bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutations Upstream of the TBX5 and PITX1 Transcription Factor Genes Are Associated with Feathered Legs in the Domestic Chicken
Authors: Li Jingyi , Lee MiOk , Davis Brian W , Lamichhaney Sangeet , Dorshorst Ben J , Siegel Paul B , Andersson* Leif
Published: April 2020

Feathered leg is a trait in domestic chickens that has undergone intense selection by fancy breeders. Previous studies have shown that two major loci controlling feathered leg are located on chromosomes 13 and 15. Here, we present genetic evidence for the identification of candidate causal mutations at these loci. This was accomplished by combining classical linkage mapping using an experimental cross segregating for feathered leg and high-resolution identical-by-descent mapping using whole-genome sequence data from 167 samples of chicken with or without feathered legs. The first predicted causal mutation is a single-base change located 25 kb upstream of the gene for the forelimb-specific transcription factor TBX5 on chromosome 15. The second is a 17.7-kb deletion located ∼200 kb upstream of the gene for the hindlimb-specific transcription factor PITX1 on chromosome 13. These mutations are predicted to activate TBX5 and repress PITX1 expression, respectively. The study reveals a remarkable convergence in the evolution of the feathered-leg phenotype in domestic chickens and domestic pigeons, as this phenotype is caused by noncoding mutations upstream of the same two genes. Furthermore, the PITX1 causal variants are large overlapping deletions, 17.7 kb in chicken and 44 kb in pigeons. The results of the present study are consistent with the previously proposed model for pigeon that feathered leg is caused by reduced PITX1 expression and ectopic expression of TBX5 in hindlimb buds resulting in a shift of limb identity from hindlimb to more forelimb-like identity.
ATP serves as a nucleotide switch coupling the genome maturation and packaging motor complexes of a virus assembly machine
Authors: Yang Qin , Catalano Carlos E
Published: April 2020

The assembly of double-stranded DNA viruses, from phages to herpesviruses, is strongly conserved. Terminase enzymes processively excise and package monomeric genomes from a concatemeric DNA substrate. The enzymes cycle between a stable maturation complex that introduces site-specific nicks into the duplex and a dynamic motor complex that rapidly translocates DNA into a procapsid shell, fueled by ATP hydrolysis. These tightly coupled reactions are catalyzed by terminase assembled into two functionally distinct nucleoprotein complexes; the maturation complex and the packaging motor complex, respectively. We describe the effects of nucleotides on the assembly of a catalytically competent maturation complex on viral DNA, their effect on maturation complex stability and their requirement for the transition to active packaging motor complex. ATP plays a major role in regulating all of these activities and may serve as a ‘nucleotide switch’ that mediates transitions between the two complexes during processive genome packaging. These biological processes are recapitulated in all of the dsDNA viruses that package monomeric genomes from concatemeric DNA substrates and the nucleotide switch mechanism may have broad biological implications with respect to virus assembly mechanisms.
Deacetylation enhances ParB–DNA interactions affecting chromosome segregation in Streptomyces coelicolor
Authors: Li Peng , Zhang Hong , Zhao Guo-Ping , Zhao Wei
Published: April 2020

Reversible lysine acetylation plays regulatory roles in diverse biological processes, including cell metabolism, gene transcription, cell apoptosis and ageing. Here, we show that lysine acetylation is involved in the regulation of chromosome segregation, a pivotal step during cell division in Streptomyces coelicolor. Specifically, deacetylation increases the DNA-binding affinity of the chromosome segregation protein ParB to the centromere-like sequence parS. Both biochemical and genetic experiments suggest that the deacetylation process is mainly modulated by a sirtuin-like deacetylase ScCobB1. The Lys-183 residue in the helix-turn-helix region of ParB is the major deacetylation site responsible for the regulation of ParB-parS binding. In-frame deletion of SccobB1 represses formation of ParB segregation complexes and leads to generation of abnormal spores. Taken together, these observations provide direct evidence that deacetylation participates in the regulation of chromosome segregation by targeting ParB in S. coelicolor.
Structural and functional characterization of the severe fever with thrombocytopenia syndrome virus L protein
Authors: Vogel Dominik , Thorkelsson Sigurdur Rafn , Quemin Emmanuelle R J , Meier Kristina , Kouba Tomas , Gogrefe Nadja , Busch Carola , Reindl Sophia , Günther Stephan , Cusack Stephen , Grünewald Kay , Rosenthal Maria
Published: April 2020

The Bunyavirales order contains several emerging viruses with high epidemic potential, including Severe fever with thrombocytopenia syndrome virus (SFTSV). The lack of medical countermeasures, such as vaccines and antivirals, is a limiting factor for the containment of any virus outbreak. To develop such antivirals a profound understanding of the viral replication process is essential. The L protein of bunyaviruses is a multi-functional and multi-domain protein performing both virus transcription and genome replication and, therefore, is an ideal drug target. We established expression and purification procedures for the full-length L protein of SFTSV. By combining single-particle electron cryo-microscopy and X-ray crystallography, we obtained 3D models covering ∼70% of the SFTSV L protein in the apo-conformation including the polymerase core region, the endonuclease and the cap-binding domain. We compared this first L structure of the Phenuiviridae family to the structures of La Crosse peribunyavirus L protein and influenza orthomyxovirus polymerase. Together with a comprehensive biochemical characterization of the distinct functions of SFTSV L protein, this work provides a solid framework for future structural and functional studies of L protein–RNA interactions and the development of antiviral strategies against this group of emerging human pathogens.
Diagnostic Accuracy of Non-Invasive Thermal Evaluation of Ventriculoperitoneal Shunt Flow in Shunt Malfunction: A Prospective, Multi-Site, Operator-Blinded Study
Authors: Madsen Joseph R , Boyle Tehnaz P , Neuman Mark I , Park Eun-Hyoung , Tamber Mandeep S , Hickey Robert W , Heuer Gregory G , Zorc Joseph J , Leonard Jeffrey R , Leonard Julie C , Keating Robert , Chamberlain James M , Frim David M , Zakrzewski Paula , Klinge Petra , Merck Lisa H , Piatt Joseph , Bennett Jonathan E , Sandberg David I , Boop Frederick A , Hameed Mustafa Q
Published: April 2020

BACKGROUND

Thermal flow evaluation (TFE) is a non-invasive method to assess ventriculoperitoneal shunt function. Flow detected by TFE is a negative predictor of the need for revision surgery. Further optimization of testing protocols, evaluation in multiple centers, and integration with clinical and imaging impressions prompted the current study.

OBJECTIVE

To compare the diagnostic accuracy of 2 TFE protocols, with micropumper (TFE+MP) or without (TFE-only), to neuro-imaging in patients emergently presenting with symptoms concerning for shunt malfunction.

METHODS

We performed a prospective multicenter operator-blinded trial of a consecutive series of patients who underwent evaluation for shunt malfunction. TFE was performed, and preimaging clinician impressions and imaging results were recorded. The primary outcome was shunt obstruction requiring neurosurgical revision within 7 d. Non-inferiority of the sensitivity of TFE vs neuro-imaging for detecting shunt obstruction was tested using a prospectively determined a priori margin of −2.5%.

RESULTS

We enrolled 406 patients at 10 centers. Of these, 68/348 (20%) evaluated with TFE+MP and 30/215 (14%) with TFE-only had shunt obstruction. The sensitivity for detecting obstruction was 100% (95% CI: 88%-100%) for TFE-only, 90% (95% CI: 80%-96%) for TFE+MP, 76% (95% CI: 65%-86%) for imaging in TFE+MP cohort, and 77% (95% CI: 58%-90%) for imaging in the TFE-only cohort. Difference in sensitivities between TFE methods and imaging did not exceed the non-inferiority margin.

CONCLUSION

TFE is non-inferior to imaging in ruling out shunt malfunction and may help avoid imaging and other steps. For this purpose, TFE only is favored over TFE+MP.
Plasminogen improves lung lesions and hypoxemia in patients with COVID-19
Authors: Wu Y , Wang T , Guo C , Zhang D , Ge X , Huang Z , Zhou X , Li Y , Peng Q , Li J
Published: April 2020

Background

Lungs from patients with coronavirus disease 2019 (COVID-19) have shown typical signs of acute respiratory distress syndrome (ARDS), formation of hyaline membrane mainly composed of fibrin and ‘ground-glass’ opacity. Previously, we showed plasminogen itself is a key regulator in fibrin degradation, wound healing and infection.

Aim

We aimed to investigate whether plasminogen can improve lung lesions and hypoxemia of COVID-19.

Design

Thirteen clinically moderate, severe or critical COVID-19 patients were treated with atomization inhalation of freeze-dried plasminogen.

Methods

Levels of their lung lesions, oxygen saturation and heart rates were compared before and after treatment by computed tomography scanning images and patient monitor.

Results

After plasminogen inhalation, conditions of lung lesions in five clinically moderate patients have quickly improved, shown as the decreased range and density of ‘ground glass’ opacity. Improvements of oxygen saturation were observed in six clinically severe patients. In the two patients with critical conditions, the oxygen levels have significantly increased from 79–82% to 91% just about 1 h after the first inhalation. In 8 of 13 patients, the heart rates had slowed down. For the five clinically moderate patients, the difference is even statistically significant. Furthermore, a general relief of chest tightness was observed.

Conclusion

Whereas it is reported that plasminogen is dramatically increased in adults with ARDS, this study suggests that additional plasminogen may be effective and efficient in treating lung lesions and hypoxemia during COVID-19 infections. Although further studies are needed, this study highlights a possible hope of efficiently combating this rapid epidemic emergency.
Changing research on research evaluation: A critical literature review to revisit the agenda
Authors: Thomas Duncan A , Nedeva Maria , Tirado Mayra M , Jacob Merle
Published: April 2020

The current range and volume of research evaluation-related literature is extensive and incorporates scholarly and policy/practice-related perspectives. This reflects academic and practical interest over many decades and trails the changing funding and reputational modalities for universities, namely increased selectivity applied to institutional research funding streams and the perceived importance of university rankings and other reputational devices. To make sense of this highly diverse body of literature, we undertake a critical review of over 350 works constituting, in our view, the ‘state-of-the-art’ on institutional performance-based research evaluation arrangements (PREAs). We focus on PREAs because they are becoming the predominant means world-wide to allocate research funds and accrue reputation for universities. We highlight the themes addressed in the literature and offer critical commentary on the balance of scholarly and policy/practice-related orientations. We then reflect on five limitations to the state-of-the-art and propose a new agenda, and a change of perspective, to progress this area of research in future studies.
An objective and reliable electrophysiological marker for implicit trustworthiness perception
Authors: Swe Derek C , Palermo Romina , Gwinn O Scott , Rhodes Gillian , Neumann Markus , Payart Shanèle , Sutherland Clare A M
Published: April 2020

Trustworthiness is assumed to be processed implicitly from faces, despite the fact that the overwhelming majority of research has only involved explicit trustworthiness judgements. To answer the question whether or not trustworthiness processing can be implicit, we apply an electroencephalography fast periodic visual stimulation (FPVS) paradigm, where electrophysiological cortical activity is triggered in synchrony with facial trustworthiness cues, without explicit judgements. Face images were presented at 6 Hz, with facial trustworthiness varying at 1 Hz. Significant responses at 1 Hz were observed, indicating that differences in the trustworthiness of the faces were reflected in the neural signature. These responses were significantly reduced for inverted faces, suggesting that the results are associated with higher order face processing. The neural responses were reliable, and correlated with explicit trustworthiness judgements, suggesting that the technique is capable of picking up on stable individual differences in trustworthiness processing. By demonstrating neural activity associated with implicit trustworthiness judgements, our results contribute to resolving a key theoretical debate. Moreover, our data show that FPVS is a valuable tool to examine face processing at the individual level, with potential application in pre-verbal and clinical populations who struggle with verbalization, understanding or memory.
Identification of Wheat Leaf Rust Resistance Genes in Chinese Wheat Cultivars and the Improved Germplasms
Authors: Wu Hui , Kang Zhanhai , Li Xing , Li Yanyan , Li Yi , Wang Shuo , Liu Daqun
Published: April 2020

Leaf rust is an important wheat disease that is a significant hindrance for wheat production in most areas of the world. Breeding resistant cultivars can effectively and economically control the disease. In the present study, a wheat collection consisting of 100 cultivars from China and 18 improved germplasms from global landrace donors together with 36 known single Lr gene lines were tested with 20 strains of Puccinia triticina Eriks. in the seedling stage to postulate the Lr gene in the cultivars and germplasms. In addition, 12 diagnostic molecular markers specific to 10 Lr genes were used to detect the presence of the Lr genes in the wheat collection. Resistance to leaf rust of these cultivars at the adult plant stage was tested in fields under natural infection during the 2016 to 2018 cropping seasons in Baoding, Hebei Province. The gene postulation combined with molecular marker detection showed that six Lr genes (Lr1, Lr26, Lr33, Lr34, Lr45, and Lr46) were identified in 44 wheat accessions, including 37 cultivars and seven improved germplasms. Among the 44 wheat accessions postulated with Lr genes, Lr1 was present in four accessions, Lr26 in 12 accessions, Lr33 in two accessions, Lr34 in 14 accessions, Lr45 in three accessions, and Lr46 in 16 accessions. In the collection of 118 cultivars/germplasms, 34 wheat lines displayed adult-plant resistance carrying Lr34, Lr46, and/or underdetermined genes. Therefore, a high level of leaf rust resistance can be achieved through the combination of all-stage resistance and adult-plant resistance genes together in wheat cultivars.
Adjuvant and neoadjuvant chemotherapy in pancreatic ductal adenocarcinoma
Authors: Leonhardt Carl S. , Traub Benno , Hackert Thilo , Klaiber Ulla , Strobel Oliver , Büchler Markus W. , Neoptolemos John P.
Published: April 2020

The management of pancreatic cancer has dramatically changed since the first major randomized trial published in 2001 by the European Study Group for Pancreatic Cancer (ESPAC) stimulated the development of multimodality oncosurgical therapies. ESPAC-1 demonstrated a survival improvement from upfront surgery of only 8%, increasing to 21% 5-year survival for 5-fluorouracil/folinic acid but only 10.8% for chemoradiotherapy. ESPAC-4 has shown a 5-year survival rate of 30% for all patients without restriction of 30% using a combination of gemcitabine and capecitabine, rising to 40% in those with an R0 resection margin, or nearly 50% in those with N0 lymph node status. In selected patients with favorable prognostic features mFOLFIRINOX can produce a 50% 5-year survival rate but with added toxicity. While a positive resection margin is associated with an increased likelihood of local recurrence, this of itself is not the contributor to reduced survival, but rather reflects the increased probability of systemic disease. Thus, strategies aimed at local control, may reduce subsequent local progression, but will not improve overall survival. Neoadjuvant chemotherapy is increasingly utilized in cases of borderline resectable or locally advanced pancreatic cancer, but there is still a lack of proof of concept studies. High-quality evidence from randomized controlled trials to identify the indications and benefits of neoadjuvant therapy in pancreatic cancer are required. The use of patient-derived tumor organoids may predict response to chemotherapy which could open a new opportunity in pancreatic cancer treatment, stratifying patients into treatment groups based on their response to these therapies in the laboratory.
Highly Reliable Case Management
Authors: White Charles William , Alejandro Jose
Published: April 2020

Health care is a highly complex system that is prone to error. Professional case managers across the continuum of care are key stakeholders who can significantly impact the effectiveness and efficiency of health care delivery at the individual and population health levels. This article explores how professional case managers can use evidence-based practice and generative knowledge to improve professional practice. In addition, the authors provide examples of how to actively support continuous change and high reliability within an organization.
Automated Pupillometry as an Adjunct to Clinical Examination in Patients With Acute Vision Loss
Authors: Bhatnagar Roshni , Birnbaum Andrea D. , Baqai Jeanine , Volpe Nicholas J.
Published: April 2020

Background:

Despite automated pupillometry's (AP) improved detection of relative afferent pupillary defects (RAPDs) compared with the Swinging Flashlight Test (SFT), AP remains uncommon in clinical practice. This study examined barriers to routine use of AP in evaluation of acute vision loss.

Methods:

(1) Ophthalmologists and optometrists' perceptions of AP were captured via electronic survey. (2) Ophthalmologists were presented with clinical vignettes to assess their use of AP in clinical decision-making. (3) Patients presenting with decreased vision to an ophthalmology urgent care clinic underwent manual SFT and AP screening to evaluate ophthalmologists' perceptions of the device.

Results:

Surveys indicated that clinicians were “neutral” to “somewhat likely” to use AP. In clinical vignettes, more physicians proceeded with workup for optic nerve pathology when presented with an RAPD by AP than SFT (77% vs 26%, P = 0.003). When SFT and AP results were discordant, more physicians proceeded with workup for optic nerve disease when AP was positive and SFT was negative than vice versa (61% vs 18%, P = 0.008). In the clinical study of 21 patients, 50% of RAPDs detected by AP were not detected by SFT, although ophthalmologists rated AP's usefulness as only “neutral” to “somewhat useful.”

Conclusion:

Clinicians value pupillary examination and trust AP over SFT; however, widespread adoption and perceived value of AP may depend on its impact on clinical outcomes. Within a comprehensive diagnostic device, AP may be an important tool, but is not necessary to screen for optic nerve disease or evaluate acute vision loss.
Clinical features, Diagnosis, and Treatment of COVID-19: A systematic review of case reports and case series
Authors: Tahvildari Azin , Arbabi Mahta , Farsi Yeganeh , Jamshidi Parnian , Hasanzadeh Saba , Calcagno Tess Moore , Nasiri Mohammad Javad , Mirsaeidi Mehdi
Published: April 2020

Objectives

The 2019 novel coronavirus (COVID-19) has been declared a public health emergency worldwide. The objective of this systematic review was to characterize the clinical, diagnostic, and treatment characteristics of patients presenting with COVID-19.

Methods

We conducted a structured search using PubMed/Medline, Embase, Web of Science and the Cochrane Library to collect both case reports and case series on COVID-19 published up to February 30, 2020.

Results

Thirty-four articles were included analyzing a total of 99 patients with a mean age of 46.2 years. The most common presenting symptom in patients who tested positive for COVID-19 was fever, reported in up to 83% of patients from 76.4% of the analyzed studies. Other symptoms including rhinorrhea, dizziness, and chills were less frequently reported. Additionally, in studies which reported C-reactive protein (CRP) measurements (44%), a large majority of patients displayed an elevated CRP (73%). Progression to acute respiratory distress syndrome (ARDS) was the most common complication of patients testing positive for COVID-19 (33%). CT images displayed ground-glass opacification (GGO) patterns (80%) as well as bilateral lung involvement (71.0%). The most commonly used antiviral treatment modalities included, lopinavir (HIV protease inhibitor), arbidiol hydrochloride (influenza fusion inhibitor), and oseltamivir (neuraminidase inhibitor).

Conclusions

Development of ARDS may play a role in estimating disease progression and mortality risk. Early detection of elevations in serum CRP, combined with a clinical COVID-19 symptom presentation may be used as a surrogate marker for presence and severity of disease. There is a paucity of data surrounding the efficacy of treatments. There is currently not a well-established gold standard therapy for the treatment of diagnosed COVID-19. Further prospective investigations are necessary.
deepMINE - Natural Language Processing based Automatic Literature Mining and Research Summarization for Early-Stage Comprehension in Pandemic Situations specifically for COVID-19
Authors: Joshi Bhrugesh , Bakarola Vishvajit , Shah Parth , Krishnamurthy Ramar
Published: April 2020

The recent pandemic created due to Novel Coronavirus (nCOV-2019) from Wuhan, China demanding a large scale of a general health emergency. This demands novel research on the vaccine to fight against this pandemic situation, re-purposing of the existing drugs, phylogenetic analysis to identify the origin and determine the similarity with other known viruses, etc. The very preliminary task from the research community is to analyze the wide verities of existing related research articles, which is very much time-consuming in such situations where each minute counts for saving hundreds of human lives. The entire manual processing is even lower down the efficiency in mining the information. We have developed a complete automatic literature mining system that delivers efficient and fast mining from existing biomedical literature databases. With the help of modern-day deep learning algorithms, our system also delivers a summarization of important research articles that provides ease and fast comprehension of critical research articles. The system is currently scanning nearly 1,46,115,136 English words from 29,315 research articles in not greater than 1.5 seconds with multiple search keywords. Our research article presents the criticality of literature mining, especially in pandemic situations with the implementation and online deployment of the system.
Predicting Mortality Risk in Patients with COVID-19 Using Artificial Intelligence to Help Medical Decision-Making
Authors: Pourhomayoun Mohammad , Shakibi Mahdi
Published: April 2020

In the wake of COVID-19 disease, caused by the SARS-CoV-2 virus, we designed and developed a predictive model based on Artificial Intelligence (AI) and Machine Learning algorithms to determine the health risk and predict the mortality risk of patients with COVID-19. In this study, we used documented data of 117,000 patients world-wide with laboratory-confirmed COVID-19. This study proposes an AI model to help hospitals and medical facilities decide who needs to get attention first, who has higher priority to be hospitalized, triage patients when the system is overwhelmed by overcrowding, and eliminate delays in providing the necessary care. The results demonstrate 93% overall accuracy in predicting the mortality rate. We used several machine learning algorithms including Support Vector Machine (SVM), Artificial Neural Networks, Random Forest, Decision Tree, Logistic Regression, and K-Nearest Neighbor (KNN) to predict the mortality rate in patients with COVID-19. In this study, the most alarming symptoms and features were also identified. Finally, we used a separate dataset of COVID-19 patients to evaluate our developed model accuracy, and used confusion matrix to make an in-depth analysis of our classifiers and calculate the sensitivity and specificity of our model.
In silicoapproach for designing of a multi-epitope based vaccine against novel Coronavirus (SARS-COV-2)
Authors: Saha Ratnadeep , Prasad Burra V L S
Published: April 2020

A novel Coronavirus (SARS-COV-2) has now become a global pandemic. Considering the severity of infection and the associated mortalities, there is an urgent need to develop an effective preventive measure against this virus. In this study, we have designed a novel vaccine construct using computational strategies. Spike (S) glycoprotein is the major antigenic component that trigger the host immune responses. Detailed investigation of S protein with various immunoinformatics tools enabled us to identify 5 MHC I and 5 MHC II B-cell derived T-cell epitopes with VaxiJen score > 1 and IC50value < 100nM. These epitopes were joined with a suitable adjuvant and appropriate linkers to form a multi-epitope based vaccine construct. Further, in silico testing of the vaccine construct for its antigenicity, allergenicity, solubility, and other physicochemical properties showed it to be safe and immunogenic. Suitable tertiary structure of the vaccine protein was generated using 3Dpro of SCRATCH suite, refined with GalaxyRefine, and validated with ProSA, PROCHECK, and ERRAT server. Finally, molecular docking studies were performed to ensure a favorable binding affinity between the vaccine construct and TLR3 receptor. The designed multi-epitope vaccine showed potential to elicit specific immune responses against the SARS-COV-2. However, further wet lab validation is necessary to confirm the actual effectiveness, safety and immunogenic potency of the vaccine construct against derived in this study.
A SARS-CoV-2 Vaccination Strategy Focused on Population-Scale Immunity
Authors: Yarmarkovich Mark , Warrington John M. , Farrel Alvin , Maris John M.
Published: April 2020

Here we propose a vaccination strategy for SARS-CoV-2 based on identification of both highly conserved regions of the virus and newly acquired adaptations that are presented by MHC class I and II across the vast majority of the population, are highly dissimilar from the human proteome, and are predicted B cell epitopes. We present 65 peptide sequences that we expect to result in a safe and effective vaccine which can be rapidly tested in DNA, mRNA, or synthetic peptide constructs. These include epitopes that are contained within evolutionarily divergent regions of the spike protein reported to increase infectivity through increased binding to the ACE2 receptor, and within a novel furin cleavage site thought to increase membrane fusion. This vaccination strategy specifically targets unique vulnerabilities of SARS-CoV-2 and should engage a robust adaptive immune response in the vast majority of the human population.
Genome Wide Epistasis Study of On-Statin Cardiovascular Events with Iterative Feature Reduction and Selection
Authors: Adams Solomon M. , Feroze Habiba , Nguyen Tara , Eum Seenae , Cornelio Cyrille K. , Harralson Arthur F.
Published: April 2020

Background

Predicting risk for major adverse cardiovascular events (MACE) is an evidence-based practice that incorporates lifestyle, history, and other risk factors. Statins reduce risk for MACE by decreasing lipids, but it is difficult to stratify risk following initiation of a statin. Genetic risk determinants for on-statin MACE are low-effect size and impossible to generalize. Our objective was to determine high-level epistatic risk factors for on-statin MACE with GWAS-scale data.

Methods

Controlled-access data for 5,980 subjects taking a statin collected from Vanderbilt University Medical Center’s BioVU were obtained from dbGaP. We used Random Forest Iterative Feature Reduction and Selection (RF-IFRS) to select highly informative genetic and environmental features from a GWAS-scale dataset of patients taking statin medications. Variant-pairs were distilled into overlapping networks and assembled into individual decision trees to provide an interpretable set of variants and associated risk.

Results

1,718 cases who suffered MACE and 4,172 controls were obtained from dbGaP. Pathway analysis showed that variants in genes related to vasculogenesis (FDR=0.024), angiogenesis (FDR=0.019), and carotid artery disease (FDR=0.034) were related to risk for on-statin MACE. We identified six gene-variant networks that predicted odds of on-statin MACE. The most elevated risk was found in a small subset of patients carrying variants in COL4A2, TMEM178B, SZT2, and TBXAS1 (OR=4.53, p<0.001).

Conclusions

The RF-IFRS method is a viable method for interpreting complex “black-box” findings from machine-learning. In this study, it identified epistatic networks that could be applied to risk estimation for on-statin MACE. Further study will seek to replicate these findings in other populations.
Knowledge and Beliefs towards Universal Safety Precautions to flatten the curve during Novel Coronavirus Disease (nCOVID-19) Pandemic among general Public in India: Explorations from a National Perspective
Authors: Gudi Sai Krishna , Undela Krishna , Venkataraman Rajesh , Mateti Uday Venkat , Chhabra Manik , Nyamagoud Sanath , Tiwari Komal Krishna
Published: April 2020

Background

The novel Coronavirus disease (COVID-19) is being considered as the most serious health threat that the world has never witnessed in the recent times and significantly affecting the daily routine of mankind by emerging as a global pandemic. Yet, as there is no treatment nor a vaccine that was approved so far, universal safety precautions (USPs) and mitigating strategies are the only way to deal with this emergency crisis. However, knowledge and beliefs towards USPs among the general public in countries such as India with a large population are lacking.

Methods

A prospective, cross-sectional, web-based online survey was conducted among the general public in India during March 2020. A 20-item self-administered survey questionnaire was developed and randomly distributed among the public using google document forms through social media networks. Descriptive statistics were used in representing the study characteristics, and the Chi-square test was used in assessing the associations among the study variables with a p-value of < 0.05 was considered as statistically significant.

Results

Of 1287 participants, 1117 have given their consent of willingness and completed the questionnaire with a response rate of 86.8%. The mean age of the study participants was 28.8 ± 10.9 years, where the majority of them belong to the age category <25 years, and sex was equally distributed. Based upon the socio-demographic information, the majority were post-graduates (32.9%), professional job holders (45%) and belonged to the upper-middle (40%) economic class. Overall, the knowledge and beliefs towards USPs and mitigating strategies among participants varied between moderate to high, with statistically significant associations with their socio-demographic characteristics.

Conclusions

Although the knowledge and beliefs of the general public in India towards USPs are encouraging, there is a need for long-term educational interventions as the dynamics and severity of COVID-19 have been changing day-by-day rapidly. The findings of this study could guide the public health authorities in making and implementing decisions to combat this pandemic.
Risk of Secondary Malignancies in Patients with prostate cancer: A Systematic Review and Meta-analysis
Authors: Heydari Keyvan , Rismantab Sahar , Shamshirian Amir , Houshmand Pouya , Lotfi Parisa , Rafati Sajjad , Aref Amir , Saravi Ali , Shamshirian Danial , Zibaei Behdad , Alizadeh-Navaei Reza
Published: April 2020

IMPORTANCE

Prostate cancer (PC) is the second most common cancer among males globally, however, the survival rate is favorable in most patients. In a small number of patients, who suffer from advanced or invasive cancer, various side effects such as secondary malignancies or treatment-related secondary malignancies (SMs) may be seen.

OBJECTIVE

To systematically asses the risk of secondary malignancies in patients with prostate cancer.

DATA SOURCES

We have searched for longitudinal studies through databases of Web of Science, Scopus and PubMed for all available data up to September 2019.

STUDY SELECTION

Studies with longitudinal design on prostate cancer patients that declared the results in SIR or those that the SIR could be calculated were eligible.

DATA EXTRACTION AND SYNTHESIS

The heterogeneity was evaluated using the I2 test. According to the results and in case of I2 ≥ 50%, the random effect model was used to combine the results. To identify the cause of heterogeneity in the studies, the analysis of sub-groups was performed based on the site of secondary malignancy, the treatment procedure, and duration of follow-up. Data were analyzed using STATA version 11.

MAIN OUTCOMES AND MEASURES

Overall SIR and based on treatment of prostate cancer and duration of follow-up.

RESULTS

Twenty-six studies involving more than 2223,704 patients with PC and more than 86034 cases of SMs were entered into this study. The meta-analysis showed that the risk of cancer after PC was 1.03 (95% CI 0.90 - 1.15) and the SIRs of some cancers such as the bladder 1.52 (1.06 - 1.99) and melanoma 1.32 (0.78 - 1.87) were higher than expected. While, malignancies such as rectum 0.92 (0.85 - 1.00), lung 0.85 (0.74 - 0.96) and liver 0.76 (0.54 - 0.98) showed lower incidence in compare to general population.

CONCLUSIONS AND RELEVANCE

The overall risk of SMs in patients with prostate cancer is not significantly different from general population, and even in patients undergoing prostatectomy or brachytherapy, the risk is lower. But the incidence of some cancers such as melanoma, bladder, and urinary tract appears to be higher than the public in all types of treatment approaches.

Key Points

Questio

Is the risk of secondary malignancy in patients with prostate cancer higher than the general population?

Findings

This systematic review and meta-analysis of 26 unique trials including 2223,704 patients, showed that the SIRs of some cancers such as the bladder and melanoma were higher than expected.

Meaning

These findings suggest that the overall risk of some cancer such as bladder and melanoma in patients with prostate cancer were higher than the general population.
Parametric analysis of early data on COVID-19 expansion in selected European countries
Authors: Spousta Martin
Published: April 2020

We analyze the early data on COVID-19 expansion in selected European countries using an analytical parametric model. A description of the time dependence of the disease expansion and a method to evaluate trends of the expansion are proposed. Several features are observed in the data, namely a high predictability of the expansion of disease in Italy and a convergence of the “pushback” parameter towards a limiting value in all the countries where restrictive measures have been adopted. Basic predictions for the evolution of the disease expansion are made for selected countries with a stable evolution in the parametric space of the model. The findings presented here should contribute to the understanding of the behavior of the disease expansion and the role of the restrictive measures on the evolution of the expansion.
Mercury methylation trait dispersed across diverse anaerobic microbial guilds in a eutrophic sulfate-enriched lake
Authors: Peterson Benjamin D. , McDaniel Elizabeth A. , Schmidt Anna G. , Lepak Ryan F. , Tran Patricia Q. , Marick Robert A. , Ogorek Jacob M. , DeWild John F. , Krabbenhoft David P. , McMahon Katherine D.
Published: April 2020

Mercury (Hg) methylation is a microbially mediated process that converts inorganic Hg into the bioaccumulative neurotoxin methylmercury (MeHg). Exploring the diversity and metabolic potential of the dominant Hg-methylating microorganisms can provide insights into how biogeochemical cycles and water quality parameters underlie MeHg production. However, our understanding of the ecophysiology of methylators in natural ecosystems is still limited. Here, we used shotgun metagenomics paired with biogeochemical data to identify likely hotspots for MeHg production in a lake with elevated sulfate levels and characterize the microbial methylators and the flanking microbial community. Identified putative methylators were dominated by hgcA sequences divergent from those in canonical, experimentally confirmed methylators. Using genome-resolved metagenomics, these sequences were identified within genomes associated with Bacteroidetes and the recently described phylum Kiritimatiellaeota. Over half of the hgcA abundance comes from genomes corresponding to obligately fermentative organisms, many of which have a large number of glucoside hydrolases for polysaccharide degradation. Sulfate-reducing genomes encoding hgcA were also identified, but only accounted for 22% of the abundance of hgcA+ genomes. This work highlights the diverse dispersal of the methylation trait across the microbial anoxic food web.
Epigenomic Diversity of Cortical Projection Neurons in the Mouse Brain
Authors: Zhang Zhuzhu , Zhou Jingtian , Tan Pengcheng , Pang Yan , Rivkin Angeline , Kirchgessner Megan A. , Williams Elora , Lee Cheng-Ta , Liu Hanqing , Franklin Alexis D. , Miyazaki Paula Assakura , Bartlett Anna , Aldridge Andrew , Vu Minh , Boggeman Lara , Fitzpatrick Conor , Nery Joseph R. , Castanon Rosa G. , Rashid Mohammad , Jacobs Matthew , Ito Tony , Dominguez Bertha , Niu Sheng-Yong , Smith Jared B. , O’Connor Carolyn , Lee Kuo-Fen , Jin Xin , Mukamel Eran A. , Behrens M. Margarita , Ecker Joseph R. , Callaway Edward M.
Published: April 2020

Neuronal cell types are classically defined by their molecular properties, anatomy, and functions. While recent advances in single-cell genomics have led to high-resolution molecular characterization of cell type diversity in the brain, neuronal cell types are often studied out of the context of their anatomical properties. To better understand the relationship between molecular and anatomical features defining cortical neurons, we combined retrograde labeling with single-nucleus DNA methylation sequencing to link epigenomic properties of cell types to neuronal projections. We examined 11,827 single neocortical neurons from 63 cortico-cortical (CC) and cortico-subcortical long-distance projections. Our results revealed unique epigenetic signatures of projection neurons that correspond to their laminar and regional location and projection patterns. Based on their epigenomes, intra-telencephalic (IT) cells projecting to different cortical targets could be further distinguished, and some layer 5 neurons projecting to extra-telencephalic targets (L5-ET) formed separate subclusters that aligned with their axonal projections. Such separation varied between cortical areas, suggesting area-specific differences in L5-ET subtypes, which were further validated by anatomical studies. Interestingly, a population of CC projection neurons clustered with L5-ET rather than IT neurons, suggesting a population of L5-ET cortical neurons projecting to both targets (L5-ET+CC). We verified the existence of these neurons by labeling the axon terminals of CC projection neurons and observed clear labeling in ET targets including thalamus, superior colliculus, and pons. These findings highlight the power of single-cell epigenomic approaches to connect the molecular properties of neurons with their anatomical and projection properties.
Translational neurophysiological biomarkers of N-methyl-D-aspartate receptor dysfunction in serine racemase knockout mice
Authors: Balla Andrea , Ginsberg Stephen , Abbas Atheir I. , Sershen Henry , Javitt Daniel C.
Published: April 2020

Alterations in glutamatergic function are well established in schizophrenia (Sz), but new treatment development is hampered by the lack of translational pathophysiological and target engagement biomarkers as well as by the lack of animal models that recapitulate the pathophysiological features of Sz. Here, we evaluated the rodent auditory steady state response (ASSR) and long-latency auditory event-related potential (aERP) as potential translational markers. These biomarkers were assessed for their sensitivity to both the N-methyl-D-aspartate receptor (NMDAR) antagonist phencyclidine (PCP) and to knock-out (KO) of Serine Racemase (SR), which is known to lead to Sz-like alterations in function of parvalbumin (PV)-type cortical interneurons. Both PCP and SRKO led to significant increases of ASSR, consistent with PV interneuron effects. Similar effects were observed in mice with selective NMDAR KO on PV interneurons. By contrast, PCP but not SRKO reduced the amplitude of the rodent analog of the human N1 potential. Overall, these findings support use of rodent ASSR and long-latency aERP, along with previously described measures such as mismatch negativity (MMN), as translational biomarkers, and support SRKO mice as a potential rodent model for PV interneuron dysfunction in Sz.
Precise electronic control of redox reactions insideEscherichia coliusing a genetic module
Authors: Baruch Moshe , Tejedor-Sanz Sara , Su Lin , Ajo-Franklin Caroline M.
Published: April 2020

Microorganisms regulate the redox state of different biomolecules to precisely control biological processes. These processes can be modulated by electrochemically coupling intracellular biomolecules to an external electrode, but current approaches afford only limited control and specificity. Here we describe specific electrochemical control of the reduction of intracellular biomolecules inEscherichia colithrough introduction of a heterologous electron transfer pathway.E. coliexpressingmtrCABfromShewanella oneidensisMR-1 consumed electrons directly from a cathode when fumarate or nitrate, both intracellular electron acceptors, were present. The fumarate-triggered current consumption occurred only when fumarate reductase was present, indicating all the electrons passed through this enzyme. Moreover, MtrCAB-expressingE. coliused current to stoichiometrically produce ammonia. Thus, our work introduces a modular genetic tool to reduce a specific intracellular redox molecule with an electrode, opening the possibility of electronically controlling biological processes such as biosynthesis and growth in any microorganism.
Integrative Network Fusion: a multi-omics approach in molecular profiling
Authors: Chierici Marco , Bussola Nicole , Marcolini Alessia , Francescatto Margherita , Zandonà Alessandro , Trastulla Lucia , Agostinelli Claudio , Jurman Giuseppe , Furlanello Cesare
Published: April 2020

Recent technological advances and international efforts, such as The Cancer Genome Atlas (TCGA), have made available several pan-cancer datasets encompassing multiple omics layers with detailed clinical information in large collection of samples. The need has thus arisen for the development of computational methods aimed at improving cancer subtyping and biomarker identification from multi-modal data. Here we apply the Integrative Network Fusion (INF) pipeline, which combines multiple omics layers exploiting Similarity Network Fusion (SNF) within a machine learning predictive framework. INF includes a feature ranking scheme (rSNF) on SNF-integrated features, used by a classifier over juxtaposed multi-omics features (juXT). In particular, we show instances of INF implementing Random Forest (RF) and linear Support Vector Machine (LSVM) as the classifier, and two baseline RF and LSVM models are also trained on juXT. A compact RF model, called rSNFi, trained on the intersection of top-ranked biomarkers from the two approaches juXT and rSNF is finally derived. All the classifiers are run in a 10×5-fold cross-validation schema to warrant reproducibility, following the guidelines for an unbiased Data Analysis Plan by the US FDA-led initiatives MAQC/SEQC. INF is demonstrated on four classification tasks on three multi-modal TCGA oncogenomics datasets. Gene expression, protein abundances and copy number variants are used to predict estrogen receptor status (BRCA-ER, N=381) and breast invasive carcinoma subtypes (BRCA-subtypes, N=305), while gene expression, miRNA expression and methylation data is used as predictor layers for acute myeloid leukemia and renal clear cell carcinoma survival (AML-OS, N=157; KIRC-OS, N=181). In test, INF achieved similar Matthews Correlation Coefficient (MCC) values and 97% to 83% smaller feature sizes (FS), compared with juXT for BRCA-ER (MCC: 0.83 vs 0.80; FS: 56 vs 1801) and BRCA-subtypes (0.84 vs 0.80; 302 vs 1801), improving KIRC-OS performance (0.38 vs 0.31; 111 vs 2319). INF predictions are generally more accurate in test than one-dimensional omics models, with smaller signatures too, where transcriptomics consistently play the leading role. Overall, the INF framework effectively integrates multiple data levels in oncogenomics classification tasks, improving over the performance of single layers alone and naive juxtaposition, and provides compact signature sizes1.
Morphological estimation of Cellularity on Neo-adjuvant treated breast cancer histological images
Authors: Ortega-Ruiz Mauricio Alberto , Karabağ Cefa , García Garduño Victor , Reyes-Aldasoro Constantino Carlos
Published: April 2020

This paper describes a methodology that extracts morphological features from histological breast cancer images stained for Hematoxilyn and Eosin (H&E). Cellularity was estimated and the correlation between features and the residual tumour size cellularity after a Neo-Adjuvant treatment (NAT) was examined. Images from whole slide imaging (WSI) were processed automatically with traditional computer vision methods to extract twenty two morphological parameters from the nuclei, epithelial region and the global image. The methodology was applied to a set of images from breast cancer under NAT. The data came from the BreastPathQ Cancer Cellularity Challenge 2019, and consisted of 2579 patches of 255×255 pixels of H&E histopatological samples from NAT treatment patients. The methodology automatically implements colour separation, segmentation and morphological analysis using traditional algorithms (K-means grouping, watershed segmentation, Otsu’s binarisation). Linear regression methods were applied to determine strongest correlation between the parameters and the cancer cellularity. The morphological parameters showed correlation with the residual tumour cancer cellularity. The strongest correlations corresponded to the stroma concentration value (r = −0.9786) and value from HSV image colour space (r = −0.9728), both from a global image parameters.