molecular biological art-defined meaning. NGS technology is typically characterized by being highly scalable, allowing the entire genome to be sequenced at once. Usually, this is accomplished by fragmenting the genome into small pieces, randomly sampling for a fragment, and sequencing it using one of a variety of technologies.

“Principal Component Analysis (PCA)” has the computer-art and molecular biological art-defined meaning. Principal component analysis is a statistical procedure that uses an orthogonal transformation to convert a set of observations of possibly correlated variables (entities each of which takes on various numerical values) into a set of values of linearly uncorrelated variables called principal components.

“Read origin protocol (ROP)” has the computer-art meaning of is a computational protocol that aims to discover the source of all reads, including those originating from repeat sequences, recombinant B and T cell receptors, and microbial communities. The Read Origin Protocol was developed to determine what the unmapped reads represented. Mangul al., “ROP: Dumpster diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues.” Genome Biology 19, 36 (2018). Recent development of Read Origin Protocol (ROP) has demonstrated that unmapped reads align to bacterial, viral, fungal, and B/T rearrangement genomes.

“Read” has the molecular biological art-defined meaning of reading sequencing results to determine nucleotide base structure.

“Sepsis” has the medical art-defined meaning of a life-threatening condition that arises when the body's response to infection injures its tissues and organs. Bone et al., “Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.” Chest, 101, 1644-1655 (1992); Singer et al., “The third international consensus definitions for sepsis and septic shock (Sepsis-3).” JAMA, 315, 801-810 (February 2016).

“STAR aligner” is the Spliced Transcripts Alignment to a Reference (STAR), a fast RNA-seq read mapper, with support for splice-junction and fusion read detection. STAR aligns reads by finding the Maximal Mappable Prefix (MMP) hits between reads (or read pairs) and the genome, using a Suffix Array index. Different parts of a read can be mapped to different genomic positions, corresponding to splicing or RNA-fusions. The genome index includes known splice-junctions from annotated gene models, allowing for sensitive detection of spliced reads. STAR performs local alignment, automatically soft clipping ends of reads with high mismatches. Dobin et al., STAR: Ultrafast universal RNA-seq aligner. Bioinformatics, 29(1), 15-21 (January 2013).

“V(D)J recombination” has the molecular biological art-defined meaning. V(D)J recombination occurs in developing lymphocytes during the early stages of T and B cell maturation, involves somatic recombination, and results in the highly diverse repertoire of antibodies/immunoglobulins and T cell receptors (TCRs) found in B cells and T cells, respectively.

“Whippet” (OMICS_29617) is a program that enables detection and quantification of alternative RNA splicing events of any complexity that has computational requirements compatible with a laptop computer. Whippet is a program that applies the concept of lightweight algorithms to event-level splicing quantification by RNAseq. The software can facilitate the analysis of simple to complex AS events that function in normal and disease physiology. Alternative splicing events with high entropy are identified using Whippet. Sterne-Weiler et al., Molecular Cell, 72, 187-200.e186 (2018).

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Materials and Methods

Mouse strains. Mice are purchased from The Jackson Laboratory. C57BL/6J, the most popular mouse model used, exhibits a Th1/more pro-inflammatory phenotype. C57BL/6J is also the background of numerous knock out animals. BALB/cJ is also another commonly used mouse and can be the background of analyses with knockout animals, but has more of a Th1/anti-inflammatory predominant repose phenotype. The CAST mouse is derived from wild mouse and genetically different from common laboratory mice. Using these three strains adjusts for the heterogeneity seen in humans.

Mouse model of sepsis; cecal ligation and puncture (CLP). A mouse model of hemorrhagic shock followed by the induction of sepsis by cecal ligation and puncture induces severe sepsis. Lomas-Neira et al., Shock, 45(2), 157-65 (2016)); Monaghan et al., Mol Med., 24(1), 32 (Jun. 18, 2018); Wu et al., PLoS One, 8(10) (2013); Monaghan et al., Annals of Surgery, 255, 158-164 (2012). Anesthetized, restrained mice in supine position catheters are inserted into both femoral arteries. Mice are bled over a 5-10-minute period to a mean blood pressure of 30 mmHg (±5 mmHg) and kept stable for 90 minutes. To achieve this level of hypotension, the mice have one mL of blood withdrawn. One mL of blood is approximately 50% of their blood volume so this correlates to class 4 hemorrhagic shock in humans. Mice are resuscitated intravenously (IV) with Ringers lactate at four times drawn blood volume. Sham hemorrhage are performed as a control in which femoral arteries ligated, but no blood are drawn to mimic the tissue destruction. The following day, sepsis is induced as a secondary challenge by cecal ligation and puncture. The timing of this secondary challenged is based on previous findings that hemorrhagic shock followed twenty-four hours by the induction of sepsis produced results in line with critical illness such as altering PaO2to FIO2ratios. The mouse model uses a double hit of hemorrhagic shock followed by cecal ligation and puncture correlates to a missed bowel injury in humans after hemorrhagic shock. This mouse model correlates with an injury severity score (ISS) of twenty-five. The dual challenge of hemorrhagic shock followed by septic shock is in line with the sepsis patients who are critically ill. Sometimes patients present with bleeding from wounds and a bowel injury that is missed upon initial assessment.

Sample sizes for these assays are based upon results from the inventor's previous work looking at the alternative splicing of sPD-1 and an effect size of Cohen's d=2.85 standard deviations difference between groups was calculated. With such a large effect size, power analysis poorly justifies sample size since, if the effect size is tenable, it would be exceedingly rare for assays of any sample size to fail to reach statistical significance. However, small sample sizes provide poor point estimates and may be very unstable. the inventors chose a sample size of six mice per group based on feasibility and hoping to provide a reasonable point estimate for each group.

Mice of both sexes are used, because there are significant sex differences in the response to bleeding from trauma. Deitch et al., Annals of Surgery, 246(3), 447-53; discussion 53-5 (2007).

Human subjects. Patients are recruited from the Trauma Intensive Care Unit (TICU) at Rhode Island Hospital with Institutional Review Board approval and consent. The patient population at Rhode Island Hospital (a level 1 trauma center) is sufficient for this EXAMPLE. Over 3700 trauma patients were admitted to the hospital in 2018. The TICU admitted 765 patients in 2018. This would cause over 3000 patients admitted to the intensive care unit over the 4-year project. Using the advanced technology of the hospital's electronic health records (EPIC) combined with the mandated trauma registry there are streamlined efforts to recruit and retain patients. Since the mouse model correlates to an injury severity score (ISS) of twenty-five, the goal are to ensure that the average ISS for all the patients is twenty-five. Minimal risk to the patient are maintained since there is no direct benefit; the blood collected are less than 50 mL over an 8-week period and not collected more than twice a week. Blood samples from patients are taken on admission (25 mL) and during the TICU stay when a complication is developed (25 mL). This should cause the maximum for the initial 8-week period after the trauma. When the patient is recovered, at least 8 weeks after the last blood draw, a final blood draw 50 mL of are done in the outpatient setting. A power analysis was done based upon previous results from human patients. The effect size of Cohen's d=0.8 using a power of 80% and alpha of 0.05 the inventors calculated a sample size of twenty-six per group. The mortality of patients in the TICU is 5%. To enroll twenty-six patients who die after trauma, the inventors need 520 TICU patients (26/0.05=520). No enrollment is planned in the last six months to ensure adequate follow up, data collection and analysis. Fourteen % of patients in the TICU have complications after trauma. Due to the correlation to the mouse model of an ISS of twenty-five, the average ISS for the enrolled patients are targeted at twenty-five. This causes the recruitment of some patients who are not used, however the samples are banked and not sent for RNA sequencing. After twenty-six patients who die and twenty-six patients with a complication are enrolled and the entire set of patients has an average ISS of twenty-five then recruitment will conclude.

Where patients are being recruited, variables such as age, weight, and medical co-morbidities are collected and compared across groups. If these variables are different (t test or rank sum), these factors are adjusted for in the analysis by regression.

In the human studies, both sexes are recruited and analyzed in the GTEx data set. Age, weight, and other health problems are constant in the mouse assays.

Sample collection and sequencing. Mouse blood and lung samples were obtained as described. Monaghan et al., Annals of Surgery, 255, 158-164 (2012). Data for humans was obtained from GTEx by their protocols. RNA was extracted using the MasterPure Complete DNA/RNA Purification kit (epicenter, Madison Wis., USA) followed by the Globin Clear Kit (ThermoScientific, Waltham, Mass., USA). RNA was then sent to Genewiz (South Plainfield, N.J., USA) for sequencing as 1400 ng RNA in forty μL of fluid.

The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS and the data used for the analyses were obtained from the GTEx Portal and dbGaP accession number phs000424.v6.p1.

Cloud based computing. All computational biology work are performed on cloud-based computing by Lifespan-RI Hospital approved and supported Microsoft Azure environment. This server manages all large data sets from RNA sequencing. An intentional decision was made to use cloud-based computing for this project. Due to the depth of sequencing that is needed for RNA splicing analysis (100 million reads vs. forty million), more data is generated from both sequencing and analysis (a small study generated one terabyte of sequencing data and another terabyte from the alignment to the genome). With such a large amount of data predicted available for the EXAMPLE, the ability to expand and contract the storage space and computing power in the cloud is the ideal choice. This server stores and analyzes data from both mouse and human samples. Since RNA sequencing data is always identifiable, the data from humans are treated as though it is protected health information (PHI), even though none of the typical identifiers (such as name, date of birth, etc.) are associated with the data. The server was created in collaboration with the Information Technology department at Rhode Island Hospital to ensure data security. The cloud server is only accessible through a hospital virtual desktop and data are saved only to the Azure server or a hospital computer. Data are encrypted while stored, and when in transit to or from the hospital. Any link to typical identifiers (name, date of birth, etc.) are kept separate from the sequencing data. The cloud-based server allows for large data analysis with computing and storage needs changing on a per-use basis. The Azure server is Linux based and uses programming in R and Python. The following pipeline encompasses the typical analysis: differential expression, RNA analysis is done with Whippet. This also includes an entropy measure, and genes of interest undergo GO term analysis. Genes with alternative transcription start and end sites identified through Whippet are correlated with findings from the mountainClimber analysis.

Computational analysis and statistics. RNA sequencing data from the mouse was first checked for quality using FASTQC. RNA-sequencing data collected from the GTEx consortium and the mouse ARDS model was analyzed with the Whippet software for differential gene processing. Alternative transcription events are those events identified by Whippet as ‘tandem transcription start site,’ ‘tandem alternative polyadenylation site,’ ‘alternative first exon,’ and ‘alternative last exon.’ Alternative RNA splicing events are those events labeled ‘core exon,’ ‘alternative acceptor splice site,’ ‘alternative donor splice site,’ and ‘retained intron.’ Alternative mRNA processing events where determined by a log 2 fold change of greater than 1.5+/−0.2. Statistical significance was calculated by the chi-square p-value of a contingency table based on 1000 simulations of the probability of each result.

Gene ontology (GO) was assessed using The Gene Ontology Resource Knowledgebase. Ashburner et al., Nature Genetics, 25, 25-29 (2000); The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Research, 47, D330-d338 (2019). Genes from the analyses were entered and outputs displayed. Outputs from gene ontology do not correlate with actual increase or decrease in a gene's expression but are related to expected based upon the set of genes entered.

Blood sample collection. Blood samples are collected on day 0 of ICU admission. Clinical data including COVID specific therapies was collected prospectively from the electronic medical record and participants were followed until hospital discharge or death. Ordinal scale can be collected as previously described by Beigel et al., (2020) New England Journal of Medicine; along with sepsis and associated SOFA score [See Singer et al., (2016) The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA, 315: 801-810], and the diagnosis of ARDS [See Ferguson et al. (2012) The Berlin definition of ARDS: An expanded rationale, justification, and supplementary material. Intensive Care Medicine, 38: 1573-1582].

RNA extraction and sequencing. Whole blood can be collected in PAXgene tubes (Qiagen, Germantown, Md.) and sent to Genewiz (South Plainfield, N.J., USA) for RNA extraction, ribosomal RNA depletion and sequencing. Sequencing can be done on Illumina HiSeq machines to provide 150 base pair, paired-end reads. Libraries were prepared to have three samples per lane. Each lane provided 350 million reads ensuring each sample had >100 million reads.

Computational Biology and Statistical Analysis. All computational analysis can be done blinded to the clinical data. The data can be assessed for quality control using FastQC [Andrews (2014) A quality control tool for high throughput sequence data. FastQC]. RNA sequencing data can be aligned to the human genome utilizing the STAR aligner [Dobin et al. (2013) Bioinformatics (Oxford, England), 29: 15-21]. Reads that aligned to the human genome can be separated and referred to as ‘mapped’ reads. Reads that do not align to the human genome, which are typically discarded during standard RNA sequencing analysis, were kept and identified as ‘unmapped’ reads. The unmapped reads then aligns to the releavant comparator and counted per sample using Magic-BLAST [Boratyn et al. (2019) BMC Bioinformatics, 20: 405]. The unmapped reads were further analyzed with Kraken2 [Wood, Lu, & Langmead, (2019) Genome Biology, 20: 257] using the PlusPFP index to identify other bacterial, fungal, archaeal and viral pathogens [see Kraken 2/Bracken Refseq indexes maintained by BenLangmead. It uses Kutay B. Sezginel's modified version of the minimal GitHub pages theme].

Reads that align to the human genome, the mapped reads, also can undergo analysis for gene expression, alternative RNA splicing, and alternative transcription start/end via Whippet [Sterne-Weiler et al., (2018) Molecular Cell, 72: 187-200.e186]. When comparisons are made between groups (died vs. survived) differential gene expression can be set with thresholds of both p<0.05 and +/−1.5 log 2 fold change. Alternative splicing was defined as core exon, alternative acceptor splice site, alternative donor splice site, retained intron, alternative first exon and alternative last exon. Alternative transcription start/end events can be defined as tandem transcription start site and tandem alternative polyadenylation site. Alternative RNA splicing and alternative transcription start/end events can be compared between groups [Sterne-Weiler et al., (2018) Molecular Cell, 72: 187-200.e186]. Significance was set at great than 2 log 2 fold change as previously described [Fredericks et al., (2020) Intensive Care Medicine]. Genes identified from the analysis of mapped reads can be evaluated by GO enrichment analysis (PANTHER Overrepresentation released 20200728) [Mi et al. (2013) Nature Protocols, 8: 1551-1566].

Whippet can be used to generate an entropy value for every identified alternative splicing and transcription event of each gene. These entropy values are created without the need for groups used in the gene expression analysis. To visualize this data a principal component analysis (PCA) can be conducted to reduce the dimensionality of the dataset and to obtain an unsupervised overview of trends in entropy values among the samples. Raw entropy values from all samples can be concatenated into one matrix and missing values were replaced with column means. Mortality can be overlaid onto the PCA plot to assess the ability of these raw entropy values to predict this outcome in this sample set. This analysis was done in R (version 3.6.3).

The following EXAMPLES are provided to illustrate the invention and should not be considered to limit its scope.

Unmapped Bacterial Reads to Identify Bacteria Causing Sepsis

Because bacterial infections are a common cause of morbidity in trauma patients, unmapped reads that align with bacteria are useful for the diagnosis and treatment of trauma patients. Unmapped reads from RNA sequencing data provide a valuable tool for the trauma patient. The decrease in the number of bacterial reads in the blood may be due to increased immune response. Some bacteria keep constant levels between groups, which signifies a virulent pathogen.

The technique of RNA sequencing has resulted in creating massive amounts of data. The first step with public RNA sequencing data is usually to align the reads to the reference genome of interest. RNA sequences that do not align with the reference genome (10-30%) are usually discarded when they cannot be mapped.

The inventors use a mouse model of hemorrhagic shock followed by cecal ligation and puncture. The inventors isolate RNA from blood and lung samples and had the RNA sequenced using standard techniques. They compare RNA from the test mice to sham controls. They analyze the RNA data that did not map to the mouse genome. Unmapped reads aligned to common bacterial pathogens, includingAcinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, andStreptococcus pyogenes. The inventors also identify specific genes with high read counts.

In one assay, the blood samples from the test mice exposed to trauma had fewer reads mapping to bacteria (365,974) as compared to the control mice (902,063, p=0.02). In the lung, the bacteria counts were similar. Despite an overall decrease in mapped bacterial RNA reads in the test mice, the threeStreptococcusspecies andStaphylococcus aureushad a similar number of reads mapping between the test mice and the control mice. The most common RNA read mapped to aldo/keto reductase gene from group B strep (82793634[uid]). There was more expression of this gene in the blood of mice after trauma (15,096) compared to controls (3671, p=0.006). This difference was not seen in the lung compartment (13,691 vs. 15,996, p=0.24). In the blood of the test mice, most of the identified bacterial sequences were reduced in counts compared to the blood of the control mice (43 vs. 16).

Unmapped Viral Reads to Identify Sepsis or Viral Reactivation

Unmapped data have been aligned to regions in the genomes of viruses. In critical illness, not only does the percentage of unmapped reads suggest a biomarker, but also the alignment of unmapped reads to some viral genomes. The percentage of unmapped reads in these organs during periods of critical illness can be a biomarker of severity and outcomes.

To assess the impact of critical illness on unmapped reads and their composition, the inventors expose mice (e.g., C57BL6 mice) to sequential treatment of hemorrhagic shock followed by sepsis. This treatment produces indirect acute respiratory distress syndrome (ARDS). RNA is extracted from lung and blood samples and sequenced via next-generation RNA-sequencing. Reads are aligned to the mm9 reference genome. The sources of unmapped reads were aligned by Read Origin Protocol (ROP). Changes in the viral signature of the unmapped reads are different when comparing blood to the lung.

In a second assay, the blood samples of critically ill mice averaged 31.9 million reads versus 32.1 million reads in healthy mice, and lung samples of critically ill mice averaged 33 million reads versus 33.7 million reads in healthy mice. The blood of critically ill mice had an average of 1.5 million unmapped reads (4.74%), more than the average 52,000 unmapped reads (0.16%) in the blood of healthy mice (p=0.000082). The lungs of critically ill mice had, on average, 194,331 unmapped reads (0.58%), which was more than the average 130,480 unmapped reads (0.39%) seen in the lungs of healthy mice (p=0.031665). In blood samples, unmapped reads from critically ill mice were less likely to be viral than healthy mice (average 3480 in critically ill vs. 4866 in healthy, p=0.025955). In lung samples, unmapped reads from critically ill mice were more likely to be viral than those from healthy mice (average 6959 in critically ill vs. 3877 in healthy, p=0.031959). The results were notable for higher viral loads in lungs of critically ill mice, showing that viral RNA loads can be a biomarker of critical illness.

Human correlates can translate into a clinical setting.

Unmapped B/T V(D)J Use to Identify Sepsis

In immune systems, V(D)J recombination allows for a diversity of antibodies in B cells and T cell receptors in T cells. During critical illness, the variety of these recombination events reduces, but recovers. RNA sequencing better characterizes V(D)J recombination events. RNA sequencing shows more diversity in critical illness compared to what was described previously. B and T cell composition could prove to be an important marker in critical illness and predicting outcomes of sepsis.

The inventors subject mice (e.g., C57BL6 mice) to sequential treatments of hemorrhagic shock followed by sepsis. This treatment induces acute respiratory distress syndrome (ARDS). Lung and blood samples are collected. RNA from the samples are sequenced by next-generation sequencing. Reads from critically ill and healthy mice are aligned to GRCm38 annotation and then mapped to the V(D)J annotation by Read Origin Protocol (ROP).

In a third assay, the inventors recovered ˜thirty million reads were recovered from RNA-seq data generated from lung tissue of critically ill mice and healthy controls. Alignment with STAR aligner showed an average of 7.77% unaligned reads in the healthy control, and 8.78% unaligned reads in the samples extracted from critically ill mice. Unmapped reads then underwent a secondary alignment to assay for V(D)J recombinants. Healthy mice have an average of 629 recombinant epitopes, whereas critically ill mice had an average of only 208 recombinant epitopes. Assays were done in triplicate with littermates.

Analysis of unmapped reads shows that critical illness inhibits the generation of B cell and T cell epitopes by the immune system during critical illness. Although the percentage of unmapped reads between healthy mice and critically ill mice was not significant, the composition of B and T cell epitopes differs vastly in critically ill mice.

Principal Component Analysis of RNA Splicing Entropy to Identify Sepsis

Next Generation Sequencing is useful for the diagnosis and treatment of diseases.

The effect of alternative RNA splicing before translation has not been studied much, especially in the critically ill patient. Previous work showed an association between cancer and the level of global alternative splicing entropy. Elias & Dias, Cancer Microenvironment, 1(1), 131-9 (2008); Ritchie et al., PLoS Computational Biology, 4(3), e1000011 (2008). RNA splicing entropy is correlated with acute respiratory distress syndrome (ARDS) across multiple tissues. Evaluating splicing entropy can provide insights about biological processes and gene targets in the critical illness setting.

The inventors induce a mouse model of ARDS by subjecting mice to hemorrhagic shock, followed by cecal ligation and puncture. Blood and lung samples are collected from three mice undergoing ARDS and three sham controls. RNA is purified.

Next-generation RNA sequencing is performed. Alternative splicing (AS) entropy levels are determined using Whippet (v 0.11) on Julia (v 0.6.4). Principal Component Analysis (PCA) is conducted using base R (v 3.4.0). Alternative splicing events with a proportion of spliced in values between 0.05 and 0.95 are analyzed. A threshold of 1.5 is applied to determine the percentage of high entropy events. Proportions of high entropy events across tissues and experimental groups are compared using Mann Whitney U tests.

In a fourth assay, Principal Component Analysis of the blood samples was performed. Samples clustered based on tissue type and ARDS status on a Principal Component Analysis plot This result suggested that splicing entropy can serve as a biomarker for ARDS status. The inventors observed differential levels of splicing entropy across tissue types, with the most entropy in the lung.

RNA Lariats to Identify Sepsis

This EXAMPLE demonstrates the collecting of RNA sequencing data from a complex tissue (blood), rather than a cell line, and uses computational biology techniques to analyze the data.

RNA splicing occurs directly after DNA transcription, but before protein translation. RNA splicing by a two-step esterification process with the formation of an intermediary lariat formed by the intron and joining of the 5′ and 3′ splice sites. Introns typically degrade rapidly.

The biology of lariats has recently been identified as important as it relates to viral biology. The DBR1 gene encodes for the only RNA debranching enzyme. Mutations of DBR1 increase susceptibility to HSV1 and increase viral brainstem infections in humans. Assessing the RNA lariat counts in the critically ill trauma patients could predict poor outcomes or prolonged immune suppression. The inventers undertook the mouse model of critical illness (CLP). Assessing for the resolution or return to a healthy level of lariat counts could be a marker to identify immune suppression or those patients at risk for a complication.

The identification of lariats from RNA sequencing data has been difficult. However, the William G. Fairbrother laboratory created a method to count lariats from RNA sequencing data. Taggart et al., Nature Structural & Molecular Biology, 19, 719-721 (2012).

In a fifth assay, the preliminary data suggests that in the critically ill mouse, the typical metabolism of RNA lariats is changed, resulting in an accumulation of lariats in the blood. The inventors found that the blood of mice with the critical illness have higher lariat counts compared to the control mice.

Traumatic Shock

Lungs from healthy mice had an average of 3877 viral reads. Lungs from critically ill mice had on average 6956 viral reads. Blood from healthy mice had 4866 viral reads. Blood from critically ill mice had 3480 viral reads. Lungs from critically ill mice were more likely to have unmapped reads originating from viral genomes when compared to lungs from healthy mice (0.36% in critically ill, 0.21% in healthy; p-value=0.032). This could be due to critical illness leading to a compromised immune response that allows for viral reactivation and a higher viral load in lungs of critically ill mice. Traylen et al., Future Virol., 6(4), 451-63 (April 2011).

Blood of healthy mice were more likely to have unmapped reads originating from viral genomes than blood of critically ill mice (0.05% in critically ill, 0.11% in healthy; p-value=0.026). There are several explanations for why healthy mice could have increased viral loads in the blood compared to critically ill mice. Mature lymphocytes are constantly recirculating through blood and lymphatic organs. Charles et al., Immunobiol. Immune Syst. Health Dis. 5th Ed. (2001). In critical illness, the release of pro-inflammatory mediators may compound the intensity of immune surveillance, as documented in patients with systemic inflammatory response syndrome (SIRS). Duggal et al., Science Reports, 8(1), 1-11 (Jul. 5, 2018).

Change in leukocyte populations in critically ill mice may lead to a higher number of RNA-producing polymorphonucleocytes (PMN) in blood, which reduces the total viral RNA signal in critically ill mouse blood. Therefore, steps are taken to enrich for lymphocytes and monocytes to reduce RNA reads from PMNs.

This traumatic shock EXAMPLE demonstrated an association between critical illness and higher viral loads in mouse lung, lending promise to the clinical use of viral loads as a marker of critical illness.

Processing RNA Sequencing Data to Aid in the Care of Sepsis Patients

More should be known about RNA biology, specifically alternative RNA splicing, in the sepsis population.

Over 90% of human genes with multiple exons require alternative splicing events to produce functional proteins. Pan et al., Nature Genetics 40, 1413-1415 ((2008). RNA splicing creates a large natural source of variation of the transcribed gene to the produced protein product. RNA splicing is under exquisite control under normal conditions. Fever, hypothermia, and osmotic stress from fluid shifts can influence RNA splicing in vitro and change RNA splicing, altering protein expression. Gultyaev et al., TSitologiia i Genetika, 48, 40-44 (2014); Lemieux et al., PloS One 10, e0126654 (2015); Mahen et al., PLoS Biology 8, e1000307 (2010). Acidosis influences RNA splicing. Elias & Dias, Cancer Microenvironment, 1 131-139 (2008). Hypoxia also influences RNA splicing. Romero-Garcia et al., Experimental Lung Research 40, 12-21 (2014); Kasim et al., The Journal of Biological Chemistry, 289, 26973-26988 (2014). The effects of physiologic stress on RNA splicing should be better known. The pathological significance of changes induced RNA splicing process and proteins should be better understood.

This EXAMPLE shows the use of deep RNA sequencing data using computational biology methods (RNA splicing entropy, lariat counts, viral identification, and B and T cell epitope creation) and apply these methods to three distinct data sets: mouse of different strains undergoing sepsis, deceased sepsis patients who participated in the GTEx project, and human sepsis patients.

RNA splicing entropy after sepsis. RNA splicing is a basic molecular function in all cells. This EXAMPLE uses the global index/marker of RNA splicing called ‘RNA splicing entropy’ a calculation of the precision of RNA splicing typically occurring. The entropy and thus the disorder, is maximal when the probability of all events P (xi) is equally likely and the outcome is most uncertain. This calculation are done for each type of alternative splicing event: skipped exon, retained intron, alternative donor (3′ splice site), and alternative acceptor (5′ splice site). The alternative splicing events with high entropy are identified using Whippet.

A lower percentage of RNA slicing entropy may predict increased mortality or more complications, particularly infections, in patients with sepsis. Previous work on cancer samples has shown that RNA splicing entropy is increased in the tumor compared to the healthy tissue in many cancer types. From the preliminary data in mice with and without ARDS after sepsis, RNA splicing entropy is less in the blood, 7.7% vs 10.7%, p=0.1. RNA splicing entropy was calculated for total white blood cell components of mice with critical illness caused by hemorrhage and cecal ligation and puncture and compared to controls. The RNA from blood and the lungs of mice was extracted, processed and then subjected to deep RNA sequencing.

Obtaining this data demonstrates the ability to isolate RNA samples from the target organ tissues of interest in the mouse model system. This EXAMPLE demonstrates the ability to process the complex data using computational biology and custom scripts that result from RNA sequencing. This preliminary data suggests that the process of RNA splicing in critical illness is different compared to the controls. changes in RNA splicing entropy may be a reflection/response to or a mechanism driving pathological processes that drive mortality and morbidity in patients with sepsis. Genes with significant alternative splicing and high entropy in the mouse after sepsis may be target for intervention. These genes of interest are identified using machine-learning techniques and compared across both humans and mice.

Assessment of viral activity after sepsis. In the initial assessment of RNA sequencing data, the reads are aligned to the genome of the species the sample came from. The unmapped reads can account for up to 20% of the data and this data is typically discarded. From this Read Origin Protocol analysis of multiple data sets (including GTEx data), the inventors found their protocol accounted for 99.9% of all reads. The data typically discarded was then analyzed in a seven-step process. Two of those steps are of particular interest because of the relevance to critical care: Viral reads and B and T cell receptor rearrangement.

Identification of viruses after sepsis is a marker of immune suppression since there is data suggesting sepsis re-activates herpes infections. Cook et al., Critical Care Medicine, 31, 1923-1929 ((2003)). Much current research is focused on these mechanisms and interventions. Viral counts could correlate with immune suppression or complications. This is important because of the re-activation data. RNA sequencing data from the lungs of control mice showed fewer viral reads (3877) compared to mice after sepsis (6956, p=0.032). In the blood the opposite was true. Control had 4866 counts versus sepsis with 3480 counts (p=0.026). This difference between tissue types could be due to a multitude of reasons, such as latent infections, like CMV, in the lung. Because blood is the most accessible tissue type, the efforts for the human samples should focus on the blood.

Assessment of immune cell epitopes after sepsis. During critical illness, the immune system is activated and likely creating new receptors to respond to challenges/pathogens. These epitopes come from lymphocytes, known to be reduced in sepsis with resolution to normal levels linked to recovery. Heffernan et al., Critical Care, 16, R12 (2012). While the count of lymphocytes themselves is useful, measuring the number and diversity of the epitopes could provide further insights into immune suppression after sepsis.

In the mouse model, preliminary data shows fewer epitopes in the lung of mice after sepsis, compared to control. This demonstrates the ability to analyze data from a mouse model and characterize B and T cell epitopes via computational methods. Like lymphocytes, the production of epitopes may reduce. Recovery should correlate with a return to normal immune state.

The above-described methods to assess for immune suppression in sepsis patients by analysis of RNA sequencing data to understand RNA biology are applied to these samples.

For analysis of RNA splicing entropy, lariat counts, viral identification, and B and T cell epitope creation in the mouse model, using pilot data, using forty mice (twenty critically ill, twenty healthy controls) should have 80% power to detect a difference at a two-tailed alpha of 0.05. This method is used for each of the three mouse variants.

At the time points of twenty-four hours after cecal ligation and puncture and fourteen days after cecal ligation and puncture, mice are sacrificed and organs procured. Organs to be collected are brain, lung, heart, kidney, liver, spleen, and blood. RNA from these samples are isolated as described below. The time point of twenty-four hours after CLP is selected as that is the time of most significant organ dysfunction. The time point of fourteen days is selected, since this is the point at which a mouse would be considered a survivor after this challenge.

RNA from blood samples in the mouse are processed using the MasterPure Complete RNA Purification (epicenter, Madison Wis., USA) kit for mice. Due to the high concentration of globin RNA in blood samples, these samples can then be further processed with the GLOBINclear Kit (epicenter, Madison Wis., USA). From blood one of skill in the molecular biological art can get 30-50 nanograms per microliter, with a total blood volume isolated from the mouse of about one mL. RNA from lung, heart, brain, kidney, liver, and spleen samples are extracted using MasterPure Complete RNA Purification kit for mice. After RNA samples are processed, the RNA was sequenced using standard techniques, for example by Deep RNA sequencing with a goal of 100,000,000 reads per sample. All samples should require at least 1400 nanograms of RNA for deep sequencing.

Human samples. Patients are recruited under Institutional Review Board approval and after consent is obtained. Blood samples are obtained from pre-existing catheters to minimize the risk. Blood samples are collected on admission and serially while the patient is in the intensive care unit. Samples are collected in PAXgene tubes and stored in an −80 C freezer until isolation of RNA for sequencing is needed. RNA sequencing are done in batches to minimize cost. For this experiment, it is expected 300 sepsis patients are recruited (average of 100 the first three years to allow analysis over the final two years of the project).

Control samples are obtained from healthy patients undergoing routine laboratory analysis at outpatient facilities. Blood from these patients are collected in PAXgene tubes and stored in an −80 C freezer until isolation of RNA for sequencing is needed. RNA sequencing are done in batches to minimize cost. Healthy controls are matched to sepsis patients based upon demographic/clinical data. Recruitment aims for 300 patients total (average 100 each year over the first three years). Sample size calculations for the recruitment of humans was done based upon initial results from the mice assays. Preliminary data from humans with sepsis shows more variation compared to the mice data. These differences from humans are accounted for by several things such as age, sex, medical co-morbidities, and variations in the timing of collection from the point of the sepsis.

RNA from blood samples from humans are processed using the MasterPure Complete RNA Purification (epicenter, Madison Wis., USA) kit for humans. Due to the high concentration of globin RNA in blood samples, these samples can then be further processed with the GLOBINclear Kit (epicenter, Madison Wis., USA). All samples require at least 1400 nanograms of RNA for deep sequencing, e.g., by Deep RNA sequencing with a goal of 100,000,000 reads per sample.

Genotype Tissue Expression (GTEx). The GTEx data has over 500 patients included with at least one sample that has undergone RNA sequencing. Extensive clinical data is available on these participants. The data can stratify the patients into early deaths (<36 hours) and late deaths (>36 hours). This classification and comparison between the groups was done as it highlights a population who could be intervened upon. The patients who die later die because of immune suppression leading to complications from sepsis. Earlier identification of immune suppression could change outcomes. The GTEx samples have been collected and undergone RNA sequencing. This sequencing data are analyzed as described above.

Innovativeness. RNA sequencing technology affords an avenue to bring precision medicine to sepsis patients. The inventors used blood samples from sepsis patients, process them and obtain RNA sequencing data of similar quality to that of cell lines or solid tissue samples. Monaghan et al., Shock, 47, 100 (2017). RNA sequencing allows for understanding not only the gene expression but also RNA biology. RNA is unstable compared to DNA. Kara & Zacharias, Biopolymers, 101, 418-427 (2014). RNA is influenced by the specific cellular environment (altered in sepsis).

Conceptual Innovation. Past work on sepsis and molecular mechanisms has been focused on gene transcription and protein expression. The process of alternative RNA splicing also can influence the expression of a protein independent of the gene expression. Chang et al., Combinatorial Chemistry & High Throughput Screening, 13, 242-252 (2010); Fredericks et al., Biomolecules, 5, 893-909 (2015).

By comparing findings in mice to humans using the publicly available RNA sequencing data from GTEx and human samples from the Intensive Care Unit, the inventors can establish the nature/type of RNA splicing common across species.

By determining the temporal relationship of changes in RNA splicing entropy, RNA lariats, viral identification, and B and T cell epitope creation with developing complications/mortality, the inventors can establish whether RNA biology can provide insight to immune suppression after sepsis.

Assessing information in the unmapped reads (viral and B/T cell epitopes) to determine clinical significance is using data that is typically discarded. This is similar to the use of lymphocyte counts to predict sepsis outcomes. Heffernan et al., Critical Care, 16, R12 (2012).

Technical innovation. RNA are isolated from complex tissues from both mice and humans. The isolate RNA are of high enough quality to allow for deep RNA sequencing. This analysis has only previously been done on cell line or cancer samples.

The inventors can use a series of analytical algorithms; initially, using the STAR aligner, then Whippet to assess and characterize splicing events and splicing entropy. This analysis are done across GTEx data, mice with sepsis and humans with sepsis.

The inventors can use the Read Origin Protocol as a basis. The inventors can modify as appropriate to assess viral content and B/T cell epitopes in data obtained from mouse models of sepsis, GTEx, and humans with sepsis.

The inventors can apply the scripts used previously to calculate lariat counts from RNA sequencing data. Taggart et al., Nature Structural & Molecular Biology, 19, 719-721 (2012). The RNA sequencing data is obtained from mouse models of sepsis, GTEx, and humans with sepsis.

Assaying the large amount of data that comes from RNA sequencing is commonly not successful due to several reasons. The analyses have biases for which controls are not in place. the large data should produce a statistically significant result but is it biologically and clinically significant. Using multiple biologic outputs (RNA splicing entropy, lariat counts, viral identification, and B and T cell epitope creation) across three samples (GTEx, mouse model, and humans) will mitigate.

By assaying RNA splicing entropy, lariat counts, viral identification, and B and T cell epitope creation, one of ordinary skill in the molecular biological art can identify patients with this prolonged immune suppression.

Analyzing data already collected, such as using the GTEx data, and data like the unmapped reads from RNA sequencing supports creativity. This data would typically be ignored, but with the proper clinical relevance, the data can be reanalyzed and potentially find new biomarkers. The lymphocyte count on a complete blood count with differential, a potential biomarker in the sepsis population. Heffernan et al., Critical Care, 16, R12 (2012).

Analysis of RNA sequencing data can provide one marker of the severity of the critical illness.

Evaluating RNA biology and outcomes after sepsis. Next generation RNA sequencing allows for the analysis of the RNA and assessment of not only gene expression but also other biological processes (alternative splicing, changes in transcription start and end). Correlating genomic information from high throughput sequencing technologies about a patient on arrival to the hospital with outcomes such as death and complications like infection should improve care. Since RNA is not as stable as DNA, assessing RNA are more sensitive to the physiologic stress in sepsis. The inventors can assess how the physiologic stress of sepsis influences RNA biology and alters proteins. Assaying RNA biology in critical care sepsis patients should translate to other patients with critical care after diseases.

By high throughput RNA sequencing the inventors can assay gene expression and the RNA processing events of alternative transcription start/end and alternative RNA splicing of from leukocytes in the blood. All three of these biological processes influence protein expression via generation of the RNA (gene expression), changing the beginning and end of the RNA (alternative transcription start/end), and changing the isoforms that are expressed (alternative RNA splicing). The combination of these three modalities creates a ‘transcriptomic phenotype’ and better identifies expressed proteins in the sepsis population as compared to the typical use of gene expression alone. compared to DNA, RNA is more influenced by the physiologic derangements seen in sepsis such as hypoxia and acidosis in cell culture. Elias & Dias, Cancer Microenvironment, 1(1), 131-9 (2008); Kasim et al., The Journal of Biological Chemistry, 289(39), 26973-88 (2014).

In an intensive care unit, monitoring of physiology correlates to improved clinical outcome. Clinicians do not monitor how this physiology impacts RNA biology. Using high throughput sequencing, the inventors assay RNA biology in sepsis patients. The understanding of RNA biology at the time of injury should predict mortality, complications, and other outcomes in sepsis patients. Three aims are tested using a mouse model of sepsis, data from GTEx of sepsis patients, and blood from sepsis patients with correlation to outcomes.

Aim 1: Identify changes in RNA biology (gene expression, alternative transcription start/end, and alternative RNA splicing) in the blood before and after a pre-clinical mouse model of sepsis and compare to controls.

Aim 2: Using the data available from the Genotype Tissue Expression (GTEx) project correlate findings in the mouse model to these sepsis patients (81 patients).

Aim 3: Enroll critically ill sepsis patients and identify aspects of RNA biology that identify and predict outcomes (mortality, infection).

These analyses use data from high throughput sequencing and cloud computing to establish findings of RNA biology that correlate and predict outcomes in sepsis patients. This data comes from an ancestrally diverse sepsis population and can be applied to sepsis patients across the country and to multiple critically ill patient populations.

New technology has come that allows for analysis of all genes, not just those identified by the technology at the time. Tompkins, The Journal of Trauma and Acute Care Surgery, 78(4), 671-86 (2015). With RNA sequencing technology, particularly at the depth proposed (80-100 million reads) needed for RNA biology assessment, the inventors can assess all genes transcribed, not just those identified as important with older technology. The analysis of all transcribed genes allows for the identification of genes that may be important for trauma, that in the past were overlooked, likely due to low transcription levels. with RNA sequencing technology the inventors can assay RNA biology (alternative transcription start/end and alternative RNA splicing), for a complete understanding of what genes are ultimately translated to functional proteins. Hardwick et al., Frontiers in Genetics, 10, 709 (2019).

Over 90% of human genes with multiple exons require alternative splicing events to produce functional proteins, creating a potentially large natural source of variation of the transcribed gene to the produced protein product. Pan et al., Nature Genetics, 40(12), 1413-5 (2008). Splicing is under exquisite control under normal conditions. Some conditions common in trauma, such as fever, hypothermia, and osmotic stress from fluid shifts can influence RNA splicing in vitro and change RNA splicing, altering protein expression. Gultyaev et al., TSitologiia i Genetika, 48(6), 40-4 (2014); Lemieux et al., PloS One, 10(5), e0126654 (2015); Mahen et al., PLoS Biology, 8(2), e1000307 (2010).

Using a mouse model of trauma caused by hemorrhage followed by cecal ligation and puncture, the inventors reported that alternative RNA splicing results in expression of varied isoforms of an immune modulating protein (programmed cell death receptor-1, PD-1). Preliminary data on RNA splicing entropy indicate that global RNA splicing is modified in the mouse model of trauma. Ritchie et al., PLoS Computational Biology, 4(3), e1000011 (2008). Increased RNA splicing entropy is also present in other pathologic conditions, such as cancers, as compared to normal tissue. Ritchie et al., PLoS Computational Biology, 4(3), e1000011 (2008). Increased entropy is characteristic of disease states and could be a marker of critical illness after sepsis.

Sepsis patients are a good population in which to assay critical illness and generalize the findings to other patients. A population of sepsis patients is an ideal group to assay genomic factors as previous research has been hindered by lack of racial and ethnic diversity. Multiple factors cause minorities to avoid healthcare. Chikani et al., Public Health Reports, 131(5), 704-10 (2016). By assaying sepsis patients, the inventors can collect data from a diverse population that is more in line with the general population and not the population that seeks healthcare. The findings are more generalizable, especially among an ancestrally diverse population.

Protocols for sepsis have improved outcomes. Rhodes et al., Intensive Care Medicine, 41(9), 1620-8 (2015). Sepsis can cause critical illness in a young population. The response to sepsis should not be influenced by co-morbidities associated with an increasingly aged population, but the inventors can collect co-morbidities to assess if there is an impact.

Genomic medicine is an ideal target for sepsis patients but is limited by sequencing technologies. Although genomic medicine is typically defined as using genomic information about an individual patient as part of their clinical care, this definition cannot be applied to sepsis patients or any critically ill patients.

Next generation RNA sequencing takes about 18 hours on an Illumina machine, but this does not include time for data analysis. Since the data are delayed until the outcome of the patient is known, data analysis can be blinded to allow for more robust conclusions. through this work, the efficiencies in computation biology can be elucidated so that when the sequencing technology speeds up, the analysis are quick enough to have a clinically relevant time frame (less than one hour) from sample acquisition to actionable result.

Thus, there is value in understanding of how stressors associated with sepsis can affect RNA biology (RNA splicing (and entropy) and alternative transcription start/end) and how changes in the RNA biology leads to altered protein product expression, contributing to potential dysfunction at a cell and tissue level.

Innovation. Past work focusing on trauma and molecular mechanisms has been focused on gene transcription and protein expression. The process of alternative RNA splicing and alternative transcription start/end both have the potential to influence the expression of a protein independent of the gene expression. Chang et al., Combinatorial Chemistry & High Throughput Screening, 13(3), 242-52 (2010); Fredericks et al., Biomolecules, 5(2), 893-909 (2015). By comparing findings in mice to humans using the publicly available RNA sequencing data from GTEx and human samples from the Trauma Intensive Care Unit the inventors can establish the nature/type of RNA biology that is common across species.

In determining the temporal relationship of changes in RNA biology with developing complications/mortality, the inventors can establish whether RNA biology can provide insight to immune suppression after sepsis.

Knowledge of RNA biology in the critically ill is useful because previous work on this process has focused largely on chronic diseases and genetic diseases.

The combination of gene expression, RNA splicing, and transcription start/end create a ‘transcriptomic phenotype’ that can be followed during the patients hospital stay.

RNA are isolated from complex tissues from both mice and humans. The isolate RNA are of high enough quality to allow for deep RNA sequencing. This analysis has only previously been done on cell line or cancer samples.

The inventors can use a series of analytical algorithms using the STAR aligner, then Whippet, to assess and characterize RNA biology. Results from Whippet are compared to mountainClimber to ensure accurate data as it pertains to alternative transcription start and end. This analysis are done across GTEx data, mice with sepsis and humans with sepsis.

Using multiple biologic outputs (alternative RNA splicing, including entropy, alternative transcription start/end) across three different samples (GTEx, mouse model, and humans in the trauma intensive care unit) should mitigate some of the potential flaws.

Preliminary data regarding trauma. In a small cohort of trauma patients from GTEx, three patients form the early death cohort (<48 hours) were compared to six patients from the late death cohort (>/=48 hours). In this comparison, 524 genes are significantly increased in the late death versus the early death. In the late death group, 2331 genes are decreased compared to the early death group. The GO terms associated with the genes that decreased expression in the late group compared to the early group are valid based upon previous research. The terms with a decrease in expected representation in the GO terms reference mitochondrial biology. This decrease in GO terms likely represents that genes are increased in expression at the early death time point. Mitochondrial molecular patterns have been a component of the early response to trauma and those genes would be increased in the early group.(37, 38) anemia occurs during trauma. In the late group, genes associated with erythrocyte development are over-represented, suggesting increase expression in the late death group compared to the early death group. These few GO terms and correlation to phenotypes of trauma, suggest use of early versus late death is a valid clinical tool. This preliminary data shows the ability to access, manage, and analyze GTEx data with clinically significant groups using novel computational biology techniques. Using GO terms allows us to prove clinical relevance. This project aims to obtain and analyze all the trauma samples from GTEx. The inventors can also use similar computational approaches with the prospectively collected data from trauma patients.

Multiple alternative RNA splicing events and alternative transcription start and events are detected, but there are fewer that are significant. Using the same cohort as above, this preliminary date from GTEx data, alternative splicing and alternative transcription events are characterized using Whippet. Multiple events were identified to be alternative RNA splicing and alternative transcription start/end in the blood samples. When comparing the groups there were only significant differences when assessing alternative RNA splicing and not alternative transcription start and end. This data confirms that alternative RNA splicing is an active process during trauma and could predict mortality and outcomes in trauma patients. genes with changes in splicing, and potentially transcription start/end could identify novel targets. The combination of gene expression, splicing and transcription start/end could alter what proteins were thought to have increased gene expression and subsequent protein transcription have altered processing resulting in new isoforms or changes in transcription. These findings highlight the ability to access GTEx data, categorize the samples in a clinically relevant manner, and process the RNA sequencing data with advanced computational methods, such as Whippet.

RNA splicing, specifically RNA splicing entropy shows differences after trauma. From the preliminary data in mice with and without, the inventors can show that in the blood there is less RNA splicing entropy, 7.7% versus 10.7%, p=0.1. RNA splicing entropy was calculated using Whippet. The percentage of each type of splicing event with an entropy of >1.5 (Alternative Donor, Alternative Acceptor, Retained Intron, and Skipped Exon). Using the mouse model of trauma, RNA splicing entropy was calculated for total white blood cell components of mice after trauma caused by hemorrhage with cecal ligation and puncture (n=3) and compared to controls (n=3). The RNA from blood was extracted, processed and then subjected to deep RNA sequencing. This preliminary data suggests that the process of RNA splicing in critical illness is different compared to the controls. changes in RNA splicing entropy may be a reflection/response to or a mechanism driving pathological processes that drive mortality and morbidity in patients with trauma. Obtaining this data demonstrates the ability to isolate RNA samples from the target organ tissues of interest in the mouse model system. This EXAMPLE demonstrates the ability to process the complex data using computational biology and custom scripts that result from RNA sequencing.

The trauma patients in the intensive care unit provide an ancestrally diverse population and adequate numbers to correlate mortality and other complications. The trauma intensive care unit admits over 750 patients a year with 20% of those patients coming from an ancestrally diverse background. The enrollment is in line with the general population, even though underrepresented minorities seek medical care at a reduced rate. One aspect to this invention is the correlation of the RNA sequencing data to mortality and complications.

This EXAMPLE shows the importance of not only predicting mortality, but also using RNA sequencing data to predict complications as patients with complications had a higher mortality (7.7%). Mortality could be influenced. This data shows the trauma center has the volume of patients in the intensive care unit to have an appropriately powered study.

Over four years, 520 patients can be enrolled based on sample size calculations, with fewer than the 3000 expected admissions proving feasibility.

TABLE 1AimSuggested Type of ResearchApplication1Integration of other data types,A model organism (mousesuch as environmental data, familyafter trauma) will providehistory, transcriptomics,the basis for otherepigenomics, functional data, oranalyses in humans aftermodel organism data to improvetrauma. Multiple strainsassessment of clinical validity orwill mimic the diverseclinical utility of genomichuman population.information.2Assessment of improvedGTEx data are re-analyzedapproaches for reanalyzing patientusing modern approaches andgenomic data and understandinga unique population (earlyits impact on clinical care.versus late trauma deaths)3Evaluation of modern approachesTrauma patients will provideto interpreting genomic data inan ancestrally diverseancestrally diverse populations inpopulation to assay thisclinical settingsclinical genomic date.

This approach uses RNA sequencing data from a mouse model of trauma, re-analysis of existing genomic data in GTEx about early versus late trauma deaths, and samples from ancestrally diverse critically ill trauma patients uniquely suited to provide clinical information applicable across many clinical scenarios; particularly critically ill patients with cancer, sepsis, stroke, or myocardial infarction. The analysis of the RNA data from next generation sequencing technology create a ‘transcriptomic phenotype’ for each trauma patient. Understanding the RNA biology at the time of injury can predict outcomes (mortality and complications) in trauma patients. The method to test the three aims, the expected result, and the potential impact are summarized in TABLE 2.

TABLE 2AimMethodResultImpact1Mouse model ofChanges in RNA biologyThese findings provide thetrauma, assessingpredict mortality after thefoundation for predictingblood beforemouse model of trauma.mortality and complicationstrauma, afterThe results seen at 24in critically ill traumatrauma, and inhours differ from thosepatients. Data seen at 24survivorsidentified at 14 days.hours and 14 days correlatewith patients who die earlyversus late.281 deceasedChanges in RNA biologyThis are the foundation fortrauma patientsare identified in earlyanalysis of RNA data fromfrom GTEx, 23versus late trauma deathstrauma patients during theirearly deaths andand these correlate withhospital stay.58 late deathsmouse data.3Critically ill traumaChanges in RNA biologyUsing RNA sequencing datapatients assessingon admission predictpredict mortality andblood oncomplications andcomplications and enhanceadmission andmortality, changes overcare of trauma patients withthroughout coursethe hospital courseapplicability to all intensivecorrelate with long-termcare unit patients.outcomes.

Aim 1: Identify changes in RNA biology (gene expression, alternative transcription start/end, and alternative RNA splicing) in the blood before and after a pre-clinical mouse model of trauma and compare to controls.

Rationale: to determine if altered RNA biology in its various forms can predict outcomes, RNA sequencing data must be collected at various time points during the traumatic injury. The inventors can establish the equivalency of such a pre-clinical animal model to what is encountered clinically. The inventors previously used a mouse model of hemorrhagic shock followed my septic shock by cecal ligation and puncture (CLP). Monaghan et al., J. Transl. Med., 14(1), 312 (2016). This mouse model mimics a trauma patient with hemorrhagic shock from an extremity injury who then had a missed bowel injury resulting in severe critical illness. Using this mouse model, the inventors can obtain blood at the initial injury and assess if changes in RNA biology, to predict mortality from the severe trauma model. Using a mouse model allows for acquisition of blood samples at multiple time points (twenty-four hours after injury and in those mice that survived). The inventors can first assess if RNA biology in the blood can predict mortality, if changes in RNA biology are seen twenty-four hours after injury, and how these correlate to the RNA biology of survivors at fourteen days.

Test 1: Assess RNA sequencing data and identify genes with changes in expression, alternative RNA splicing, and alternative transcription start/end to develop the ‘transcriptomic phenotype’ from shed blood in the mouse model of trauma to predict outcomes. Mice (8-12 weeks old) undergo hemorrhagic shock followed by CLP to mimic the critical illness that a trauma would undergo after hemorrhagic shock from an extremity injury complicated by a missed small bowel injury. Mice are used from the background of C57BL/6J, BALB/cJ, and CAST to simulate the heterogeneity of humans. Each group has twenty-four (twelve sham and twelve trauma) mice for each strain based upon statistical calculations. C57BL/6J mice have a 30% survival at fourteen days. The shed blood from the hemorrhage component are collected. Although this blood is collected before the effects of hemorrhage, this time point can mimic an early time point in trauma, since the mice have undergone anesthesia and isolation/catheter insertion of the artery. RNA are isolated, sequenced and analyzed as described. The mice that survive to fourteen days can also be sacrificed and used in Test 2.

Test 2: Assess RNA sequencing data and identify genes with changes in expression, alternative RNA splicing, and alternative transcription start/end to develop the ‘transcriptomic phenotype’ from the blood of mice at twenty-four hours and fourteen days after trauma. Mice (8-12 weeks old) undergo hemorrhagic shock followed by CLP to mimic a severe trauma. Mice are used from the background of C57BL/6J, BALB/cJ, and CAST. Mice are sacrificed at twenty-four hours after CLP. Mice that survive to fourteen days are also sacrificed to assess RNA biology at that point among the survivors. Appropriate controls for each type of background mice undergo sham procedures. Based upon previous work, six mice are needed for each group. After mice are sacrificed (CO2overdose followed by direct cardiac puncture) at either twenty-four hours or fourteen days after CLP blood are harvested. RNA from blood samples in the mouse are processed.

Human samples. Through collaboration with the military, soldiers in combat areas could be consented to donate blood before deployment. This blood would then undergo RNA sequencing and be compared to samples collected if there was an unfortunate traumatic injury. Many previous efforts using animal models to treat diseases such as sepsis failed to translate to humans. Fink & Warren, Nature Reviews Drug Discovery, 13(10), 741-58 (2014). The inventors previously studied conditions in mice with correlation to humans. Monaghan et al., J. Transl. Med., 14(1), 312 (2016); Monaghan et al., Molecular Medicine, 24(1), 32 (2018); Monaghan et al., Journal of the American College of Surgeons, 213(3), S54-S5 (2011); Monaghan et al. Annals of Surgery 255(1), 158-64 (2012). Trauma research may have better translatable results because of the timing of the disease. In trauma, the time of the event is known. This timing correlates with the induced trauma in the mouse. In sepsis, the time point at which sepsis started in the mouse is known. However, in humans, the time at which sepsis starts is impossible to know, as exemplified by inability to understand when an appendix may perforate. Iacobellis et al., Seminars in Ultrasound, CT, and MR, 37(1), 31-6 (2016). This is limited because it is a controlled traumatic challenge and should produce very consistent response to trauma. In humans, no trauma is the same. The number of humans needed to detect a difference is more since the traumas are not similar. Humans have more heterogeneity adjusted for by using multiple mouse strains. The inventors can account for differences in trauma by using the Injury Severity Score. The ISS of this challenge on the mouse is twenty-five, and this is the target average ISS of patients enrolled.

Aim 2: Using the data available from the Genotype Tissue Expression (GTEx) project correlate findings in the mouse model to these trauma patients (81 patients).

Rationale. Using the GTEx data, the inventors can assess RNA biology in the blood of trauma patients. The GTEx data has over 500 patients included with at least one sample that has undergone RNA sequencing. The patients in the GTEx data set have extensive clinical data available. Unfortunately, all patients in this data set are deceased. This should be considered in interpretation of the data. To adjust for the fact all patients are deceased, the inventors use the time to procurement of the RNA from the death of the patient as a variable due to adjust for RNA degradation and other metrics as suggested by the GTEx consortium.(50) Trauma patients are selected (n=81) and identified as early (<48 hours) versus late death (>/=48 hours). The inventors can compare RNA biology between trauma patients who died early versus late and compare it to findings in a mouse model of mice who died early (twenty-four hours) versus survivors (fourteen days)

Test 1: Assess RNA sequencing data and identify genes with changes in expression, alternative RNA splicing, and alternative transcription start/end to develop the ‘transcriptomic phenotype’ the blood of deceased trauma patients and compare among early and late deaths. There are 81 unique trauma patients in the data set with blood samples. These patients are aged 20-68, in line with the age of typical trauma patients. The GTEx samples have been collected and undergone RNA sequencing. RNA sequencing data are aligned to the human genome with STAR. RNA Splicing events are assessed using Whippet and characterized into one of the five alternative splicing events: skipped exon, retained intron, mutually exclusive exon, alternative 3′ splice site, and alternative 5′ splice site. Entropy calculation are completed using Whippet. Alternative transcription events from Whippet are compared to outputs from mountainClimber.

Test 2: Correlation of changes in expression, alternative RNA splicing, and alternative transcription start/end (the ‘transcriptomic phenotype’) in the blood of humans to the mouse samples. From mouse model (Aim 1) changes in expression, alternative RNA splicing, and alternative transcription are identified and these are compared to findings in the human GTEx data (Aim 2, Test 1). The mouse model data are taken from mice at twenty-four hours after CLP and at fourteen days after CLP. This data are compared to the human data of early (<48 hours) and late (>/=48 hours) death. The identical genetic background of laboratory mice (despite coming from three strains) allows for assumptions to be made about significance of changes at a higher resolution, due to the certainty of the genetic model. Simultaneously it creates uncertainty about the validity of findings, due to a lack of comparability to humans that experience conditions outside of the laboratory. Human data is plagued by an equal and opposite effect as data derived from animal models. The homogeneity of the mouse model is replaced with heterogeneity due to factors such as age, sex, co-morbidities, and differences in the trauma. By coupling the certainty provided by the homogeneity of the mouse model, and the uncertainty provided by the heterogeneity of the human model, the inventors create a powerful tool with the potential to validate results from mouse analyses in humans. Comparing events across species can identify RNA biology events and genes that are important at both the early and late time point. These findings are compared to those found in the prospective collected data from trauma patients.

Human samples. In this sample set, all the patients are dead. Since RNA is unstable compared to DNA, adjustments in the comparisons between groups during the analysis must be made for the time it took for samples to be collected and RNA isolated. The mouse work is comparing to mice that are alive but were sacrificed. The GTEx consortium, to adjust for problems associated with deceased donors, has described multiple methods. Carithers et al., Biopreservation and Biobanking, 13(5), 311-9(2015).

Aim 3: Enroll critically ill trauma patients and identify aspects of RNA biology that identify and predict outcomes (mortality, infection).

Rationale: A current challenge with the data from the animal models is ensuring translation to humans. This aim allows for complete translation of mouse data to humans. The human population of interest are patients admitted to the Trauma Intensive Care Unit (TICU).

Test 1: Assess RNA sequencing data and identify genes with changes in expression, alternative RNA splicing, and alternative transcription start/end in the blood can be prospectively detected and use this ‘transcriptomic phenotype’ in trauma patients on arrival and be correlated to mortality. Trauma patients are recruited from the trauma intensive care unit, which has an average of over 750 patients, admitted each year (over the last three years) and an average injury severity score (ISS) of 13, but the goal are to enroll patients with an average ISS of 25 to mimic the mouse model. Blood are collected in PAXgene tubes and stored at −80 C after informed consent is obtained. Samples are collected serially while in the ICU. Blood samples from patients are taken on admission (25 mL) and during the TICU stay when a complication is developed (25 mL). This causes the maximum for the initial 8-week period after the trauma. When the patient is recovered, at least 8 weeks after the last blood draw, a final blood draw 50 mL of are done, potentially in the outpatient setting. Patients who survive the trauma are compared to patients who died. Clinical information for the trauma patients are collected from the trauma registry. The trauma registry is a database required as part of verification by the American College of Surgeons to be a trauma center. The data are standardized across the entire recruitment period. RNA are isolated using the PAXgene RNA Kit. RNA was sequenced (goal 80 to 100 million reads). RNA sequencing data are aligned to the human genome using the STAR aligner. Changes in expression, alternative RNA splicing, alternative transcription start/end, and RNA splicing entropy are identified with Whippet. Alternative transcription findings are correlated with mountainClimber.

Test 2: Assess RNA sequencing data and identify genes with changes in expression, alternative RNA splicing, and alternative transcription start/end in the blood can be prospectively detected in trauma patients on arrival and use the ‘transcriptomic phenotype’ to correlate to outcomes and complications. Patients from the trauma intensive care unit identify differences in RNA biology between the healthy controls and trauma patients will predict outcomes and complications. Outcomes and complications are recorded from the medical record and are defined in the trauma registry (and decided by trained coders). The trauma registry will also provide some demographic data; such as injury severity score to better quantify and adjust for the severity of the trauma across patients. Outcomes to follow and use as potential for prediction include mortality, hospital length of stay, intensive care unit length of stay, ventilator free days, and discharge disposition. Complications to be recorded again are taken from the trauma registry and will include items such as infections (pneumonia, surgical site infections, urinary tract infection, bacteremia, sepsis), unplanned return to the operating room, unplanned return to the intensive care unit, tracheostomy, and feeding tube placement.

Human samples: In this sample set, all the patients are critically ill. Consenting patient who are critically ill requires a proxy and this can sometimes be difficult in the unexpected nature of trauma. The inventors have past success in consenting these patients. Human heterogeneity may make finding a significant difference between two groups difficult. Drastic difference (trauma patients in the intensive care unit survive versus die and those with complications) should allow for the identification of differences in RNA biology (‘transcriptomic phenotype’). All samples for this assay come from living patients.

Survival Assay

All the test mice have the traumatic injury. They are maintained for fourteen days. At fourteen days all mice are sacrificed. The survival rate at fourteen days for the double hit model is 30%. The rate goes up to 70%. Monaghan et al. Annals of Surgery 255(1), 158-64 (2012). These estimates result in an effect size of h=0.823. A sample size of twenty-four per group during analysis would exceed 80% power at a 2-tailed alpha of 0.05 by a chi-square test of independent proportions. for survival analyses the inventors will use twenty-four mice per group. This are done to ensure enough power to detect if RNA splicing at the initial challenge can predict survivors. Sham mice are operated (8 from each mouse background strain) at this time to procure samples at the 14-day time point.

RNA isolation and sequencing. RNA data from GTEx is extracted and sequenced per their protocols. RNA from mouse blood samples are processed using the MasterPure Complete RNA Purification (epicenter, Madison Wis., USA) kit for mice. Due to the high concentration of globin RNA in blood samples, these samples will then be further processed with the GLOBINclear Kit (epicenter, Madison Wis., USA). From blood the inventors can get approximately 30-50 nanogram per microliter, with a total blood volume isolated from the mouse of about one mL. After RNA samples are processed, they are sequenced. All samples will require at least 1400 nanograms of RNA for deep sequencing. Each sample are sent out (due to advancing technologies, costs of sequencing change frequently, therefore outside facility are chosen based upon cost during sample send out) for Deep RNA sequencing with a goal of 80 million to 100 million reads per sample.

Blood from trauma patients and healthy human control samples are collected using the PAXgene tubes (PreAnalytiX, Switzerland) and isolated using the PAXgene RNA kit (PreAnalytiX, Switzerland). Since it is impossible to predict the patients who will die or have a complication on admission to the ICU, banked samples are used since the cost to perform RNA sequencing on the blood of all TICU patients at Rhode Island Hospital is impossible.

Assessment of clinical information. Clinical data relevant to the patient samples are collected from the trauma registry and the electronic medical record. This will allow for collection of endpoints such as mortality, ICU length of stay, hospital length of stay, ventilator days, renal failure, ARDS, pneumonia and other infectious complications. Besides data in the chart, the inventors will also perform functional assessments at follow up after discharge. These would be based upon previous work in critical illness and use the 36-item short form (SF-36). The assessment are done at the 8+ week follow up.

Alternative RNA Splicing and Alternative Transcription Start/End in Acute Respiratory Distress Syndrome

The objective of this EXAMPLE is to use RNA sequencing data and analysis to identify novel gene targets in sepsis.

Alternatively spliced RNA arise from co/post-transcriptional events facilitated by the spliceosome, introns are removed to form the mature RNA from which protein isoforms are translated. Alternatively transcribed genes are the product of changes in promoter usage, polyadenylation signals, and RNA polymerase II interactions with DNA which can lead to changes in isoform usage similar to alternative splicing events. These are identified from the analysis of RNA sequencing data. Significant differentially alternatively transcribed genes and alternative spliced genes were identified and were overlapped with genes reported as ARDS related. See, Reilly et al., American Journal of Respiratory and Critical Care Medicine (2017). Of 89 reported ARDS related genes, 38 were confirmed in at least one differential category confirming that the use of humans and mice with DAD/ARDS is appropriate and robust (p=1.25 e-14). Eleven previously reported genes were present in all categories. These eleven genes were evaluated for the change in alternative splicing and alternative transcription GO term enrichment analysis was performed on the eleven overlapping genes, revealing twenty significant biological processes including ontology related to aging, and response to abiotic/environmental stimuli. SeeFIG.1. 1639 genes show overlap in alternative splicing and alternative transcription not previously in the literature. These genes were assessed for directionality alternative splicing and alternative transcription and GO terms (TABLE 3, TABLE 4).

Assaying the underlying changes in RNA processing (alternative splicing and alternative transcription start/end) not expands basic knowledge only of pathogenicity, but also provides additional targets for therapeutics. The most enriched GO term from the alternative splicing set, carboxy-terminal domain protein kinase complex (GO:0032806) refers to phosphorylation of the CTD of RNA polymerase II, which is vital in regulating transcription and RNA processing. RNA polymerase complex binding (GO:0000993), and transport of the SLBP Independent/Dependent mature mRNA (R-HSA-159227; R-HSA-159230) are among the most enriched. Alternative pre-mRNA splicing may have the dominate role in isoform usage in genes where expressions levels do not change, whereas alternative transcription may regulate isoform usage in genes that are more dynamically expressed during critical illness. Alternative splicing and alternative transcription may have separate roles in DAD/ARDS by regulating different genes to perform distinctive functions.

In this analysis of RNA sequencing data from deceased patients with ARDS identified by DAD and a clinically relevant mouse model of ARDS, novel genes are identified.

Overview. The inventors used RNA sequencing to identify changes in mRNA processing events (RNA splicing and transcription start/end sites) can be studied with RNA sequencing data. The inventors' strategy was to use the contrast how the processing of mRNA changes in lung and blood of patients with ARDS and compare to the lung and blood of a mouse model of ARDS.

Data. For this EXAMPLE, two main approaches were taken to obtain samples. The first was to use a validated mouse model of ARDS. Ayala et al., The American Journal of Pathology, 161, 2283-2294 (2002); Monaghan et al., Molecular Medicine (Cambridge, Mass., USA), 24, 32 (2018). All experiments were done according to guidelines from the National Institutes of Health (Bethesda, Md.). For the mouse model of ARDS, C57BL/6 male mice (The Jackson Laboratory, Bar Harbor, Me., USA) between 10 and 12 weeks of age were used. ARDS was induced in the mice by hemorrhage (non-lethal shock) followed by cecal ligation and puncture (CLP). The control group was sham hemorrhage followed by sham CLP.

The second approach was to identify patients in the GTEx Project with ARDS. All patients in the GTEx projects used in this EXAMPLE are deceased. A pathologist, blinded to the specimen ID and history, identified diffuse alveolar damage in lung samples from patients in GTEx. Most cases of clinical ARDS will have diffuse alveolar damage (DAD) morphologically. Zander & Farver, Pulmonary pathology e-book: A volume in foundations in diagnostic pathology series. (Elsevier Health Sciences, 2016). Classic DAD was identified based histologic features (For full description, please see supplement). Patients with evidence of diffuse alveolar damage in the lung and a corresponding blood and lung sample that had undergone RNA sequencing were placed in the ARDS group. Patients who had no evidence of diffuse alveolar damage in the pathology sample and a blood and lung sample with RNA sequencing were placed in the control group. Most cases of clinical acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) will have diffuse alveolar damage (DAD) morphologically, which is divided into 2 phases: the acute/exudative phase and the organizing/proliferative phase. Other histologic patterns encountered in a clinical setting of ALI/ARDS include diffuse alveolar hemorrhage, acute eosinophilic pneumonia (AEP), and the acute fibrinous and organizing pneumonia (AFOP). Eight patterns of acute lung injury are evaluated in this EXAMPLE. Zander & Farver, Pulmonary pathology e-book: A volume in foundations in diagnostic pathology series. (Elsevier Health Sciences, 2016). Classic DAD are was graded 1-4 based on the histologic features. Other patterns of injury were scored using a semiquantitative system for extent and histologic characteristics. For extent, grade was assigned: grade 1 (1 point): up to 10% tissue involved, grade 2 (2 points): 11-30% tissue involved, grade 3 (3 points): 31-50% tissue involved and grade 4 (4 points): >50% tissue involved. Histologic characteristics including intra-alveolar fibrin (1 point), cellular alveolar debris (I point), type II pneumocyte hyperplasia (1 point) and capillaritis/vasculitis. Total points 6 or higher were considered as DAD. Despite this complex method for categorizing diffuse alveolar damage, using this to diagnose ARDS is a major limitation. DAD could be present in other pulmonary diseases. The value RNA sequencing data from the lungs and blood of patients can provide biologic insights despite these limitations.

Results. Alternative splicing events were observed at 2-fold higher abundance as compared to alternative transcription events, yet significant alternative transcription events between groups were observed at a 6-fold higher prevalence (p=2.2 e-16). Eighty-two alternative transcription events were common across all ARDS tissues (human and mouse, blood and lung, p=2.72 e-16). No significant alternative splicing events were detected across all four tissues. As alternative splicing is species and tissue specific, it is unlikely to find an event that occurs in lung tissue and blood tissue in both human and mouse. GO term analysis was also performed on the significant differentially processing events.

The full list is TABLE 3 below.

TABLE 3Complete list of GO Terms from Significantly Alternative Splicing and AlternativeTranscription Start/End Events Alternative Splicing n = 2362GO TermlogFCAmine ligand-binding receptors (R-HSA-375280)−6.64385619Amine-derived hormones (R-HSA-209776)−6.64385619axonemal dynein complex (GO:0005858)−6.64385619bitter taste receptor activity (GO:0033038)−6.64385619calcium-independent cell-cell adhesion via plasma membrane−6.64385619cell-adhesion molecules (GO:0016338)catecholamine binding (GO:1901338)−6.64385619chondrocyte morphogenesis (GO:0090171)−6.64385619chondrocyte morphogenesis involved in endochondral bone−6.64385619morphogenesis (GO:0003414)connexin complex (GO:0005922)−6.64385619Defective C1GALT1C1 causes Tn polyagglutination syndrome−6.64385619(TNPS) (R-HSA-5083632)Defective GALNT12 causes colorectal cancer 1 (CRCS1) (R-−6.64385619HSA-5083636)Defective GALNT3 causes familial hyperphosphatemic tumoral−6.64385619calcinosis (HFTC) (R-HSA-5083625)delayed rectifier potassium channel activity (GO:0005251)−6.64385619detection of chemical stimulus involved in sensory perception−6.64385619(GO:0050907)detection of chemical stimulus involved in sensory perception of−6.64385619bitter taste (GO:0001580)detection of chemical stimulus involved in sensory perception of−6.64385619smell (GO:0050911)detection of chemical stimulus involved in sensory perception of−6.64385619taste (GO:0050912)Eicosanoid ligand-binding receptors (R-HSA-391903)−6.64385619FGFR2 ligand binding and activation (R-HSA-190241)−6.64385619G protein-coupled serotonin receptor activity (GO:0004993)−6.64385619G protein-coupled serotonin receptor signaling pathway−6.64385619(GO:0098664)GABA receptor complex (GO:1902710)−6.64385619GABA-A receptor complex (GO:1902711)−6.64385619growth plate cartilage chondrocyte morphogenesis−6.64385619(GO:0003429)growth plate cartilage morphogenesis (GO:0003422)−6.64385619ligand-gated anion channel activity (GO:0099095)−6.64385619odorant binding (GO:0005549)−6.64385619olfactory receptor activity (GO:0004984)−6.64385619piRNA metabolic process (GO:0034587)−6.64385619positive regulation of peptidyl-serine phosphorylation of STAT−6.64385619protein (GO:0033141)regulation of circadian sleep/wake cycle (GO:0042749)−6.64385619serotonin receptor activity (GO:0099589)−6.64385619serotonin receptor signaling pathway (GO:0007210)−6.64385619taste receptor activity (GO:0008527)−6.64385619Creation of C4 and C2 activators (R-HSA-166786)−5.058893689immunoglobulin complex, circulating (GO:0042571)−5.058893689Olfactory Signaling Pathway (R-HSA-381753)−5.058893689Classical antibody-mediated complement activation (R-HSA-−4.64385619173623)G protein-coupled amine receptor activity (GO:0008227)−4.64385619sensory perception of smell (GO:0007608)−4.64385619detection of stimulus involved in sensory perception−4.321928095(GO:0050906)transmitter-gated ion channel activity involved in regulation of−4.321928095postsynaptic membrane potential (GO:1904315)Class C/3 (Metabotropic glutamate/pheromone receptors) (R-−4.058893689HSA-420499)sensory perception of chemical stimulus (GO:0007606)−4.058893689detection of chemical stimulus (GO:0009593)−3.836501268immunoglobulin complex (GO:0019814)−3.836501268keratin filament (GO:0045095)−3.64385619transmitter-gated channel activity (GO:0022835)−3.64385619transmitter-gated ion channel activity (GO:0022824)−3.64385619complement activation, classical pathway (GO:0006958)−3.473931188Keratinization (R-HSA-6805567)−3.473931188Phase 2 - plateau phase (R-HSA-5576893)−3.473931188Digestion and absorption (R-HSA-8963743)−3.321928095exogenous drug catabolic process (GO:0042738)−3.321928095neurotransmitter receptor activity involved in regulation of−3.321928095postsynaptic membrane potential (GO:0099529)regulation of mesonephros development (GO:0061217)−3.321928095keratinization (GO:0031424)−3.184424571postsynaptic neurotransmitter receptor activity (GO:0098960)−3.184424571sodium channel complex (GO:0034706)−3.184424571Collagen chain trimerization (R-HSA-8948216)−3.058893689Digestion (R-HSA-8935690)−3.058893689extracellular matrix structural constituent conferring tensile−3.058893689strength (GO:0030020)G protein-coupled neurotransmitter receptor activity−3.058893689(GO:0099528)G protein-coupled receptor activity (GO:0004930)−3.058893689Initial triggering of complement (R-HSA-166663)−3.058893689Phase 0 - rapid depolarisation (R-HSA-5576892)−3.058893689complement activation (GO:0006956)−2.943416472immunoglobulin receptor binding (GO:0034987)−2.943416472neurotransmitter receptor activity (GO:0030594)−2.943416472steroid hydroxylase activity (GO:0008395)−2.943416472Beta defensins (R-HSA-1461957)−2.836501268voltage-gated potassium channel activity (GO:0005249)−2.836501268humoral immune response mediated by circulating−2.736965594immunoglobulin (GO:0002455)neuron fate specification (GO:0048665)−2.736965594neuropeptide receptor binding (GO:0071855)−2.736965594oxidoreductase activity, acting on paired donors, with−2.736965594incorporation or reduction of molecular oxygen, reduced flavin orflavoprotein as one donor, and incorporation of one atom ofoxygen (GO:0016712)calcium-dependent cell-cell adhesion via plasma membrane cell−2.64385619adhesion molecules (GO:0016339)Formation of the cornified envelope (R-HSA-6809371)−2.64385619G alpha (s) signalling events (R-HSA-418555)−2.64385619gap junction (GO:0005921)−2.64385619extracellular ligand-gated ion channel activity (GO:0005230)−2.556393349phagocytosis, recognition (GO:0006910)−2.556393349sensory perception of bitter taste (GO:0050913)−2.556393349cornification (GO:0070268)−2.473931188NCAM1 interactions (R-HSA-419037)−2.473931188Voltage gated Potassium channels (R-HSA-1296072)−2.473931188CD22 mediated BCR regulation (R-HSA-5690714)−2.395928676sodium channel activity (GO:0005272)−2.395928676cornified envelope (GO:0001533)−2.321928095Scavenging of heme from plasma (R-HSA-2168880)−2.251538767Defensins (R-HSA-1461973)−2.184424571detection of visible light (GO:0009584)−2.184424571potassium channel activity (GO:0005267)−2.184424571Complement cascade (R-HSA-166658)−2.120294234integral component of postsynaptic specialization membrane−2.120294234(GO:0099060)sensory perception of taste (GO:0050909)−2.120294234voltage-gated cation channel activity (GO:0022843)−2.120294234hormone activity (GO:0005179)−2.058893689chloride channel complex (GO:0034707)−2Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)−2collagen trimer (GO:0005581)−2GPCR ligand binding (R-HSA-500792)−2regulation of catecholamine secretion (GO:0050433)−2Regulation of Complement cascade (R-HSA-977606)−2regulation of dopamine secretion (GO:0014059)−2cardiac muscle cell action potential involved in contraction−1.943416472(GO:0086002)phospholipase C-activating G protein-coupled receptor signaling−1.943416472pathway (GO:0007200)intermediate filament (GO:0005882)−1.888968688keratinocyte differentiation (GO:0030216)−1.888968688sensory perception (GO:0007600)−1.888968688transmission of nerve impulse (GO:0019226)−1.888968688detection of stimulus (GO:0051606)−1.836501268intrinsic component of postsynaptic specialization membrane−1.836501268(GO:0098948)integral component of postsynaptic membrane (GO:0099055)−1.785875195neuropeptide signaling pathway (GO:0007218)−1.785875195potassium channel complex (GO:0034705)−1.785875195sulfotransferase activity (GO:0008146)−1.785875195antigen binding (GO:0003823)−1.736965594homophilic cell adhesion via plasma membrane adhesion−1.736965594molecules (GO:0007156)neuropeptide receptor activity (GO:0008188)−1.736965594regulation of complement activation (GO:0030449)−1.736965594Potassium Channels (R-HSA-1296071)−1.689659879axoneme part (GO:0044447)−1.64385619intrinsic component of postsynaptic membrane (GO:0098936)−1.64385619T cell receptor complex (GO:0042101)−1.64385619voltage-gated potassium channel complex (GO:0008076)−1.64385619peptide receptor activity (GO:0001653)−1.59946207cell fate specification (GO:0001708)−1.556393349cilium movement (GO:0003341)−1.556393349detection of light stimulus (GO:0009583)−1.556393349FCGR activation (R-HSA-2029481)−1.556393349integral component of postsynaptic density membrane−1.556393349(GO:0099061)membrane depolarization (GO:0051899)−1.556393349voltage-gated channel activity (GO:0022832)−1.556393349voltage-gated ion channel activity (GO:0005244)−1.556393349extracellular matrix component (GO:0044420)−1.514573173G protein-coupled peptide receptor activity (GO:0008528)−1.514573173ligand-gated channel activity (GO:0022834)−1.514573173ligand-gated ion channel activity (GO:0015276)−1.514573173positive regulation of synapse assembly (GO:0051965)−1.514573173transmembrane signaling receptor activity (GO:0004888)−1.514573173Class B/2 (Secretin family receptors) (R-HSA-373080)−1.473931188ion gated channel activity (GO:0022839)−1.473931188cytokine activity (GO:0005125)−1.434402824epidermal cell differentiation (GO:0009913)−1.434402824extracellular matrix structural constituent (GO:0005201)−1.434402824growth factor activity (GO:0008083)−1.434402824receptor ligand activity (GO:0048018)−1.434402824receptor regulator activity (GO:0030545)−1.434402824regulation of humoral immune response (GO:0002920)−1.434402824serine-type endopeptidase inhibitor activity (GO:0004867)−1.434402824Assembly of collagen fibrils and other multimeric structures (R-−1.395928676HSA-2022090)Collagen biosynthesis and modifying enzymes (R-HSA-1650814)−1.395928676G protein-coupled receptor signaling pathway (GO:0007186)−1.395928676gated channel activity (GO:0022836)−1.395928676Peptide ligand-binding receptors (R-HSA-375276)−1.395928676signaling receptor activator activity (GO:0030546)−1.395928676humoral immune response (GO:0006959)−1.358453971integral component of synaptic membrane (GO:0099699)−1.358453971Antimicrobial peptides (R-HSA-6803157)−1.321928095ion channel complex (GO:0034702)−1.321928095multicellular organismal signaling (GO:0035637)−1.321928095cation channel complex (GO:0034703)−1.286304185cell-cell adhesion via plasma-membrane adhesion molecules−1.286304185(GO:0098742)detection of external stimulus (GO:0009581)−1.286304185ligand-gated cation channel activity (GO:0099094)−1.286304185monooxygenase activity (GO:0004497)−1.286304185potassium ion transmembrane transporter activity (GO:0015079)−1.286304185Role of LAT2/NTAL/LAB on calcium mobilization (R-HSA-−1.2863041852730905)B cell mediated immunity (GO:0019724)−1.251538767cation channel activity (GO:0005261)−1.251538767immunoglobulin mediated immune response (GO:0016064)−1.251538767intrinsic component of synaptic membrane (GO:0099240)−1.251538767potassium ion transmembrane transport (GO:0071805)−1.251538767regulation of postsynaptic membrane potential (GO:0060078)−1.251538767postsynaptic specialization membrane (GO:0099634)−1.217591435regulation of amine transport (GO:0051952)−1.217591435detection of abiotic stimulus (GO:0009582)−1.184424571nervous system process (GO:0050877)−1.184424571phagocytosis, engulfment (GO:0006911)−1.184424571action potential (GO:0001508)−1.152003093cardiac conduction (GO:0061337)−1.152003093channel activity (GO:0015267)−1.152003093GPCR downstream signalling (R-HSA-388396)−1.152003093ion channel activity (GO:0005216)−1.152003093passive transmembrane transporter activity (GO:0022803)−1.152003093Signaling by GPCR (R-HSA-372790)−1.152003093signaling receptor activity (GO:0038023)−1.152003093transmembrane transporter complex (GO:1902495)−1.152003093actin-mediated cell contraction (GO:0070252)−1.120294234adenylate cydase-activating G protein-coupled receptor signaling−1.120294234pathway (GO:0007189)G protein-coupled receptor signaling pathway, coupled to cyclic−1.120294234nucleotide second messenger (GO:0007187)serine-type endopeptidase activity (GO:0004252)−1.089267338synapse assembly (GO:0007416)−1.089267338transporter complex (GO:1990351)−1.089267338basement membrane (GO:0005604)−1.058893689digestion (GO:0007586)−1.058893689heparin binding (GO:0008201)−1.058893689intermediate filament cytoskeleton (GO:0045111)−1.058893689potassium ion transport (GO:0006813)−1.058893689regulation of synapse assembly (GO:0051963)−1.058893689sensory perception of light stimulus (GO:0050953)−1.058893689Unclassified (UNCLASSIFIED)−1.058893689adenylate cyclase-modulating G protein-coupled receptor−1.029146346signaling pathway (GO:0007188)Collagen formation (R-HSA-1474290)−1.029146346epidermis development (GO:0008544)−1.029146346extracellular matrix (GO:0031012)−1.029146346intrinsic component of presynaptic membrane (GO:0098889)−1.029146346molecular transducer activity (GO:0060089)−1.029146346skin development (GO:0043588)−1.029146346visual perception (GO:0007601)−1.029146346Binding and Uptake of Ligands by Scavenger Receptors (R-HSA-−12173782)Golgi lumen (GO:0005796)−0.971430848antimicrobial humoral response (GO:0019730)−0.943416472cAMP-mediated signaling (GO:0019933)−0.943416472Cardiac conduction (R-HSA-5576891)−0.915935735anchored component of membrane (GO:0031225)−0.888968688collagen-containing extracellular matrix (GO:0062023)−0.888968688sodium ion transmembrane transporter activity (GO:0015081)−0.888968688plasma membrane invagination (GO:0099024)−0.836501268postsynaptic membrane (GO:0045211)−0.836501268cell recognition (GO:0008037)−0.810966176sensory perception of sound (GO:0007605)−0.810966176system process (GO:0003008)−0.810966176anterograde trans-synaptic signaling (GO:0098916)−0.785875195chemical synaptic transmission (GO:0007268)−0.785875195cyclic-nucleotide-mediated signaling (GO:0019935)−0.785875195Degradation of the extracellular matrix (R-HSA-1474228)−0.785875195sensory perception of mechanical stimulus (GO:0050954)−0.785875195trans-synaptic signaling (GO:0099537)−0.785875195glycosaminoglycan binding (GO:0005539)−0.76121314immunoglobulin production (GO:0002377)−0.76121314Neuronal System (R-HSA-112316)−0.76121314serine-type peptidase activity (GO:0008236)−0.76121314defense response to bacterium (GO:0042742)−0.713118852hydrolase activity, acting on acid phosphorus-nitrogen bonds−0.689659879(GO:0016825)serine hydrolase activity (GO:0017171)−0.689659879cell fate commitment (GO:0045165)−0.666576266synaptic signaling (GO:0099536)−0.666576266inner ear development (GO:0048839)−0.64385619ear development (GO:0043583)−0.621488377metal ion transmembrane transporter activity (GO:0046873)−0.621488377sensory organ morphogenesis (GO:0090596)−0.621488377epithelial cell differentiation (GO:0030855)−0.59946207integral component of plasma membrane (GO:0005887)−0.59946207synaptic membrane (GO:0097060)−0.59946207lymphocyte mediated immunity (GO:0002449)−0.577766999Muscle contraction (R-HSA-397014)−0.577766999G alpha (I) signalling events (R-HSA-418594)−0.556393349intrinsic component of plasma membrane (GO:0031226)−0.556393349regionalization (GO:0003002)−0.556393349monovalent inorganic cation transmembrane transporter activity−0.535331733(GO:0015077)pattern specification process (GO:0007389)−0.535331733receptor complex (GO:0043235)−0.535331733extracellular matrix organization (GO:0030198)−0.514573173adaptive immune response (GO:0002250)−0.473931188plasma membrane receptor complex (GO:0098802)−0.473931188inorganic cation transmembrane transporter activity−0.434402824(GO:0022890)plasma membrane protein complex (GO:0098797)−0.434402824regulation of membrane potential (GO:0042391)−0.434402824sensory organ development (GO:0007423)−0.434402824calcium ion binding (GO:0005509)−0.415037499external side of plasma membrane (GO:0009897)−0.415037499inorganic molecular entity transmembrane transporter activity−0.377069649(GO:0015318)animal organ morphogenesis (GO:0009887)−0.358453971cation transmembrane transporter activity (GO:0008324)−0.358453971epithelium development (GO:0060429)−0.340075442cell adhesion (GO:0007155)−0.321928095cell surface (GO:0009986)−0.321928095DNA-binding transcription factor activity, RNA polymerase II-−0.321928095specific (GO:0000981)biological adhesion (GO:0022610)−0.304006187plasma membrane part (GO:0044459)−0.304006187ion transmembrane transporter activity (GO:0015075)−0.286304185DNA-binding transcription factor activity (GO:0003700)−0.251538767integral component of membrane (GO:0016021)−0.234465254intrinsic component of membrane (GO:0031224)−0.234465254plasma membrane (GO:0005886)−0.234465254tissue development (GO:0009888)−0.234465254cell periphery (GO:0071944)−0.217591435extracellular region (GO:0005576)−0.120294234multicellular organismal process (GO:0032501)−0.120294234membrane part (GO:0044425)−0.089267338cellular component (GO:0005575)0.097610797membrane (GO:0016020)0.124328135biological process (GO:0008150)0.137503524response to stimulus (GO:0050896)0.137503524cation binding (GO:0043169)0.150559677regulation of transcription by RNA polymerase II (GO:0006357)0.150559677biological regulation (GO:0065007)0.163498732cell surface receptor signaling pathway (GO:0007166)0.163498732cellular response to stimulus (GO:0051716)0.163498732metal ion binding (GO:0046872)0.163498732molecular_function (GO:0003674)0.163498732regulation of biological process (GO:0050789)0.163498732cell (GO:0005623)0.176322773cell part (GO:0044464)0.176322773regulation of cellular process (GO:0050794)0.176322773regulation of multicellular organismal development (GO:2000026)0.176322773regulation of multicellular organismal process (GO:0051239)0.176322773positive regulation of multicellular organismal process0.189033824(GO:0051240)regulation of cell differentiation (GO:0045595)0.201633861regulation of cell population proliferation (GO:0042127)0.201633861regulation of developmental process (GO:0050793)0.201633861membrane protein complex (GO:0098796)0.214124805immune response (GO:0006955)0.22650853regulation of anatomical structure morphogenesis (GO:0022603)0.22650853response to endogenous stimulus (GO:0009719)0.22650853cellular response to endogenous stimulus (GO:0071495)0.23878686regulation of transcription, DNA-templated (GO:0006355)0.23878686cellular process (GO:0009987)0.250961574regulation of biological guality (GO:0065008)0.250961574regulation of localization (GO:0032879)0.250961574regulation of nucleic acid-templated transcription (GO:1903506)0.250961574regulation of RNA biosynthetic process (GO:2001141)0.250961574regulation of transport (GO:0051049)0.250961574response to hormone (GO:0009725)0.250961574transition metal ion binding (GO:0046914)0.250961574binding (GO:0005488)0.263034406cellular homeostasis (GO:0019725)0.263034406homeostatic process (GO:0042592)0.263034406ion binding (GO:0043167)0.263034406multi-organism process (GO:0051704)0.263034406regulation of cellular component movement (GO:0051270)0.263034406positive regulation of protein phosphorylation (GO:0001934)0.275007047positive regulation of transcription by RNA polymerase II0.275007047(GO:0045944)positive regulation of response to stimulus (GO:0048584)0.286881148enzyme linked receptor protein signaling pathway (GO:0007167)0.298658316lipid binding (GO:0008289)0.298658316positive regulation of phosphate metabolic process0.298658316(GO:0045937)positive regulation of phosphorus metabolic process0.298658316(GO:0010562)positive regulation of phosphorylation (GO:0042327)0.298658316regulation of cell motility (GO:2000145)0.298658316regulation of locomotion (GO:0040012)0.298658316regulation of RNA metabolic process (GO:0051252)0.298658316cellular response to chemical stimulus (GO:0070887)0.310340121cellular response to hormone stimulus (GO:0032870)0.310340121cytoplasmic region (GO:0099568)0.310340121regulation of cell migration (GO:0030334)0.310340121regulation of response to stimulus (GO:0048583)0.310340121response to oxygen-containing compound (GO:1901700)0.310340121Transport of small molecules (R-HSA-382551)0.310340121zinc ion binding (GO:0008270)0.310340121actin filament-based process (GO:0030029)0.321928095negative regulation of nucleic acid-templated transcription0.321928095(GO:1903507)negative regulation of RNA biosynthetic process (GO:1902679)0.321928095negative regulation of transcription by RNA polymerase II0.321928095(GO:0000122)negative regulation of transcription, DNA-templated0.321928095(GO:0045892)regulation of cell communication (GO:0010646)0.321928095regulation of cellular biosynthetic process (GO:0031326)0.321928095regulation of cellular macromolecule biosynthetic process0.321928095(GO:2000112)regulation of nucleobase-containing compound metabolic0.321928095process (GO:0019219)regulation of signaling (GO:0023051)0.321928095positive regulation of biological process (GO:0048518)0.333423734regulation of biosynthetic process (GO:0009889)0.333423734regulation of cell activation (GO:0050865)0.333423734regulation of cell projection organization (GO:0031344)0.333423734regulation of leukocyte activation (GO:0002694)0.333423734regulation of macromolecule biosynthetic process (GO:0010556)0.333423734regulation of plasma membrane bounded cell projection0.333423734organization (GO:0120035)cytoskeleton (GO:0005856)0.344828497Hemostasis (R-HSA-109582)0.344828497negative regulation of cellular process (GO:0048523)0.344828497negative regulation of RNA metabolic process (GO:0051253)0.344828497organic acid metabolic process (GO:0006082)0.344828497positive regulation of transcription, DNA-templated0.344828497(GO:0045893)regulation of gene expression (GO:0010468)0.344828497regulation of nitrogen compound metabolic process0.344828497(GO:0051171)regulation of primary metabolic process (GO:0080090)0.344828497response to organic substance (GO:0010033)0.344828497small molecule biosynthetic process (GO:0044283)0.344828497cellular response to organic substance (GO:0071310)0.35614381cytoskeletal part (GO:0044430)0.35614381intracellular (GO:0005622)0.35614381intracellular part (GO:0044424)0.35614381negative regulation of biological process (GO:0048519)0.35614381negative regulation of catalytic activity (GO:0043086)0.35614381negative regulation of molecular function (GO:0044092)0.35614381organelle (GO:0043226)0.35614381oxoacid metabolic process (GO:0043436)0.35614381positive regulation of cell communication (GO:0010647)0.35614381positive regulation of cell motility (GO:2000147)0.35614381positive regulation of cellular component movement0.35614381(GO:0051272)positive regulation of cellular process (GO:0048522)0.35614381positive regulation of locomotion (GO:0040017)0.35614381positive regulation of signaling (GO:0023056)0.35614381regulation of macromolecule metabolic process (GO:0060255)0.35614381regulation of protein phosphorylation (GO:0001932)0.35614381activation of immune response (GO:0002253)0.367371066cellular response to oxygen-containing compound (GO:1901701)0.367371066cytokine-mediated signaling pathway (GO:0019221)0.367371066immune response-activating cell surface receptor signaling0.367371066pathway (GO:0002429)immune system process (GO:0002376)0.367371066lipid metabolic process (GO:0006629)0.367371066negative regulation of cell communication (GO:0010648)0.367371066negative regulation of nucleobase-containing compound0.367371066metabolic process (GO:0045934)negative regulation of response to stimulus (GO:0048585)0.367371066negative regulation of signaling (GO:0023057)0.367371066oxidoreductase activity (GO:0016491)0.367371066protein dimerization activity (GO:0046983)0.367371066regulation of cellular metabolic process (GO:0031323)0.367371066regulation of metabolic process (GO:0019222)0.367371066regulation of signal transduction (GO:0009966)0.367371066actin cytoskeleton (GO:0015629)0.378511623cellular response to nitrogen compound (GO:1901699)0.378511623cellular response to organonitrogen compound (GO:0071417)0.378511623localization (GO:0051179)0.378511623negative regulation of apoptotic process (GO:0043066)0.378511623negative regulation of cell death (GO:0060548)0.378511623negative regulation of programmed cell death (GO:0043069)0.378511623positive regulation of gene expression (GO:0010628)0.378511623positive regulation of intracellular signal transduction0.378511623(GO:1902533)positive regulation of protein modification process (GO:0031401)0.378511623positive regulation of signal transduction (GO:0009967)0.378511623regulation of cell adhesion (GO:0030155)0.378511623regulation of response to external stimulus (GO:0032101)0.378511623carbohydrate metabolic process (GO:0005975)0.389566812carboxylic acid metabolic process (GO:0019752)0.389566812cellular response to drug (GO:0035690)0.389566812cytoskeleton organization (GO:0007010)0.389566812Generic Transcription Pathway (R-HSA-212436)0.389566812immune response-regulating cell surface receptor signaling0.389566812pathway (GO:0002768)positive regulation of immune system process (GO:0002684)0.389566812positive regulation of nucleic acid-templated transcription0.389566812(GO:1903508)positive regulation of RNA biosynthetic process (GO:1902680)0.389566812positive regulation of transport (GO:0051050)0.389566812protein binding (GO:0005515)0.389566812regulation of Wnt signaling pathway (GO:0030111)0.389566812small molecule catabolic process (GO:0044282)0.389566812carbohydrate derivative biosynthetic process (GO:1901137)0.40053793carbohydrate derivative metabolic process (GO:1901135)0.40053793cytoskeletal protein binding (GO:0008092)0.40053793hydrolase activity (GO:0016787)0.40053793intracellular organelle (GO:0043229)0.40053793negative regulation of cellular biosynthetic process0.40053793(GO:0031327)negative regulation of signal transduction (GO:0009968)0.40053793positive regulation of cell migration (GO:0030335)0.40053793regulation of apoptotic process (GO:0042981)0.40053793response to abiotic stimulus (GO:0009628)0.40053793response to inorganic substance (GO:0010035)0.40053793actin cytoskeleton organization (GO:0030036)0.411426246endoplasmic reticulum (GO:0005783)0.411426246in utero embryonic development (GO:0001701)0.411426246membrane-bounded organelle (GO:0043227)0.411426246negative regulation of biosynthetic process (GO:0009890)0.411426246negative regulation of cellular macromolecule biosynthetic0.411426246process (GO:2000113)negative regulation of immune system process (GO:0002683)0.411426246negative regulation of macromolecule biosynthetic process0.411426246(GO:0010558)negative regulation of nitrogen compound metabolic process0.411426246(GO:0051172)plasma membrane bounded cell projection assembly0.411426246(GO:0120031)positive regulation of immune response (GO:0050778)0.411426246positive regulation of RNA metabolic process (GO:0051254)0.411426246regulation of cell death (GO:0010941)0.411426246regulation of cell-cell adhesion (GO:0022407)0.411426246regulation of immune system process (GO:0002682)0.411426246regulation of programmed cell death (GO:0043067)0.411426246response to light stimulus (GO:0009416)0.411426246transmembrane receptor protein tyrosine kinase signaling0.411426246pathway (GO:0007169)transport vesicle (GO:0030133)0.411426246alcohol metabolic process (GO:0006066)0.422233001antigen receptor-mediated signaling pathway (GO:0050851)0.422233001cell projection assembly (GO:0030031)0.422233001heterocyclic compound binding (GO:1901363)0.422233001immune response-activating signal transduction (GO:0002757)0.422233001nucleic acid binding (GO:0003676)0.422233001organic cyclic compound binding (GO:0097159)0.422233001positive regulation of biosynthetic process (GO:0009891)0.422233001positive regulation of cell projection organization (GO:0031346)0.422233001positive regulation of cellular biosynthetic process (GO:0031328)0.422233001positive regulation of macromolecule metabolic process0.422233001(GO:0010604)positive regulation of nitrogen compound metabolic process0.422233001(GO:0051173)regulation of actin cytoskeleton organization (GO:0032956)0.422233001regulation of molecular function (GO:0065009)0.422233001regulation of neuron death (GO:1901214)0.422233001regulation of phosphate metabolic process (GO:0019220)0.422233001regulation of phosphorus metabolic process (GO:0051174)0.422233001regulation of phosphorylation (GO:0042325)0.422233001response to nitrogen compound (GO:1901698)0.422233001response to peptide hormone (GO:0043434)0.422233001small molecule metabolic process (GO:0044281)0.422233001cellular lipid metabolic process (GO:0044255)0.432959407coagulation (GO:0050817)0.432959407cytoplasm (GO:0005737)0.432959407establishment of localization (GO:0051234)0.432959407immune response-regulating signaling pathway (GO:0002764)0.432959407negative regulation of cellular metabolic process (GO:0031324)0.432959407phosphoric ester hydrolase activity (GO:0042578)0.432959407positive regulation of cellular metabolic process (GO:0031325)0.432959407positive regulation of macromolecule biosynthetic process0.432959407(GO:0010557)positive regulation of metabolic process (GO:0009893)0.432959407positive regulation of nucleobase-containing compound0.432959407metabolic process (GO:0045935)regulation of hydrolase activity (GO:0051336)0.432959407regulation of supramolecular fiber organization (GO:1902903)0.432959407response to organonitrogen compound (GO:0010243)0.432959407transport (GO:0006810)0.432959407blood coagulation (GO:0007596)0.443606651cellular amino acid metabolic process (GO:0006520)0.443606651cellular component organization (GO:0016043)0.443606651negative regulation of macromolecule metabolic process0.443606651(GO:0010605)positive regulation of cellular protein metabolic process0.443606651(GO:0032270)protein homodimerization activity (GO:0042803)0.443606651regulation of immune response (GO:0050776)0.443606651response to stress (GO:0006950)0.443606651vesicle (GO:0031982)0.443606651Axon guidance (R-HSA-422475)0.454175893cell cortex (GO:0005938)0.454175893hemostasis (GO:0007599)0.454175893intracellular signal transduction (GO:0035556)0.454175893negative regulation of gene expression (GO:0010629)0.454175893negative regulation of metabolic process (GO:0009892)0.454175893organelle assembly (GO:0070925)0.454175893positive regulation of cytokine production (GO:0001819)0.454175893positive regulation of protein metabolic process (GO:0051247)0.454175893purine-containing compound metabolic process (GO:0072521)0.454175893regulation of protein modification process (GO:0031399)0.454175893response to peptide (GO:1901652)0.454175893cellular component organization or biogenesis (GO:0071840)0.464668267cellular response to cytokine stimulus (GO:0071345)0.464668267cofactor binding (GO:0048037)0.464668267endoplasmic reticulum part (GO:0044432)0.464668267extracellular exosome (GO:0070062)0.464668267extracellular organelle (GO:0043230)0.464668267extracellular vesicle (GO:1903561)0.464668267intracellular membrane-bounded organelle (GO:0043231)0.464668267nuclear division (GO:0000280)0.464668267phospholipid binding (GO:0005543)0.464668267positive regulation of cell adhesion (GO:0045785)0.464668267regulation of cellular component size (GO:0032535)0.464668267regulation of intracellular signal transduction (GO:1902531)0.464668267regulation of MAP kinase activity (GO:0043405)0.464668267regulation of proteolysis (GO:0030162)0.464668267response to extracellular stimulus (GO:0009991)0.464668267response to radiation (GO:0009314)0.464668267catalytic activity (GO:0003824)0.475084883cell death (GO:0008219)0.475084883endomembrane system (GO:0012505)0.475084883hydrolase activity, acting on ester bonds (GO:0016788)0.475084883identical protein binding (GO:0042802)0.475084883membrane microdomain (GO:0098857)0.475084883membrane region (GO:0098589)0.475084883microtubule-based process (GO:0007017)0.475084883programmed cell death (GO:0012501)0.475084883regulation of catalytic activity (GO:0050790)0.475084883regulation of stress-activated MAPK cascade (GO:0032872)0.475084883regulation of vesicle-mediated transport (GO:0060627)0.475084883response to antibiotic (GO:0046677)0.475084883response to cytokine (GO:0034097)0.475084883response to nutrient levels (GO:0031667)0.475084883anion binding (GO:0043168)0.485426827cell-cell signaling by wnt (GO:0198738)0.485426827enzyme regulator activity (GO:0030234)0.485426827extrinsic component of membrane (GO:0019898)0.485426827GTPase activity (GO:0003924)0.485426827membrane raft (GO:0045121)0.485426827microtubule cytoskeleton organization (GO:0000226)0.485426827organelle fission (GO:0048285)0.485426827oxidation-reduction process (GO:0055114)0.485426827positive regulation of cellular component biogenesis0.485426827(GO:0044089)positive regulation of protein kinase activity (GO:0045860)0.485426827positive regulation of protein serine/threonine kinase activity0.485426827(GO:0071902)regulation of cellular component organization (GO:0051128)0.485426827regulation of cellular protein metabolic process (GO:0032268)0.485426827regulation of protein metabolic process (GO:0051246)0.485426827regulation of Ras protein signal transduction (GO:0046578)0.485426827regulation of stress-activated protein kinase signaling cascade0.485426827(GO:0070302)RNA Polymerase II Transcription (R-HSA-73857)0.485426827Wnt signaling pathway (GO:0016055)0.485426827carbohydrate derivative binding (GO:0097367)0.495695163catalytic activity, acting on a protein (GO:0140096)0.495695163negative regulation of cellular component organization0.495695163(GO:0051129)nucleus (GO:0005634)0.495695163protein complex oligomerization (GO:0051259)0.495695163regulation of peptide transport (GO:0090087)0.495695163regulation of small GTPase mediated signal transduction0.495695163(GO:0051056)secretory vesicle (GO:0099503)0.495695163cellular response to abiotic stimulus (GO:0071214)0.50589093cellular response to environmental stimulus (GO:0104004)0.50589093cytoplasmic part (GO:0044444)0.50589093establishment or maintenance of cell polarity (GO:0007163)0.50589093Fatty acid metabolism (R-HSA-8978868)0.50589093leukocyte mediated immunity (GO:0002443)0.50589093Metabolism of amino acids and derivatives (R-HSA-71291)0.50589093organonitrogen compound metabolic process (GO:1901564)0.50589093positive regulation of kinase activity (GO:0033674)0.50589093positive regulation of response to external stimulus0.50589093(GO:0032103)purine nucleotide metabolic process (GO:0006163)0.50589093regulation of cytoskeleton organization (GO:0051493)0.50589093regulation of leukocyte differentiation (GO:1902105)0.50589093anchoring junction (GO:0070161)0.516015147cellular response to peptide hormone stimulus (GO:0071375)0.516015147cellular response to tumor necrosis factor (GO:0071356)0.516015147cytoplasmic vesicle membrane (GO:0030659)0.516015147microtubule (GO:0005874)0.516015147negative regulation of cellular protein metabolic process0.516015147(GO:0032269)negative regulation of protein metabolic process (GO:0051248)0.516015147post-translational protein modification (GO:0043687)0.516015147purine ribonucleotide metabolic process (GO:0009150)0.516015147regulation of cellular component biogenesis (GO:0044087)0.516015147regulation of leukocyte cell-cell adhesion (GO:1903037)0.516015147regulation of lipid metabolic process (GO:0019216)0.516015147regulation of protein transport (GO:0051223)0.516015147response to virus (GO:0009615)0.516015147activation of protein kinase activity (GO:0032147)0.526068812cell cortex part (GO:0044448)0.526068812cellular response to molecule of bacterial origin (GO:0071219)0.526068812Golgi apparatus (GO:0005794)0.526068812Golgi apparatus part (GO:0044431)0.526068812guanyl nucleotide binding (GO:0019001)0.526068812guanyl ribonucleotide binding (GO:0032561)0.526068812membrane organization (GO:0061024)0.526068812metabolic process (GO:0008152)0.526068812microtubule binding (GO:0008017)0.526068812organic substance metabolic process (GO:0071704)0.526068812positive regulation of cytoskeleton organization (GO:0051495)0.526068812positive regulation of hemopoiesis (GO:1903708)0.526068812positive regulation of immune effector process (GO:0002699)0.526068812positive regulation of protein transport (GO:0051222)0.526068812regulation of cell projection assembly (GO:0060491)0.526068812regulation of cytokine production (GO:0001817)0.526068812regulation of protein serine/threonine kinase activity0.526068812(GO:0071900)response to tumor necrosis factor (GO:0034612)0.526068812transcription factor complex (GO:0005667)0.526068812DNA conformation change (GO:0071103)0.5360529immune effector process (GO:0002252)0.5360529Metabolism (R-HSA-1430728)0.5360529monosaccharide metabolic process (GO:0005996)0.5360529organic cyclic compound catabolic process (GO:1901361)0.5360529phosphatase activity (GO:0016791)0.5360529positive regulation of molecular function (GO:0044093)0.5360529positive regulation of transferase activity (GO:0051347)0.5360529primary metabolic process (GO:0044238)0.5360529protein-containing complex (GO:0032991)0.5360529protein-DNA complex assembly (GO:0065004)0.5360529proteolysis (GO:0006508)0.5360529regulation of cellular localization (GO:0060341)0.5360529regulation of defense response (GO:0031347)0.5360529regulation of myeloid cell differentiation (GO:0045637)0.5360529regulation of plasma membrane bounded cell projection0.5360529assembly (GO:0120032)regulation of protein kinase activity (GO:0045859)0.5360529ribonucleotide metabolic process (GO:0009259)0.5360529small molecule binding (GO:0036094)0.5360529TCF dependent signaling in response to WNT (R-HSA-201681)0.5360529tubulin binding (GO:0015631)0.5360529vesicle membrane (GO:0012506)0.5360529adherens junction (GO:0005912)0.545968369cellular component assembly (GO:0022607)0.545968369cofactor metabolic process (GO:0051186)0.545968369dephosphorylation (GO:0016311)0.545968369Disorders of transmembrane transporters (R-HSA-5619115)0.545968369drug binding (GO:0008144)0.545968369Gene expression (Transcription) (R-HSA-74160)0.545968369MAPK cascade (GO:0000165)0.545968369microtubule-based transport (GO:0099111)0.545968369nucleoside phosphate metabolic process (GO:0006753)0.545968369nudeoside-triphosphatase activity (GO:0017111)0.545968369organelle part (GO:0044422)0.545968369positive regulation of catalytic activity (GO:0043085)0.545968369positive regulation of cell-cell adhesion (GO:0022409)0.545968369positive regulation of cellular component organization0.545968369(GO:0051130)protein dephosphorylation (GO:0006470)0.545968369protein metabolic process (GO:0019538)0.545968369regulation of establishment of protein localization (GO:0070201)0.545968369regulation of phosphatase activity (GO:0010921)0.545968369regulation of protein localization (GO:0032880)0.545968369regulation of protein polymerization (GO:0032271)0.545968369secretion (GO:0046903)0.545968369secretory granule (GO:0030141)0.545968369Signaling by Receptor Tyrosine Kinases (R-HSA-9006934)0.545968369Signaling by WNT (R-HSA-195721)0.545968369T cell activation (GO:0042110)0.545968369cell adhesion molecule binding (GO:0050839)0.555816155cellular response to peptide (GO:1901653)0.555816155clarthin-coated vesicle (GO:0030136)0.555816155hydrolase activity, acting on acid anhydrides (GO:0016817)0.555816155hydrolase activity, acting on acid anhydrides, in phosphorus-0.555816155containing anhydrides (GO:0016818)intracellular non-membrane-bounded organelle (GO:0043232)0.555816155lipid biosynthetic process (GO:0008610)0.555816155nitrogen compound metabolic process (GO:0006807)0.555816155non-membrane-bounded organelle (GO:0043228)0.555816155protein binding, bridging (GO:0030674)0.555816155pyrophosphatase activity (GO:0016462)0.555816155regulation of carbohydrate metabolic process (GO:0006109)0.555816155regulation of cysteine-type endopeptidase activity (GO:2000116)0.555816155regulation of kinase activity (GO:0043549)0.555816155regulation of response to stress (GO:0080134)0.555816155cellular response to external stimulus (GO:0071496)0.565597176cytoplasmic vesicle (GO:0031410)0.565597176early endosome membrane (GO:0031901)0.565597176endocytic vesicle (GO:0030139)0.565597176GTP binding (GO:0005525)0.565597176immune system development (GO:0002520)0.565597176intracellular vesicle (GO:0097708)0.565597176leukocyte differentiation (GO:0002521)0.565597176membrane lipid metabolic process (GO:0006643)0.565597176negative regulation of phosphate metabolic process0.565597176(GO:0045936)negative regulation of phosphorus metabolic process0.565597176(GO:0010563)nucleobase-containing small molecule metabolic process0.565597176(GO:0055086)nucleotide metabolic process (GO:0009117)0.565597176perinuclear region of cytoplasm (GO:0048471)0.565597176Platelet degranulation (R-HSA-114608)0.565597176positive regulation of cell death (GO:0010942)0.565597176positive regulation of establishment of protein localization0.565597176(GO:1904951)positive regulation of hydrolase activity (GO:0051345)0.565597176positive regulation of Wnt signaling pathway (GO:0030177)0.565597176protein phosphorylation (GO:0006468)0.565597176purine nucleoside binding (GO:0001883)0.565597176purine ribonucleoside binding (GO:0032550)0.565597176regulation of lymphocyte differentiation (GO:0045619)0.565597176regulation of nuclear division (GO:0051783)0.565597176regulation of T cell activation (GO:0050863)0.565597176regulation of transferase activity (GO:0051338)0.565597176response to insulin (GO:0032868)0.565597176ribose phosphate metabolic process (GO:0019693)0.565597176signal transduction by protein phosphorylation (GO:0023014)0.565597176cellular metabolic process (GO:0044237)0.575312331cellular response to biotic stimulus (GO:0071216)0.575312331cellular response to radiation (GO:0071478)0.575312331condensed chromosome (GO:0000793)0.575312331export from cell (GO:0140352)0.575312331macromolecule metabolic process (GO:0043170)0.575312331Metabolism of lipids (R-HSA-556833)0.575312331negative regulation of cytokine production (GO:0001818)0.575312331nucleoside binding (GO:0001882)0.575312331positive regulation of apoptotic process (GO:0043065)0.575312331positive regulation of programmed cell death (GO:0043068)0.575312331protein kinase regulator activity (GO:0019887)0.575312331protein localization to plasma membrane (GO:0072659)0.575312331regulation of GTPase activity (GO:0043087)0.575312331regulation of leukocyte mediated immunity (GO:0002703)0.575312331regulation of microtubule-based process (GO:0032886)0.575312331response to decreased oxygen levels (GO:0036293)0.575312331response to hypoxia (GO:0001666)0.575312331Rho GTPase cycle (R-HSA-194840)0.575312331ribonucleoside binding (GO:0032549)0.575312331cellular protein modification process (GO:0006464)0.584962501endoplasmic reticulum membrane (GO:0005789)0.584962501Glycerophospholipid biosynthesis (R-HSA-1483206)0.584962501hematopoietic or lymphoid organ development (GO:0048534)0.584962501Immune System (R-HSA-168256)0.584962501intracellular organelle part (GO:0044446)0.584962501macromolecule modification (GO:0043412)0.584962501negative regulation of apoptotic signaling pathway (GO:2001234)0.584962501negative regulation of organelle organization (GO:0010639)0.584962501negative regulation of phosphorylation (GO:0042326)0.584962501nuclear outer membrane-endoplasmic reticulum membrane0.584962501network (GO:0042175)phosphate-containing compound metabolic process0.584962501(GO:0006796)positive regulation of endopeptidase activity (GO:0010950)0.584962501protein kinase activity (GO:0004672)0.584962501protein modification process (GO:0036211)0.584962501protein-containing complex binding (GO:0044877)0.584962501protein-DNA complex subunit organization (GO:0071824)0.584962501purine nucleotide biosynthetic process (GO:0006164)0.584962501purine ribonucleotide biosynthetic process (GO:0009152)0.584962501regulation of cellular ketone metabolic process (GO:0010565)0.584962501regulation of cysteine-type endopeptidase activity involved in0.584962501apoptotic process (GO:0043281)Response to elevated platelet cytosolic Ca2+ (R-HSA-76005)0.584962501response to oxygen levels (GO:0070482)0.584962501transcription corepressor activity (GO:0003714)0.584962501catabolic process (GO:0009056)0.59454855cellular component biogenesis (GO:0044085)0.59454855cellular response to extracellular stimulus (GO:0031668)0.59454855cellular response to toxic substance (GO:0097237)0.59454855chromosome segregation (GO:0007059)0.59454855cortical cytoskeleton (GO:0030863)0.59454855Cytokine Signaling in Immune system (R-HSA-1280215)0.59454855Fc-epsilon receptor signaling pathway (GO:0038095)0.59454855glycerolipid metabolic process (GO:0046486)0.59454855hemopoiesis (GO:0030097)0.59454855kinase regulator activity (GO:0019207)0.59454855microtubule cytoskeleton (GO:0015630)0.59454855negative regulation of protein phosphorylation (GO:0001933)0.59454855organic substance catabolic process (GO:1901575)0.59454855organic substance transport (GO:0071702)0.59454855organonitrogen compound biosynthetic process (GO:1901566)0.59454855organophosphate metabolic process (GO:0019637)0.59454855phosphorus metabolic process (GO:0006793)0.59454855Platelet activation, signaling and aggregation (R-HSA-76002)0.59454855positive regulation of GTPase activity (GO:0043547)0.59454855purine-containing compound biosynthetic process (GO:0072522)0.59454855RAF/MAP kinase cascade (R-HSA-5673001)0.59454855Signaling by Nuclear Receptors (R-HSA-9006931)0.59454855apoptotic process (GO:0006915)0.604071324bounding membrane of organelle (GO:0098588)0.604071324chromatin binding (GO:0003682)0.604071324coenzyme binding (GO:0050662)0.604071324cysteine-type peptidase activity (GO:0008234)0.604071324DNA recombination (GO:0006310)0.604071324Golgi membrane (GO:0000139)0.604071324lymphocyte differentiation (GO:0030098)0.604071324MAPK1/MAPK3 signaling (R-HSA-5684996)0.604071324organonitrogen compound catabolic process (GO:1901565)0.604071324positive regulation of cell cycle process (GO:0090068)0.604071324positive regulation of defense response (GO:0031349)0.604071324positive regulation of DNA-binding transcription factor activity0.604071324(GO:0051091)Post-translational protein modification (R-HSA-597592)0.604071324purine ribonucleotide binding (GO:0032555)0.604071324ribonucleotide binding (GO:0032553)0.604071324transferase activity (GO:0016740)0.604071324actin filament (GO:0005884)0.613531653aromatic compound catabolic process (GO:0019439)0.613531653cytosolic ribosome (GO:0022626)0.613531653Golgi stack (GO:0005795)0.613531653Interferon Signaling (R-HSA-913531)0.613531653isomerase activity (GO:0016853)0.613531653negative regulation of intracellular signal transduction0.613531653(GO:1902532)organelle membrane (GO:0031090)0.613531653organelle organization (GO:0006996)0.613531653positive regulation of canonical Wnt signaling pathway0.613531653(GO:0090263)positive regulation of cell cycle (GO:0045787)0.613531653positive regulation of peptidase activity (GO:0010952)0.613531653positive regulation of T cell activation (GO:0050870)0.613531653purine nucleotide binding (GO:0017076)0.613531653regulation of small molecule metabolic process (GO:0062012)0.613531653secretion by cell (GO:0032940)0.613531653Signaling by the B Cell Receptor (BCR)(R-HSA-983705)0.613531653adenyl ribonucleotide binding (GO:0032559)0.622930351biosynthetic process (GO:0009058)0.622930351cellular macromolecule metabolic process (GO:0044260)0.622930351cellular nitrogen compound catabolic process (GO:0044270)0.622930351generation of precursor metabolites and energy (GO:0006091)0.622930351intracellular receptor signaling pathway (GO:0030522)0.622930351molecular adaptor activity (GO:0060090)0.622930351nucleoside phosphate binding (GO:1901265)0.622930351nucleotide binding (GO:0000166)0.622930351phosphorylation (GO:0016310)0.622930351phosphotransferase activity, alcohol group as acceptor0.622930351(GO:0016773)positive regulation of leukocyte cell-cell adhesion (GO:1903039)0.622930351protein localization to membrane (GO:0072657)0.622930351purine ribonucleoside triphosphate binding (GO:0035639)0.622930351regulation of DNA-binding transcription factor activity0.622930351(GO:0051090)regulation of endocytosis (GO:0030100)0.622930351ribonucleotide biosynthetic process (GO:0009260)0.622930351T cell differentiation (GO:0030217)0.622930351vesicle-mediated transport (GO:0016192)0.622930351adenyl nucleotide binding (GO:0030554)0.632268215centriole (GO:0005814)0.632268215coated vesicle membrane (GO:0030662)0.632268215early endosome (GO:0005769)0.632268215kinase activity (GO:0016301)0.632268215macromolecule localization (GO:0033036)0.632268215MAPK family signaling cascades (R-HSA-5683057)0.632268215organic substance biosynthetic process (GO:1901576)0.632268215regulation of dephosphorylation (GO:0035303)0.632268215Signaling by Interleukins (R-HSA-449147)0.632268215ATP binding (GO:0005524)0.641546029ATPase activity (GO:0016887)0.641546029cellular biosynthetic process (GO:0044249)0.641546029cellular protein metabolic process (GO:0044267)0.641546029cellular response to nutrient levels (GO:0031669)0.641546029cytoplasmic vesicle part (GO:0044433)0.641546029heterocycle catabolic process (GO:0046700)0.641546029Innate Immune System (R-HSA-168249)0.641546029methylation (GO:0032259)0.641546029negative regulation of protein modification process0.641546029(GO:0031400)nucleoside phosphate biosynthetic process (GO:1901293)0.641546029regulation of adaptive immune response (GO:0002819)0.641546029regulation of organelle organization (GO:0033043)0.641546029ribose phosphate biosynthetic process (GO:0046390)0.641546029transferase activity, transferring acyl groups (GO:0016746)0.641546029cellular response to insulin stimulus (GO:0032869)0.650764559coenzyme metabolic process (GO:0006732)0.650764559COPII-coated ER to Golgi transport vesicle (GO:0030134)0.650764559cytoplasmic side of plasma membrane (GO:0009898)0.650764559cytosolic part (GO:0044445)0.650764559Estrogen-dependent gene expression (R-HSA-9018519)0.650764559Fc epsilon receptor (FCERI)signaling (R-HSA-2454202)0.650764559monocarboxylic acid catabolic process (GO:0072329)0.650764559negative regulation of transferase activity (GO:0051348)0.650764559organic cyclic compound biosynthetic process (GO:1901362)0.650764559phosphatidylinositol binding (GO:0035091)0.650764559protein domain specific binding (GO:0019904)0.650764559Ras guanyl-nucleotide exchange factor activity (GO:0005088)0.650764559regulation of apoptotic signaling pathway (GO:2001233)0.650764559regulation of binding (GO:0051098)0.650764559Rho GTPase binding (GO:0017048)0.650764559vacuolar lumen (GO:0005775)0.650764559whole membrane (GO:0098805)0.650764559cell leading edge (GO:0031252)0.659924558cellular catabolic process (GO:0044248)0.659924558coated vesicle (GO:0030135)0.659924558Disease (R-HSA-1643685)0.659924558enzyme activator activity (GO:0008047)0.659924558hexose metabolic process (GO:0019318)0.659924558membrane fusion (GO:0061025)0.659924558Metabolism of carbohydrates (R-HSA-71387)0.659924558Metabolism of proteins (R-HSA-392499)0.659924558microtubule organizing center (GO:0005815)0.659924558negative regulation of catabolic process (GO:0009895)0.659924558negative regulation of kinase activity (GO:0033673)0.659924558nucleotide biosynthetic process (GO:0009165)0.659924558organic cyclic compound metabolic process (GO:1901360)0.659924558protein heterooligomerization (GO:0051291)0.659924558regulation of hemopoiesis (GO:1903706)0.659924558regulation of microtubule cytoskeleton organization0.659924558(GO:0070507)regulation of multi-organism process (GO:0043900)0.659924558B cell activation (GO:0042113)0.669026766EPH-Ephrin signaling (R-HSA-2682334)0.669026766glucose metabolic process (GO:0006006)0.669026766lymphocyte activation (GO:0046649)0.669026766maintenance of location (GO:0051235)0.669026766microbody part (GO:0044438)0.669026766microtubule organizing center part (GO:0044450)0.669026766nuclear transcription factor complex (GO:0044798)0.669026766peroxisomal part (GO:0044439)0.669026766regulation of mitotic nuclear division (GO:0007088)0.669026766regulation of protein dephosphorylation (GO:0035304)0.669026766RNA Polymerase I Transcription (R-HSA-73864)0.669026766transferase activity, transferring phosphorus-containing groups0.669026766(GO:0016772)Adaptive Immune System (R-HSA-1280218)0.678071905ESR-mediated signaling (R-HSA-8939211)0.678071905GTPase activator activity (GO:0005096)0.678071905inclusion body (GO:0016234)0.678071905negative regulation of protein kinase activity (GO:0006469)0.678071905positive regulation of proteolysis (GO:0045862)0.678071905Processing of DNA double-strand break ends (R-HSA-5693607)0.678071905protein-containing complex assembly (GO:0065003)0.678071905protein-containing complex subunit organization (GO:0043933)0.678071905regulation of protein complex assembly (GO:0043254)0.678071905Selenoamino acid metabolism (R-HSA-2408522)0.678071905sister chromatid segregation (GO:0000819)0.678071905transcription factor binding (GO:0008134)0.678071905transcription initiation from RNA polymerase II promoter0.678071905(GO:0006367)cell cycle arrest (GO:0007050)0.687060688cellular aromatic compound metabolic process (GO:0006725)0.687060688cytoplasmic side of membrane (GO:0098562)0.687060688cytosol (GO:0005829)0.687060688Formation of a pool of free 40S subunits (R-HSA-72689)0.687060688kinase binding (GO:0019900)0.687060688neuron projection cytoplasm (GO:0120111)0.687060688phospholipid metabolic process (GO:0006644)0.687060688recycling endosome (GO:0055037)0.687060688regulation of cellular response to stress (GO:0080135)0.687060688regulation of reactive oxygen species metabolic process0.687060688(GO:2000377)aromatic compound biosynthetic process (GO:0019438)0.695993813ATP metabolic process (GO:0046034)0.695993813cell activation (GO:0001775)0.695993813cell-substrate junction (GO:0030055)0.695993813cellular carbohydrate metabolic process (GO:0044262)0.695993813cellular localization (GO:0051641)0.695993813cellular response to leukemia inhibitory factor (GO:1990830)0.695993813cytoplasmic ribonucleoprotein granule (GO:0036464)0.695993813glycerophospholipid metabolic process (GO:0006650)0.695993813GTPase regulator activity (GO:0030695)0.695993813negative regulation of cellular catabolic process (GO:0031330)0.695993813negative regulation of DNA-binding transcription factor activity0.695993813(GO:0043433)negative regulation of intrinsic apoptotic signaling pathway0.695993813(GO:2001243)nuclease activity (GO:0004518)0.695993813protein localization (GO:0008104)0.695993813regulation of DNA repair (GO:0006282)0.695993813regulation of nucleotide metabolic process (GO:0006140)0.695993813response to leukemia inhibitory factor (GO:1990823)0.695993813response to reactive oxygen species (GO:0000302)0.695993813RUNX1 regulates transcription of genes involved in differentiation0.695993813of HSCs (R-HSA-8939236)small GTPase mediated signal transduction (GO:0007264)0.695993813transcription coregulator activity (GO:0003712)0.695993813transferase activity, transferring acyl groups other than amino-0.695993813acyl groups (GO:0016747)transport along microtubule (GO:0010970)0.695993813cell cycle (GO:0007049)0.704871964cell-substrate adherens junction (GO:0005924)0.704871964endosome (GO:0005768)0.704871964hormone receptor binding (GO:0051427)0.704871964macromolecule biosynthetic process (GO:0009059)0.704871964macromolecule methylation (GO:0043414)0.704871964microbody (GO:0042579)0.704871964mitotic DNA integrity checkpoint (GO:0044774)0.704871964negative regulation of protein binding (GO:0032091)0.704871964nitrogen compound transport (GO:0071705)0.704871964non-canonical Wnt signaling pathway (GO:0035567)0.704871964pattern recognition receptor signaling pathway (GO:0002221)0.704871964peptidyl-amino acid modification (GO:0018193)0.704871964peptidyl-serine modification (GO:0018209)0.704871964peroxisome (GO:0005777)0.704871964positive regulation of organelle organization (GO:0010638)0.704871964protein phosphatase binding (GO:0019903)0.704871964regulation of cell cycle G1/S phase transition (GO:1902806)0.704871964regulation of protein binding (GO:0043393)0.704871964response to interleukin-1 (GO:0070555)0.704871964stress-activated MAPK cascade (GO:0051403)0.704871964cellular amide metabolic process (GO:0043603)0.713695815cellular macromolecule localization (GO:0070727)0.713695815cellular nitrogen compound metabolic process (GO:0034641)0.713695815cellular protein localization (GO:0034613)0.713695815DNA metabolic process (GO:0006259)0.713695815enzyme binding (GO:0019899)0.713695815focal adhesion (GO:0005925)0.713695815heterocycle metabolic process (GO:0046483)0.713695815intrinsic component of organelle membrane (GO:0031300)0.713695815methyltransferase activity (GO:0008168)0.713695815nucleobase-containing compound catabolic process0.713695815(GO:0034655)positive regulation of endocytosis (GO:0045807)0.713695815protein kinase binding (GO:0019901)0.713695815regulation of response to biotic stimulus (GO:0002831)0.713695815regulation of response to DNA damage stimulus (GO:2001020)0.713695815regulation of symbiosis, encompassing mutualism through0.713695815parasitism (GO:0043903)ribonucleoprotein granule (GO:0035770)0.713695815RNA modification (GO:0009451)0.713695815secretory granule membrane (GO:0030667)0.713695815SH3 domain binding (GO:0017124)0.713695815signal transduction by p53 class mediator (GO:0072331)0.713695815Signaling by Rho GTPases (R-HSA-194315)0.713695815Signaling by TGF-beta family members (R-HSA-9006936)0.713695815Sphingolipid metabolism (R-HSA-428157)0.713695815transcription by RNA polymerase II (GO:0006366)0.713695815transferase activity, transferring one-carbon groups0.713695815(GO:0016741)vesicle lumen (GO:0031983)0.713695815apoptotic signaling pathway (GO:0097190)0.722466024cell cycle process (GO:0022402)0.722466024cellular response to interleukin-1 (GO:0071347)0.722466024chromosome organization (GO:0051276)0.722466024COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)0.722466024cytoplasmic vesicle lumen (GO:0060205)0.722466024exocytosis (GO:0006887)0.722466024extrinsic apoptotic signaling pathway (GO:0097191)0.722466024gene silencing by RNA (GO:0031047)0.722466024heterocycle biosynthetic process (GO:0018130)0.722466024intracellular organelle lumen (GO:0070013)0.722466024lipid modification (GO:0030258)0.722466024maintenance of location in cell (GO:0051651)0.722466024membrane-enclosed lumen (GO:0031974)0.722466024Metabolism of nucleotides (R-HSA-15869)0.722466024mitochondrion (GO:0005739)0.722466024mitotic DNA damage checkpoint (GO:0044773)0.722466024Mitotic Prophase (R-HSA-68875)0.722466024negative regulation of cellular protein localization (GO:1903828)0.722466024nucleobase-containing compound biosynthetic process0.722466024(GO:0034654)nudeoside-triphosphatase regulator activity (GO:0060589)0.722466024organelle lumen (GO:0043233)0.722466024organelle outer membrane (GO:0031968)0.722466024outer membrane (GO:0019867)0.722466024positive regulation of mitotic cell cycle (GO:0045931)0.722466024Ras GTPase binding (GO:0017016)0.722466024Ras protein signal transduction (GO:0007265)0.722466024regulation of cell cycle (GO:0051726)0.722466024regulation of cellular protein localization (GO:1903827)0.722466024regulation of DNA metabolic process (GO:0051052)0.722466024regulation of purine nucleotide metabolic process (GO:1900542)0.722466024small GTPase binding (GO:0031267)0.722466024cellular macromolecule biosynthetic process (GO:0034645)0.731183242Cellular Senescence (R-HSA-2559583)0.731183242chromatin (GO:0000785)0.731183242DNA biosynthetic process (GO:0071897)0.731183242establishment of localization in cell (GO:0051649)0.731183242Fc receptor signaling pathway (GO:0038093)0.731183242Golgi subcompartment (GO:0098791)0.731183242Golgi-associated vesicle membrane (GO:0030660)0.731183242guanyl-nucleotide exchange factor activity (GO:0005085)0.731183242Nonsense Mediated Decay (NMD) enhanced by the Exon0.731183242Junction Complex (EJC)(R-HSA-975957)Nonsense-Mediated Decay (NMD) (R-HSA-927802)0.731183242nuclear chromosome (GO:0000228)0.731183242organelle subcompartment (GO:0031984)0.731183242organophosphate biosynthetic process (GO:0090407)0.731183242positive regulation of NF-kappaB transcription factor activity0.731183242(GO:0051092)protein serine/threonine kinase activity (GO:0004674)0.731183242regulated exocytosis (GO:0045055)0.731183242regulation of G1/S transition of mitotic cell cycle (GO:2000045)0.731183242regulation of viral process (GO:0050792)0.731183242respiratory chain complex (GO:0098803)0.731183242Ub-specific processing proteases (R-HSA-5689880)0.731183242ubiguitin protein ligase activity (GO:0061630)0.731183242cellular component disassembly (GO:0022411)0.739848103chromatin organization (GO:0006325)0.739848103cytoskeleton-dependent intracellular transport (GO:0030705)0.739848103gene silencing (GO:0016458)0.739848103Golgi-associated vesicle (GO:0005798)0.739848103HDR through Homologous Recombination (HRR) or Single0.739848103Strand Annealing (SSA) (R-HSA-5693567)interaction with host (GO:0051701)0.739848103L13a-mediated translational silencing of Ceruloplasmin0.739848103expression (R-HSA-156827)leukocyte activation (GO:0045321)0.739848103mitochondrial membrane organization (GO:0007006)0.739848103mRNA binding (GO:0003729)0.739848103negative regulation of NF-kappaB transcription factor activity0.739848103(GO:0032088)nuclear chromosome part (GO:0044454)0.739848103nucleobase-containing compound metabolic process0.739848103(GO:0006139)phosphatase binding (GO:0019902)0.739848103positive regulation of response to DNA damage stimulus0.739848103(GO:2001022)respirasome (GO:0070469)0.739848103response to oxidative stress (GO:0006979)0.739848103secretory granule lumen (GO:0034774)0.739848103ubiguitin-like protein ligase activity (GO:0061659)0.739848103Vesicle-mediated transport (R-HSA-5653656)0.739848103catalytic activity, acting on DNA (GO:0140097)0.748461233cellular nitrogen compound biosynthetic process (GO:0044271)0.748461233cellular response to hypoxia (GO:0071456)0.748461233cellular response to oxygen levels (GO:0071453)0.748461233Chaperonin-mediated protein folding (R-HSA-390466)0.748461233chromatin remodeling (GO:0006338)0.748461233establishment of protein localization to peroxisome0.748461233(GO:0072663)GTPase binding (GO:0051020)0.748461233integral component of organelle membrane (GO:0031301)0.748461233ligase activity (GO:0016874)0.748461233mitotic cell cycle checkpoint (GO:0007093)0.748461233modification of morphology or physiology of other organism0.748461233involved in symbiotic interaction (GO:0051817)Neddylation (R-HSA-8951664)0.748461233negative regulation of mitotic cell cycle (GO:0045930)0.748461233nuclear chromatin (GO:0000790)0.748461233peroxisomal transport (GO:0043574)0.748461233phosphatidylinositol metabolic process (GO:0046488)0.748461233Phospholipid metabolism (R-HSA-1483257)0.748461233positive regulation of I-kappaB kinase/NF-kappaB signaling0.748461233(GO:0043123)positive regulation of protein catabolic process (GO:0045732)0.748461233positive regulation of response to biotic stimulus (GO:0002833)0.748461233protein localization to peroxisome (GO:0072662)0.748461233protein targeting to peroxisome (GO:0006625)0.748461233regulation of cytokine-mediated signaling pathway (GO:0001959)0.748461233regulation of I-kappaB kinase/NF-kappaB signaling0.748461233(GO:0043122)regulation of organelle assembly (GO:1902115)0.748461233regulation of protein localization to nucleus (GO:1900180)0.748461233ribonuclease activity (GO:0004540)0.748461233Transcriptional regulation by RUNX2 (R-HSA-8878166)0.748461233Wnt signaling pathway, planar cell polarity pathway0.748461233(GO:0060071)Biosynthesis of the N-glycan precursor (dolichol lipid-linked0.757023247oligosaccharide, LLO)and transfer to a nascent protein (R-HSA-446193)cell division (GO:0051301)0.757023247cellular response to decreased oxygen levels (GO:0036294)0.757023247cytoskeleton-dependent cytokinesis (GO:0061640)0.757023247DNA-binding transcription factor binding (GO:0140297)0.757023247DNA-templated transcription, initiation (GO:0006352)0.757023247electron transport chain (GO:0022900)0.757023247homeostasis of number of cells (GO:0048872)0.757023247Homology Directed Repair (R-HSA-5693538)0.757023247inner mitochondrial membrane protein complex (GO:0098800)0.757023247magnesium ion binding (GO:0000287)0.757023247maintenance of protein location (GO:0045185)0.757023247myeloid cell differentiation (GO:0030099)0.757023247nuclear part (GO:0044428)0.757023247nucleic acid-templated transcription (GO:0097659)0.757023247oxidoreductase activity, acting on NAD(P)H (GO:0016651)0.757023247positive regulation of neuron death (GO:1901216)0.757023247positive regulation of protein complex assembly (GO:0031334)0.757023247protein ubiquitination (GO:0016567)0.757023247regulation of cell cycle process (GO:0010564)0.757023247regulation of generation of precursor metabolites and energy0.757023247(GO:0043467)regulation of innate immune response (GO:0045088)0.757023247regulation of phagocytosis (GO:0050764)0.757023247regulation of response to cytokine stimulus (GO:0060759)0.757023247response to hydrogen peroxide (GO:0042542)0.757023247RNA polymerase II transcription factor complex (GO:0090575)0.757023247transcription, DNA-templated (GO:0006351)0.757023247amide transport (GO:0042886)0.765534746cellular protein-containing complex assembly (GO:0034622)0.765534746fatty acid catabolic process (GO:0009062)0.765534746GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-0.76553474672706)Hedgehog ‘on’ state (R-HSA-5632684)0.765534746negative regulation of cell cycle (GO:0045786)0.765534746positive regulation of binding (GO:0051099)0.765534746positive regulation of catabolic process (GO:0009896)0.765534746positive regulation of cellular protein localization (GO:1903829)0.765534746positive regulation of innate immune response (GO:0045089)0.765534746positive regulation of multi-organism process (GO:0043902)0.765534746protein alkylation (GO:0008213)0.765534746Protein folding (R-HSA-391251)0.765534746protein methylation (GO:0006479)0.765534746protein targeting to membrane (GO:0006612)0.765534746RNA biosynthetic process (GO:0032774)0.765534746Signaling by Hedgehog (R-HSA-5358351)0.765534746spindle assembly (GO:0051225)0.765534746SRP-dependent cotranslational protein targeting to membrane0.765534746(GO:0006614)SRP-dependent cotranslational protein targeting to membrane0.765534746(R-HSA-1799339)tertiary granule (GO:0070820)0.765534746ubiquitin-protein transferase activity (GO:0004842)0.765534746vacuole (GO:0005773)0.765534746Cell death signalling via NRAGE, NRIF and NADE (R-HSA-0.773996325204998)cellular response to starvation (GO:0009267)0.773996325cellular response to stress (GO:0033554)0.773996325chromosomal part (GO:0044427)0.773996325endomembrane system organization (GO:0010256)0.773996325endosomal part (GO:0044440)0.773996325establishment of protein localization to membrane (GO:0090150)0.773996325intrinsic apoptotic signaling pathway (GO:0097193)0.773996325MHC class II antigen presentation (R-HSA-2132295)0.773996325Mitochondrial biogenesis (R-HSA-1592230)0.773996325mitochondrial outer membrane (GO:0005741)0.773996325mitochondrial transmembrane transport (GO:1990542)0.773996325nuclear lumen (GO:0031981)0.773996325nucleic acid metabolic process (GO:0090304)0.773996325nucleic acid phosphodiester bond hydrolysis (GO:0090305)0.773996325peptide transport (GO:0015833)0.773996325protein autophosphorylation (GO:0046777)0.773996325protein-containing complex localization (GO:0031503)0.773996325response to starvation (GO:0042594)0.773996325Signaling by ROBO receptors (R-HSA-376176)0.773996325ubiquitin-like protein transferase activity (GO:0019787)0.773996325ATPase activity, coupled (GO:0042623)0.782408565cellular response to antibiotic (GO:0071236)0.782408565chromosome (GO:0005694)0.782408565cotranslational protein targeting to membrane (GO:0006613)0.782408565DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-0.782408565HSA-168928)endoplasmic reticulum-Golgi intermediate compartment0.782408565membrane (GO:0033116)establishment of protein localization (GO:0045184)0.782408565establishment of protein localization to endoplasmic reticulum0.782408565(GO:0072599)HATs acetylate histones (R-HSA-3214847)0.782408565lamellipodium (GO:0030027)0.782408565mitochondrial part (GO:0044429)0.782408565mitotic sister chromatid segregation (GO:0000070)0.782408565Organelle biogenesis and maintenance (R-HSA-1852241)0.782408565positive regulation of apoptotic signaling pathway (GO:2001235)0.782408565positive regulation of protein binding (GO:0032092)0.782408565positive regulation of protein ubiguitination (GO:0031398)0.782408565PPARA activates gene expression (R-HSA-1989781)0.782408565protein stabilization (GO:0050821)0.782408565Protein ubiquitination (R-HSA-8852135)0.782408565regulation of chromatin organization (GO:1902275)0.782408565Regulation of expression of SLITs and ROBOs (R-HSA-0.7824085659010553)Regulation of lipid metabolism by Peroxisome proliferator-0.782408565activated receptor alpha (PPARalpha) (R-HSA-400206)regulation of mitotic cell cycle (GO:0007346)0.782408565regulation of protein catabolic process (GO:0042176)0.782408565RHO GTPase Effectors (R-HSA-195258)0.782408565RNA polymerase II-specific DNA-binding transcription factor0.782408565binding (GO:0061629)Transcriptional regulation by RUNX1 (R-HSA-8878171)0.782408565Cap-dependent Translation Initiation (R-HSA-72737)0.790772038cell division site part (GO:0032155)0.790772038chaperone binding (GO:0051087)0.790772038Cilium Assembly (R-HSA-5617833)0.790772038endosome membrane (GO:0010008)0.790772038Eukaryotic Translation Initiation (R-HSA-72613)0.790772038lysosome (GO:0005764)0.790772038lytic vacuole (GO:0000323)0.790772038mitochondrial membrane (GO:0031966)0.790772038negative regulation of gene expression, epigenetic0.790772038(GO:0045814)organelle localization (GO:0051640)0.790772038peptidyl-lysine methylation (GO:0018022)0.790772038peptidyl-serine phosphorylation (GO:0018105)0.790772038peptidyl-threonine modification (GO:0018210)0.790772038protein folding (GO:0006457)0.790772038protein localization to endoplasmic reticulum (GO:0070972)0.790772038protein modification by small protein conjugation (GO:0032446)0.790772038protein targeting to ER (GO:0045047)0.790772038protein transport (GO:0015031)0.790772038Rab GTPase binding (GO:0017137)0.790772038regulation of stem cell differentiation (GO:2000736)0.790772038RNA phosphodiester bond hydrolysis (GO:0090501)0.790772038Signaling by NOTCH (R-HSA-157118)0.790772038toll-like receptor signaling pathway (GO:0002224)0.790772038transcription coactivator activity (GO:0003713)0.790772038unfolded protein binding (GO:0051082)0.790772038vacuolar part (GO:0044437)0.790772038antigen processing and presentation of peptide or polysaccharide0.799087306antigen via MHC class II (GO:0002504)Beta-catenin independent WNT signaling (R-HSA-3858494)0.799087306cell activation involved in immune response (GO:0002263)0.799087306coenzyme biosynthetic process (GO:0009108)0.799087306cofactor biosynthetic process (GO:0051188)0.799087306envelope (GO:0031975)0.799087306histone methylation (GO:0016571)0.799087306Interleukin-12 family signaling (R-HSA-447115)0.799087306leukocyte activation involved in immune response (GO:0002366)0.799087306mitochondrial envelope (GO:0005740)0.799087306negative regulation of chromosome organization (GO:2001251)0.799087306nuclear envelope (GO:0005635)0.799087306nuclear-transcribed mRNA catabolic process, nonsense-0.799087306mediated decay (GO:0000184)nucleoside monophosphate metabolic process (GO:0009123)0.799087306organelle envelope (GO:0031967)0.799087306organelle inner membrane (GO:0019866)0.799087306oxidoreductase complex (GO:1990204)0.799087306protein modification by small protein conjugation or removal0.799087306(GO:0070647)recombinational repair (GO:0000725)0.799087306regulation of intrinsic apoptotic signaling pathway (GO:2001242)0.799087306response to ionizing radiation (GO:0010212)0.799087306stress-activated protein kinase signaling cascade (GO:0031098)0.799087306vesicle fusion (GO:0006906)0.799087306vesicle organization (GO:0016050)0.799087306Antigen processing: Ubiquitination & Proteasome degradation0.807354922(R-HSA-983168)axon cytoplasm (GO:1904115)0.807354922cellular response to oxidative stress (GO:0034599)0.807354922cellular response to reactive oxygen species (GO:0034614)0.807354922centrosome (GO:0005813)0.807354922condensed chromosome kinetochore (GO:0000777)0.807354922condensed chromosome, centromeric region (GO:0000779)0.807354922cullin-RING ubiquitin ligase complex (GO:0031461)0.807354922establishment of organelle localization (GO:0051656)0.807354922glycerolipid biosynthetic process (GO:0045017)0.807354922histone deacetylase binding (GO:0042826)0.807354922innate immune response-activating signal transduction0.807354922(GO:0002758)intrinsic component of endoplasmic reticulum membrane0.807354922(GO:0031227)macromolecule catabolic process (GO:0009057)0.807354922mitochondrial membrane part (GO:0044455)0.807354922mitochondrial transport (GO:0006839)0.807354922negative regulation of cell cycle phase transition (GO:1901988)0.807354922negative regulation of translation (GO:0017148)0.807354922peptide metabolic process (GO:0006518)0.807354922phosphoprotein binding (GO:0051219)0.807354922positive regulation of cellular catabolic process (GO:0031331)0.807354922positive regulation of proteolysis involved in cellular protein0.807354922catabolic process (GO:1903052)protein localization to organelle (GO:0033365)0.807354922protein serine/threonine phosphatase activity (GO:0004722)0.807354922regulation of catabolic process (GO:0009894)0.807354922regulation of intracellular transport (GO:0032386)0.807354922regulation of protein ubiguitination (GO:0031396)0.807354922RNA metabolic process (GO:0016070)0.807354922structural constituent of ribosome (GO:0003735)0 807354922antigen processing and presentation of exogenous peptide0.815575429antigen via MHC class II (GO:0019886)DNA damage checkpoint (GO:0000077)0.815575429DNA integrity checkpoint (GO:0031570)0.815575429double-strand break repair via homologous recombination0.815575429(GO:0000724)energy derivation by oxidation of organic compounds0.815575429(GO:0015980)heat shock protein binding (GO:0031072)0.815575429intracellular transport (GO:0046907)0.815575429N-methyltransferase activity (GO:0008170)0.815575429negative regulation of cellular amide metabolic process0.815575429(GO:0034249)negative regulation of mitotic cell cycle phase transition0.815575429(GO:1901991)nucleoplasm (GO:0005654)0.815575429p75 NTR receptor-mediated signalling (R-HSA-193704)0.815575429positive regulation of protein localization to nucleus0.815575429(GO:1900182)regulation of cellular catabolic process (GO:0031329)0.815575429regulation of chromosome segregation (GO:0051983)0.815575429regulation of gene silencing (GO:0060968)0.815575429response to unfolded protein (GO:0006986)0.815575429RNA methylation (GO:0001510)0.815575429ruffle membrane (GO:0032587)0.815575429activation of innate immune response (GO:0002218)0.82374936antigen processing and presentation of peptide antigen via MHC0.82374936class II (GO:0002495)cadherin binding (GO:0045296)0.82374936cell cycle checkpoint (GO:0000075)0.82374936cellular response to unfolded protein (GO:0034620)0.82374936cytoplasmic stress granule (GO:0010494)0.82374936DNA Double-Strand Break Repair (R-HSA-5693532)0.82374936endoplasmic reticulum-Golgi intermediate compartment0.82374936(GO:0005793)intracellular protein transport (GO:0006886)0.82374936mitochondrial inner membrane (GO:0005743)0.82374936mitochondrion organization (GO:0007005)0.82374936myeloid leukocyte activation (GO:0002274)0.82374936negative regulation of cell cycle process (GO:0010948)0.82374936nuclear membrane (GO:0031965)0.82374936phagocytic vesicle membrane (GO:0030670)0.82374936positive regulation of cellular protein catabolic process0.82374936(GO:1903364)protein C-terminus binding (GO:0008022)0.82374936regulation of protein stability (GO:0031647)0.82374936signal transduction in response to DNA damage (GO:0042770)0.82374936trans-Golgi network (GO:0005802)0.82374936transcriptional repressor complex (GO:0017053)0.82374936cellular response to UV (GO:0034644)0.831877241Deubiquitination (R-HSA-5688426)0.831877241gene expression (GO:0010467)0.831877241interspecies interaction between organisms (GO:0044419)0.831877241late endosome (GO:0005770)0.831877241lipid phosphorylation (GO:0046834)0.831877241microtubule cytoskeleton organization involved in mitosis0.831877241(GO:1902850)mitochondrial respirasome (GO:0005746)0.831877241N-acyltransferase activity (GO:0016410)0.831877241negative regulation of protein catabolic process (GO:0042177)0.831877241nucleotidyltransferase activity (GO:0016779)0.831877241organelle transport along microtubule (GO:0072384)0.831877241P-body (GQ:0000932)0.831877241positive regulation of DNA metabolic process (GO:0051054)0.831877241positive regulation of histone modification (GO:0031058)0.831877241positive regulation of macroautophagy (GO:0016239)0.831877241positive regulation of mitochondrion organization (GO:0010822)0.831877241positive regulation of protein modification by small protein0.831877241conjugation or removal (GO:1903322)positive regulation of translation (GO:0045727)0.831877241protein catabolic process (GO:0030163)0.831877241regulation of cell cycle phase transition (GO:1901987)0.831877241regulation of cellular amine metabolic process (GO:0033238)0.831877241regulation of proteolysis involved in cellular protein catabolic0.831877241process (GO:1903050)Signaling by NTRKs (R-HSA-166520)0.831877241spindle (GO:0005819)0.831877241spindle organization (GO:0007051)0.831877241trans-Golgi network membrane (GO:0032588)0.831877241Transcriptional regulation of white adipocyte differentiation (R-0.831877241HSA-381340)Cargo recognition for clathrin-mediated endocytosis (R-HSA-0.8399595878856825)Class I MHC mediated antigen processing & presentation (R-0.839959587HSA-983169)cytokinesis (GO:0000910)0.839959587fatty acid oxidation (GO:0019395)0.839959587glycerophospholipid biosynthetic process (GO:0046474)0.839959587integral component of endoplasmic reticulum membrane0.839959587(GO:0030176)mitotic spindle organization (GO:0007052)0.839959587nuclear receptor transcription coactivator activity (GO:0030374)0.839959587positive regulation of cellular amide metabolic process0.839959587(GO:0034250)positive regulation of gene expression, epigenetic (GO:0045815)0.839959587positive regulation of mRNA metabolic process (GO:1903313)0.839959587positive regulation of ubiquitin-dependent protein catabolic0.839959587process (GO:2000060)protein N-linked glycosylation (GO:0006487)0.839959587protein targeting (GO:0006605)0.839959587regulation of mitochondrion organization (GO:0010821)0.839959587response to topologically incorrect protein (GO:0035966)0.839959587single-stranded RNA binding (GO:0003727)0.839959587Transport to the Golgi and subsequent modification (R-HSA-0.839959587948021)vesicle-mediated transport to the plasma membrane0.839959587(GO:0098876)cellular response to DNA damage stimulus (GO:0006974)0.847996907Cellular responses to stress (R-HSA-2262752)0.847996907centrosome cycle (GO:0007098)0.847996907clarthin-coated pit (GO:0005905)0.847996907Clathrin-mediated endocytosis (R-HSA-8856828)0.847996907Costimulation by the CD28 family (R-HSA-388841)0.847996907Diseases of signal transduction (R-HSA-5663202)0.847996907establishment of protein localization to organelle (GO:0072594)0.847996907Golgi-to-ER retrograde transport (R-HSA-8856688)0.847996907histone lysine methylation (GO:0034968)0.847996907Influenza Infection (R-HSA-168254)0.847996907Influenza Viral RNA Transcription and Replication (R-HSA-0.847996907168273)lipid oxidation (GO:0034440)0.847996907microtubule organizing center organization (GO:0031023)0.847996907organelle fusion (GO:0048284)0.847996907organelle membrane fusion (GO:0090174)0.847996907oxidative phosphorylation (GO:0006119)0.847996907positive regulation of chromatin organization (GO:1905269)0.847996907regulation of cellular protein catabolic process (GO:1903362)0.847996907regulation of histone modification (GO:0031056)0.847996907TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)0.847996907ubiguitin-like protein ligase binding (GO:0044389)0.847996907viral life cycle (GO:0019058)0.847996907amide biosynthetic process (GO:0043604)0.855989697Asparagine N-linked glycosylation (R-HSA-446203)0.855989697Cellular responses to external stimuli (R-HSA-8953897)0.855989697mitotic cell cycle (GO:0000278)0.855989697mitotic spindle (GO:0072686)0.855989697modification-dependent protein catabolic process (GO:0019941)0.855989697nuclear receptor binding (GO:0016922)0.855989697peptidyl-threonine phosphorylation (GO:0018107)0.855989697phospholipid biosynthetic process (GO:0008654)0.855989697regulation of chromosome organization (GO:0033044)0.855989697regulation of gene expression, epigenetic (GO:0040029)0.855989697regulation of mRNA catabolic process (GO:0061013)0.855989697regulation of protein modification by small protein conjugation or0.855989697removal (GO:1903320)regulation of RNA splicing (GO:0043484)0.855989697regulation of signal transduction by p53 class mediator0.855989697(GO:1901796)RNA methyltransferase activity (GO:0008173)0.855989697S-adenosylmethionine-dependent methyltransferase activity0.855989697(GO:0008757)spindle pole (GO:0000922)0.855989697The citric acid (TCA) cycle and respiratory electron transport (R-0.855989697HSA-1428517)tRNA modification (GO:0006400)0.855989697ubiquitin protein ligase binding (GO:0031625)0.855989697ubiquitin-dependent protein catabolic process (GO:0006511)0.855989697cellular macromolecule catabolic process (GO:0044265)0.86393845cellular response to topologically incorrect protein (GO:0035967)0.86393845Death Receptor Signalling (R-HSA-73887)0.86393845Epigenetic regulation of gene expression (R-HSA-212165)0.86393845Influenza Life Cycle (R-HSA-168255)0.86393845microbody membrane (GO:0031903)0.86393845midbody (GO:0030496)0.86393845mitochondrial matrix (GO:0005759)0.86393845mitotic nuclear division (GO:0140014)0.86393845modification-dependent macromolecule catabolic process0.86393845(GO:0043632)negative regulation of autophagy (GO:0010507)0.86393845negative regulation of protein ubiquitination (GO:0031397)0.86393845nuclear-transcribed mRNA catabolic process (GO:0000956)0.86393845nucleus organization (GO:0006997)0.86393845organelle localization by membrane tethering (GO:0140056)0.86393845PCP/CE pathway (R-HSA-4086400)0.86393845peroxisomal membrane (GO:0005778)0.86393845positive regulation of intracellular transport (GO:0032388)0.86393845positive regulation of proteasomal protein catabolic process0.86393845(GO:1901800)protein localization to chromosome (GO:0034502)0.86393845protein methyltransferase activity (GO:0008276)0.86393845protein polyubiquitination (GO:0000209)0.86393845proteolysis involved in cellular protein catabolic process0.86393845(GO:0051603)regulation of intracellular protein transport (GO:0033157)0.86393845regulation of sister chromatid segregation (GO:0033045)0.86393845Respiratory electron transport, ATP synthesis by chemiosmotic0.86393845coupling, and heat production by uncoupling proteins. (R-HSA-163200)response to UV (GO:0009411)0.86393845specific granule (GO:0042581)0.86393845tumor necrosis factor-mediated signaling pathway (GO:0033209)0.86393845vesicle localization (GO:0051648)0.86393845cellular protein catabolic process (GO:0044257)0.871843649cellular response to hydrogen peroxide (GO:0070301)0.871843649endoplasmic reticulum to Golgi vesicle-mediated transport0.871843649(GO:0006888)histone binding (GO:0042393)0.871843649Intracellular signaling by second messengers (R-HSA-9006925)0.871843649mitotic cell cycle process (GO:1903047)0.871843649myeloid cell activation involved in immune response0.871843649(GO:0002275)myeloid cell homeostasis (GO:0002262)0.871843649nuclear body (GO:0016604)0.871843649p53 binding (GO:0002039)0.871843649positive regulation of autophagy (GO:0010508)0.871843649protein import into nucleus (GO:0006606)0.871843649regulation of autophagy (GO:0010506)0.871843649regulation of DNA biosynthetic process (GO:2000278)0.871843649regulation of mitotic cell cycle phase transition (GO:1901990)0.871843649regulation of TOR signaling (GO:0032006)0.871843649Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-0.871843649HSA-1445148)vacuolar membrane (GO:0005774)0.871843649azurophil granule lumen (GO:0035578)0.879705766chaperone-mediated protein folding (GO:0061077)0.879705766DNA repair (GO:0006281)0.879705766Formation of the ternary complex, and subsequently, the 43S0.879705766complex (R-HSA-72695)granulocyte activation (GO:0036230)0.879705766heterochromatin (GO:0000792)0.879705766Interleukin-12 signaling (R-HSA-9020591)0.879705766Interleukin-3, Interleukin-5 and GM-CSF signaling (R-HSA-0.879705766512988)large ribosomal subunit (GO:0015934)0.879705766leukocyte degranulation (GO:0043299)0.879705766membrane docking (GO:0022406)0.879705766mRNA catabolic process (GO:0006402)0.879705766myeloid leukocyte mediated immunity (GO:0002444)0.879705766nucleolus (GO:0005730)0.879705766PIP3 activates AKT signaling (R-HSA-1257604)0.879705766positive regulation of intracellular protein transport (GO:0090316)0.879705766positive regulation of proteasomal ubiquitin-dependent protein0.879705766catabolic process (GO:0032436)protein acylation (GO:0043543)0.879705766protein kinase complex (GO:1902911)0.879705766Pyruvate metabolism and Citric Acid (TCA) cycle (R-HSA-71406)0.879705766regulation of cellular amide metabolic process (GO:0034248)0.879705766regulation of glycolytic process (GO:0006110)0.879705766regulation of proteasomal protein catabolic process0.879705766(GO:0061136)regulation of RNA stability (GO:0043487)0.879705766RNA catabolic process (GO:0006401)0.879705766steroid hormone receptor binding (GO:0035258)0.879705766symbiotic process (GO:0044403)0.879705766cell redox homeostasis (GO:0045454)0.887525271chromosome, centromeric region (GO:0000775)0.887525271cytoplasmic translation (GO:0002181)0.887525271double-strand break repair (GO:0006302)0.887525271endoplasmic reticulum organization (GO:0007029)0.887525271erythrocyte differentiation (GO:0030218)0.887525271Membrane Trafficking (R-HSA-199991)0.887525271Metabolism of polyamines (R-HSA-351202)0.887525271negative regulation of protein modification by small protein0.887525271conjugation or removal (GO:1903321)negative regulation of proteolysis involved in cellular protein0.887525271catabolic process (GO:1903051)neutrophil activation (GO:0042119)0.887525271neutrophil activation involved in immune response (GO:0002283)0.887525271neutrophil degranulation (GO:0043312)0.887525271Neutrophil degranulation (R-HSA-6798695)0.887525271neutrophil mediated immunity (GO:0002446)0.887525271protein localization to nucleus (GO:0034504)0.887525271regulation of ATP metabolic process (GO:1903578)0.887525271regulation of carbohydrate catabolic process (GO:0043470)0.887525271regulation of centrosome cycle (GO:0046605)0.887525271regulation of mRNA splicing, via spliceosome (GO:0048024)0.887525271regulation of mRNA stability (GO:0043488)0.887525271regulation of nucleocytoplasmic transport (GO:0046822)0.887525271Resolution of Sister Chromatid Cohesion (R-HSA-2500257)0.887525271ribosomal large subunit biogenesis (GO:0042273)0.887525271ribosomal subunit (GO:0044391)0.887525271chromosomal region (GO:0098687)0.895302621Circadian Clock (R-HSA-400253)0.895302621erythrocyte homeostasis (GO:0034101)0.895302621Golgi vesicle transport (GO:0048193)0.895302621Hedgehog ‘off’ state (R-HSA-5610787)0.895302621import into nucleus (GO:0051170)0.895302621integral component of mitochondrial inner membrane0.895302621(GO:0031305)intrinsic component of mitochondrial inner membrane0.895302621(GO:0031304)mitotic cytokinesis (GO:0000281)0.895302621nuclear hormone receptor binding (GO:0035257)0.895302621nucleobase-containing compound transport (GO:0015931)0.895302621organelle envelope lumen (GO:0031970)0.895302621protein localization to vacuole (GO:0072665)0.895302621regulation of antigen receptor-mediated signaling pathway0.895302621(GO:0050854)regulation of translation (GO:0006417)0.895302621regulation of ubiquitin-dependent protein catabolic process0.895302621(GO:2000058)RHO GTPases Activate Formins (R-HSA-5663220)0.895302621single-stranded DNA binding (GO:0003697)0.895302621small ribosomal subunit (GO:0015935)0.895302621viral transcription (GO:0019083)0.895302621aerobic respiration (GO:0009060)0.90303827antigen processing and presentation (GO:0019882)0.90303827catalytic activity, acting on atRNA (GO:0140101)0.90303827cell cycle G1/S phase transition (GO:0044843)0.90303827establishment of vesicle localization (GO:0051650)0.90303827G1/S transition of mitotic cell cycle (GO:0000082)0.90303827Golgi organization (GO:0007030)0.90303827kinetochore (GO:0000776)0.90303827mitochondrial intermembrane space (GO:0005758)0.90303827NAD binding (GO:0051287)0.90303827negative regulation of cellular protein catabolic process0.90303827(GO:1903363)negative regulation of proteasomal protein catabolic process0.90303827(GO:1901799)protein deubiquitination (GO:0016579)0.90303827protein K48-linked ubiquitination (GO:0070936)0.90303827regulation of mitotic sister chromatid segregation (GO:0033047)0.90303827regulation of mRNA metabolic process (GO:1903311)0.90303827ribosome (GO:0005840)0.90303827RNA binding (GO:0003723)0.90303827serine/threonine protein kinase complex (GO:1902554)0.90303827T cell receptor signaling pathway (GO:0050852)0.90303827Toll-Like Receptors Cascades (R-HSA-168898)0.90303827ABC-family proteins mediated transport (R-HSA-382556)0.910732662Apoptosis (R-HSA-109581)0.910732662catalytic activity, acting on RNA (GO:0140098)0.910732662endoplasmic reticulum unfolded protein response (GO:0030968)0.910732662endosome organization (GO:0007032)0.910732662ER to Golgi Anterograde Transport (R-HSA-199977)0.910732662G2/M Checkpoints (R-HSA-69481)0.910732662Homologous DNA Pairing and Strand Exchange (R-HSA-0.9107326625693579)peptidyl-lysine modification (GO:0018205)0.910732662posttranscriptional regulation of gene expression (GO:0010608)0.910732662rRNA processing (R-HSA-72312)0.910732662Signaling by EGFR (R-HSA-177929)0.910732662Signaling byVEGF (R-HSA-194138)0.910732662tertiary granule membrane (GO:0070821)0.910732662Translation initiation complex formation (R-HSA-72649)0.910732662translational initiation (GO:0006413)0.910732662ubiquitin ligase complex (GO:0000151)0.910732662viral process (GO:0016032)0.910732662clathrin coat (GO:0030118)0.918386234Cyclin D associated events in G1 (R-HSA-69231)0.918386234G1 Phase (R-HSA-69236)0.918386234late endosome membrane (GO:0031902)0.918386234lysosomal membrane (GO:0005765)0.918386234lytic vacuole membrane (GO:0098852)0.918386234melanosome (GO:0042470)0.918386234mRNA metabolic process (GO:0016071)0.918386234nuclear pore (GO:0005643)0.918386234nucleoplasm part (GO:0044451)0.918386234phagocytic vesicle (GO:0045335)0.918386234pigment granule (GO:0048770)0.918386234positive regulation of nudeocytoplasmic transport (GO:0046824)0.918386234Programmed Cell Death (R-HSA-5357801)0.918386234regulation of histone methylation (GO:0031060)0.918386234response to endoplasmic reticulum stress (GO:0034976)0.918386234ribonucleoprotein complex (GO:1990904)0.918386234ruffle (GO:0001726)0.918386234viral gene expression (GO:0019080)0.918386234Activation of the mRNA upon binding of the cap-binding complex0.925999419and eIFs, and subsequent binding to 43S (R-HSA-72662)Cell Cycle (R-HSA-1640170)0.925999419cellular respiration (GO:0045333)0.925999419covalent chromatin modification (GO:0016569)0.925999419endosomal transport (GO:0016197)0.925999419peptide biosynthetic process (GO:0043043)0.925999419proteasomal protein catabolic process (GO:0010498)0.925999419proteasome-mediated ubiquitin-dependent protein catabolic0.925999419process (GO:0043161)protein acetylation (GO:0006473)0.925999419rRNA processing in the nucleus and cytosol (R-HSA-8868773)0.925999419Signaling by NOTCH1 (R-HSA-1980143)0.925999419translation regulator activity (GO:0045182)0.925999419tRNA processing (GO:0008033)0.925999419Asymmetric localization of PCP proteins (R-HSA-4608870)0.933572638autophagosome (GO:0005776)0.933572638azurophil granule (GO:0042582)0.933572638catalytic complex (GO:1902494)0.933572638Cell Cycle Checkpoints (R-HSA-69620)0.933572638chromosome, telomeric region (GO:0000781)0.933572638COPI-independent Golgi-to-ER retrograde traffic (R-HSA-0.9335726386811436)COPI-mediated anterograde transport (R-HSA-6807878)0.933572638COPII-mediated vesicle transport (R-HSA-204005)0.933572638DNA-dependent ATPase activity (GO:0008094)0.933572638innate immune response activating cell surface receptor0.933572638signaling pathway (GO:0002220)Major pathway of rRNA processing in the nucleolus and cytosol0.933572638(R-HSA-6791226)myeloid cell development (GO:0061515)0.933572638ncRNA metabolic process (GO:0034660)0.933572638nuclear speck (GO:0016607)0.933572638oxidoreductase activity, acting on NAD(P)H, quinone or similar0.933572638compound as acceptor (GO:0016655)positive regulation of DNA biosynthetic process (GO:2000573)0.933572638positive regulation of intrinsic apoptotic signaling pathway0.933572638(GO:2001244)positive regulation of type I interferon production (GO:0032481)0.933572638primary lysosome (GO:0005766)0.933572638protein modification by small protein removal (GO:0070646)0.933572638regulation of cholesterol metabolic process (GO:0090181)0.933572638regulation of proteasomal ubiquitin-dependent protein catabolic0.933572638process (GO:0032434)Signaling by NTRK1 (TRKA) (R-HSA-187037)0.933572638SUMO E3 ligases SUMOylate target proteins (R-HSA-3108232)0.933572638SUMOylation (R-HSA-2990846)0.933572638TBC/RABGAPs (R-HSA-8854214)0.933572638telomere organization (GO:0032200)0.933572638vascular endothelial growth factor receptor signaling pathway0.933572638(GO:0048010)antigen processing and presentation of exogenous antigen0.941106311(GO:0019884)cell cycle phase transition (GO:0044770)0.941106311DNA helicase activity (GO:0003678)0.941106311histone methyltransferase activity (GO:0042054)0.941106311Intra-Golgi and retrograde Golgi-to-ER traffic (R-HSA-6811442)0.941106311iron-sulfur cluster binding (GO:0051536)0.941106311metal cluster binding (GO:0051540)0.941106311mitochondrial ATP synthesis coupled electron transport0.941106311(GO:0042775)mitochondrial protein complex (GO:0098798)0.941106311mitotic cell cycle phase transition (GO:0044772)0.941106311modification-dependent protein binding (GO:0140030)0.941106311nucleic acid transport (GO:0050657)0.941106311repressing transcription factor binding (GO:0070491)0.941106311respiratory electron transport chain (GO:0022904)0.941106311RNA transport (GO:0050658)0.941106311telomere maintenance (GO:0000723)0.941106311The role of GTSE1 in G2/M progression after G2 checkpoint (R-0.941106311HSA-8852276)ATP synthesis coupled electron transport (GO:0042773)0.948600847Chromatin modifying enzymes (R-HSA-3247509)0.948600847Chromatin organization (R-HSA-4839726)0.948600847establishment of RNA localization (GO:0051236)0.948600847fatty acid beta-oxidation (GO:0006635)0.948600847fibrillar center (GO:0001650)0.948600847G2/M transition of mitotic cell cycle (GO:0000086)0.948600847HDR through Homologous Recombination (HRR) (R-HSA-0.9486008475685942)histone modification (GO:0016570)0.948600847mitochondrial respiratory chain complex assembly (GO:0033108)0.948600847mRNA processing (GO:0006397)0.948600847positive regulation of viral life cycle (GO:1903902)0.948600847protein import (GO:0017038)0.948600847regulation of telomerase activity (GO:0051972)0.948600847ribonucleoside monophosphate metabolic process (GO:0009161)0.948600847Ribosomal scanning and start codon recognition (R-HSA-72702)0.948600847vesicle budding from membrane (GO:0006900)0.948600847autophagosome assembly (GO:0000045)0.956056652cell cycle G2/M phase transition (GO:0044839)0.956056652damaged DNA binding (GO:0003684)0.956056652DNA Repair (R-HSA-73894)0.956056652DNA synthesis involved in DNA repair (GO:0000731)0.956056652Gene and protein expression by JAK-STAT signaling after0.956056652Interleukin-12 stimulation (R-HSA-8950505)M Phase (R-HSA-68886)0.956056652protein transmembrane transport (GO:0071806)0.956056652protein-containing complex disassembly (GO:0032984)0.956056652regulation of DNA replication (GO:0006275)0.956056652regulation of interferon-beta production (GO:0032648)0.956056652RNA localization (GO:0006403)0.956056652RNA processing (GO:0006396)0.956056652transferase complex (GO:1990234)0.956056652transferase complex, transferring phosphorus-containing groups0.956056652(GO:0061695)translation regulator activity, nucleic acid binding (GO:0090079)0.956056652vesicle tethering complex (GO:0099023)0.956056652acetyltransferase activity (GO:0016407)0.963474124antigen processing and presentation of exogenous peptide0.963474124antigen (GO:0002478)antigen processing and presentation of peptide antigen0.963474124(GO:0048002)Cell Cycle, Mitotic (R-HSA-69278)0.963474124ciliary basal body-plasma membrane docking (GO:0097711)0.963474124coated membrane (GO:0048475)0.963474124COPII-coated vesicle budding (GO:0090114)0.963474124cytosolic transport (GO:0016482)0.963474124DNA replication (GO:0006260)0.963474124integral component of mitochondrial membrane (GO:0032592)0.963474124Intrinsic Pathway for Apoptosis (R-HSA-109606)0.963474124membrane coat (GO:0030117)0.963474124mRNA transport (GO:0051028)0.963474124phosphatidylinositol biosynthetic process (GO:0006661)0.963474124Presynaptic phase of homologous DNA pairing and strand0.963474124exchange (R-HSA-5693616)protein sumoylation (GO:0016925)0.963474124regulation of cell cycle G2/M phase transition (GO:1902749)0.963474124regulation of macroautophagy (GO:0016241)0.963474124regulation of type I interferon production (GO:0032479)0.963474124regulation of viral transcription (GO:0046782)0.963474124Transcriptional Regulation by TP53 (R-HSA-3700989)0.963474124translation (GO:0006412)0.963474124Amplification of signal from unattached kinetochores via a MAD20.970853654inhibitory signal (R-HSA-141444)Amplification of signal from the kinetochores (R-HSA-141424)0.970853654Anchoring of the basal body to the plasma membrane (R-HSA-0.9708536545620912)autophagosome organization (GO:1905037)0.970853654DNA geometric change (GO:0032392)0.970853654I-kappaB kinase/NF-kappaB signaling (GO:0007249)0.970853654internal protein amino acid acetylation (GO:0006475)0.970853654intrinsic component of mitochondrial membrane (GO:0098573)0.970853654nudeocytoplasmic transport (GO:0006913)0.970853654polysome (GO:0005844)0.970853654positive regulation of chromosome organization (GO:2001252)0.970853654posttranscriptional gene silencing by RNA (GO:0035194)0.970853654regulation of G2/M transition of mitotic cell cycle (GO:0010389)0.970853654stimulatory C-type lectin receptor signaling pathway0.970853654(GO:0002223)Toll Like Receptor 4 (TLR4)Cascade (R-HSA-166016)0.970853654transcription by RNA polymerase III (GO:0006383)0.970853654Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer0.970853654(R-HSA-2173793)ABC transporter disorders (R-HSA-5619084)0.97819563autophagy (GO:0006914)0.97819563Infectious disease (R-HSA-5663205)0.97819563intracellular protein transmembrane transport (GO:0065002)0.97819563nuclear chromosome, telomeric region (GO:0000784)0.97819563nuclear transport (GO:0051169)0.97819563nucleolar part (GO:0044452)0.97819563PI Metabolism (R-HSA-1483255)0.97819563postreplication repair (GO:0006301)0.97819563posttranscriptional gene silencing (GO:0016441)0.97819563process utilizing autophagic mechanism (GO:0061919)0.97819563Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)0.97819563regulation of gene silencing by RNA (GO:0060966)0.97819563regulation of mRNA processing (GO:0050684)0.97819563regulation of posttranscriptional gene silencing (GO:0060147)0.97819563Regulation of RUNX2 expression and activity (R-HSA-8939902)0.97819563regulation of transcription from RNA polymerase II promoter in0.97819563response to stress (GO:0043618)retrograde vesicle-mediated transport, Golgi to endoplasmic0.97819563reticulum (GO:0006890)RNA 3′-end processing (GO:0031123)0.97819563Signaling by RAS mutants (R-HSA-6802949)0.97819563Transcriptional activation of mitochondrial biogenesis (R-HSA-0.978195632151201)tRNA metabolic process (GO:0006399)0.97819563cellular protein complex disassembly (GO:0043624)0.98550043COPII vesicle coating (GO:0048208)0.98550043core promoter binding (GO:0001047)0.98550043Interleukin-1 family signaling (R-HSA-446652)0.98550043Mitotic Prometaphase (R-HSA-68877)0.98550043N-acetyltransferase activity (GO:0008080)0.98550043ncRNA processing (GO:0034470)0.98550043nuclear envelope organization (GO:0006998)0.98550043phosphatase complex (GO:1903293)0.98550043protein serine/threonine phosphatase complex (GO:0008287)0.98550043regulation of DNA-templated transcription in response to stress0.98550043(GO:0043620)regulation of gene silencing by miRNA (GO:0060964)0.98550043replication fork (GO:0005657)0.98550043TRAF6 mediated induction of NFkB and MAP kinases upon0.98550043TLR7/8 or 9 activation (R-HSA-975138)vesicle targeting, rough ER to cis-Golgi (GO:0048207)0.98550043Activation of ATR in response to replication stress (R-HSA-0.992768431176187)Cajal body (GO:0015030)0.992768431Cellular response to heat stress (R-HSA-3371556)0.992768431MyD88 dependent cascade initiated on endosome (R-HSA-0.992768431975155)non-membrane spanning protein tyrosine kinase activity0.992768431(GO:0004715)organelle disassembly (GO:1903008)0.992768431regulation of translational initiation (GO:0006446)0.992768431ribosomal small subunit biogenesis (GO:0042274)0.992768431ribosome biogenesis (GO:0042254)0.992768431RNA helicase activity (GO:0003724)0.992768431SCF-dependent proteasomal ubiquitin-dependent protein0.992768431catabolic process (GO:0031146)TAK1 activates NFkB by phosphorylation and activation of IKKs0.992768431complex (R-HSA-445989)Toll Like Receptor 7/8 (TLR7/8)Cascade (R-HSA-168181)0.992768431TP53 Regulates Metabolic Genes (R-HSA-5628897)0.992768431tRNA processing (R-HSA-72306)0.992768431C-type lectin receptors (CLRs) (R-HSA-5621481)1ERAD pathway (GO:0036503)1helicase activity (GO:0004386)1Interleukin-17 signaling (R-HSA-448424)1internal peptidyl-lysine acetylation (GO:0018393)1MAPK6/MAPK4 signaling (R-HSA-5687128)1Mitotic Spindle Checkpoint (R-HSA-69618)1PKMTs methylate histone lysines (R-HSA-3214841)1ribonucleoprotein complex subunit organization (GO:0071826)1ubiquitin-dependent ERAD pathway (GO:0030433)1vesicle targeting, to, from or within Golgi (GO:0048199)1Constitutive Signaling by NOTCH1 HD + PEST Domain Mutants1.007195501(R-HSA-2894862)Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-1.007195501HSA-2644606)DNA duplex unwinding (GO:0032508)1.007195501DNA-dependent DNA replication (GO:0006261)1.007195501Golgi vesicle budding (GO:0048194)1.007195501negative regulation of cell cycle G2/M phase transition1.007195501(GO:1902750)nuclear periphery (GO:0034399)1.007195501Oncogenic MAPK signaling (R-HSA-6802957)1.007195501PcG protein complex (GO:0031519)1.007195501peptidyl-lysine acetylation (GO:0018394)1.007195501regulation of G0 to G1 transition (GO:0070316)1.007195501Regulation of HSF1-mediated heat shock response (R-HSA-1.0071955013371453)Regulation of TP53 Activity (R-HSA-5633007)1.007195501retrograde transport, endosome to Golgi (GO:0042147)1.007195501Signaling by NOTCH1 HD + PEST Domain Mutants in Cancer (R-1.007195501HSA-2894858)Signaling by NOTCH1 in Cancer (R-HSA-2644603)1.007195501Signaling by NOTCH1 PEST Domain Mutants in Cancer (R-HSA-1.0071955012644602)specific granule membrane (GO:0035579)1.007195501Toll Like Receptor 9 (TLR9)Cascade (R-HSA-168138)1.007195501VEGFA-VEGFR2 Pathway (R-HSA-4420097)1.007195501vesicle coating (GO:0006901)1.007195501androgen receptor binding (GO:0050681)1.014355293azurophil granule membrane (GO:0035577)1.014355293core promoter sequence-specific DNA binding (GO:0001046)1.014355293Golgi to plasma membrane transport (GO:0006893)1.014355293histone acetylation (GO:0016573)1.014355293mitotic prometaphase (GO:0000236)1.014355293negative regulation of ubiquitin-dependent protein catabolic1.014355293process (GO:2000059)protein localization to mitochondrion (GO:0070585)1.014355293protein targeting to mitochondrion (GO:0006626)1.014355293Regulation of PTEN gene transcription (R-HSA-8943724)1.014355293ribonucleoprotein complex assembly (GO:0022618)1.014355293RNA splicing (GO:0008380)1.014355293Separation of Sister Chromatids (R-HSA-2467813)1.014355293vacuole organization (GO:0007033)1.014355293DNA-dependent DNA replication maintenance of fidelity1.021479727(GO:0045005)Glucose metabolism (R-HSA-70326)1.021479727Hedgehog ligand biogenesis (R-HSA-5358346)1.021479727lysosomal transport (GO:0007041)1.021479727MAP2K and MAPK activation (R-HSA-5674135)1.021479727Mitochondrial protein import (R-HSA-1268020)1.021479727negative regulation of G2/M transition of mitotic cell cycle1.021479727(GO:0010972)Negative regulation of MAPK pathway (R-HSA-5675221)1.021479727NOD1/2 Signaling Pathway (R-HSA-168638)1.021479727nuclear matrix (GO:0016363)1.021479727PML body (GO:0016605)1.021479727protein deacylation (GO:0035601)1.021479727regulation of DNA-dependent DNA replication (GO:0090329)1.021479727regulation of response to endoplasmic reticulum stress1.021479727(GO:1905897)tau protein binding (GO:0048156)1.021479727toxin transport (GO:1901998)1.021479727establishment of protein localization to mitochondrion1.028569152(GO:0072655)macromolecule deacylation (GO:0098732)1.028569152mitochondrial respiratory chain complex I (GO:0005747)1.028569152mitochondrial respiratory chain complex I assembly1.028569152(GO:0032981)Mitotic Anaphase (R-HSA-68882)1.028569152NADH dehydrogenase (quinone)activity (GO:0050136)1.028569152NADH dehydrogenase (ubiquinone)activity (GO:0008137)1.028569152NADH dehydrogenase activity (GO:0003954)1.028569152NADH dehydrogenase complex (GO:0030964)1.028569152NADH dehydrogenase complex assembly (GO:0010257)1.028569152post-Golgi vesicle-mediated transport (GO:0006892)1.028569152Regulation of TP53 Activity through Phosphorylation (R-HSA-1.0285691526804756)respiratory chain complex I (GO:0045271)1.028569152spliceosomal complex assembly (GO:0000245)1.028569152Toll Like Receptor 2 (TLR2)Cascade (R-HSA-181438)1.028569152Toll Like Receptor TLR1:TLR2 Cascade (R-HSA-168179)1.028569152UCH proteinases (R-HSA-5689603)1.028569152vacuolar transport (GO:0007034)1.028569152CD28 co-stimulation (R-HSA-389356)1.03562391exonuclease activity (GO:0004527)1.03562391macroautophagy (GO:0016236)1.03562391Mitotic G2-G2/M phases (R-HSA-453274)1.03562391Mitotic Metaphase and Anaphase (R-HSA-2555396)1.03562391protein monoubiguitination (GO:0006513)1.03562391ribonucleoprotein complex biogenesis (GO:0022613)1.03562391Signaling by high-kinase activity BRAF mutants (R-HSA-1.035623916802948)Signaling by TGF-beta Receptor Complex (R-HSA-170834)1.03562391small nuclear ribonucleoprotein complex (GO:0030532)1.03562391tRNA binding (GO:0000049)1.03562391cellular response to glucose starvation (GO:0042149)1.042644337G2/M Transition (R-HSA-69275)1.042644337methyltransferase complex (GO:0034708)1.042644337MyD88 cascade initiated on plasma membrane (R-HSA-975871)1.042644337nuclear replication fork (GO:0043596)1.042644337Rab regulation of trafficking (R-HSA-9007101)1.042644337regulation of cellular amino acid metabolic process1.042644337(GO:0006521)regulation of cellular response to heat (GO:1900034)1.042644337Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)1.042644337Regulation of TNFR1 signaling (R-HSA-5357905)1.042644337Respiratory electron transport (R-HSA-611105)1.042644337rRNA metabolic process (GO:0016072)1.042644337site of DNA damage (GO:0090734)1.042644337Termination of translesion DNA synthesis (R-HSA-5656169)1.042644337TNF signaling (R-HSA-75893)1.042644337Toll Like Receptor 10 (TLR10)Cascade (R-HSA-168142)1.042644337Toll Like Receptor 5 (TLR5)Cascade (R-HSA-168176)1.042644337Translation (R-HSA-72766)1.042644337vesicle coat (GO:0030120)1.042644337vesicle targeting (GO:0006903)1.042644337ficolin-1-rich granule (GO:0101002)1.049630768ficolin-1-rich granule lumen (GO:1904813)1.049630768Metabolism of RNA (R-HSA-8953854)1.049630768mRNA splicing, via spliceosome (GO:0000398)1.049630768nuclear-transcribed mRNA catabolic process, deadenylation-1.049630768dependent decay (GO:0000288)positive regulation of viral process (GO:0048524)1.049630768regulation of cholesterol biosynthetic process (GO:0045540)1.049630768regulation of sterol biosynthetic process (GO:0106118)1.049630768RNA splicing, via transesterification reactions (GO:0000375)1.049630768RNA splicing, via transesterification reactions with bulged1.049630768adenosine as nucleophile (GO:0000377)rRNA processing (GO:0006364)1.049630768site of double-strand break (GO:0035861)1.049630768Downstream TCR signaling (R-HSA-202424)1.056583528histone H4 acetylation (GO:0043967)1.056583528IRE1-mediated unfolded protein response (GO:0036498)1.056583528M phase (GO:0000279)1.056583528mitochondrial nucleoid (GO:0042645)1.056583528mitotic M phase (GO:0000087)1.056583528nucleoid (GO:0009295)1.056583528Oncogene Induced Senescence (R-HSA-2559585)1.056583528protein deacetylation (GO:0006476)1.056583528protein N-terminus binding (GO:0047485)1.056583528regulation of telomere maintenance via telomerase1.056583528(GO:0032210)Signaling by BRAF and RAF fusions (R-HSA-6802952)1.056583528Sm-like protein family complex (GO:0120114)1.056583528spliceosomal snRNP complex (GO:0097525)1.0565835285′-3′ RNA polymerase activity (GO:0034062)1.063502942DNA-templated transcription, termination (GO:0006353)1.063502942Loss of Nip from mitotic centrosomes (R-HSA-380259)1.063502942Loss of proteins required for interphase microtubule organization1.063502942from the centrosome (R-HSA-380284)negative regulation of response to endoplasmic reticulum stress1.063502942(GO:1903573)Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)1.063502942NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-1.0635029422122947)RNA polymerase activity (GO:0097747)1.063502942biological phase (GO:0044848)1.070389328cell cycle phase (GO:0022403)1.070389328Cellular response to hypoxia (R-HSA-2262749)1.070389328H4 histone acetyltransferase complex (GO:1902562)1.070389328maturation of SSU-rRNA (GO:0030490)1.070389328mitotic cell cycle phase (GO:0098763)1.070389328Paradoxical activation of RAF signaling by kinase inactive BRAF1.070389328(R-HSA-6802955)preribosome (GO:0030684)1.070389328regulation of hematopoietic progenitor cell differentiation1.070389328(GO:1901532)Regulation of Hypoxia-inducible Factor (HIF)by oxygen (R-HSA-1.0703893281234174)regulation of telomere maintenance via telomere lengthening1.070389328(GO:1904356)response to amino acid starvation (GO:1990928)1.070389328Signaling by moderate kinase activity BRAF mutants (R-HSA-1.0703893286802946)SUMOylation of chromatin organization proteins (R-HSA-1.0703893284551638)SWI/SNF superfamily-type complex (GO:0070603)1.070389328transcription elongation factor complex (GO:0008023)1.070389328ubiquitin-like protein binding (GO:0032182)1.070389328Antigen processing-Cross presentation (R-HSA-1236975)1.077242999Antiviral mechanism by IFN-stimulated genes (R-HSA-1169410)1.077242999AURKA Activation by TPX2 (R-HSA-8854518)1.077242999gene silencing by miRNA (GO:0035195)1.077242999histone methyltransferase complex (GO:0035097)1.077242999ISG15 antiviral mechanism (R-HSA-1169408)1.077242999lysosome organization (GO:0007040)1.077242999Lysosome Vesicle Biogenesis (R-HSA-432720)1.077242999lytic vacuole organization (GO:0080171)1.077242999Mitotic G1-G1/S phases (R-HSA-453279)1.077242999MyD88:Mal cascade initiated on plasma membrane (R-HSA-1.077242999166058)nuclear export (GO:0051168)1.077242999RNA polymerase complex (GO:0030880)1.077242999RNA Polymerase III Abortive And Retractive Initiation (R-HSA-1.077242999749476)RNA Polymerase III Transcription (R-HSA-74158)1.077242999Synthesis of PIPs at the plasma membrane (R-HSA-1660499)1.077242999Toll Like Receptor TLR6:TLR2 Cascade (R-HSA-168188)1.077242999Unfolded Protein Response (UPR)(R-HSA-381119)1.077242999anaphase (GO:0051322)1.084064265ATPase complex (GO:1904949)1.084064265AUF1 (hnRNP D0)binds and destabilizes mRNA (R-HSA-1.084064265450408)G1/S DNA Damage Checkpoints (R-HSA-69615)1.084064265Golgi Associated Vesicle Biogenesis (R-HSA-432722)1.084064265histone deacetylation (GO:0016575)1.084064265host cell (GO:0043657)1.084064265host cellular component (GO:0018995)1.084064265mitotic anaphase (GO:0000090)1.084064265MyD88-independent TLR4 cascade (R-HSA-166166)1.084064265nuclear transcriptional repressor complex (GO:0090568)1.084064265Nucleotide-binding domain, leucine rich repeat containing1.084064265receptor (NLR)signaling pathways (R-HSA-168643)protein export from nucleus (GO:0006611)1.084064265regulation of autophagosome assembly (GO:2000785)1.084064265Regulation of TP53 Expression and Degradation (R-HSA-1.0840642656806003)rRNA modification in the nucleus and cytosol (R-HSA-6790901)1.084064265Synthesis of active ubiquitin: roles of E1 and E2 enzymes (R-1.084064265HSA-8866652)TCR signaling (R-HSA-202403)1.084064265TNFR1-induced NFkappaB signaling pathway (R-HSA-5357956)1.084064265Toll Like Receptor 3 (TLR3)Cascade (R-HSA-168164)1.084064265TRIF(TICAM1)-mediated TLR4 signaling (R-HSA-937061)1.084064265ubiquitin binding (GO:0043130)1.08406426590S preribosome (GO:0030686)1.09085343cellular response to amino acid starvation (GO:0034198)1.09085343Centrosome maturation (R-HSA-380287)1.09085343Complex I biogenesis (R-HSA-6799198)1.09085343double-strand break repair via nonhomologous end joining1.09085343(GO:0006303)Endosomal Sorting Complex Required For Transport1.09085343(ESCRT)(R-HSA-917729)G1/S Transition (R-HSA-69206)1.09085343general transcription initiation factor binding (GO:0140296)1.09085343histone acetyltransferase complex (GO:0000123)1.09085343Intra-Golgi traffic (R-HSA-6811438)1.09085343mitochondrial electron transport, NADH to ubiquinone1.09085343(GO:0006120)non-recombinational repair (GO:0000726)1.09085343protein targeting to vacuole (GO:0006623)1.09085343Recruitment of mitotic centrosome proteins and complexes (R-1.09085343HSA-380270)Regulation of RAS by GAPs (R-HSA-5658442)1.09085343regulation of vacuole organization (GO:0044088)1.09085343Activation of APC/C and APC/C:Cdc20 mediated degradation of1.097610797mitotic proteins (R-HSA-176814)Association of TriC/CCT with target proteins during biosynthesis1.097610797(R-HSA-390471)Cytosolic sensors of pathogen-associated DNA (R-HSA-1.0976107971834949)DNA Replication (R-HSA-69306)1.097610797DNA strand elongation (R-HSA-69190)1.097610797negative regulation of telomere maintenance (GO:0032205)1.097610797peptidase complex (GO:1905368)1.097610797phagophore assembly site (GO:0000407)1.097610797RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)1.097610797ribonucleoprotein complex export from nucleus (GO:0071426)1.097610797ribonucleoprotein complex localization (GO:0071166)1.097610797RNA polymerase II, holoenzyme (GO:0016591)1.097610797spliceosomal complex (GO:0005681)1.097610797spliceosomal tri-snRNP complex (GO:0097526)1.097610797Transcriptional regulation by RUNX3 (R-HSA-8878159)1.097610797translation factor activity, RNA binding (GO:0008135)1.097610797U4/U6 x U5 tri-snRNP complex (GO:0046540)1.097610797acetyltransferase complex (GO:1902493)1.10433666antigen processing and presentation of peptide antigen via MHC1.10433666class I (GO:0002474)AP-type membrane coat adaptor complex (GO:0030119)1.10433666Calnexin/calreticulin cycle (R-HSA-901042)1.10433666Clathrin derived vesicle budding (R-HSA-421837)1.10433666DNA damage response, detection of DNA damage1.10433666(GO:0042769)endosome to lysosome transport (GO:0008333)1.10433666ER-Phagosome pathway (R-HSA-1236974)1.10433666Hh mutants abrogate ligand secretion (R-HSA-5387390)1.10433666histone deacetylase complex (GO:0000118)1.10433666negative regulation of GO to G1 transition (GO:0070317)1.10433666negative regulation of type I interferon production (GO:0032480)1.10433666p53-Dependent G1 DNA Damage Response (R-HSA-69563)1.10433666p53-Dependent G1/S DNA damage checkpoint (R-HSA-69580)1.10433666polyubiquitin modification-dependent protein binding1.10433666(GO:0031593)protein acetyltransferase complex (GO:0031248)1.10433666PTEN Regulation (R-HSA-6807070)1.10433666regulation of transcription from RNA polymerase II promoter in1.10433666response to hypoxia (GO:0061418)RNA export from nucleus (GO:0006405)1.10433666TP53 Regulates Transcription of DNA Repair Genes (R-HSA-1.104336666796648)trans-Golgi Network Vesicle Budding (R-HSA-199992)1.10433666transcription factor TFIID complex (GO:0005669)1.10433666Translesion synthesis by Y family DNA polymerases bypasses1.10433666lesions on DNA template (R-HSA-110313)Activation of gene expression by SREBF (SREBP)(R-HSA-1.1110313122426168)Activation of the pre-replicative complex (R-HSA-68962)1.111031312antigen processing and presentation of exogenous peptide1.111031312antigen via MHC class I (GO:0042590)APC/C-mediated degradation of cell cycle proteins (R-HSA-1.111031312174143)COPI-coated vesicle (GO:0030137)1.111031312Glycolysis (R-HSA-70171)1.111031312histone H3 acetylation (GO:0043966)1.111031312maintenance of protein localization in organelle (GO:0072595)1.111031312Mitophagy (R-HSA-5205647)1.111031312negative regulation of DNA replication (GO:0008156)1.111031312NIK/NF-kappaB signaling (GO:0038061)1.111031312nuclear DNA-directed RNA polymerase complex (GO:0055029)1.111031312Oxygen-dependent proline hydroxylation of Hypoxia-inducible1.111031312Factor Alpha (R-HSA-1234176)Regulation of cholesterol biosynthesis by SREBP (SREBF)(R-1.111031312HSA-1655829)regulation of hematopoietic stem cell differentiation1.111031312(GO:1902036)Regulation of mitotic cell cycle (R-HSA-453276)1.111031312RNA Polymerase III Transcription Initiation From Type 21.111031312Promoter (R-HSA-76066)S Phase (R-HSA-69242)1.111031312SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577)1.111031312Signaling by NOTCH4 (R-HSA-9013694)1.111031312XBP1(S)activates chaperone genes (R-HSA-381038)1.111031312antigen processing and presentation of exogenous peptide1.117695043antigen via MHC class I, TAP-dependent (GO:0002479)APC/C:Cdc20 mediated degradation of mitotic proteins (R-HSA-1.117695043176409)Cul4-RING E3 ubiquitin ligase complex (GO:0080008)1.117695043Cyclin E associated events during G1/S transition (R-HSA-1.11769504369202)DNA-directed RNA polymerase complex (GO:0000428)1.117695043double-stranded RNA binding (GO:0003725)1.117695043Macroautophagy (R-HSA-1632852)1.117695043Pausing and recovery of Tat-mediated HIV elongation (R-HSA-1.117695043167238)positive regulation of telomere maintenance via telomerase1.117695043(GO:0032212)regulation of telomere maintenance (GO:0032204)1.117695043regulation of type I interferon-mediated signaling pathway1.117695043(GO:0060338)Switching of origins to a post-replicative state (R-HSA-69052)1.117695043Tat-mediated HIV elongation arrest and recovery (R-HSA-1.117695043167243)4 iron, 4 sulfur cluster binding (GO:0051539)1.124328135aminoacyl-tRNA ligase activity (GO:0004812)1.124328135Cyclin A:Cdk2-associated events at S phase entry (R-HSA-1.12432813569656)Degradation of DVL (R-HSA-4641258)1.124328135DNA Damage Bypass (R-HSA-73893)1.124328135DNA-directed 5′-3′ RNA polymerase activity (GO:0003899)1.124328135HIV Life Cycle (R-HSA-162587)1.124328135IRE1 alpha activates chaperones (R-HSA-381070)1.124328135Late Phase of HIV Life Cycle (R-HSA-162599)1.124328135ligase activity, forming carbon-oxygen bonds (GO:0016875)1.124328135multi-organism localization (GO:1902579)1.124328135multi-organism transport (GO:0044766)1.124328135N-glycan trimming in the ER and Calnexin/Calreticulin cycle (R-1.124328135HSA-532668)Orel removal from chromatin (R-HSA-68949)1.124328135PERK regulates gene expression (R-HSA-381042)1.124328135regulation of autophagy of mitochondrion (GO:1903146)1.124328135Regulation of TP53 Degradation (R-HSA-6804757)1.124328135RNA Polymerase III Transcription Initiation From Type 11.124328135Promoter (R-HSA-76061)RNA Polymerase III Transcription Initiation From Type 31.124328135Promoter (R-HSA-76071)SUMOylation of DNA damage response and repair proteins (R-1.124328135HSA-3108214)SUMOylation of RNA binding proteins (R-HSA-4570464)1.124328135Synthesis of DNA (R-HSA-69239)1.124328135transport of virus (GO:0046794)1.124328135tRNA aminoacylation (GO:0043039)1.124328135amino acid activation (GO:0043038)1.13093087APC:Cdc20 mediated degradation of cell cycle proteins prior to1.13093087satisfation of the cell cycle checkpoint (R-HSA-179419)CDK-mediated phosphorylation and removal of Cdc6 (R-HSA-1.1309308769017)Cleavage of Growing Transcript in the Termination Region (R-1.13093087HSA-109688)Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-1.13093087380972)ER-nudeus signaling pathway (GO:0006984)1.13093087HIV elongation arrest and recovery (R-HSA-167287)1.13093087Interleukin-1 signaling (R-HSA-9020702)1.13093087mitochondrial gene expression (GO:0140053)1.13093087nuclear ubiguitin ligase complex (GO:0000152)1.13093087Pausing and recovery of HIV elongation (R-HSA-167290)1.13093087positive regulation of telomere maintenance (GO:0032206)1.13093087Regulation of APC/C activators between G1/S and early1.13093087anaphase (R-HSA-176408)Regulation of mRNA stability by proteins that bind AU-rich1.13093087elements (R-HSA-450531)ribonucleoprotein complex binding (GO:0043021)1.13093087RNA Polymerase II Transcription Termination (R-HSA-73856)1.13093087RNA Polymerase III Transcription Initiation (R-HSA-76046)1.13093087RUNX1 interacts with co-factors whose precise effect on RUNX11.13093087targets is not known (R-HSA-8939243)anaphase-promoting complex-dependent catabolic process1.137503524(GO:0031145)Assembly of the pre-replicative complex (R-HSA-68867)1.137503524CDT1 association with the CDC6:ORC:origin complex (R-HSA-1.13750352468827)Degradation of beta-catenin by the destruction complex (R-HSA-1.137503524195253)Degradation of GLI1 by the proteasome (R-HSA-5610780)1.137503524HDR through Single Strand Annealing (SSA)(R-HSA-5685938)1.137503524interleukin-1-mediated signaling pathway (GO:0070498)1.137503524mRNA 3′-end processing (GO:0031124)1.137503524mRNA Splicing - Minor Pathway (R-HSA-72165)1.137503524Nuclear import of Rev protein (R-HSA-180746)1.137503524positive regulation of telomere maintenance via telomere1.137503524lengthening (GO:1904358)telomeric DNA binding (GO:0042162)1.137503524DNA Replication Pre-lnitiation (R-HSA-69002)1.14404637M/G1 Transition (R-HSA-68874)1.14404637MAPK targets/ Nuclear events mediated by MAP kinases (R-1.14404637HSA-450282)mediator complex (GO:0016592)1.14404637Mitochondrial calcium ion transport (R-HSA-8949215)1.14404637mRNA export from nucleus (GO:0006406)1.14404637mRNA-containing ribonucleoprotein complex export from nucleus1.14404637(GO:0071427)Nuclear Envelope Breakdown (R-HSA-2980766)1.14404637nudeotide-excision repair (GO:0006289)1.14404637peptide N-acetyltransferase activity (GO:0034212)1.14404637Rab guanyl-nudeotide exchange factor activity (GO:0017112)1.14404637Recognition of DNA damage by PCNA-containing replication1.14404637complex (R-HSA-110314)Regulation of PTEN stability and activity (R-HSA-8948751)1.14404637ribosome binding (GO:0043022)1.14404637tRNA aminoacylation for protein translation (GO:0006418)1.14404637U2-type spliceosomal complex (GO:0005684)1.14404637APC/C:Cdh1 mediated degradation of Cdc20 and other1.150559677APC/C:Cdh1 targeted proteins in late mitosis/early G1 (R-HSA-174178)Cdc20:Phospho-APC/C mediated degradation of Cyclin A (R-1.150559677HSA-174184)FBXL7 down-regulates AURKA during mitotic entry and in early1.150559677mitosis (R-HSA-8854050)HIV Infection (R-HSA-162906)1.150559677Host Interactions with Influenza Factors (R-HSA-168253)1.150559677MAP kinase activation (R-HSA-450294)1.150559677MicroRNA (miRNA)biogenesis (R-HSA-203927)1.150559677mRNA Splicing (R-HSA-72172)1.150559677Nuclear Pore Complex (NPC)Disassembly (R-HSA-3301854)1.150559677nucleotide-excision repair, DNA incision (GO:0033683)1.150559677exonuclease activity, active with either ribo- or deoxyribonucleic1.15704371acids and producing 5′-phosphomonoesters (GO:0016796)histone acetyltransferase activity (GO:0004402)1.15704371Interactions of Rev with host cellular proteins (R-HSA-177243)1.15704371mRNA Splicing - Major Pathway (R-HSA-72163)1.15704371multivesicular body sorting pathway (GO:0071985)1.15704371Retrograde transport at the Trans-Golgi-Network (R-HSA-1.157043716811440)transcription by RNA polymerase I (GO:0006360)1.15704371Transcription of the HIV genome (R-HSA-167172)1.15704371Degradation of GLI2 by the proteasome (R-HSA-5610783)1.163498732Downregulation of TGF-beta receptor signaling (R-HSA-1.1634987322173788)Gap-filling DNA repair synthesis and ligation in GG-NER (R-1.163498732HSA-5696397)GLI3 is processed to GLI3R by the proteasome (R-HSA-1.1634987325610785)peptide-lysine-N-acetyltransferase activity (GO:0061733)1.163498732preribosome, large subunit precursor (GO:0030687)1.163498732Processing of Capped Intron-Containing Pre-mRNA (R-HSA-1.16349873272203)RNA Polymerase II Pre-transcription Events (R-HSA-674695)1.163498732Transcriptional Regulation by E2F6 (R-HSA-8953750)1.163498732translational elongation (GO:0006414)1.163498732DAP12 signaling (R-HSA-2424491)1.169925001Defective CFTR causes cystic fibrosis (R-HSA-5678895)1.169925001p53-lndependent DNA Damage Response (R-HSA-69610)1.169925001p53-lndependent G1/S DNA damage checkpoint (R-HSA-69613)1.169925001translational termination (GO:0006415)1.169925001tRNA processing in the nucleus (R-HSA-6784531)1.169925001Ubiquitin Mediated Degradation of Phosphorylated Cdc25A (R-1.169925001HSA-69601)Ubiquitin-dependent degradation of Cyclin D (R-HSA-75815)1.169925001Ubiguitin-dependent degradation of Cyclin D1 (R-HSA-69229)1.1699250013′-5′ exonuclease activity (GO:0008408)1.176322773Base Excision Repair (R-HSA-73884)1.176322773Degradation of AXIN (R-HSA-4641257)1.176322773Host Interactions of HIV factors (R-HSA-162909)1.176322773intracellular transport of virus (GO:0075733)1.176322773Resolution of Abasic Sites (AP sites)(R-HSA-73933)1.176322773The role of Nef in HIV-1 replication and disease pathogenesis (R-1.176322773HSA-164952)1.182692298Deadenylation-dependent mRNA decay (R-HSA-429914)Formation of HIV-1 elongation complex containing HIV-1 Tat (R-1.182692298HSA-167200)Hh mutants that don't undergo autocatalytic processing are1.182692298degraded by ERAD (R-HSA-5362768)HIV Transcription Elongation (R-HSA-167169)1.182692298HIV Transcription Initiation (R-HSA-167161)1.182692298immunological synapse (GO:0001772)1.182692298ncRNA transcription (GO:0098781)1.182692298NS1 Mediated Effects on Host Pathways (R-HSA-168276)1.182692298nudeotide-excision repair, DNA incision, 5′-to lesion1.182692298(GO:0006296)nudeotide-sugar metabolic process (GO:0009225)1.182692298proteasome complex (GO:0000502)1.182692298Regulation of Glucokinase by Glucokinase Regulatory Protein1.182692298(R-HSA-170822)RNA Polymerase II HIV Promoter Escape (R-HSA-167162)1.182692298RNA Polymerase II Promoter Escape (R-HSA-73776)1.182692298RNA Polymerase II Transcription Initiation (R-HSA-75953)1.182692298RNA Polymerase II Transcription Initiation And Promoter1.182692298Clearance (R-HSA-76042)RNA Polymerase II Transcription Pre-lnitiation And Promoter1.182692298Opening (R-HSA-73779)Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)1.182692298transcription initiation from RNA polymerase I promoter1.182692298(GO:0006361)APC/C:Cdc20 mediated degradation of Securin (R-HSA-174154)1.189033824endopeptidase complex (GO:1905369)1.189033824Export of Viral Ribonucleoproteins from Nucleus (R-HSA-1.189033824168274)Formation of HIV elongation complex in the absence of HIV Tat1.189033824(R-HSA-167152)histone deacetylase activity (GO:0004407)1.189033824Metabolism of non-coding RNA (R-HSA-194441)1.189033824mitochondrial large ribosomal subunit (GO:0005762)1.189033824mitochondrial ribosome (GO:0005761)1.189033824mitochondrial small ribosomal subunit (GO:0005763)1.189033824negative regulation of mRNA processing (GO:0050686)1.189033824organellar large ribosomal subunit (GO:0000315)1.189033824organellar ribosome (GO:0000313)1.189033824organellar small ribosomal subunit (GO:0000314)1.189033824production of miRNAs involved in gene silencing by miRNA1.189033824(GO:0035196)snRNA binding (GO:0017069)1.189033824snRNP Assembly (R-HSA-191859)1.189033824Cross-presentation of soluble exogenous antigens1.195347598(endosomes)(R-HSA-1236978)CTLA4 inhibitory signaling (R-HSA-389513)1.195347598Formation of RNA Pol II elongation complex (R-HSA-112382)1.195347598Inactivation of APC/C via direct inhibition of the APC/C complex1.195347598(R-HSA-141430)Inflammasomes (R-HSA-622312)1.195347598Inhibition of the proteolytic activity of APC/C required for the1.195347598onset of anaphase by mitotic spindle checkpoint components (R-HSA-141405)mitochondrial translation (GO:0032543)1.195347598mTOR signalling (R-HSA-165159)1.195347598positive requlation of viral transcription (GO:0050434)1.195347598precatalytic spliceosome (GO:0071011)1.195347598protein deacetylase activity (GO:0033558)1.195347598Regulation of activated PAK-2p34 by proteasome mediated1.195347598degradation (R-HSA-211733)regulation of DNA-templated transcription, elongation1.195347598(GO:0032784)RNA Polymerase II Transcription Elongation (R-HSA-75955)1.195347598U2-type catalytic step 2 spliceosome (GO:0071007)1.195347598U2-type precatalytic spliceosome (GO:0071005)1.195347598Autodegradation of the E3 ubiquitin ligase COP1 (R-HSA-1.201633861349425)Formation of Incision Complex in GG-NER (R-HSA-5696395)1.201633861Regulation of Apoptosis (R-HSA-169911)1.201633861regulation of defense response to virus by virus (GO:0050690)1 201633861Rev-mediated nuclear export of HIV RNA (R-HSA-165054)1.201633861RNA Polymerase I Transcription Termination (R-HSA-73863)1.201633861SUMOylation of SUMOylation proteins (R-HSA-4085377)1.201633861termination of RNA polymerase I transcription (GO:0006363)1.201633861TGF-beta receptor signaling activates SMADs (R-HSA-2173789)1.201633861tRNA Aminoacylation (R-HSA-379724)1.201633861Vif-mediated degradation of APOBEC3G (R-HSA-180585)1.201633861Vpu mediated degradation of CD4 (R-HSA-180534)1.2016338617-methylguanosine mRNA capping (GO:0006370)1.207892852catalytic step 2 spliceosome (GO:0071013)1.207892852Citric acid cycle (TCA cycle)(R-HSA-71403)1.207892852ERK/MAPK targets (R-HSA-198753)1.207892852interphase (GO:0051325)1.207892852Mitochondrial translation elongation (R-HSA-5389840)1.207892852Mitochondrial translation initiation (R-HSA-5368286)1.207892852Mitochondrial translation termination (R-HSA-5419276)1.207892852mitochondrial translational elongation (GO:0070125)1.207892852mitochondrial translational termination (GO:0070126)1.207892852mitotic interphase (GO:0051329)1.207892852nuclear DNA replication (GO:0033260)1.207892852SCF-beta-TrCP mediated degradation of Emil (R-HSA-174113)1.207892852Stabilization of p53 (R-HSA-69541)1.2078928527-methylguanosine RNA capping (GO:0009452)1.214124805cell cycle DNA replication (GO:0044786)1.214124805Mitochondrial translation (R-HSA-5368287)1.214124805mRNA 3′-end processing (R-HSA-72187)1.214124805mTORCI-mediated signalling (R-HSA-166208)1.214124805RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)1.214124805RNA capping (GO:0036260)1.214124805CLEC7A (Dectin-1 Signaling (R-HSA-5607764)1.220329955Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-1.2203299555674400)Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-1.2203299555607761)NIK-->noncanonical NF-kB signaling (R-HSA-5676590)1.220329955RNA polymerase binding (GO:0070063)1.220329955tRNA transport (GO:0051031)1.220329955Autodegradation of Cdh1 by Cdh1:APC/C (R-HSA-174084)1.22650853DNA Damage Recognition in GG-NER (R-HSA-5696394)1.22650853exosome (RNase complex)(GO:0000178)1.22650853Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-1.226508536782210)ncRNA export from nucleus (GO:0097064)1.22650853negative regulation of DNA-dependent DNA replication1.22650853(GO:2000104)Nuclear Events (kinase and transcription factor activation)(R-1.22650853HSA-198725)Regulation of ornithine decarboxylase (ODC)(R-HSA-350562)1.22650853transcription elongation from RNA polymerase II promoter1.22650853(GO:0006368)Activation of NF-kappaB in B cells (R-HSA-1169091)1.232660757DNA-templated transcription, elongation (GO:0006354)1.232660757Downstream signaling events of B Cell Receptor (BCR)(R-HSA-1.2326607571168372)Dual incision in TC-NER (R-HSA-6782135)1.232660757exoribonuclease complex (GO:1905354)1.232660757Formation of TC-NER Pre-lncision Complex (R-HSA-6781823)1.232660757histone ubiquitination (GO:0016574)1.232660757maturation of 5.8S rRNA (GO:0000460)1.232660757mitotic S phase (GO:0000084)1.232660757Negative regulation of NOTCH4 signaling (R-HSA-9604323)1.232660757S phase (GO:0051320)1.232660757translation initiation factor activity (GO:0003743)1.232660757Transport of Mature Transcript to Cytoplasm (R-HSA-72202)1.232660757basal RNA polymerase II transcription machinery binding1.23878686(GO:0001099)basal transcription machinery binding (GO:0001098)1.23878686Dual Incision in GG-NER (R-HSA-5696400)1.23878686Global Genome Nucleotide Excision Repair (GG-NER)(R-HSA-1.238786865696399)INO80-type complex (GO:0097346)1.23878686NEP/NS2 Interacts with the Cellular Export Machinery (R-HSA-1.23878686168333)Nucleotide Excision Repair (R-HSA-5696398)1.23878686RNA phosphodiester bond hydrolysis, exonucleolytic1.23878686(GO:0090503)snRNA transcription (GO:0009301)1.23878686snRNA transcription by RNA polymerase II (GO:0042795)1.23878686SUMOylation of DNA replication proteins (R-HSA-4615885)1.23878686Transport of Mature mRNA derived from an Intron-Containing1.23878686Transcript (R-HSA-159236)Extension of Telomeres (R-HSA-180786)1.244887059histone monoubiquitination (GO:0010390)1.244887059nucleotide-excision repair, preincision complex assembly1.244887059(GO:0006294)Regulation of TP53 Activity through Acetylation (R-HSA-1.2448870596804758)regulation of transcription elongation from RNA polymerase II1.244887059promoter (GO:0034243)RNA Polymerase I Promoter Escape (R-HSA-73772)1.244887059RNA polymerase II transcribes snRNA genes (R-HSA-6807505)1.244887059transcription elongation from RNA polymerase I promoter1.244887059(GO:0006362)transcription-coupled nucleotide-excision repair (GO:0006283)1.244887059positive regulation of DNA-templated transcription, elongation1.250961574(GO:0032786)RNA polymerase core enzyme binding (GO:0043175)1.250961574RNA Polymerase I Transcription Initiation (R-HSA-73762)1.250961574Transcription-Coupled Nucleotide Excision Repair (TC-NER)(R-1.250961574HSA-6781827)3′-5′-exoribonuclease activity (GO:0000175)1.257010618exonucleolytic catabolism of deadenylated mRNA (GO:0043928)1.257010618Interactions of Vpr with host cellular proteins (R-HSA-176033)1.257010618tRNA export from nucleus (GO:0006409)1.257010618tRNA-containing ribonucleoprotein complex export from nucleus1.257010618(GO:0071431)exoribonuclease activity, producing 5′-phosphomonoesters1.263034406(GO:0016896)nuclear-transcribed mRNA catabolic process, exonucleolytic1.263034406(GO:0000291)Regulation of RUNX3 expression and activity (R-HSA-8941858)1.263034406exoribonuclease activity (GO:0004532)1.269033146Lagging Strand Synthesis (R-HSA-69186)1.269033146Transport of Mature mRNA Derived from an Intronless Transcript1.269033146(R-HSA-159231)Transport of Mature mRNAs Derived from Intronless Transcripts1.269033146(R-HSA-159234)Viral Messenger RNA Synthesis (R-HSA-168325)1.269033146PCNA-Dependent Long Patch Base Excision Repair (R-HSA-1.2750070475651801)Abortive elongation of HIV-1 transcript in the absence of Tat (R-1.280956314HSA-167242)proteasome regulatory particle (GO:0005838)1.280956314proteasome accessory complex (GO:0022624)1.286881148Resolution of AP sites via the multiple-nucleotide patch1.286881148replacement pathway (R-HSA-110373)Telomere C-strand (Lagging Strand)Synthesis (R-HSA-174417)1.286881148telomere maintenance via semi-conservative replication1.286881148(GO:0032201)mRNA Capping (R-HSA-72086)1.292781749RNA Pol II CTD phosphorylation and interaction with CE (R-1.292781749HSA-77075)RNA Pol II CTD phosphorylation and interaction with CE during1.292781749HIV infection (R-HSA-167160)Transport of Ribonucleoproteins into the Host Nucleus (R-HSA-1.292781749168271)Formation of the Early Elongation Complex (R-HSA-113418)1.298658316Formation of the HIV-1 Early Elongation Complex (R-HSA-1.298658316167158)MLL1 complex (GO:0071339)1.298658316MLL1/2 complex (GO:0044665)1.298658316Transport of the SLBP Dependant Mature mRNA (R-HSA-1.298658316159230)Transport of the SLBP independent Mature mRNA (R-HSA-1.298658316159227)Vpr-mediated nuclear import of PICs (R-HSA-180910)1.298658316RNA polymerase II complex binding (GO:0000993)1.304511042SUMOylation of ubiquitinylation proteins (R-HSA-3232142)1.304511042carboxy-terminal domain protein kinase complex (GO:0032806)1.344828497Cytosolic tRNA aminoacylation (R-HSA-379716)1.344828497nudeotide-excision repair, preincision complex stabilization1.344828497(GO:0006293)RAF activation (R-HSA-5673000)1.344828497Synthesis of PIPs at the early endosome membrane (R-HSA-1.3448284971660516)Alternative Trascription Start/End n = 835bitter taste receptor activity (GO:0033038)−6.64385619regulation of peptidyl-serine phosphorylation of STAT protein−6.64385619(GO:0033139)immunoglobulin complex (GO:0019814)−4.058893689immunoglobulin complex, circulating (GO:0042571)−4.058893689detection of chemical stimulus involved in sensory perception of−3.321928095smell (GO:0050911)olfactory receptor activity (GO:0004984)−3.321928095Classical antibody-mediated complement activation (R-HSA-−3.184424571173623)detection of chemical stimulus involved in sensory perception−3.184424571(GO:0050907)detection of chemical stimulus involved in sensory perception of−2.943416472bitter taste (GO:0001580)odorant binding (GO:0005549)−2.943416472Olfactory Signaling Pathway (R-HSA-381753)−2.943416472Creation of C4 and C2 activators (R-HSA-166786)−2.836501268complement activation, classical pathway (GO:0006958)−2.736965594CD22 mediated BCR regulation (R-HSA-5690714)−2.64385619immunoglobulin receptor binding (GO:0034987)−2.64385619keratin filament (GO:0045095)−2.64385619sensory perception of smell (GO:0007608)−2.64385619detection of chemical stimulus involved in sensory perception of−2.556393349taste (GO:0050912)detection of stimulus involved in sensory perception−2.556393349(GO:0050906)sensory perception of bitter taste (GO:0050913)−2.556393349detection of chemical stimulus (GO:0009593)−2.473931188Initial triggering of complement (R-HSA-166663)−2.473931188sensory perception of chemical stimulus (GO:0007606)−2.395928676humoral immune response mediated by circulating−2.321928095immunoglobulin (GO:0002455)phagocytosis, recognition (GO:0006910)−2.321928095complement activation (GO:0006956)−2.251538767Scavenging of heme from plasma (R-HSA-2168880)−2.251538767T cell receptor complex (GO:0042101)−2.120294234Keratinization (R-HSA-6805567)−2.058893689FCGR activation (R-HSA-2029481)−2keratinization (GO:0031424)−1.888968688detection of stimulus (GO:0051606)−1.556393349G alpha (s signalling events (R-HSA-418555))−1.556393349antigen binding (GO:0003823)−1.514573173keratinocyte differentiation (GO:0030216)−1.395928676nucleosome (GO:0000786)−1.395928676regulation of complement activation (GO:0030449)−1.395928676Complement cascade (R-HSA-166658)−1.358453971phaqocytosis, engulfment (GO:0006911)−1.358453971Formation of the cornified envelope (R-HSA-6809371)−1.321928095Regulation of Complement cascade (R-HSA-977606)−1.321928095Antimicrobial peptides (R-HSA-6803157)−1.286304185intermediate filament (GO:0005882)−1.251538767immunoglobulin production (GO:0002377)−1.184424571B cell mediated immunity (GO:0019724)−1.152003093immunoglobulin mediated immune response (GO:0016064)−1.152003093G protein-coupled receptor activity (GO:0004930)−1.120294234plasma membrane invagination (GO:0099024)−1.120294234cornification (GO:0070268)−1.089267338humoral immune response (GO:0006959)−1.089267338membrane invagination (GO:0010324)−1.089267338epidermal cell differentiation (GO:0009913)−1.058893689regulation of humoral immune response (GO:0002920)−1.058893689B cell receptor signaling pathway (GO:0050853)−1.029146346sensory perception (GO:0007600)−0.915935735defense response to bacterium (GO:0042742)−0.888968688intermediate filament cytoskeleton (GO:0045111)−0.888968688production of molecular mediator of immune response−0.888968688(GO:0002440)Unclassified (UNCLASSIFIED)−0.785875195cytokine activity (GO:0005125)−0.736965594skin development (GO:0043588)−0.736965594G protein-coupled receptor signaling pathway (GO:0007186)−0.666576266epidermis development (GO:0008544)−0.64385619adaptive immune response (GO:0002250)−0.621488377lymphocyte mediated immunity (GO:0002449)−0.59946207GPCR downstream signalling (R-HSA-388396)−0.577766999Signaling by GPCR (R-HSA-372790)−0.577766999nervous system process (GO:0050877)−0.473931188transmembrane signaling receptor activity (GO:0004888)−0.454031631signaling receptor activity (GO:0038023)−0.304006187system process (GO:0003008)−0.286304185molecular transducer activity (GO:0060089)−0.251538767cellular component (GO:0005575)0.084064265biological process (GO:0008150)0.111031312membrane (GO:0016020)0.111031312signal transduction (GO:0007165)0.124328135signaling (GO:0023052)0.124328135anatomical structure development (GO:0048856)0.137503524cell (GO:0005623)0.137503524cell communication (GO:0007154)0.137503524cell part (GO:0044464)0.137503524cellular developmental process (GO:0048869)0.137503524developmental process (GO:0032502)0.137503524molecular function (GO:0003674)0.137503524response to chemical (GO:0042221)0.137503524response to stimulus (GO:0050896)0.137503524multicellular organism development (GO:0007275)0.150559677system development (GO:0048731)0.150559677multi-organism process (GO:0051704)0.163498732regulation of biological process (GO:0050789)0.163498732biological regulation (GO:0065007)0.176322773cellular process (GO:0009987)0.176322773cellular response to stimulus (GO:0051716)0.176322773regulation of cellular process (GO:0050794)0.176322773transcription regulator activity (GO:0140110)0.189033824binding (GO:0005488)0.201633861DNA binding (GO:0003677)0.201633861cation binding (GO:0043169)0.214124805cell surface receptor signaling pathway (GO:0007166)0.214124805regulation of immune system process (GO:0002682)0.214124805extracellular exosome (GO:0070062)0.22650853extracellular organelle (GO:0043230)0.22650853metal ion binding (GO:0046872)0.22650853anatomical structure morphogenesis (GO:0009653)0.23878686extracellular vesicle (GO:1903561)0.23878686intracellular (GO:0005622)0.23878686intracellular part (GO:0044424)0.23878686organelle (GO:0043226)0.23878686chemical homeostasis (GO:0048878)0.250961574cytoskeletal part (GO:0044430)0.250961574homeostatic process (GO:0042592)0.250961574Innate Immune System (R-HSA-168249)0.250961574ion binding (GO:0043167)0.250961574nucleic acid binding (GO:0003676)0.250961574positive regulation of response to stimulus (GO:0048584)0.250961574regulation of transcription by RNA polymerase II (GO:0006357)0.250961574heterocyclic compound binding (GO:1901363)0.263034406intracellular organelle (GO:0043229)0.263034406negative regulation of developmental process (GO:0051093)0.263034406negative regulation of molecular function (GO:0044092)0.263034406negative regulation of multicellular organismal process0.263034406(GO:0051241)nervous system development (GO:0007399)0.263034406organic cyclic compound binding (GO:0097159)0.263034406plasma membrane region (GO:0098590)0.263034406protein dimerization activity (GO:0046983)0.263034406proteolysis (GO:0006508)0.263034406regulation of cell population proliferation (GO:0042127)0.263034406regulation of multicellular organismal development (GO:2000026)0.263034406secretory granule (GO:0030141)0.263034406transport (GO:0006810)0.263034406biological adhesion (GO:0022610)0.275007047catalytic activity (GO:0003824)0.275007047cell adhesion (GO:0007155)0.275007047cell development (GO:0048468)0.275007047cell projection part (GO:0044463)0.275007047cytoskeleton (GO:0005856)0.275007047establishment of localization (GO:0051234)0.275007047localization (GO:0051179)0.275007047membrane-bounded organelle (GO:0043227)0.275007047neuron differentiation (GO:0030182)0.275007047organic acid metabolic process (GO:0006082)0.275007047oxoacid metabolic process (GO:0043436)0.275007047plasma membrane bounded cell projection part (GO:0120038)0.275007047protein-containing complex (GO:0032991)0.275007047regulation of multicellular organismal process (GO:0051239)0.275007047regulation of response to stimulus (GO:0048583)0.275007047response to stress (GO:0006950)0.275007047secretory vesicle (GO:0099503)0.275007047cellular response to endogenous stimulus (GO:0071495)0.286881148intracellular membrane-bounded organelle (GO:0043231)0.286881148neurogenesis (GO:0022008)0.286881148neuron projection (GO:0043005)0.286881148nucleus (GO:0005634)0.286881148organonitrogen compound metabolic process (GO:1901564)0.286881148plasma membrane bounded cell projection (GO:0120025)0.286881148positive regulation of biological process (GO:0048518)0.286881148regulation of nervous system development (GO:0051960)0.286881148regulation of nitrogen compound metabolic process0.286881148(GO:0051171)regulation of primary metabolic process (GO:0080090)0.286881148response to endogenous stimulus (GO:0009719)0.286881148somatodendritic compartment (GO:0036477)0.286881148tube development (GO:0035295)0.286881148vesicle (GO:0031982)0.286881148carboxylic acid metabolic process (GO:0019752)0.298658316cell projection (GO:0042995)0.298658316cellular response to chemical stimulus (GO:0070887)0.298658316circulatory system development (GO:0072359)0.298658316cytoplasm (GO:0005737)0.298658316generation of neurons (GO:0048699)0.298658316head development (GO:0060322)0.298658316Immune System (R-HSA-168256)0.298658316metabolic process (GO:0008152)0.298658316Metabolism (R-HSA-1430728)0.298658316negative regulation of protein metabolic process (GO:0051248)0.298658316positive regulation of transcription by RNA polymerase II0.298658316(GO:0045944)protein binding (GO:0005515)0.298658316protein metabolic process (GO:0019538)0.298658316regulation of anatomical structure morphogenesis (GO:0022603)0.298658316regulation of biological quality (GO:0065008)0.298658316regulation of biosynthetic process (GO:0009889)0.298658316regulation of cellular biosynthetic process (GO:0031326)0.298658316regulation of cellular metabolic process (GO:0031323)0.298658316regulation of developmental process (GO:0050793)0.298658316regulation of macromolecule metabolic process (GO:0060255)0.298658316regulation of metabolic process (GO:0019222)0.298658316regulation of nucleic acid-templated transcription (GO:1903506)0.298658316regulation of response to external stimulus (GO:0032101)0.298658316regulation of RNA biosynthetic process (GO:2001141)0.298658316regulation of secretion (GO:0051046)0.298658316regulation of transcription, DNA-templated (GO:0006355)0.298658316small molecule binding (GO:0036094)0.298658316catalytic activity, acting on a protein (GO:0140096)0.310340121cell death (GO:0008219)0.310340121cytokine-mediated signaling pathway (GO:0019221)0.310340121enzyme linked receptor protein signaling pathway (GO:0007167)0.310340121intracellular non-membrane-bounded organelle (GO:0043232)0.310340121lipid metabolic process (GO:0006629)0.310340121negative regulation of biological process (GO:0048519)0.310340121negative regulation of cellular process (GO:0048523)0.310340121negative regulation of cellular protein metabolic process0.310340121(GO:0032269)negative regulation of response to stimulus (GO:0048585)0.310340121neuron part (GO:0097458)0.310340121nitrogen compound metabolic process (GO:0006807)0.310340121non-membrane-bounded organelle (GO:0043228)0.310340121organic substance metabolic process (GO:0071704)0.310340121positive regulation of cellular process (GO:0048522)0.310340121positive regulation of multicellular organismal process0.310340121(GO:0051240)primary metabolic process (GO:0044238)0.310340121programmed cell death (GO:0012501)0.310340121protein-containing complex subunit organization (GO:0043933)0.310340121regulation of cellular macromolecule biosynthetic process0.310340121(GO:2000112)regulation of cellular protein metabolic process (GO:0032268)0.310340121regulation of defense response (GO:0031347)0.310340121regulation of hydrolase activity (GO:0051336)0.310340121regulation of macromolecule biosynthetic process (GO:0010556)0.310340121regulation of multi-organism process (GO:0043900)0.310340121regulation of protein metabolic process (GO:0051246)0.310340121response to abiotic stimulus (GO:0009628)0.310340121response to organic substance (GO:0010033)0.310340121small molecule metabolic process (GO:0044281)0.310340121anion binding (GO:0043168)0.321928095carbohydrate derivative metabolic process (GO:1901135)0.321928095cellular amide metabolic process (GO:0043603)0.321928095cellular component biogenesis (GO:0044085)0.321928095cellular component organization (GO:0016043)0.321928095cellular component organization or biogenesis (GO:0071840)0.321928095cellular response to organic substance (GO:0071310)0.321928095enzyme regulator activity (GO:0030234)0.321928095leukocyte activation (GO:0045321)0.321928095macromolecule metabolic process (GO:0043170)0.321928095membrane organization (GO:0061024)0.321928095negative regulation of cell communication (GO:0010648)0.321928095negative regulation of signal transduction (GO:0009968)0.321928095negative regulation of signaling (GO:0023057)0.321928095organonitrogen compound biosynthetic process (GO:1901566)0.321928095organonitrogen compound catabolic process (GO:1901565)0.321928095positive regulation of biosynthetic process (GO:0009891)0.321928095positive regulation of cell population proliferation (GO:0008284)0.321928095positive regulation of cellular biosynthetic process (GO:0031328)0.321928095positive regulation of developmental process (GO:0051094)0.321928095positive regulation of nucleic acid-templated transcription0.321928095(GO:1903508)positive regulation of signaling (GO:0023056)0.321928095positive regulation of transcription, DNA-templated0.321928095(GO:0045893)protein-containing complex assembly (GO:0065003)0.321928095regulation of cell development (GO:0060284)0.321928095regulation of cell differentiation (GO:0045595)0.321928095regulation of gene expression (GO:0010468)0.321928095regulation of localization (GO:0032879)0.321928095regulation of molecular function (GO:0065009)0.321928095regulation of RNA metabolic process (GO:0051252)0.321928095regulation of transport (GO:0051049)0.321928095response to oxygen-containing compound (GO:1901700)0.321928095Transport of small molecules (R-HSA-382551)0.321928095tube morphogenesis (GO:0035239)0.321928095carbohydrate derivative binding (GO:0097367)0.333423734cellular component assembly (GO:0022607)0.333423734cellular metabolic process (GO:0044237)0.333423734cytoplasmic part (GO:0044444)0.333423734endoplasmic reticulum (GO:0005783)0.333423734export from cell (GO:0140352)0.333423734immune system development (GO:0002520)0.333423734neuron development (GO:0048666)0.333423734organelle part (GO:0044422)0.333423734organic substance catabolic process (GO:1901575)0.333423734positive regulation of cell communication (GO:0010647)0.333423734positive regulation of cellular metabolic process (GO:0031325)0.333423734positive regulation of gene expression (GO:0010628)0.333423734positive regulation of macromolecule biosynthetic process0.333423734(GO:0010557)positive regulation of metabolic process (GO:0009893)0.333423734positive regulation of nitrogen compound metabolic process0.333423734(GO:0051173)positive regulation of RNA biosynthetic process (GO:1902680)0.333423734postsynapse (GO:0098794)0.333423734regulation of catalytic activity (GO:0050790)0.333423734regulation of cell communication (GO:0010646)0.333423734regulation of neurogenesis (GO:0050767)0.333423734regulation of nucleobase-containing compound metabolic0.333423734process (GO:0019219)regulation of protein modification process (GO:0031399)0.333423734regulation of protein phosphorylation (GO:0001932)0.333423734regulation of signal transduction (GO:0009966)0.333423734regulation of signaling (GO:0023051)0.333423734response to nitrogen compound (GO:1901698)0.333423734response to organonitrogen compound (GO:0010243)0.333423734secretion (GO:0046903)0.333423734small molecule biosynthetic process (GO:0044283)0.333423734vesicle-mediated transport (GO:0016192)0.333423734amide biosynthetic process (GO:0043604)0.344828497catabolic process (GO:0009056)0.344828497cell activation (GO:0001775)0.344828497cellular lipid metabolic process (GO:0044255)0.344828497cellular response to nitrogen compound (GO:1901699)0.344828497cellular response to organic cyclic compound (GO:0071407)0.344828497cellular response to oxygen-containing compound (GO:1901701)0.344828497chromatin organization (GO:0006325)0.344828497chromosome organization (GO:0051276)0.344828497endomembrane system (GO:0012505)0.344828497hematopoietic or lymphoid organ development (GO:0048534)0.344828497intracellular organelle part (GO:0044446)0.344828497mitochondrial envelope (GO:0005740)0.344828497mitochondrial membrane (GO:0031966)0.344828497mitochondrion (GO:0005739)0.344828497negative regulation of macromolecule metabolic process0.344828497(GO:0010605)negative regulation of metabolic process (GO:0009892)0.344828497negative regulation of nitrogen compound metabolic process0.344828497(GO:0051172)nucleoside phosphate binding (GO:1901265)0.344828497nucleotide binding (GO:0000166)0.344828497positive regulation of cellular protein metabolic process0.344828497(GO:0032270)positive regulation of macromolecule metabolic process0.344828497(GO:0010604)positive regulation of nervous system development0.344828497(GO:0051962)positive regulation of nucleobase-containing compound0.344828497metabolic process (GO:0045935)positive regulation of phosphate metabolic process0.344828497(GO:0045937)positive regulation of phosphorus metabolic process0.344828497(GO:0010562)positive regulation of protein modification process (GO:0031401)0.344828497positive regulation of protein phosphorylation (GO:0001934)0.344828497positive regulation of RNA metabolic process (GO:0051254)0.344828497positive regulation of transport (GO:0051050)0.344828497protein homodimerization activity (GO:0042803)0.344828497regulation of apoptotic process (GO:0042981)0.344828497regulation of cell death (GO:0010941)0.344828497regulation of phosphate metabolic process (GO:0019220)0.344828497regulation of phosphorus metabolic process (GO:0051174)0.344828497regulation of programmed cell death (GO:0043067)0.344828497response to lipid (GO:0033993)0.344828497secretion by cell (GO:0032940)0.344828497synapse part (GO:0044456)0.344828497cell morphogenesis involved in differentiation (GO:0000904)0.35614381cellular protein metabolic process (GO:0044267)0.35614381cellular protein modification process (GO:0006464)0.35614381cytoplasmic vesicle membrane (GO:0030659)0.35614381dendrite (GO:0030425)0.35614381dendritic tree (GO:0097447)0.35614381drug binding (GO:0008144)0.35614381endoplasmic reticulum part (GO:0044432)0.35614381envelope (GO:0031975)0.35614381Generic Transcription Pathway (R-HSA-212436)0.35614381identical protein binding (GO:0042802)0.35614381macromolecule modification (GO:0043412)0.35614381microtubule-based process (GO:0007017)0.35614381negative regulation of cellular metabolic process (GO:0031324)0.35614381neuron projection development (GO:0031175)0.35614381organelle envelope (GO:0031967)0.35614381organic cyclic compound biosynthetic process (GO:1901362)0.35614381organic cyclic compound metabolic process (GO:1901360)0.35614381positive regulation of protein metabolic process (GO:0051247)0.35614381positive regulation of signal transduction (GO:0009967)0.35614381protein complex oligomerization (GO:0051259)0.35614381protein modification process (GO:0036211)0.35614381regulation of phosphorylation (GO:0042325)0.35614381regulation of vesicle-mediated transport (GO:0060627)0.35614381vesicle membrane (GO:0012506)0.35614381biosynthetic process (GO:0009058)0.367371066cellular aromatic compound metabolic process (GO:0006725)0.367371066cellular macromolecule metabolic process (GO:0044260)0.367371066cellular nitrogen compound metabolic process (GO:0034641)0.367371066chromatin (GO:0000785)0.367371066cytoplasmic region (GO:0099568)0.367371066exocytosis (GO:0006887)0.367371066macromolecule biosynthetic process (GO:0009059)0.367371066Metabolism of proteins (R-HSA-392499)0.367371066microtubule cytoskeleton (GO:0015630)0.367371066microtubule organizing center (GO:0005815)0.367371066mitochondrial matrix (GO:0005759)0.367371066mitochondrial part (GO:0044429)0.367371066negative regulation of protein modification process0.367371066(GO:0031400)organelle organization (GO:0006996)0.367371066organic substance biosynthetic process (GO:1901576)0.367371066organic substance transport (GO:0071702)0.367371066positive regulation of cell differentiation (GO:0045597)0.367371066positive regulation of establishment of protein localization0.367371066(GO:1904951)positive regulation of phosphorylation (GO:0042327)0.367371066positive regulation of response to external stimulus0.367371066(GO:0032103)Post-translational protein modification (R-HSA-597592)0.367371066presynapse (GO:0098793)0.367371066purine nucleotide binding (GO:0017076)0.367371066purine ribonucleoside triphosphate binding (GO:0035639)0.367371066purine ribonucleotide binding (GO:0032555)0.367371066regulated exocytosis (GO:0045055)0.367371066regulation of innate immune response (GO:0045088)0.367371066regulation of intracellular signal transduction (GO:1902531)0.367371066regulation of protein complex assembly (GO:0043254)0.367371066response to hormone (GO:0009725)0.367371066response to peptide (GO:1901652)0.367371066ribonucleotide binding (GO:0032553)0.367371066RNA Polymerase II Transcription (R-HSA-73857)0.367371066cellular biosynthetic process (GO:0044249)0.378511623cellular catabolic process (GO:0044248)0.378511623cellular nitrogen compound biosynthetic process (GO:0044271)0.378511623cellular response to cytokine stimulus (GO:0071345)0.378511623cytoplasmic vesicle (GO:0031410)0.378511623Golgi apparatus part (GO:0044431)0.378511623hemopoiesis (GO:0030097)0.378511623intracellular vesicle (GO:0097708)0.378511623lipid binding (GO:0008289)0.378511623monocarboxylic acid metabolic process (GO:0032787)0.378511623negative regulation of intracellular signal transduction0.378511623(GO:1902532)organelle membrane (GO:0031090)0.378511623positive regulation of cellular component biogenesis0.378511623(GO:0044089)positive regulation of intracellular signal transduction0.378511623(GO:1902533)aromatic compound biosynthetic process (GO:0019438)0.389566812ATP binding (GO:0005524)0.389566812cell-cell junction (GO:0005911)0.389566812cellular macromolecule biosynthetic process (GO:0034645)0.389566812cellular response to lipid (GO:0071396)0.389566812chromosome (GO:0005694)0.389566812Cytokine Signaling in Immune system (R-HSA-1280215)0.389566812cytoplasmic vesicle part (GO:0044433)0.389566812Gene expression (Transcription)(R-HSA-74160)0.389566812heterocycle biosynthetic process (GO:0018130)0.389566812heterocycle metabolic process (GO:0046483)0.389566812lipid biosynthetic process (GO:0008610)0.389566812macromolecule localization (GO:0033036)0.389566812negative regulation of cell death (GO:0060548)0.389566812negative regulation of nucleic acid-templated transcription0.389566812(GO:1903507)negative regulation of RNA biosynthetic process (GO:1902679)0.389566812negative regulation of transcription by RNA polymerase II0.389566812(GO:0000122)nucleobase-containing small molecule metabolic process0.389566812(GO:0055086)nucleoside phosphate metabolic process (GO:0006753)0.389566812plasma membrane bounded cell projection organization0.389566812(GO:0120036)positive regulation of apoptotic process (GO:0043065)0.389566812positive regulation of molecular function (GO:0044093)0.389566812positive regulation of multi-organism process (GO:0043902)0.389566812positive regulation of protein transport (GO:0051222)0.389566812regulation of cellular component movement (GO:0051270)0.389566812regulation of cellular component organization (GO:0051128)0.389566812regulation of response to stress (GO:0080134)0.389566812ribonucleoprotein complex (GO:1990904)0.389566812synapse (GO:0045202)0.389566812vacuolar part (GO:0044437)0.389566812adenyl nucleotide binding (GO:0030554)0.40053793adenyl ribonucleotide binding (GO:0032559)0.40053793amide transport (GO:0042886)0.40053793cell junction (GO:0030054)0.40053793cell morphogenesis (GO:0000902)0.40053793cell projection organization (GO:0030030)0.40053793cellular component morphogenesis (GO:0032989)0.40053793chromatin binding (GO:0003682)0.40053793chromosomal part (GO:0044427)0.40053793cytoskeleton organization (GO:0007010)0.40053793endoplasmic reticulum membrane (GO:0005789)0.40053793gene expression (GO:0010467)0.40053793negative regulation of apoptotic process (GO:0043066)0.40053793negative regulation of biosynthetic process (GO:0009890)0.40053793negative regulation of programmed cell death (GO:0043069)0.40053793negative regulation of transcription, DNA-templated0.40053793(GO:0045892)nitrogen compound transport (GO:0071705)0.40053793nuclear envelope (GO:0005635)0.40053793nucleic acid metabolic process (GO:0090304)0.40053793nucleobase-containing compound metabolic process0.40053793(GO:0006139)nucleolus (GO:0005730)0.40053793nucleotide metabolic process (GO:0009117)0.40053793organophosphate metabolic process (GO:0019637)0.40053793peptide transport (GO:0015833)0.40053793perinuclear region of cytoplasm (GO:0048471)0.40053793positive regulation of catalytic activity (GO:0043085)0.40053793positive regulation of cell death (GO:0010942)0.40053793positive regulation of cell development (GO:0010720)0.40053793positive regulation of hydrolase activity (GO:0051345)0.40053793positive regulation of neurogenesis (GO:0050769)0.40053793positive regulation of programmed cell death (GO:0043068)0.40053793protein catabolic process (GO:0030163)0.40053793protein-containing complex binding (GO:0044877)0.40053793regulation of cytokine production (GO:0001817)0.40053793regulation of cytoskeleton organization (GO:0051493)0.40053793regulation of locomotion (GO:0040012)0.40053793regulation of neuron differentiation (GO:0045664)0.40053793regulation of peptide transport (GO:0090087)0.40053793response to cytokine (GO:0034097)0.40053793response to inorganic substance (GO:0010035)0.40053793RNA binding (GO:0003723)0.40053793vacuole (GO:0005773)0.40053793Vesicle-mediated transport (R-HSA-5653656)0.40053793apoptotic process (GO:0006915)0.411426246axon part (GO:0033267)0.411426246bounding membrane of organelle (GO:0098588)0.411426246cell cycle process (GO:0022402)0.411426246Cell Cycle, Mitotic (R-HSA-69278)0.411426246centrosome (GO:0005813)0.411426246cytoskeletal protein binding (GO:0008092)0.411426246DNA metabolic process (GO:0006259)0.411426246glutamatergic synapse (GO:0098978)0.411426246Golgi apparatus (GO:0005794)0.411426246intracellular organelle lumen (GO:0070013)0.411426246intrinsic component of organelle membrane (GO:0031300)0.411426246lysosome (GO:0005764)0.411426246lytic vacuole (GO:0000323)0.411426246macromolecule catabolic process (GO:0009057)0.411426246membrane-enclosed lumen (GO:0031974)0.411426246microtubule cytoskeleton organization (GO:0000226)0.411426246negative regulation of cellular biosynthetic process0.411426246(GO:0031327)negative regulation of gene expression (GO:0010629)0.411426246negative regulation of macromolecule biosynthetic process0.411426246(GO:0010558)negative regulation of nucleobase-containing compound0.411426246metabolic process (GO:0045934)negative regulation of organelle organization (GO:0010639)0.411426246negative regulation of phosphate metabolic process0.411426246(GO:0045936)negative regulation of phosphorus metabolic process0.411426246(GO:0010563)negative regulation of RNA metabolic process (GO:0051253)0.411426246neuron projection morphogenesis (GO:0048812)0.411426246nuclear outer membrane-endoplasmic reticulum membrane0.411426246network (GO:0042175)nucleobase-containing compound biosynthetic process0.411426246(GO:0034654)organelle lumen (GO:0043233)0.411426246phosphate-containing compound metabolic process0.411426246(GO:0006796)phosphorus metabolic process (GO:0006793)0.411426246positive regulation of catabolic process (GO:0009896)0.411426246positive regulation of cellular component movement0.411426246(GO:0051272)positive regulation of cytokine production (GO:0001819)0.411426246positive regulation of GTPase activity (GO:0043547)0.411426246protein localization (GO:0008104)0.411426246protein localization to organelle (GO:0033365)0.411426246protein transport (GO:0015031)0.411426246protein ubiquitination (GO:0016567)0.411426246regulation of cell motility (GO:2000145)0.411426246regulation of cellular component biogenesis (GO:0044087)0.411426246regulation of establishment of protein localization (GO:0070201)0.411426246regulation of protein serine/threonine kinase activity0.411426246(GO:0071900)regulation of transferase activity (GO:0051338)0.411426246RNA metabolic process (GO:0016070)0.411426246transferase activity (GO:0016740)0.411426246transmembrane receptor protein tyrosine kinase signaling0.411426246pathway (GO:0007169)axon (GO:0030424)0.422233001cellular macromolecule localization (GO:0070727)0.422233001cellular protein localization (GO:0034613)0.422233001cytosol (GO:0005829)0.422233001Disease (R-HSA-1643685)0.422233001establishment of protein localization (GO:0045184)0.422233001extrinsic component of membrane (GO:0019898)0.422233001negative regulation of cell cycle (GO:0045786)0.422233001negative regulation of cellular component organization0.422233001(GO:0051129)negative regulation of cellular macromolecule biosynthetic0.422233001process (GO:2000113)negative regulation of protein phosphorylation (GO:0001933)0.422233001nuclear chromosome (GO:0000228)0.422233001nuclear chromosome part (GO:0044454)0.422233001plasma membrane bounded cell projection morphogenesis0.422233001(GO:0120039)positive regulation of locomotion (GO:0040017)0.422233001positive regulation of response to biotic stimulus (GO:0002833)0.422233001protein targeting (GO:0006605)0.422233001regulation of actin filament-based process (GO:0032970)0.422233001regulation of GTPase activity (GO:0043087)0.422233001regulation of hemopoiesis (GO:1903706)0.422233001regulation of protein kinase activity (GO:0045859)0.422233001regulation of protein localization (GO:0032880)0.422233001regulation of protein transport (GO:0051223)0.422233001cell cycle (GO:0007049)0.432959407Cell Cycle (R-HSA-1640170)0.432959407cell projection morphogenesis (GO:0048858)0.432959407cell-cell signaling by wnt (GO:0198738)0.432959407cellular localization (GO:0051641)0.432959407cellular protein catabolic process (GO:0044257)0.432959407establishment of localization in cell (GO:0051649)0.432959407glycerolipid metabolic process (GO:0046486)0.432959407Golgi membrane (GO:0000139)0.432959407intracellular protein transport (GO:0006886)0.432959407intracellular signal transduction (GO:0035556)0.432959407Metabolism of lipids (R-HSA-556833)0.432959407nuclear chromatin (GO:0000790)0.432959407nuclear part (GO:0044428)0.432959407phospholipid metabolic process (GO:0006644)0.432959407positive regulation of cell cycle (GO:0045787)0.432959407positive regulation of cell motility (GO:2000147)0.432959407positive regulation of cellular catabolic process (GO:0031331)0.432959407postsynaptic specialization (GO:0099572)0.432959407protein modification by small protein conjugation (GO:0032446)0.432959407protein modification by small protein conjugation or removal0.432959407(GO:0070647)proteolysis involved in cellular protein catabolic process0.432959407(GO:0051603)regulation of cell projection organization (GO:0031344)0.432959407regulation of cellular localization (GO:0060341)0.432959407regulation of kinase activity (GO:0043549)0.432959407regulation of mitotic cell cycle (GO:0007346)0.432959407regulation of neuron projection development (GO:0010975)0.432959407regulation of plasma membrane bounded cell projection0.432959407organization (GO:0120035)RNA processing (GO:0006396)0.432959407Wnt signaling pathway (GO:0016055)0.432959407Axon guidance (R-HSA-422475)0.443606651catalytic complex (GO:1902494)0.443606651cell projection assembly (GO:0030031)0.443606651cellular macromolecule catabolic process (GO:0044265)0.443606651cellular response to hormone stimulus (GO:0032870)0.443606651Cellular responses to external stimuli (R-HSA-8953897)0.443606651Class I MHC mediated antigen processing & presentation (R-0.443606651HSA-983169)covalent chromatin modification (GO:0016569)0.443606651endocytic vesicle (GO:0030139)0.443606651integral component of organelle membrane (GO:0031301)0.443606651intracellular transport (GO:0046907)0.443606651modification-dependent protein catabolic process (GO:0019941)0.443606651negative regulation of phosphorylation (GO:0042326)0.443606651nucleic acid-templated transcription (GO:0097659)0.443606651phosphorylation (GO:0016310)0.443606651plasma membrane bounded cell projection assembly0.443606651(GO:0120031)positive regulation of cellular component organization0.443606651(GO:0051130)positive regulation of innate immune response (GO:0045089)0.443606651protein kinase binding (GO:0019901)0.443606651regulation of cell cycle phase transition (GO:1901987)0.443606651regulation of cell migration (GO:0030334)0.443606651regulation of protein catabolic process (GO:0042176)0.443606651RNA biosynthetic process (GO:0032774)0.443606651transcription, DNA-templated (GO:0006351)0.443606651ubiquitin-dependent protein catabolic process (GO:0006511)0.443606651whole membrane (GO:0098805)0.443606651actin cytoskeleton (GO:0015629)0.454175893actin filament-based process (GO:0030029)0.454175893enzyme activator activity (GO:0008047)0.454175893enzyme binding (GO:0019899)0.454175893interspecies interaction between organisms (GO:0044419)0.454175893kinase binding (GO:0019900)0.454175893late endosome (GO:0005770)0.454175893modification-dependent macromolecule catabolic process0.454175893(GO:0043632)negative regulation of catabolic process (GO:0009895)0.454175893nuclear lumen (GO:0031981)0.454175893organophosphate biosynthetic process (GO:0090407)0.454175893positive regulation of neuron differentiation (GO:0045666)0.454175893positive regulation of transferase activity (GO:0051347)0.454175893protein localization to membrane (GO:0072657)0.454175893regulation of apoptotic signaling pathway (GO:2001233)0.454175893regulation of cell adhesion (GO:0030155)0.454175893regulation of cell cycle (GO:0051726)0.454175893regulation of DNA-binding transcription factor activity0.454175893(GO:0051090)regulation of small GTPase mediated signal transduction0.454175893(GO:0051056)regulation of T cell activation (GO:0050863)0.454175893Signaling by Interleukins (R-HSA-449147)0.454175893transcription by RNA polymerase II (GO:0006366)0.454175893transcription coregulator activity (GO:0003712)0.454175893transferase activity, transferring phosphorus-containing groups0.454175893(GO:0016772)activation of protein kinase activity (GO:0032147)0.464668267Antigen processing: Ubiquitination & Proteasome degradation0.464668267(R-HSA-983168)cell cortex (GO:0005938)0.464668267cell part morphogenesis (GO:0032990)0.464668267Cellular responses to stress (R-HSA-2262752)0.464668267Metabolism of RNA (R-HSA-8953854)0.464668267neuron to neuron synapse (GO:0098984)0.464668267nuclear membrane (GO:0031965)0.464668267peptidyl-amino acid modification (GO:0018193)0.464668267posttranscriptional regulation of gene expression (GO:0010608)0.464668267protein phosphorylation (GO:0006468)0.464668267regulation of cell morphogenesis (GO:0022604)0.464668267regulation of cell-cell adhesion (GO:0022407)0.464668267regulation of leukocyte cell-cell adhesion (GO:1903037)0.464668267regulation of mitotic cell cycle phase transition (GO:1901990)0.464668267ubiguitin-protein transferase activity (GO:0004842)0.464668267vacuolar membrane (GO:0005774)0.464668267vesicle organization (GO:0016050)0.464668267actin cytoskeleton organization (GO:0030036)0.475084883cell division (GO:0051301)0.475084883cellular response to external stimulus (GO:0071496)0.475084883early endosome (GO:0005769)0.475084883endosome (GO:0005768)0.475084883glycerophospholipid metabolic process (GO:0006650)0.475084883histone modification (GO:0016570)0.475084883lytic vacuole membrane (GO:0098852)0.475084883negative regulation of cell cycle process (GO:0010948)0.475084883phosphotransferase activity, alcohol group as acceptor0.475084883(GO:0016773)positive regulation of cell migration (GO:0030335)0.475084883positive regulation of cell projection organization (GO:0031346)0.475084883positive regulation of protein kinase activity (GO:0045860)0.475084883positive regulation of proteolysis (GO:0045862)0.475084883protein kinase activity (GO:0004672)0.475084883regulation of catabolic process (GO:0009894)0.475084883regulation of cell cycle process (GO:0010564)0.475084883regulation of cellular response to stress (GO:0080135)0.475084883regulation of DNA metabolic process (GO:0051052)0.475084883regulation of intracellular transport (GO:0032386)0.475084883regulation of organelle organization (GO:0033043)0.475084883regulation of transporter activity (GO:0032409)0.475084883response to oxidative stress (GO:0006979)0.475084883supramolecular fiber organization (GO:0097435)0.475084883asymmetric synapse (GO:0032279)0.485426827cellular response to DNA damage stimulus (GO:0006974)0.485426827cellular response to stress (GO:0033554)0.485426827DNA repair (GO:0006281)0.485426827Golgi vesicle transport (GO:0048193)0.485426827kinase activity (GO:0016301)0.485426827lysosomal membrane (GO:0005765)0.485426827MAPK cascade (GO:0000165)0.485426827membrane region (GO:0098589)0.485426827mitotic cell cycle process (GO:1903047)0.485426827mRNA metabolic process (GO:0016071)0.485426827nucleoside-triphosphatase regulator activity (GO:0060589)0.485426827positive regulation of cell adhesion (GO:0045785)0.485426827positive regulation of DNA-binding transcription factor activity0.485426827(GO:0051091)positive regulation of neuron projection development0.485426827(GO:0010976)positive regulation of protein serine/threonine kinase activity0.485426827(GO:0071902)postsynaptic density (GO:0014069)0.485426827regulation of translation (GO:0006417)0.485426827regulation of transmembrane transporter activity (GO:0022898)0.485426827RNA splicing (GO:0008380)0.485426827transcription factor binding (GO:0008134)0.485426827ubiquitin-like protein transferase activity (GO:0019787)0.485426827autophagy (GO:0006914)0.495695163endosomal part (GO:0044440)0.495695163Golgi subcompartment (GO:0098791)0.495695163membrane raft (GO:0045121)0.495695163mitotic cell cycle (GO:0000278)0.495695163mRNA processing (GO:0006397)0.495695163negative regulation of cellular catabolic process (GO:0031330)0.495695163nucleoplasm (GO:0005654)0.495695163positive regulation of kinase activity (GO:0033674)0.495695163process utilizing autophagic mechanism (GO:0061919)0.495695163proteasome-mediated ubiquitin-dependent protein catabolic0.495695163process (GO:0043161)regulation of cellular catabolic process (GO:0031329)0.495695163RNA splicing, via transesterification reactions (GO:0000375)0.495695163signal transduction by protein phosphorylation (GO:0023014)0.495695163actin binding (GO:0003779)0.50589093coenzyme metabolic process (GO:0006732)0.50589093DNA Repair (R-HSA-73894)0.50589093establishment of organelle localization (GO:0051656)0.50589093membrane microdomain (GO:0098857)0.50589093mRNA splicing, via spliceosome (GO:0000398)0.50589093organelle outer membrane (GO:0031968)0.50589093organelle subcompartment (GO:0031984)0.50589093outer membrane (GO:0019867)0.50589093peptidyl-lysine modification (GO:0018205)0.50589093proteasomal protein catabolic process (GO:0010498)0.50589093regulation of cellular amide metabolic process (GO:0034248)0.50589093RNA splicing, via transesterification reactions with bulged0.50589093adenosine as nucleophile (GO:0000377)Signaling by Receptor Tyrosine Kinases (R-HSA-9006934)0.50589093spindle (GO:0005819)0.50589093trans-Golgi network (GO:0005802)0.50589093transcription coactivator activity (GO:0003713)0.50589093Transcriptional Regulation by TP53 (R-HSA-3700989)0.50589093cell adhesion molecule binding (GO:0050839)0.516015147Diseases of signal transduction (R-HSA-5663202)0.516015147positive regulation of cell-cell adhesion (GO:0022409)0.516015147positive regulation of organelle organization (GO:0010638)0.516015147protein polyubiquitination (GO:0000209)0.516015147protein serine/threonine kinase activity (GO:0004674)0.516015147symbiotic process (GO:0044403)0.516015147transferase complex (GO:1990234)0.516015147ubiquitin ligase complex (GO:0000151)0.516015147biological phase (GO:0044848)0.526068812cell cycle phase (GO:0022403)0.526068812endosome membrane (GO:0010008)0.526068812GTPase binding (GO:0051020)0.526068812Membrane Trafficking (R-HSA-199991)0.526068812mitotic cell cycle phase (GO:0098763)0.526068812organelle localization (GO:0051640)0.526068812phospholipid biosynthetic process (GO:0008654)0.526068812positive regulation of cellular protein localization (GO:1903829)0.526068812regulation of cellular protein localization (GO:1903827)0.526068812regulation of gene expression, epigenetic (GO:0040029)0.526068812viral process (GO:0016032)0.526068812DNA-binding transcription factor binding (GO:0140297)0.5360529glycerophospholipid biosynthetic process (GO:0046474)0.5360529mRNA binding (GO:0003729)0.5360529RNA polymerase II-specific DNA-binding transcription factor0.5360529binding (GO:0061629)Intracellular signaling by second messengers (R-HSA-9006925)0.545968369mitochondrial outer membrane (GO:0005741)0.545968369Neddylation (R-HSA-8951664)0.545968369Platelet activation, signaling and aggregation (R-HSA-76002)0.545968369positive regulation of leukocyte cell-cell adhesion (GO:1903039)0.545968369regulation of autophagy (GO:0010506)0.545968369anchoring junction (GO:0070161)0.555816155chromosomal region (GO:0098687)0.555816155endomembrane system organization (GO:0010256)0.555816155glycerolipid biosynthetic process (GO:0045017)0.555816155protein localization to cell periphery (GO:1990778)0.555816155Ras GTPase binding (GO:0017016)0.555816155actin filament organization (GO:0007015)0.565597176cadherin binding (GO:0045296)0.565597176cellular response to oxidative stress (GO:0034599)0.565597176cellular response to steroid hormone stimulus (GO:0071383)0.565597176molecular adaptor activity (GO:0060090)0.565597176nuclear speck (GO:0016607)0.565597176peptidyl-serine modification (GO:0018209)0.565597176Ras protein signal transduction (GO:0007265)0.565597176regulation of axonogenesis (GO:0050770)0.565597176regulation of cell morphogenesis involved in differentiation0.565597176(GO:0010769)regulation of intracellular protein transport (GO:0033157)0.565597176small GTPase binding (GO:0031267)0.565597176cell-substrate adhesion (GO:0031589)0.575312331DNA replication (GO:0006260)0.575312331double-strand break repair (GO:0006302)0.575312331nucleoplasm part (GO:0044451)0.575312331Processing of Capped Intron-Containing Pre-mRNA (R-HSA-0.57531233172203)protein binding, bridging (GO:0030674)0.575312331regulation of leukocyte migration (GO:0002685)0.575312331small GTPase mediated signal transduction (GO:0007264)0.575312331viral life cycle (GO:0019058)0.575312331regulation of chromosome organization (GO:0033044)0.584962501adherens junction (GO:0005912)0.59454855mitotic cell cycle phase transition (GO:0044772)0.59454855nuclear body (GO:0016604)0.59454855positive regulation of I-kappaB kinase/NF-kappaB signaling0.59454855(GO:0043123)growth cone (GO:0030426)0.604071324protein localization to plasma membrane (GO:0072659)0.604071324protein stabilization (GO:0050821)0.604071324regulation of cell cycle G1/S phase transition (GO:1902806)0.604071324regulation of cytokine-mediated signaling pathway (GO:0001959)0.604071324regulation of mRNA catabolic process (GO:0061013)0.604071324regulation of mRNA metabolic process (GO:1903311)0.604071324regulation of mRNA stability (GO:0043488)0.604071324response to reactive oxygen species (GO:0000302)0.604071324site of polarized growth (GO:0030427)0.604071324ubiquitin-like protein ligase binding (GO:0044389)0.604071324cell cycle phase transition (GO:0044770)0.613531653membrane docking (GO:0022406)0.613531653organelle localization by membrane tethering (GO:0140056)0.613531653protein domain specific binding (GO:0019904)0.613531653regulation of I-kappaB kinase/NF-kappaB signaling0.613531653(GO:0043122)regulation of protein stability (GO:0031647)0.613531653regulation of response to cytokine stimulus (GO:0060759)0.613531653cell-substrate adherens junction (GO:0005924)0.632268215cell-substrate junction (GO:0030055)0.632268215focal adhesion (GO:0005925)0.632268215interaction with host (GO:0051701)0.632268215peptidyl-serine phosphorylation (GO:0018105)0.632268215protein C-terminus binding (GO:0008022)0.632268215regulation of G1/S transition of mitotic cell cycle (GO:2000045)0.632268215ubiquitin protein ligase binding (GO:0031625)0.632268215SUMO E3 ligases SUMOylate target proteins (R-HSA-3108232)0.641546029regulation of mRNA processing (GO:0050684)0.650764559cell leading edge (GO:0031252)0.659924558SUMOylation (R-HSA-2990846)0.659924558regulation of RNA splicing (GO:0043484)0.669026766G2/M transition of mitotic cell cycle (GO:0000086)0.678071905cell cycle G2/M phase transition (GO:0044839)0.687060688nuclear hormone receptor binding (GO:0035257)0.687060688stress-activated protein kinase signaling cascade (GO:0031098)0.695993813Golgi organization (GO:0007030)0.704871964positive regulation of chromosome organization (GO:2001252)0.704871964Clathrin-mediated endocytosis (R-HSA-8856828)0.722466024Death Receptor Signalling (R-HSA-73887)0.722466024intracellular receptor signaling pathway (GO:0030522)0.722466024steroid hormone mediated signaling pathway (GO:0043401)0.722466024chromosome, telomeric region (GO:0000781)0.731183242positive regulation of cell morphogenesis involved in0.731183242differentiation (GO:0010770)actin filament (GO:0005884)0.739848103lamellipodium (GO:0030027)0.757023247ruffle (GO:0001726)0.782408565Signaling by VEGF (R-HSA-194138)0.790772038cellular response to leukemia inhibitory factor (GO:1990830)0.799087306nuclear chromosome, telomeric region (GO:0000784)0.799087306PML body (GO:0016605)0.799087306response to leukemia inhibitory factor (GO:1990823)0.799087306regulation of telomere maintenance (GO:0032204)0.815575429VEGFA-VEGFR2 Pathway (R-HSA-4420097)0.815575429SH3 domain binding (GO:0017124)0.82374936regulation of cell junction assembly (GO:1901888)0.831877241cis-Golgi network (GO:0005801)0.86393845

TABLE 4Direction and Tissue of Change for Genes with SignificantAlternative Splicing and Alternative Transcription Start/EndAlternative TranscriptionAlternative SplicingGeneHLMLHBMBHLMLHBMBAACS0.062————0.058—0.426AAMDC—−0.149—0.070———0.369ABCB6—0.327—−0.412———0.353ABCB8−0.007——0.584———−0.751ABCC1———−0.561———0.464ABCC2—0.340——−0.318———ABCG1———0.094—0.041——ABHD11—−0.528—————0.647ABI20.000——0.127———0.226ABL1———0.172———−0.305ABR——−0.0040.299———0.073ABTB1———0.386———0.039ACAD10—−0.402—0.399———0.599ACADSB———0.161———0.134ACADVL—−0.284—————−0.258ACAP2—−0.440—−0.322—0.162——ACBD5—0.178—−0.530———0.591ACE−0.1900.002—0.254—0.009——ACIN1—0.244—0.070———0.174ACOT7—−0.0710.0450.030—0.024——ACOX3———−0.808———−0.284ACSS1——0.025−0.783———0.291ACTB——−0.007−0.209—0.013——ACTN4———0.236———0.092ACTR10———0.116———0.279ACTR1A—0.039—−0.015———0.072ADAL—−0.399———0.178——ADAM17—−0.192−0.0050.135———0.240ADAM33—0.131—−0.621—−0.595——ADAM8———0.333———−0.153ADAMTS10—0.029—0.733—0.142——ADARB1—−0.312———0.297——ADCY6—0.022—−0.287———0.243ADD1—0.001—−0.219—0.151——ADD3———0.038———−0.146ADGRE5—0.002—0.020———0.111ADK—0.193—−0.888—0.029——ADRM1—0.108—0.390———0.293AFDN———−0.277—0.044——AFF4———−0.340———0.163AGBL2——0.535——−0.237——AGER—0.005——0.0030.016——AGL———−0.655—0.454——AGPAT3———0.098———−0.492AGTPBP1—0.129—0.446———0.470AHCTF1——−0.0220.416———0.522AHCYL1—0.039—0.117———0.435AHCYL2−0.005−0.124—0.305—0.063—0.255AHNAK—−0.325—0.294—−0.350—0.059AHSA1—0.184—0.348———0.067AIFM1——0.191————0.701AKAP2−0.001————0.010——AKAP8——0.3600.021———0.255AKAP8L—−0.041—−0.301—0.112——AKTIP—−0.4570.005——0.065——ALAS1—0.162—0.209———0.216ALDH18A1—0.247—0.563———−0.556ALDH3A2———−0.186—0.129——ALDH3B1——0.003——0.057——ALKBH6—0.417—————0.496AMN1—−0.235—−0.584———0.505AMPD3−0.013——0.192—−0.063——ANAPC16—−0.189—0.151———0.337ANK2−0.009−0.336———0.352——ANK30.0120.115—−0.048—0.0800.2030.477ANKIB1−0.024————0.118——ANKRD1—0.200———−0.031——ANKRD12—−0.235—−0.301———0.271ANKRD54—0.402—————0.572ANKZF1—−0.5090.0170.553———0.763ANO10—0.418—0.539—0.070——ANTXR1—0.259———0.043——ANTXR2———0.097—0.018——ANXA7—0.041———0.062——AP1M1———0.427———0.241AP3D1—−0.140—0.082———0.272AP3M1———0.119———−0.256AP4E1—−0.297—————−0.454APEH—−0.096—−0.275———−0.222APEX2—0.184—0.083———0.845APOBEC1—0.189—————0.283APOBEC3H———0.142———0.211APPL2——−0.009————−0.792AQR—−0.084—————0.344ARAF—−0.092—−0.526———−0.698ARAP10.017——0.133—0.126——ARAP2———−0.199——−0.446—ARFGAP1—0.223—0.054———0.249ARHGAP21———0.303—0.056——ARHGAP25———0.017—0.176—−0.185ARHGAP4———−0.057—0.158—0.091ARHGEF2—0.029—0.051———0.325ARHGEF40—0.315———0.197——ARID1A−0.002−0.098—0.224———0.447ARID5A—0.215—0.024———0.582ARL11—−0.320—0.877———0.293ARL3—0.110—0.181———0.053ARMC10—0.053—0.251———0.216ARMCX3−0.022————0.260——ARPC1B—−0.166—————0.028ARRB1—0.001—0.001—0.078—0.068ARRDC1—−0.385—————0.103ARRDC2—−0.3210.1670.433———0.797ARRDC3—0.0850.0100.265———0.347AS3MT—0.323—−0.367———0.121ASB1———0.372———0.034ASB3———−0.764—−0.150——ASH2L—0.177—−0.552———0.279ATAD2B———0.855———0.350ATAT1—0.327———0.160——ATG16L1—0.6810.0180.034———0.702ATG2B—0.262—0.610———0.295ATG4D—−0.240—————−0.332ATG7———0.019———0.282ATL3—−0.399—0.282———0.327ATP11A——0.047————−0.197ATP11B—0.325—0.417———0.067ATP13A3——0.014————0.606ATP1B2—0.128———0.114——ATP2C1—−0.275−0.1250.047—0.116—0.017ATP5F1E—−0.276—0.396———−0.126ATP5MPL−0.004—−0.0280.010———0.133ATP5PB—0.229—————0.062ATP6AP1———0.085———0.080ATP6V1B2———−0.299———0.174ATP8A1—−0.284———0.054——ATRAID—0.652—0.324———0.410ATRIP—−0.237−0.079−0.272———0.815ATRX0.093——0.035—−0.028——ATXN2L—−0.582—————−0.163AUH—0.453—0.539———0.226AUP1—0.089—0.752———0.119AZIN1———0.235—0.185——B3GALNT2—−0.274—0.236—0.352——BAD−0.033−0.167−0.056−0.203———0.225BAZ2A0.007——————−0.246BCAR3—−0.345—−0.237—−0.054——BCL2L1—0.008—0.031———0.117BCL9———−0.126—−0.375——BECN1−0.0120.323—0.024—0.089—0.019BET1L———−0.130———0.265BGN—0.054———0.034——BICD2—0.022—0.005———0.133BICDL1—0.351—0.270—−0.244—0.439BIN1—0.136—0.030———0.081BIN3—−0.123———−0.067——BIRC6———0.250———0.466BLMH———0.705———0.472BMPR1B——−0.186——−0.772——BMS1—0.270—————0.555BNIP3L——−0.293——0.064—0.345BRAT1—0.172———−0.309——BRCC3———0.360———−0.334BRD2———0.016———0.131BRD90.0090.148—0.330———0.480BSCL2———0.455—0.150——BSG—−0.016—0.098———−0.029BTBD19———−0.111———−0.814BTBD9—0.016—−0.327—0.085——BTC—0.597———0.277——BTF3—0.272—0.017—0.017——BTLA—−0.047—−0.242———−0.339BTRC——0.449−0.370—0.065—0.296C11orf1—−0.225—0.290———0.073C12orf29—−0.107———−0.176——C12orf57—0.499—0.176—0.121—0.108C16orf70———0.392———0.419C18orf21———0.164———−0.230C19orf38—0.645———−0.135—0.074C1orf122———0.452—0.365——C1orf43—0.007—0.262———−0.153C1orf610.592—0.217———−0.347—C1S—0.065——−0.6490.084——C20orf194—0.360—−0.279—0.045——C2CD2—0.030—−0.161—0.192——C3orf18−0.013—0.114———−0.345—C6orf89—0.387—−0.470———0.097C8orf34—0.119———0.600——C8orf82—−0.191—−0.402———−0.289C9orf85———0.026———0.502CACNA1D—0.039—−0.538—0.207——CACNA1E−0.269——————0.568CACNA2D1———−0.322—0.211——CADM1−0.0100.020—−0.460—0.035——CALD1———0.032—0.257—0.094CALML4—0.323—0.392———0.584CAMK1—0.038———0.319——CAMKK2—0.115—0.052———0.311CAMTA1—−0.096—0.098—−0.688——CARM1—−0.012—0.585—0.282——CARMIL20.406——————0.687CARS2———0.400———0.484CASC3———0.033———−0.648CASC4−0.0890.008—−0.385—0.028——CASP2−0.005−0.0700.0040.073———0.432CAV1−0.0040.045—−0.209—0.034——CBX7—−0.038—0.014———0.457CC2D1B—0.453—————0.719CCAR2——−0.009————0.652CCDC107—0.030———0.103——CCDC114—0.281————0.369—CCDC12———0.185———0.043CCDC25—0.051−0.136————0.240CCDC33—−0.426———−0.686——CCDC85A—0.106—0.243—−0.205——CCDC88B——−0.069————−0.484CCDC88C—−0.325———0.254——CCDC9—0.096—−0.730———0.350CCDC97———0.083———0.276CCNC——−0.0480.141———0.493CCND3—−0.446—−0.011—−0.114—−0.060CCNG2−0.0020.109—0.017———0.240CCNT2——0.039−0.347———0.169CCT50.021—−0.547————0.139CD164−0.0010.028—0.034———0.044CD200R1—0.403—−0.513———0.714CD200R1L—0.403—−0.513———0.714CD209———0.064———0.786CD22—−0.366—0.403———0.098CD226———0.069———0.029CD27—0.252—−0.397———−0.622CD2AP—0.145—−0.276———0.461CD320—−0.535—−0.431———0.731CD36—0.005—−0.623−0.301———CD44——−0.0010.030———−0.038CD47—0.194—0.001—0.056—0.121CD52———0.074———0.041CD55−0.1210.060——0.007———CD59——0.0080.382———0.044CD8A———−0.141———0.837CDC25B———−0.267———0.252CDC34———0.304———0.118CDC42BPA———0.420—0.029—0.244CDCA80.152——————0.315CDH13−0.016————0.068——CDIPT—−0.035—0.060—0.115——CDK10−0.009————0.330——CDK14—0.109———0.018——CDK2—0.271—0.279———0.196CDKN1A—−0.069—−0.348—−0.202——CDKN2D———0.028———−0.067CEACAM10.019—−0.0440.077———0.370CEACAM3———0.077———0.370CEACAM5———0.077———0.370CEACAM6———0.077———0.370CEACAM7———0.077———0.370CEACAM8———0.077———0.370CENPC—0.346—0.246—0.264—0.468CENPT———0.792———−0.601CEP57———0.052———−0.673CEP83———−0.421———0.190CEP95———0.766———0.757CEPT10.067—0.257————−0.147CFAP20—−0.075—————0.570CFP——−0.0100.285———−0.286CGRRF1—0.279—0.274———0.763CHCHD1———0.334—0.081—0.260CHCHD2———0.195———0.028CHCHD70.008—−0.016−0.417———0.083CHD8—−0.047—−0.047———0.708CHD9———0.508———0.211CHID1—−0.452—————0.510CHMP6—0.249—0.131———0.341CHP1—−0.125—−0.028———0.108CHPT1—0.175———0.025—−0.659CHTF8———0.167———−0.139CIC—0.196—————0.076CINP—−0.153—0.023———0.472CIR10.0320.2980.033————−0.466CIRBP——0.066−0.311———−0.252CITED2———−0.319———0.356CKAP5—−0.652—0.443———0.131CKB−0.0440.016−0.058——0.092——CLCN3—−0.262—0.277———0.212CLCN7———0.937———0.769CLEC2D——0.011——0.587——CLEC4C0.720−0.111—−0.455—0.257——CLIP1−0.001——0.640———0.527CLK3——−0.0110.310———−0.323CLK4—−0.161—0.031———0.423CLTA——−0.0070.112—0.016—0.028CMC2—0.057—0.479———0.452CMTM7—−0.418—0.375———0.208CMTR1—0.283—0.286—0.107—−0.165CNKSR2−0.027————−0.609——CNN3—0.030—0.322———0.422CNOT10.011—0.0480.229———0.316CNOT10—0.029—0.210———0.367CNP0.001−0.3320.006————0.099CNPY3—0.134—0.600—0.060——COBL—0.111———0.073——COCH−0.359—−0.362———0.244—COLEC12—−0.124—−0.083—0.028——COMMD3——−0.054−0.330———0.568COMMD4———0.443———0.290COMMD6———−0.334———0.502COPS6———0.188———0.195COPS9——−0.067————0.127COPZ10.017—0.026−0.219———0.103COQ4———0.166—0.354——COX4I1—0.161———0.031——COX6B1———0.008———0.005COX6B2—0.027—————0.155COX7A1——−0.269————0.334COX7A2L———0.002———0.012CPEB3—−0.062———0.572——CPED1—−0.2220.562——0.034——CPQ—0.024—−0.797—0.060——CPSF3—0.165—0.120———0.420CPSF7−0.007—0.007−0.323—−0.089——CR1———0.388———0.387CRCP———0.105———0.266CREB1—−0.267—————0.051CRK—−0.055—0.285—0.205——CROCC—0.617—−0.856—−0.462——CRTC2—−0.208—0.579———−0.579CSDE1−0.016−0.218−0.0050.069—−0.014——CSNK1G2———0.066———0.244CSPP1—−0.104—−0.151———0.688CTAGE1—0.104—————0.236CTAGE15—0.104—————0.236CTAGE4—0.104—————0.236CTAGE6—0.104—————0.236CTAGE8—0.104—————0.236CTAGE9—0.104—————0.236CTNNB1——−0.261—0.015———CTNND1———0.261———0.381CTSF———−0.072—0.179——CUL9—0.263———0.319——CUTA———0.605—0.155—0.489CUX1———0.043———0.143CWF19L1———−0.846———−0.652CYB5A—0.047—0.015———0.006CYBC1—−0.052−0.0100.191———0.287CYFIP1——0.006————0.436CYLD—0.157—−0.538—−0.036—0.294CYP17A1−0.195—−0.1920.801——−0.120—CYP27A1———−0.842———0.703CYP3A5−0.036—−0.549———0.216—CYP4B10.047————−0.029——CYP4F8—0.279—−0.751—−0.4270.780DAAM1—−0.426———0.166—0.433DAB2—0.126———−0.052——DAG1−0.0010.019———0.017——DAZAP2−0.004—0.0000.001———0.011DBF4−0.0230.4540.0390.171———0.567DBI——−0.0070.202———0.082DCAF11———0.079———0.213DCAF8—0.026—−0.026———0.065DCN———0.678——−0.089—DDX27—−0.269—−0.198———0.557DDX47—0.346−0.120————0.291DDX49—0.232—————−0.214DDX54———0.446———−0.219DDX58—0.282—0.380———0.314DECR2—0.727—0.453—0.354—0.517DEF8—−0.949———0.133——DENND6A—−0.070—0.154———0.334DENND6B—−0.089—0.586———0.678DERA———0.490———0.128DERPC———0.167———−0.139DGAT1———−0.310———−0.244DGUOK—−0.879———0.253—0.320DHDDS−0.0020.468—0.195—0.137——DHODH———−0.232———0.384DHX33−0.003——−0.204———0.516DHX36—0.307—−0.275———0.633DIABLO—−0.1380.685————−0.343DIAPH3—−0.383—−0.112———0.216DIDO1—−0.102—−0.199———−0.163DIXDC1−0.0110.628———0.097——DLG1———0.158———0.434DLG2—−0.175—————0.061DLGAP4———0.009———0.113DMKN——−0.333——0.212——DMTN—0.449—0.631—0.283——DNAH8—0.102—0.180———0.801DNAJB14—0.404—−0.394———0.471DNAJC11———−0.537—0.262——DNAJC28—0.070—0.4220.284———DNAJC5———0.238———−0.199DNAJC8———−0.345———0.082DNASE1L1—0.414—0.057———0.449DNM1L−0.0010.1070.007−0.085—0.145—0.147DNMBP—0.349—————0.468DNMT3A−0.676——−0.380———0.239DOCK4—0.221———0.027——DOCK7—0.296—−0.057———0.753DOCK8——−0.018−0.470———−0.323DOCK9———−0.532—−0.187—0.533DOK1—−0.658———0.390—0.184DOLPP1—0.277—−0.163———0.263DOP1A—0.327—————−0.606DPH2—0.334−0.0360.596———0.478DPH5—−0.095—————0.637DPP8———0.219———0.356DSE——−0.008—0.276———DST———0.580———0.416DTNA0.356−0.050———0.148——DUSP16—0.812———0.340——DUSP22−0.032——————−0.333DYNC1I2−0.0520.233—0.324———0.057DYNC1LI2—0.288—0.461—0.088——DYRK4——−0.056———−0.149—E2F6—0.132—————0.728EBPL———0.733—0.294—0.620ECD—0.128—————0.794ECHS1—−0.147—————0.220ECI1—−0.256—−0.554—0.048——ECT2———0.273—0.353——EDEM3——0.0260.268—0.135——EEA1—−0.162—−0.382———0.361EEF1D−0.014—−0.007————0.040EEF1G−0.041——————0.061EFEMP2—−0.252———0.193——EGFL7—0.002——−0.015———EGFLAM—0.345−0.256——0.066——EHBP1L1—0.440—0.290———0.278EHMT2—0.193—————0.204EI24−0.0120.219—————−0.209EIF3A———0.377———0.211EIF4A2−0.002−0.104—0.098—0.134—0.085EIF4B−0.001——————0.262EIF4G1——−0.015————0.131EIF4G3———0.304—0.027——ELOB———0.048—0.056——ELOC———0.119———0.222ELOF1—−0.267—0.153———0.233ELP3—0.327—0.324———0.413EMC1———−0.352———−0.184EMILIN2—−0.009—0.439—−0.077——EML1—0.088———0.065——EML2—0.314—0.770———0.420EMSY———0.179—0.261——ENTPD40.004——−0.122———0.557ENTR1———0.026———0.299ENY2—0.011—−0.156———−0.251EP300−0.008——0.250———0.199EP400—0.414—0.598———0.697EPB410.0100.0360.0210.038—−0.073——EPB41L2———0.067—0.091——EPN1———0.307———−0.209EPRS———0.653———0.286ERCC2———0.165———0.414ERG—0.165—−0.075——0.507—ERGIC1———0.008———0.132ERLIN2−0.107——————−0.302ESD———0.033—0.246——ESPL1—−0.404———0.260——ESPN0.240——−0.778—−0.336——ESR2−0.4300.370−0.2720.2470.459———ESYT1−0.013—−0.030——0.151—0.198ESYT2———0.904———0.399ETV3—−0.310—−0.160———0.470ETV5———−0.936—0.030——EXD2———0.398———0.161EXOC6B—0.090—−0.190———0.803EXOC70.009————−0.083—0.510EXOSC10—0.141—————0.446EXOSC5———−0.223———−0.256EXOSC8—0.738—−0.438———0.542EXOSC9———0.208———0.514EYA1—0.491—−0.393———0.725EZH1—−0.072−0.004————0.307FADS2———0.243—0.073——FAIM———0.499—0.092——FAIM2—−0.399———0.215——FAM126A—0.308—−0.395———0.032FAM133B———0.253———0.431FAM13B—0.149—0.028—0.058—0.045FAM149B1—0.055—−0.153———0.459FAM156A—0.456—0.1400.369——−0.388FAM156B—0.456—0.140———−0.388FAM172A−0.002——0.083—0.148——FAM173A—0.604—−0.270———−0.193FAM189B—0.045—————0.487FAM192A—0.260———0.073—−0.208FAM204A———0.043———−0.261FAM214B−0.325−0.082—————0.277FAM227A—−0.224———0.596——FAM45A—−0.119—————0.177FAM47E-−0.054————−0.400——STBD1FAM53B—0.006—0.112———0.049FAM86B1——−0.227————−0.356FAM86C1−0.202—0.086————−0.356FAM91A10.009——————0.307FAS−0.0010.4550.012————0.464FASTK———0.075———0.285FAU—−0.159—0.116———0.025FBLIM1−0.001————0.089——FBXL2—−0.016—————0.026FBXL4—−0.057—————0.753FBXO240.365—−0.707—0.597———FBXW100.3160.469——0.621———FBXW2—0.034—0.271———0.055FBXW7—0.177—————0.721FCGR2A—−0.004—0.125—−0.274——FCGR2B—−0.004—0.125—−0.274——FCGR2C—−0.004—0.125—−0.274——FCHSD2−0.0010.075—−0.322———0.077FCRL1—−0.554—0.062———0.299FDX1—0.391———0.078——FECH—−0.106—−0.007———0.025FERMT3———0.010—−0.029—0.006FEZ2—0.1990.0390.184———0.518FGF11—0.350——0.399———FGFR1OP2—0.028—————0.483FGGY——−0.258——−0.131——FHL1—0.018—0.003—0.336—0.004FKBP11——−0.052——0.233——FKBP4———0.472———0.228FKBP5—−0.293—0.611—−0.104——FLNA—−0.3580.0070.339———−0.009FMC1-LUC7L2—0.003—0.111—0.091——FMO1—−0.278———0.093——FN1—−0.134—0.342———−0.212FNBP1———−0.498———0.137FOXO3——0.0010.087—0.104——FOXP4—0.246—0.343—−0.227——FOXRED1—0.232—————0.303FSIP1—−0.296———0.373——FTL———0.218—0.027——FUT8——−0.4570.099———0.362FUZ—0.091—————−0.391FXYD1−0.0410.051———0.092——FYB1−0.004−0.017—0.013———0.033FYTTD1—−0.215—−0.284—0.043——G3BP2−0.006——0.242———0.391GAB1———0.314—−0.087——GABBR1—0.675—−0.287—0.123——GABPB2—0.149—————0.385GANC—−0.195—0.085———0.512GAPVD10.003——————0.211GATD1—−0.340—−0.140———0.225GBF1—0.158—0.245———0.742GBP6—0.041—0.342—0.611——GCC2—0.476—0.320———0.185GCNT1—0.036—0.121———0.084GDA—0.011—−0.202—−0.056—−0.150GDI1—0.135—−0.358—0.068——GDI2———0.036———0.026GDPD20.332————−0.108——GEN1—0.290—−0.435———0.743GGA2———−0.284———0.277GGCT———0.367———0.627GGPS1—0.051———0.065——GGT5—0.278—−0.425—0.474−0.2270.650GHR−0.044——−0.437—0.037——GIGYF2—0.071—−0.518———0.406GJA1—−0.176−0.0590.243—0.042——GK—−0.106—0.368—0.127—0.072GK3P—−0.106—0.368—0.127—0.072GLG1———0.199—0.087——GLO1—0.048—−0.105———−0.064GLOD4−0.003——−0.333—0.056——GLT8D1—0.393−0.238————0.618GLYR1———−0.233—0.190——GMFB———0.009———0.384GMPR2−0.017——0.091———0.197GNAS—−0.462—0.273———−0.088GNB4——−0.018——0.114——GNG5—−0.059—————0.122GNPDA2———0.072———0.270GOLGA1—0.063—0.521———0.469GOLGA2———−0.554———0.280GOLGA3—0.200—————0.229GOLGA4—−0.171—−0.297———0.622GOLGA6A———−0.554———0.280GOLGA6B———−0.554———0.280GOLGA6C———−0.554———0.280GOLGA6D———−0.554———0.280GOLGA7———0.120———0.320GOLGA8A−0.004——−0.554———0.280GOLGA8B———−0.554———0.280GOLGA8F———−0.554———0.280GOLGA8G——−0.110−0.554———0.280GOLGA8H———−0.554———0.280GOLGA8J———−0.554———0.280GOLGA8K———−0.554———0.280GOLGA8M———−0.554———0.280GOLGA8N———−0.554———0.280GOLGA8O———−0.554———0.280GOLGA8Q———−0.554———0.280GOLGA8R———−0.554———0.280GOLGA8S———−0.554———0.280GOLGA8T———−0.554———0.280GOLPH3———0.022———0.234GOPC———0.332—−0.153——GORAB———0.313—−0.351——GPATCH2———0.117———−0.115GPATCH2L———−0.213———0.365GPHN0.029−0.496———0.081——GPR35—0.154—−0.185—−0.352—−0.593GPRASP1—0.310—−0.283—0.545——GPS1−0.0470.502—−0.596———0.668GPT—0.187−0.254————0.588GPX2—−0.487————−0.062—GRAMD2B———0.125———0.397GRAMD4—0.687—−0.569———0.725GRAP2—−0.154—0.191—−0.112——GRB10−0.002————0.044——GRK2—0.110—0.205———0.091GRK3—0.001—0.199———0.485GRPEL2———0.321———0.665GRSF1———−0.277———0.363GSK3B−0.005——————0.064GSTP1—−0.129—−0.274———0.173GSTZ1——−0.027−0.578———0.782GTF2A2———−0.304———0.365GTF2I—0.003—0.642—0.031—0.730GTPBP4———−0.609———0.519GYG1—−0.458—0.229—0.023——H2AFZ———0.117———0.133HAAO———0.548———0.502HADH−0.009—0.054————0.528HADHA−0.003—−0.0080.086—0.035—0.214HAUS4—0.652———0.197—0.483HBA2——0.000———0.002—HDAC1———0.185———0.286HDAC10—−0.537—0.851———0.631HDAC7—−0.005—−0.182—0.077——HDAC8−0.013—0.134——0.196——HDDC2——0.162−0.662—0.557——HEATR6—0.219—−0.843———0.708HEATR9——0.404—0.366———HERC4—0.192—0.275—−0.185——HES6—0.386—−0.767—0.135—−0.849HGFAC—−0.588———0.568——HIC1——−0.0220.351—−0.176——HINT1———−0.245———0.075HIPK1———0.031—−0.017—0.050HIVEP2———0.343—−0.328—0.840HIVEP3—0.125—−0.103—0.513——HK3———0.698———0.330HLA-DMA—0.035—0.087—0.103—0.154HLA-DMB—−0.258—0.453———0.093HLA-DOB0.2020.464—0.486———0.261HLA-DQB1—−0.017—0.413—0.046——HLA-DQB2—−0.017—0.413—0.046——HMBOX1−0.0360.280—————−0.631HMBS−0.014−0.2930.0260.602———0.310HMGA1—−0.350−0.0020.080—−0.046——HMGN2−0.002——0.034———0.311HMGN3———−0.405———0.539HMGN4———0.034———0.311HNRNPA2B1—−0.0120.0430.036—−0.506——HNRNPK———0.006———0.033HNRNPL———0.033———0.051HNRNPR−0.0020.094—0.411———−0.164HOMEZ———0.286———−0.446HOOK3———−0.149———0.177HPS3—−0.096—−0.555———0.223HPS5—0.039—−0.319———0.652HRAS———0.338—0.103——HSBP1—0.003−0.058——0.010—0.015HSF1—0.011—−0.210———−0.280HSP90AA1———0.059———0.039HSP90B1———0.103———0.404HSPB1—−0.081—−0.271—−0.035——HYOU1—−0.017—————0.333IDH3A———0.216———−0.206IFI16—0.287—−0.531———0.685IFRD1—−0.330—0.414———0.194IFT46—−0.088—0.261———−0.363IGF2BP2—0.044—0.558—−0.157——IL12A———−0.416———0.476IL15———0.484———0.638IL16—−0.526—0.188—0.337——IL17RA———0.096———0.382IL1R1———−0.830—−0.554——IL27RA———0.318———0.196IL33—−0.225———0.071——IL4R—−0.042−0.003——−0.022——ILF3—0.243—−0.577———0.747ILK—0.158—0.231———0.037ILVBL—0.390—0.831———0.352IMMT—−0.450—0.322———0.338IMPA1−0.015——−0.112—0.122—−0.134IMPDH1———−0.583—0.031——ING4—−0.056—0.297———0.247INPP5D—0.060—0.165———0.066INPP5E—−0.053—0.249—0.238——INPP5F—0.169−0.254————0.787INSR———−0.267———0.661INTS100.070————−0.237—0.441INTS2—−0.390—————0.597INVS———0.644—0.068——IP6K2—0.294—−0.249———0.356IPMK———0.283———0.666IQCC—0.817—————0.347IRAK10.0830.329—0.307—0.299——IRF2———0.081—0.022—0.090IRF7—0.054−0.007−0.845———−0.139IRF9—−0.418—0.327—0.308—0.426ISG20———0.024———0.019ITCH—−0.160—0.075———0.277ITFG2—−0.081—————0.552ITGA1—0.006———0.017——ITGA40.068——————0.042ITGA6−0.003−0.069———0.105—0.008ITGA8—0.041—−0.877—0.025——ITGB1−0.002——0.221—0.024—0.008ITGB1BP1—0.117—————0.177ITGB3BP—−0.531—————−0.625ITGB5—0.616—−0.234—0.072—0.029ITK—−0.429———0.380——ITPR2—−0.264—0.047—0.037—0.083ITSN1—0.317−0.292−0.087—0.185—0.438JAG2—−0.296———0.283——JARID2—0.170—−0.471———0.033JKAMP———−0.251———0.765JMJD6—−0.103—−0.612———0.397JMJD8——−0.028——0.389——KANSL1−0.0010.274—0.420———0.320KAT5———−0.487———0.345KAT6B0.0020.111−0.3000.644———0.591KCNAB20.356−0.111−0.2700.111———−0.168KCNN4—0.367—————0.366KCNQ1—0.064———0.238——KCNQ5—−0.184————−0.371—KCNT1—−0.075———−0.257——KCTD2−0.001————0.448——KDM2A—0.113−0.005−0.555———0.091KDM2B———0.244—0.269——KDM3B—−0.167—0.397———0.094KEAP1—0.076—0.288———0.402KHNYN−0.001—0.009−0.279—0.145——KIAA00400.010—0.0040.606—0.134——KIAA05130.012————0.041——KIAA1109—0.826—0.334———0.731KIAA1211—−0.314—0.104———0.176KIF24———−0.682—0.165——KLC2——0.0580.628—0.263——KLHDC10———−0.291———0.565KLHDC2—−0.765−0.264———0.312KLHL12—0.108−0.0610.329———−0.229KLHL13—−0.246———0.146——KLHL20—−0.238—————0.288KLHL5—−0.263—0.036—0.083—0.503KLRB1———0.348—−0.462——KLRC1———0.294———0.464KLRC2———0.294———0.464KLRC3———0.294———0.464KLRC4———0.294———0.464KLRC4-KLRK1———0.294———0.464KMT5A———0.148———−0.659KNDC1—0.244———−0.098——KPNA3——−0.018————0.641KPTN—0.291—−0.382—−0.260——KRI1—0.118−0.030————−0.344KRIT1−0.014—−0.1920.788———0.269KTN1———0.459———0.518L3MBTL3—0.315—−0.796—0.250—0.787LAPTM5———0.010———0.010LARP4—−0.003—−0.260———0.371LAS1L−0.016−0.202—————0.246LAT2———0.100———−0.330LCORL—0.150—0.390———0.275LDB1———−0.540———−0.197LDHA0.032——0.324———0.121LENG8———0.297———0.325LETMD1———−0.330———0.580LGI3—0.029———0.066——LHFPL6———0.7320.207———LIFR—−0.158———0.034——LIMD1———0.280———0.458LIMS1−0.002−0.449———0.015—0.032LIMS2—−0.510———0.037——LIMS3—−0.449———0.015—0.032LIMS4—−0.449———0.015—0.032LIPA—−0.143——0.723———LIPE———0.857—−0.133——LMAN1—0.287—0.635—0.073—0.666LMBRD1——−0.009——−0.126——LMF1———0.340—0.174——LMF2—−0.080—0.589———−0.282LMNA—0.064—0.065—0.227——LMO2—−0.068—0.009—0.046——LMO7—0.025———−0.371——LPCAT1—0.068—0.019—0.014——LPIN2—−0.241—0.007———0.132LRBA—0.3270.166————0.604LRCH1———0.207———0.364LRIG2—0.115—0.309———0.271LRP6———0.129———0.677LRRFIP1—−0.105−0.0150.535—0.032——LRRK1—−0.180—0.759———0.390LRWD1———0.326———0.261LSM3—0.387—0.013———0.300LSP10.5830.323—0.128———0.059LTB———−0.235—0.408—0.035LTBP1—0.023−0.305−0.064—0.088—−0.172LUC7L2—0.003—0.111—0.091——LY6G6C—0.465—0.052———0.036LY9—0.619—0.203———0.404LZTR1−0.0010.052—0.035—0.066——MACO1———0.772———0.202MADD———0.026—0.087—0.264MALT1—−0.323—−0.368—−0.150—−0.227MAN1A1———0.322—0.104—0.068MAP2K2—0.085———0.118—−0.421MAP3K12—−0.042−0.0020.190—0.323——MAP3K4—0.020—−0.461———0.508MAP4K2—0.076—0.048—−0.103—0.191MAP4K4———−0.568———−0.499MAP7D1———−0.624———−0.414MAPK1—0.029—0.045———0.021MAPK100.012————−0.267——MAPK11—−0.476———0.262—0.472MAPK14—0.081—−0.090—0.018—0.183MAPK1IP1L—−0.169—−0.306—−0.340——MAPK8IP3—−0.103—0.039———0.545MAPKAPK3—0.750−0.0030.260———−0.354MARCH7———0.022———−0.393MARK2——−0.0030.020———0.518MARS—−0.506—−0.224———0.716MATR3—−0.074—−0.076———0.167MAU2—−0.1840.001−0.202———−0.139MBNL1———0.027—−0.136—0.037MBNL2−0.0020.0630.0820.064—0.189—0.036MBTD1—0.007—0.367———0.584MCF2L—0.005———0.053—0.139MCM2−0.714——————0.593MCM3−0.013−0.2040.014————0.467MCM9—−0.429—0.364———0.297MCRS1—0.747—0.617———0.222MDM1—−0.170—0.045———0.121MDM40.0050.022—0.005—0.033——MECOM0.0060.014—0.532—0.461——MED20—0.313—0.350———0.328MEF2A−0.003——0.290———−0.256MEF2C—−0.118—−0.113—0.063—0.083MEIS10.0140.162—−0.852———0.431MEST—0.422—−0.263———0.249METRNL—−0.269—————−0.165METTL14—0.157———0.211—0.613METTL16—0.061—————0.604METTL22—0.508—————0.591METTL23−0.012−0.353—−0.225———0.473METTL25—−0.402———0.517——METTL3—−0.032—0.089———0.812METTL4———0.529———−0.464METTL7A—0.003−0.0290.273—0.004——MFF−0.127——0.010———0.071MFGE8—0.031−0.029——0.007—0.481MFSD2B———0.248———0.011MGAT1—−0.1090.000−0.302———0.249MGLL—0.004−0.014−0.115—0.031——MIA2—0.104−0.009————0.236MICU2−0.0260.065—0.177———0.039MIER1———0.007—0.049——MIF———0.049———0.062MILR1—−0.032—0.358—−0.351—−0.272MINDY1———0.408———0.168MINDY3—0.082—0.323———0.108MIS18A—−0.557—−0.574———0.347MLH1−0.013−0.387−0.038−0.797———−0.556MME———−0.715—0.277——MMS19—0.166—0.288———0.826MOB1B−0.0010.123—−0.522———0.253MOB4−0.017——————0.209MON1A−0.4710.479—−0.264———0.193MPC1———0.492———0.202MPP6—0.443—−0.308———0.316MPP70.0200.049———0.117——MRAS0.0070.007—0.433——0.331—MRGBP—−0.114—−0.557———0.194MROH1−0.025——————−0.350MRPL28———0.275———0.155MRPL52−0.021——————0.348MRPS18C—0.564—————0.242MRPS24———−0.150—0.247——MRPS5———−0.457———0.451MS4A4A—0.358—−0.270———0.111MS4A4E—0.358—−0.270———0.111MSH3—−0.551—−0.769———−0.356MSL1—−0.026−0.002−0.114———0.338MSLN—0.312−0.384——0.052——MSMO1—0.443—0.623———0.415MSTO1——−0.093————0.751MT2A—−0.196———−0.070——MTCH1—−0.058—————0.270MTCH2———−0.161———0.244MTCL1—−0.108———0.049——MTDH———0.006———0.059MTF2−0.0090.032−0.0090.021———0.510MTHFS—−0.114—0.147—0.127——MTMR3———−0.323———−0.345MTREX———0.348———0.297MTSS1—0.0020.0270.023—0.142—0.770MTSS2—0.031—0.210—0.103——MTUS10.700——0.446—−0.099——MUS81—0.299—−0.544———0.460MX1—0.194—0.285—0.248——MXD3———0.172———−0.736MXI1———0.025—0.173——MYBBP1A———0.232———0.538MYCBP20.080—0.143————−0.394MYEF2−0.020−0.178−0.3290.610———0.565MYH10——−0.068——0.030——MYH7—0.698———0.368——MYH9—0.088—————−0.006MYL12A———0.314—0.080——MYL12B———0.188—0.005—0.022MYLK−0.001—−0.3510.010—0.016—−0.626MYO1C−0.001——————0.197MYOF—−0.137—0.286———0.553NAA15———0.463———0.630NAA16———0.475———0.706NAA40−0.003−0.442—−0.085———−0.375NAA60——−0.0020.384———0.282NADK2———0.053———0.164NCALD—0.173—0.282—0.355——NCAPD3—−0.296—−0.358———0.461NCK2—0.269———0.074——NCKAP1L—−0.222—0.025———0.287NCOA4——0.000————0.063NCOA7———0.171———0.498NCOR2−0.0030.407—0.039———−0.736NDFIP2—−0.168—0.003———0.114NDRG1———0.087———0.192NDRG2−0.011——−0.309—0.0760.094—NDUFA11———−0.421———0.046NDUFA4———0.036———0.041NDUFAF2—0.521—0.400———0.705NDUFS1———0.325———0.469NDUFS4———0.332———0.024NDUFS6———0.415———0.141NDUFS7——0.181————0.197NEDD4L—−0.199−0.0340.220—0.058——NEK1—0.384—0.466—−0.210——NEK4—0.197—−0.295—0.212——NEMF—0.118−0.0330.354———0.400NEURL1—0.649—————0.269NFATC3−0.279——0.328———0.109NFE2L1−0.003−0.043—−0.446—0.026——NFE2L2——−0.003——0.415——NFKB2———−0.440———0.659NFU1———0.817———0.337NFX1———0.324———0.206NFYB—0.184—0.322———0.241NGLY1——−0.024————0.261NIPSNAP2——−0.039————0.111NISCH—0.054—0.377—0.052—0.778NKTR—−0.337—————−0.205NME2———0.389——0.030—NMNAT3—0.476−0.2870.464———−0.645NMT2———0.368———0.204NOL4L—−0.227———−0.363——NOL7—−0.299—−0.770———0.099NOL8—0.072—−0.085—0.188——NOL9—0.256—————0.469NOLC1—0.026—————0.416NOP56———0.322———0.361NOX4—0.022———0.030——NPNT—0.000—−0.096—0.066——NPTN———0.031———0.011NR3C1−0.0160.207—0.555———0.179NRBP1—0.070—0.023———0.072NRF1—−0.319—0.477—0.134——NSG1———−0.301—0.230——NSMCE2—0.119—————−0.306NSUN2———0.203———0.599NSUN4———−0.377———0.281NTMT1—0.341—−0.299———−0.232NUBP2—0.039———0.288——NUCB2——−0.132————0.231NUDCD1—0.057—−0.050———−0.554NUDT13—−0.057—−0.213———0.657NUDT16———0.180———0.671NUP88—0.078—−0.311———0.551NUP98—−0.068—0.301———−0.124NXPE2———0.393———−0.607ODC1−0.405——————0.026OGDH———0.467———0.125OGFOD2—−0.474—————−0.606OLFML3——−0.385——0.172——ORC3——−0.081————0.479OSBPL6———0.413—0.088——OSGEPL1—0.5460.599————0.827OTUD5—−0.207—————0.077OXNAD1———0.248———0.584P2RY14—−0.676—————0.728P4HA1—0.170—0.274—−0.456——P4HTM—0.409———0.326——PACS1———0.432—0.178—0.345PACSIN2———0.151———0.020PAIP2—−0.003−0.5240.012———0.008PAN2—0.239—————0.284PAPOLA—0.0740.023————0.244PAQR7—0.107—−0.582—0.181——PAQR8—0.026—−0.551—0.078——PARD6A—0.462—0.037———−0.340PARN——−0.035————0.764PARP10−0.007——————0.547PARP6—−0.049—−0.866———0.476PARP9——−0.035————0.509PAXX—−0.127—————0.474PBDC1——−0.062−0.125—0.348—−0.354PCBP2———0.010———0.053PCED1A—−0.069—0.372———0.352PCMT1—−0.567—0.006—0.064—0.011PCNT———0.599———0.587PCOLCE—0.055———0.180——PCSK7—0.298—————−0.259PCYT2———−0.417———0.842PDE1B——0.542——−0.536——PDGFA———0.330———0.083PDGFRA———−0.626—−0.012——PDLIM5—0.084———0.181——PDLIM7———0.308—−0.156—0.044PDPR0.004—−0.008————−0.607PDRG1———−0.306———−0.118PDZD2—0.002———0.060——PDZK1IP1—0.237—0.327———0.016PEX2—0.139—−0.254———0.618PFKFB2—0.052———−0.117——PFKFB30.004−0.036———−0.020——PFN1—0.125—−0.111———−0.067PGAP20.0050.160−0.0220.192———0.621PGGT1B—0.120—0.007———−0.205PHF21A———−0.539—0.133——PHF7—−0.249−0.345−0.197—−0.375——PHIP—0.129—0.571———0.590PHKB—0.211—0.302—0.070——PI16—0.299—0.271—0.213——PI4K2A—0.145—————0.586PIEZO2—−0.149———0.099——PIGC—0.099—0.135———0.502PIGH—−0.167−0.020————−0.240PIGN−0.266−0.206−0.0530.228———0.034PIK3CD—−0.184−0.001−0.560—−0.213——PIK3CG———0.316———0.139PIK3R4—0.105—0.319—0.127——PIKFYVE—−0.070—————0.738PIM1—−0.145—−0.018———−0.112PJA1———−0.398—0.240——PKIG—−0.013—0.102———−0.402PKN2—−0.263−0.046−0.204———0.143PKN3—−0.279—0.275—0.374——PLA2G12A0.031−0.061—0.287———0.028PLA2G4F0.024−0.285———0.269——PLA2G7—−0.086—−0.035—−0.137—−0.061PLCB2−0.043——————−0.204PLCB4—−0.113—0.785—0.252——PLCE1———0.542—0.071——PLEKHA1——−0.0260.125———−0.561PLEKHA6—−0.060—−0.295—0.444——PLEKHG5—0.540———0.224——PLK4—−0.4730.422————0.749PLP2———0.518———0.242PLPBP—−0.049—−0.183———0.279PLS3—−0.037———0.094——PLSCR1—−0.366—0.403———−0.195PLTP—0.064−0.008————−0.400PLXNC1−0.004—−0.002————−0.191PM20D1−0.780—−0.294———0.568—PML—0.370———0.122——PMM1—−0.495—0.061———0.464PNN———−0.675———−0.295PNPLA6—−0.390———0.178——PNPLA8———0.101———0.026POC1A—−0.729———−0.292——PODN—0.356———0.270——POFUT2—−0.681—0.307———0.453POLR2I−0.059−0.552—−0.170———0.200POLR3H—0.608—−0.241———0.753PON2−0.003——0.384———0.200POPDC3——−0.457—−0.171———POSTN—0.002−0.205——0.035——PPAT—−0.190————0.6490.606PPFIBP1—−0.396—————0.744PPHLN1—0.074—−0.370———0.673PPIP5K1—−0.517—————0.581PPP1CA———0.003—0.009——PPP1CC—−0.077—0.179———0.196PPP1R18—0.063—0.221———0.122PPP2R1A———0.326———0.095PPP2R2D—−0.369—————0.571PPP6R2—0.119−0.0070.438—−0.296——PQBP1———−0.199—0.121—0.115PQLC1—0.486—0.326———−0.304PQLC3—0.071—————−0.117PRC1—−0.290—————0.737PRDM6—−0.441———0.076——PRDX2—0.659———0.059——PRDX5———0.016———0.010PRDX6—0.193—0.041———0.041PRICKLE2—0.095———0.053——PRKCD———0.009———0.041PRKDC−0.019——————−0.618PRKG1—−0.119−0.4170.168—0.063——PRMT2—0.450—0.069—0.065——PRMT9———−0.522———0.735PRPF19———0.320———0.357PRPS2———−0.372—0.187——PRPSAP2−0.005−0.323−0.016——−0.528——PRR14——−0.036−0.820———0.544PRRG2—−0.235—————0.203PSAT1—−0.663—0.347———−0.295PSD3−0.0080.069—−0.517—0.059—0.092PSG1———0.077———0.370PSG11———0.077———0.370PSG2———0.077———0.370PSG3———0.077———0.370PSG4———0.077———0.370PSG5———0.077———0.370PSG6———0.077———0.370PSG7———0.077———0.370PSG8———0.077———0.370PSG9———0.077———0.370PSMB9—0.017—−0.300———0.294PSMD110.020—−0.029————0.398PSMD13—−0.114—0.278—0.133—0.070PSMD5———0.175———0.675PSME1———−0.135———0.037PSMG3—−0.638—−0.805———0.515PTGR2—0.050———0.074——PTK2—0.157—−0.262—−0.085—0.130PTK2B———0.373———0.204PTP4A3—−0.308—0.320—0.150——PTPN6—−0.438—0.054———0.066PTPRA—−0.140—−0.369———0.099PTPRC—0.155—0.172———0.109PTPRG—−0.347—−0.560—0.074——PTPRK—−0.1080.566——0.087——PTPRM—0.003———0.018——PTPRS—0.009—0.456—0.040—0.830PUM2−0.002−0.0290.0100.004———0.093PXYLP1—0.474—0.293—0.248——PYHIN1—0.287—−0.531———0.685PYROXD1−0.0150.275−0.053————0.617QARS−0.0180.131—————0.271R3HDM1—0.426—−0.531—−0.166—0.292R3HDM4———0.017———0.014RAB11B—0.338—————0.057RAB2B—−0.308—————0.638RAB44—−0.641—————−0.754RAB7A—0.150—0.374—0.016——RABEP1—−0.121—————0.552RABGGTA———0.406———0.675RAC1−0.002—−0.0050.008———0.004RACK1——0.0080.026———0.012RAD1—0.353—————0.383RAD17—0.065—−0.161——−0.2850.487RAD18—0.254−0.536−0.102—−0.230——RAD51——0.1330.436———0.802RALBP1—−0.077—0.236—0.031——RALGAPA2—−0.595—————0.304RALGAPB−0.007——————0.595RALGPS1—0.229—−0.117—−0.541——RALGPS2—−0.129—−0.052———0.364RAMAC—−0.286—−0.266———0.029RAMACL—−0.286—−0.266———0.029RAMP1———0.252———0.109RAMP2—0.024———0.242——RANBP3—0.907—————0.548RANGAP1———0.145—0.368—0.237RAPGEF2———−0.323—0.055—0.718RARRES2—0.043———0.108——RASA4—−0.5680.029————0.218RASA4B0.055−0.568—————0.218RASAL3—0.144—−0.208———0.450RASGRP3—−0.092—−0.370———0.145RB1CC1−0.169——−0.387—0.086——RBL2—0.078—−0.384———−0.184RBM25———0.109—0.448——RBM3—−0.648—−0.603—−0.142——RBM5———0.060———0.186RBM6—0.211———0.199——RBM7———0.506—0.421—0.193RBMS20.0110.1820.039————0.613RBX1—0.089—————0.273RCBTB2—0.300—−0.210———0.560RCC2——−0.004————0.130RCOR3—−0.235−0.005−0.815———0.568RDX——0.799−0.432—0.040——RELB—0.036—————0.337RELCH—0.026—0.415———0.746RETREG10.189——0.158—−0.054——RETREG2—−0.062—0.346———0.329REX1BD—0.302—————0.238REXO1—0.120—————−0.394REXO5—0.435−0.535——−0.433—0.659RFC1—−0.191—0.029———0.255RFFL—−0.367—0.475———0.517RFX3———0.014—0.173—0.593RFX5—0.263—0.600———0.596RFX7—−0.300—0.854———−0.418RGS1—−0.749—−0.072———−0.449RGS12—0.003—0.759——0.189—RHOJ——−0.2110.271———0.046RHOT1−0.0030.134—−0.378———0.355RHOT2——0.049−0.335———0.742RIC8A—0.129−0.0070.033———0.228RIDA—0.635—0.058———0.025RIF1—0.012—−0.285———0.826RIN2−0.030————−0.118——RIOK1—0.212—0.048———0.394RMC1−0.095——————−0.310RMI1—−0.071—0.328———−0.362RNF103—0.185—0.311———−0.305RNF123−0.0170.435—————−0.408RNF13—−0.064—————0.119RNF138———−0.192———0.092RNF14—0.026—0.282———0.063RNF141———−0.552—0.019——RNF167−0.003−0.008—0.050———0.509RNF181———0.005—0.128—0.126RNF38−0.001——0.138—0.200——RNF4—0.311—−0.273———0.103RNF44—0.062—0.050———−0.056RNF5—0.520—————0.166ROCK2−0.008——0.157—0.027—0.069RPA1———0.461—0.154——RPIA—0.277—————0.516RPL10A—−0.156—0.138—0.052——RPL11———0.016———0.046RPL22L1—−0.086—−0.516———0.053RPL23———0.010———0.138RPL28−0.003—−0.011−0.103−0.030—−0.028—RPL30——−0.004−0.317———0.069RPL35A−0.060——0.017———0.059RPL37A——−0.005−0.244———0.032RPL8———0.055———0.053RPP30—0.141———0.225——RPP40———0.284———0.357RPRD1B———0.438—0.149——RPS13—0.107—0.090———0.030RPS23—0.206—0.076———0.184RPS24———0.003———0.004RPS27L—−0.071—0.344———0.047RPS6———0.011———0.038RPS6KB1—0.1460.039——−0.109—−0.139RRAGC−0.009——0.324———−0.087RREB1−0.008——0.194———0.169RRP36———0.261———0.619RRP8———0.297———0.431RSAD2—0.154—0.092—−0.087—−0.035RSBN1—0.029———−0.159——RSRC2—0.108—−0.240—0.052——RTKN2—0.009———−0.7750.387—RTN30.012−0.033———0.030——RUFY3—−0.192—−0.676———0.760RUSC2−0.006−0.340———0.127——RYBP—0.072—————0.431S100A1—−0.398—0.018———0.009SAA1—−0.116———−0.129——SAA2—−0.116———−0.129——SAAL1—−0.621—————0.634SAFB2———−0.669———−0.339SAMHD1−0.006—0.0160.008—0.128—0.269SAP18———0.094———0.178SARS———0.271———0.250SART1———0.298———0.280SART3—0.325—————−0.212SAXO2—−0.613−0.259——0.249——SBF1—−0.212—−0.267———0.243SCAF11—0.046———0.0360.132SCAMP1—0.656—0.253———0.052SCART1—0.724———0.591——SCD———−0.126—0.011——SDCBP———0.022———0.006SDHAF2—−0.016—0.017———0.081SEC11C—−0.436—0.190———0.097SEC31A———−0.588—0.371——SEC61G—−0.178—−0.118—0.310—−0.063SELENOM—0.074—−0.072—0.150——SELENOP—0.003—0.051—0.017—0.055SEMA6D—0.089—0.056———0.799SENP1−0.069−0.249−0.0980.145—0.248——SENP2—0.005—−0.298———0.417SENP5——0.014——0.326——SENP7—−0.477—0.025———−0.138SEPT4—0.016———0.131——SERF2———0.007———0.010SERHL2—0.042−0.086−0.111———−0.284SERPINB6——0.0040.0670.107———SERPINF2———0.369——0.775—SERPINH1—−0.039—0.553—0.419——SETD4———−0.405—−0.436——SF3B3−0.250——−0.177—0.156—0.465SFI1——−0.011−0.071———0.716SFSWAP—0.489—0.293—−0.132——SFTPA2———−0.4890.025———SFXN5−0.403—−0.003——0.166——SGCE—0.2260.6050.177—0.074——SGK1———0.037———0.333SGK3—−0.301—0.199———0.215SGMS1—0.198—0.039—0.055——SH3KBP1—−0.113—−0.041—0.050——SH3PXD2A0.000—0.036−0.077———−0.674SHANK3—−0.551———0.030——SHARPIN———0.419———0.238SHISA5—−0.009—0.048———0.163SHKBP1———0.633———0.235SHLD2———0.743—0.198——SHROOM3—−0.010———0.099——SHTN1—0.242—————0.852SIKE1———−0.413———0.231SIL1—0.177—0.113—0.113——SIPA1L1−0.0260.038—0.292—0.115——SIRT7—0.250—0.351———0.192SIVA1———0.567———0.288SKIV2L−0.1550.378—0.619———0.175SKP2—−0.123—0.809—−0.659——SLBP—−0.032—0.188———0.164SLC12A6—−0.068—−0.290———0.577SLC12A7—−0.181—0.190———0.470SLC16A6——−0.013——−0.427——SLC17A5—0.330—0.583———−0.314SLC18A2———0.008———0.145SLC1A5−0.0110.019———−0.024—0.062SLC20A2−0.003−0.089—0.024———0.189SLC25A1—0.317—————0.682SLC25A11—−0.119———0.084——SLC25A17—0.114—0.029———0.094SLC25A39———0.052———0.052SLC25A40—0.489—0.309———0.753SLC35A5—−0.124—————0.596SLC35B2——−0.034————0.307SLC35B3—−0.090—0.034———−0.140SLC37A1—0.034—−0.326—0.057——SLC38A2——−0.0020.203———0.173SLC39A2−0.285————−0.388——SLC43A1—−0.089———−0.272——SLC44A2———−0.062———0.210SLC4A70.002—−0.4430.245———−0.107SLC50A1−0.037−0.444—————0.368SLC7A6OS—−0.299—0.811———0.337SLC7A7—0.3120.122——−0.453——SLC9A70.0080.7620.0270.086——−0.404—SLCO2B1———−0.100——−0.145—SLIT2—0.010—−0.845—0.038——SLX4—0.324———0.365——SMARCA2−0.002—−0.030——0.036——SMC4−0.008——0.050———0.240SMC6—0.379—————0.263SMCHD1—0.507—−0.263—0.179—0.421SMCO4——−0.0150.829—0.442——SMIM1—−0.017———0.316—0.141SMIM15—−0.132—0.235———0.091SNAP23−0.037—−0.0080.171—0.023—0.006SNAP47——0.473——0.209——SNRK——0.0050.210———0.791SNRNP27—0.360—————0.235SNRNP40——0.026——−0.054——SNRPC—−0.298—0.602———0.224SNX13———0.356———0.373SNX32—−0.512—−0.299—0.334——SOAT1———0.260———0.392SORBS1—0.089—————0.497SORBS2—−0.116—−0.423—−0.072——SORT1—0.185—0.287———0.100SP1100.020—0.018−0.737———0.637SP140—−0.106—−0.198—0.122—0.206SPAG1—−0.179—−0.554———0.709SPAG9———0.300———0.417SPATA5—0.422—0.280———0.752SPATS2L−0.002————0.139——SPC24———0.331———0.039SPCS1—0.076—0.006———0.043SPECC1L——−0.010——0.023——SPIN3−0.018—————0.280—SPINT10.0020.055———−0.112——SPINT2—0.012−0.0070.575———0.486SPIRE1———−0.085———0.399SPON2—0.148———0.152——SPPL2B———0.325———0.587SRCAP—0.160—————0.628SREBF1—0.259—————0.212SRGAP2———−0.406———0.731SRGAP2B———−0.406———0.731SRGAP2C———−0.406———0.731SRP14—−0.065—0.482———0.033SRPK1———−0.846———−0.317SRPRB0.019−0.080—0.349———0.440SRPX2—0.376———−0.490——SSBP3−0.0030.063—0.016———0.068SSBP4—−0.534—0.684———0.105SSH20.0010.028—0.123———0.078SSH3—0.294—————0.718SSR1—−0.814—————0.046SSR3———0.002———0.131ST20-MTHFS—−0.114—0.147—0.127——ST3GAL1——0.0260.040———0.016ST3GAL5−0.015—0.009————−0.523ST7—0.165—−0.169———0.185STARD3———0.592———−0.332STARD3NL—−0.321—0.325———0.218STAU1—0.197—0.015———0.375STBD1———0.225—0.169——STK16—0.279—−0.465———0.511STK26−0.005−0.0570.0180.018———0.101STK38———0.070———0.348STN1—0.635—0.289—0.207——STRADA—0.066—−0.242———−0.381STRADB—0.263—0.286———0.085STRN4———0.032———0.063STX7———0.073—0.177——STYX—−0.016—0.603———0.651SUCO0.003————0.464—0.765SUDS3———−0.169———0.080SUGT1———0.330—0.034—0.318SUN2———0.143———−0.149SUPT4H1−0.021————0.122——SURF2———0.299———0.325SUV39H1———0.675———0.331SWT1—−0.398—0.152———0.285SYNM—−0.031—−0.588—0.050——SYT70.014−0.308—−0.082—−0.267——SYTL1—0.778———0.605——SYTL3—0.222—0.357———0.643SYVN1—−0.055—————0.648TACC2—0.427———0.073——TAF2———0.288———0.791TAGLN2———0.0030.002——0.003TAP1—0.652—−0.244———0.133TARBP2—0.274—−0.152———0.168TARDBP—−0.118—−0.301———0.332TARS———0.448———0.645TARS2———0.405———0.638TAX1BP1−0.003——————0.027TAX1BP3—0.059—0.189———0.209TBC1D10C—−0.205—0.269———−0.260TBC1D5—0.061−0.002————0.094TBK1—0.286—0.049———−0.745TBP—−0.254—0.339———0.423TBRG1———0.452———0.323TBX4−0.1380.298———0.099——TCERG1—−0.137—0.202———0.639TCF12—−0.111———−0.200—0.087TCF19—−0.204———0.504——TCF4—0.2330.030−0.084——0.430—TEC—0.105—−0.495———0.044TECPR1———−0.455———0.612TEDC2———0.250——−0.188—TEF—0.091—−0.353—0.143——TERF1—0.138—−0.238—0.171——TERF2—−0.423—−0.406———0.535TFB1M———−0.394—0.367——TFCP2———0.425—0.186——TFDP10.7030.337−0.196————0.648TFE3—0.285—————0.400TFEC———0.619———0.656TGFB1I1—0.003—0.102———−0.104TGIF10.0040.274———0.266—0.607THBS3—0.023———0.043——TIA1—0.199—0.670———0.359TIAL1———0.197—0.236——TIAM2—0.195—−0.151———0.315TIFA———0.657—−0.056——TIMM10B—−0.088—————0.853TIMP3—0.155———0.034——TJP2−0.014−0.475−0.0110.253———−0.087TLE3−0.044——−0.094———0.270TLE5———−0.100———0.006TLK1———0.011———0.445TMBIM1—−0.018—−0.260———0.047TMC6——0.0140.298———0.326TMCC1—0.202—−0.133—0.112——TMCC2—0.334———0.267——TMCC3———0.090—0.453——TMEM123—0.339—0.272—0.087—0.027TMEM163—0.431—0.424—0.072——TMEM176A−0.010————0.061——TMEM208−0.0500.567—0.835———−0.338TMEM229B—−0.521—0.306—0.126—−0.376TMEM232—−0.092———0.192——TMEM241——−0.211−0.188———0.149TMEM256—0.423—0.192———0.082TMEM256-—0.423—0.192———0.082PLSCR3TMEM87B———0.338———0.284TMSB4X———0.133—0.002—−0.001TMSB4Y———0.133—0.002—−0.001TNFRSF190.0030.278———0.053——TNFSF13B—−0.089—0.465—0.184——TNIK—0.100—0.052—0.149—0.152TNIP2——−0.011−0.400—−0.077——TNPO3———0.272———0.797TNRC6C—0.159—————−0.428TOE1—−0.124—————0.414TOM1—−0.214———−0.094——TOR1A—−0.149—————0.470TP53I11—0.110—0.029———−0.259TPCN2———0.471———0.808TPD520.010————−0.146—0.055TPI1−0.002—−0.0020.006———0.062TPM2—0.216———0.053—−0.014TPP10.0000.128—————−0.158TPRA1−0.0190.153−0.052−0.663—0.356——TRA2A−0.0020.026—0.455—0.558——TRABD—0.422—0.139———−0.451TRAF3IP3—0.439−0.066−0.280———−0.090TRAPPC11——−0.0210.055———0.251TRAPPC13—−0.036—−0.079—0.201—0.431TRAPPC4−0.015−0.325—0.584———0.182TRAPPC8———−0.211———0.645TREM2———0.363——0.297—TREML1—−0.352—−0.018———0.010TRIM28−0.012——0.566———0.190TRMT1—−0.153—0.372———0.242TRMT112—−0.680−0.010−0.626———0.384TRNT1———0.039———−0.452TRPC1−0.008——————0.268TRPC4AP—0.089—————0.075TRPS1—−0.027—0.060—0.073——TRPV2———0.564———0.344TRUB1———−0.815—0.620——TRUB2———0.434———−0.616TSC20.0210.0210.095−0.247—0.084—0.246TSGA10———0.164———0.764TSN−0.0130.276———0.122——TSPAN32—0.429—0.021—−0.276——TSPAN9—0.018—0.141—0.066——TTC13—0.301—————0.408TTC21A0.205—0.236——0.102——TTC3—0.042—0.073—0.156——TTC37———−0.499———0.543TTPAL———0.008———0.420TUBB—0.047—0.124———0.091TUBGCP3—−0.313—0.320———−0.237TUBGCP5—0.079—−0.337———0.840TUFM—0.639———0.313——TUT7—0.020—−0.334———0.155TXN2———0.399—0.142—0.067TXNDC16———−0.832—0.095——TYRO3—0.530———0.143——U2AF1L4—0.325—−0.484———0.667U2SURP—−0.105—————0.143UBA2—0.105—————0.318UBA7—−0.178—0.075———−0.289UBAC2−0.020−0.593−0.002−0.268———0.241UBAP2L—0.307—−0.229———0.462UBASH3A0.0740.5150.054−0.769———0.503UBC———0.177—0.009—0.027UBE2D2—0.327—0.186———0.212UBE2Q1———0.316———−0.155UBFD1—0.086—0.345———0.518UBL4A—−0.175—————−0.200UBL5———0.021—0.064—0.021UBN1———0.146—−0.157——UBR2———−0.421———−0.545UBR5—−0.161—————0.272UBTF—0.016—0.143—0.039——UBXN1———−0.432———0.100UEVLD—0.382—−0.701———0.340UFC1—0.189—0.258—−0.335——UNC119—−0.163—————−0.074UPF2———0.324—0.111——UQCR11———0.028———0.016UQCRH———0.015———0.020UQCRHL———0.015———0.020USE1—−0.266—0.190———0.133USP21—0.298—————0.748USP28—−0.651—0.620—0.262——USP33———0.274———0.607USP40———−0.252———0.639USP49———−0.617−0.331———USP53——−0.247————0.609USP7—−0.096−0.018————0.256USP8———0.650———0.351USPL1—0.319—0.086———−0.372UTRN—0.012———0.047——UTY—−0.091—0.079———0.424UVRAG—−0.324−0.004−0.289—0.036—0.079VAC14—−0.250—0.411———0.282VAV1—−0.035—0.164———0.352VCAN—−0.059—−0.068—−0.434——VCL——−0.009————0.028VDAC30.009−0.079−0.0170.159———0.044VEZT−0.010——0.555———0.679VGLL40.0030.014—0.321———0.163VIM———0.006—−0.021—−0.111VLDLR—−0.379—−0.408—0.183——VPS11——0.1070.431———0.355VPS13A—−0.026−0.3540.187—−0.364——VPS13B———−0.585—0.038—0.293VPS13D−0.006——————−0.781VPS26A———0.325———0.240VPS28—−0.020—————0.070VPS53———−0.862———−0.468VPS8—0.444—−0.490—0.104——VRK1−0.337——0.387———0.305VRK2−0.0100.472—————0.122VTI1A———−0.445—0.029——WDR1—0.178—0.196———0.074WDR11—−0.319—0.325—0.264——WDR74———0.411———0.259WDR75—−0.254—————0.781WDYHV1———0.044—0.106—0.581WFDC8—−0.474———−0.180——WNK1—0.034—0.064—0.008——WRB—0.314—0.289—0.281——WRNIP1—−0.282—0.335———0.073WWP2——−0.0020.430———0.220XAB2———0.327———0.573XPO6−0.015——0.311———0.341XPO7—0.102—————0.449XPR1———−0.795—0.188—0.188YIPF4———0.418—0.147——YJU2—0.194—−0.385———0.487YPEL5———0.014———0.006YWHAQ———0.304—0.036——ZBP1—−0.394—0.312—0.573——ZBTB17———0.641———0.555ZBTB2—−0.323—−0.317———−0.273ZBTB200.035−0.383−0.070−0.278−0.312———ZBTB34———−0.086———−0.608ZBTB38−0.003−0.013—0.208———−0.543ZBTB4———0.243———0.439ZBTB7A———−0.146———−0.174ZC3H10———0.314—0.417——ZC3H7B———0.396—0.042——ZC3HC1—−0.199—−0.816———0.211ZCRB1—0.143———−0.115——ZDHHC12—0.196—0.430———−0.358ZDHHC200.011−0.006—————0.138ZDHHC4—−0.158—0.035———0.365ZDHHC6—0.208—0.300———0.659ZEB2−0.5550.1750.028−0.291———0.050ZFAND3—0.008—0.162———0.072ZFAND6———0.102—0.073——ZFP1—0.213—0.239———0.148ZFY—0.290—————0.210ZFYVE16——0.122———0.340—ZFYVE26—0.051—−0.143———0.780ZGPAT—−0.697—————0.071ZHX1—0.171—————0.580ZMYND11−0.0040.072—−0.278———−0.327ZMYND8———0.250—0.264—−0.266ZNF131—0.095—0.270———0.123ZNF148——−0.0070.258—0.120——ZNF160———0.576———0.448ZNF195—0.122—−0.284—−0.722——ZNF236———0.329—−0.122——ZNF280D—−0.274—0.205—0.327—0.639ZNF287—0.658—0.279——−0.417—ZNF32—0.053—0.082—0.212—0.624ZNF330—−0.087—0.460———0.480ZNF410—−0.317—0.503———0.179ZNF429—0.122—−0.284—−0.722——ZNF532—−0.489—−0.806—0.220——ZNF644—−0.076—−0.024———0.053ZNF665———0.576———0.448ZNF667—−0.186—0.1560.187———ZNF687—0.157—−0.242———0.493ZNF76—−0.383−0.466——−0.207——ZSWIM80.039——0.077———0.377ZWINT———−0.504———0.060

LIST OF EMBODIMENTS

Specific compositions and methods of RNA sequencing to diagnose sepsis have been described. The detailed description in this specification is illustrative and not restrictive or exhaustive. The detailed description is not intended to limit the disclosure to the precise form disclosed. Other equivalents and modifications besides those already described are possible without departing from the inventive concepts described in this specification, as those skilled in the art will recognize. When the specification or claims recite method steps or functions in order, alternative embodiments may perform the tasks in a different order or substantially concurrently. The inventive subject matter is not to be restricted except in the spirit of the disclosure.

When interpreting the disclosure, all terms should be interpreted in the broadest possible manner consistent with the context. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. This invention is not limited to the particular methodology, protocols, reagents, and the like described in this specification and, as such, can vary in practice. The terminology used in this specification is not intended to limit the scope of the invention, which is defined solely by the claims.

All patents and publications cited throughout this specification are expressly incorporated by reference to disclose and describe the materials and methods that might be used with the technologies described in this specification. The publications discussed are provided solely for their disclosure before the filing date. They should not be construed as an admission that the inventors may not antedate such disclosure under prior invention or for any other reason. If there is an apparent discrepancy between a previous patent or publication and the description provided in this specification, the present specification (including any definitions) and claims shall control. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicants and constitute no admission as to the correctness of the dates or contents of these documents. The dates of publication provided in this specification may differ from the actual publication dates. If there is an apparent discrepancy between a publication date provided in this specification and the actual publication date supplied by the publisher, the actual publication date shall control.

The terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, used, or combined with other elements, components, or steps. The singular terms “a,” “an,” and “the” include plural referents unless context indicates otherwise. Similarly, the word “or” should cover “and” unless the context indicates otherwise. The abbreviation “e.g.” is used to indicate a non-limiting example and is synonymous with the term “For example.”

When a range of values is provided, each intervening value, to the tenth of the unit of the lower limit, unless the context dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that range of values.

Some embodiments of the technology described can be defined according to the following numbered paragraphs:

1. A method of using unmapped bacterial RNA reads to identify bacteria causing sepsis.

2. A method of using unmapped viral reads to identify sepsis or viral reactivation.

3. A method of using unmapped B/T V(D)J to identify sepsis.

4. A method of using a Principal Component Analysis of RNA splicing entropy to identify sepsis.

5. A method of using RNA lariats to identify sepsis.

6. A method of using a Principal Component Analysis of gene expression, alternative RNA splicing, or alternative transcription start and end to identify sepsis.