bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing preliminary blood metabolomics-based biomarkers of insufficient sleep in humans
Authors: Depner Christopher M , Cogswell Dasha T , Bisesi Paul J , Markwald Rachel R , Cruickshank-Quinn Charmion , Quinn Kevin , Melanson Edward L , Reisdorph Nichole , Wright Kenneth P
Published: January 2020

Study Objective

Identify small molecule biomarkers of insufficient sleep using untargeted plasma metabolomics in humans undergoing experimental insufficient sleep.

Methods

We conducted a crossover laboratory study where 16 normal-weight participants (eight men; age 22 ± 5 years; body mass index < 25 kg/m2) completed three baseline days (9 hours sleep opportunity per night) followed by 5-day insufficient (5 hours sleep opportunity per night) and adequate (9 hours sleep opportunity per night) sleep conditions. Energy balanced diets were provided during baseline, with ad libitum energy intake provided during the insufficient and adequate sleep conditions. Untargeted plasma metabolomics analyses were performed using blood samples collected every 4 hours across the final 24 hours of each condition. Biomarker models were developed using logistic regression and linear support vector machine (SVM) algorithms.

Results

The top-performing biomarker model was developed by linear SVM modeling, consisted of 65 compounds, and discriminated insufficient versus adequate sleep with 74% overall accuracy and a Matthew’s Correlation Coefficient of 0.39. The compounds in the top-performing biomarker model were associated with ATP Binding Cassette Transporters in Lipid Homeostasis, Phospholipid Metabolic Process, Plasma Lipoprotein Remodeling, and sphingolipid metabolism.

Conclusion

We identified potential metabolomics-based biomarkers of insufficient sleep in humans. Although our current biomarkers require further development and validation using independent cohorts, they have potential to advance our understanding of the negative consequences of insufficient sleep, improve diagnosis of poor sleep health, and could eventually help identify targets for countermeasures designed to mitigate the negative health consequences of insufficient sleep.
Cell cycle regulation and hematologic malignancies
Authors: Dai Yun , Jin Fengyan , Wu Wei , Kumar Shaji K.
Published: January 2020

A complex network precisely regulates the cell cycle through the G1, S, G2, and M phases and is the basis for cell division under physiological and pathological conditions. On the one hand, the transition from one phase to another as well as the progression within each phase is driven by the specific cyclin-dependent kinases (CDKs; e.g., CDK1, CDK2, CDK4, CDK6, and CDK7), together with their exclusive partner cyclins (e.g., cyclin A1, B1, D1–3, and E1). On the other hand, these phases are negatively regulated by endogenous CDK inhibitors such as p16ink4a, p18ink4c, p19ink4d, p21cip1, and p27kip1. In addition, several checkpoints control the commitment of cells to replicate DNA and undergo mitosis, thereby avoiding the passage of genomic errors to daughter cells. CDKs are often constitutively activated in cancer, which is characterized by the uncontrolled proliferation of transformed cells, due to genetic and epigenetic abnormalities in the genes involved in the cell cycle. Moreover, several oncogenes and defective tumor suppressors promote malignant changes by stimulating cell cycle entry and progression or disrupting DNA damage responses, including the cell cycle checkpoints, DNA repair mechanisms, and apoptosis. Thus, genes or proteins related to cell cycle regulation remain the main targets of interest in the treatment of various cancer types, including hematologic malignancies. In this context, advances in the understanding of the cell cycle regulatory machinery provide a basis for the development of novel therapeutic approaches. The present article summarizes the pathways as well as their genetic and epigenetic alterations that regulate the cell cycle; moreover, it discusses the various approved or potential therapeutic targets associated with the cell cycle, focusing on hematologic malignancies.
Hematopoietic stem cell metabolism and stemness
Authors: Huang Dan , Chen Chiqi , Xie Li , Yu Zhuo , Zheng Junke
Published: January 2020

Hematopoietic stem cells (HSCs) are considered to originate from the aorta-gonad-mesonephros, migrate into fetal liver for a rapid expansion, and eventually reside into a unique hypoxic bone marrow niche, where they maintain their homeostasis throughout their life span. HSCs have been widely used for the treatment of many begin or malignant hematopoietic disorders. However, the unavailability of sufficient amount of HSCs still impedes their applications in the clinic. It is urgent to understand how HSC stemness or cell fates are determined at different developmental stages. Although many intrinsic and extrinsic factors (niche components) have been identified in the regulation of HSC origination, expansion, migration, and localization, the underlying mechanisms remain largely unknown. In this article, we summarize current views on the metabolic profiles of HSCs and related regulatory networks, which shows that intrinsic metabolic regulation may be critical for the cell fate determinations of HSCs: HSCs utilize glycolysis as their major energy sources; mitochondrial respiration is also required for the homeostasis of HSCs; amino acids, lipids, or other nutrient metabolisms also have unique roles in sustaining HSC activities. Mechanistically, many important regulatory pathways, such as MEIS1/HIF1A, MYC, PPM1K/CDC20, and ROS signals, are identified to fine-tune the nutrient metabolisms and cell fate commitments in HSCs. Nevertheless, more effort is required for the optimization or establishment of sensitive and specific metabolic techniques/systems for the metabolism studies in HSCs with limited cell numbers and exploring the metabolic profiles and fundamental regulatory mechanisms of different types of nutrients at each developmental stage of HSCs.
Engineered human pluripotent stem cell-derived natural killer cells: the next frontier for cancer immunotherapy
Authors: Zhu Huang , Kaufman Dan S.
Published: January 2020

Adoptive immunotherapy using immune effector cells has revolutionized cancer treatments with approval of two autologous chimeric antigen receptor (CAR) T cell therapies by the US FDA. Clinical trials using natural killer (NK) cell-based adoptive immunotherapy have been shown to be safe and effective for treatment of multiple malignancies, especially acute myelogenous leukemia. However, most of these trails use primary NK cells isolated from peripheral or cord blood which can have donor-dependent variability and can be challenging to genetic engineer to improve antitumor functions, limiting the widespread use of this promising new therapy. NK cells can now be routinely produced from human pluripotent stem cells, both human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). These pluripotent stem cells are homogenous, easy to genetically modify on a clonal level and can be used as unlimited source of NK cells, making them ideal population to develop standardized, off-the-shelf adoptive NK cell therapy products. In this review, we discuss recent advances of obtaining and expanding hESC and iPSC-derived NK cells and novel genetic engineering strategies that are being applied to improve their antitumor functions.
Vascular Access Specialist Training, Experience, and Practice in the United States
Authors: Chopra Vineet , Kuhn Latoya , Ratz David , Shader Scarlett , Vaughn Valerie M. , Saint Sanjay , Krein Sarah L.
Published: January 2020

Vascular access specialists are increasingly responsible for insertion and care of peripherally inserted central catheters in the United States. Despite proliferation of the specialty, little is known about the training, practice patterns, and experiences of these clinicians. In partnership with a vascular access and an infusion nursing organization, a Web-based survey of 1698 clinicians was conducted. Substantial variation in practices related to insertion, use of technology, dressing and flushing, and management of complications was observed. Some reported practices were inconsistent with available evidence-based recommendations. Therefore, opportunities to improve patient care and further explore reasons driving such variation exist and should be explored.
Pharmacokinetics, Safety, and Efficacy of Recombinant Factor VIII Fc Fusion Protein
Authors: Schafer Kim , Munn James , Khair Kate , Thukral Neelam , Tom Angela , McAlister Sally
Published: January 2020

Prophylaxis for hemophilia A with conventional factor VIII (FVIII) products requires frequent intravenous dosing, which may reduce adherence. Recombinant factor VIII Fc fusion protein (rFVIIIFc) has a prolonged half-life compared with conventional rFVIII, and has demonstrated safety and efficacy for the prevention and treatment of bleeding episodes in phase 3 studies of patients with severe hemophilia A. Most subjects experienced reduced prophylactic dosing frequency with rFVIIIFc compared with prestudy FVIII; the median total weekly prophylactic consumption was comparable. No subjects developed inhibitors. These results suggest that prophylaxis with rFVIIIFc in patients with hemophilia A may allow less frequent prophylactic dosing while maintaining efficacy, with comparable prophylactic consumption.
Family-Clinician Communication About End-of-Life Care in Korea
Authors: Jo Minjeong , Yoo Yang-Sook , Knafl George , Van Riper Marcia , Beeber Linda , Song Mi-Kyung
Published: January 2020

Effective communication between family members and clinicians is one of the most important factors in end-of-life care, yet little is known about the extent of such communication in Korea. The purpose of this review was to describe the state of the science in family-clinician communication about end-of-life care in Korea, including the timing of communication, family members’ communication needs, and perceived communication quality. The family-physician communication about do-not-resuscitate decision typically occurred near the patient’s death. Receiving sufficient information about patient care was one of the top priorities of family members at the end of life, yet such needs were not met. Physicians and nurses reported they lack communication skills to provide information about patients’ prognosis and end-of-life treatment options effectively. While empirical data are limited, our review suggests that family-clinician communication at the end of life in Korea is inadequate. This review provides an insight about the ways clinicians communicate with family members at the end of life in Korea, which may be helpful to determine components of communication that need to be improved.
Temporal Relationship of Computed and Structured Diagnoses in Electronic Health Record Data
Authors: Schulz Wade L. , Young H. Patrick , Coppi Andreas , Mortazavi Bobak J. , Lin Zhenqiu , Jean Raymond A. , Krumholz Harlan M.
Published: January 2020

The electronic health record (EHR) holds the prospect of providing more complete and timely access to clinical information for studies, quality assessments, and quality improvement compared to other data sources, such as administrative claims. Our goal was to assess the completeness and timeliness of structured diagnoses in the EHR compared to computed diagnoses for hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM). We determined the amount of time for a structured diagnosis to be recorded in the EHR from when an equivalent diagnosis could be computed from other structured data elements, such as vital signs and laboratory results. Using our local instance of EHR data in the PCORnet common data model (CDM) with encounters from January 1, 2012 through February 10, 2019, we identified patients with at least two observations above threshold separated by at least 30 days. The thresholds were outpatient blood pressure of ≥ 140/90 mmHg, any low-density lipoprotein ≥ 130 mg/dl, or any hemoglobin A1c ≥ 7%, respectively. The primary measure was the length of time between the computed diagnosis and the time at which a structured diagnosis could be identified within the EHR history or problem list. We found that 39.8% of those with HTN, 21.6% with HLD, and 1.0% with DM did not receive a corresponding structured diagnosis recorded in the EHR. For those who received a structured diagnosis, a mean of 389, 198, and 106 days elapsed before the patient had the corresponding diagnosis of HTN, HLD, or DM, respectively, recorded in the EHR. We identified a marked temporal delay between when a diagnosis can be computed or inferred and when an equivalent structured diagnosis is recorded within the EHR. These findings demonstrate the continued need for additional study of the EHR to avoid bias when using observational data and reinforce the need for computational approaches to identify clinical phenotypes.
Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma
Authors: Miklja Zachary , Yadav Viveka Nand , Cartaxo Rodrigo T. , Siada Ruby , Thomas Chase C. , Cummings Jessica R. , Mullan Brendan , Stallard Stefanie , Paul Alyssa , Bruzek Amy K. , Wierzbicki Kyle , Yang Tao , Garcia Taylor , Wolfe Ian , Leonard Marcia , Robertson Patricia L. , Garton Hugh J.L. , Wahl Daniel R. , Parmar Hemant , Sarkaria Jann N. , Kline Cassie , Mueller Sabine , Nicolaides Theodore , Glasser Chana , Leary Sarah E.S. , Venneti Sriram , Kumar-Sinha Chandan , Chinnaiyan Arul M. , Mody Rajen , Pai Manjunath P. , Phoenix Timothy N. , Marini Bernard L. , Koschmann Carl
Published: January 2020

Background

Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. We hypothesized that co-treatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib.

Methods

Dose response, synergism studies, P-gp inhibition and pharmacokinetic studies were performed on in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus.

Results

Dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with reduction in mTOR signaling that persists after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended survival of PPK tumor bearing mice. Pediatric patients (n=6) with glioma tolerated this combination without significant adverse events. Recurrent patients (n=4) demonstrated median overall survival of 8.5 months.

Conclusion

Efficacy of dasatinib treatment of PDGFRα-driven HGG is improved with everolimus and suggests a promising route for improving targeted therapy for this patient population.

Trial Registration

ClinicalTrials.gov NCT03352427

Funding

The authors thank the patients and their families for participation in this study. CK is supported by NIH/NINDS K08-NS099427-01, the University of Michigan Chad Carr Pediatric Brain Tumor Center, the Chad Tough Foundation, Hyundai Hope on Wheels, Catching up With Jack, Prayers from Maria Foundation, U CAN-CER VIVE FOUNDATION, Morgan Behen Golf Classic, and the DIPG Collaborative. The PEDS-MIONCOSEQ study was supported by grant 1UM1HG006508 from the National Institutes of Health Clinical Sequencing Exploratory Research Award (PI: Arul Chinnaiyan).
The use of wearable technology to objectively measure sleep quality and physical activity among pregnant women in urban Lima, Peru: A pilot feasibility study
Authors: Galea Jerome T. , Ramos Karen , Coit Julia , Friedman Lauren E. , Contreras Carmen , Dueñas Milagros , Hernandez Giuliana Noris , Muster Caroline , Lecca Leonid , Gelaye Bizu
Published: January 2020

Sleep quality and physical activity can affect the mental and physical health of pregnant women and their unborn babies. We investigated the feasibility of assessing sleep quality and physical activity among pregnant women in Peru. Twenty women maintained sleep logs and wore ActiSleep devices for seven consecutive days; 13 had sufficient data for analysis. Mean sleep duration was 6.9 hours (SD = 1.4). Sleep efficiency was 77.9%. Participants averaged of 6,029 steps per day (SD = 3,087). Objective assessment of sleep quality and physical activity was feasible. Wearable technology has applications in healthcare to improve sleep quality and physical activity.
Taxonomic Signatures of Long-Term Mortality Risk in Human Gut Microbiota
Authors: Salosensaari Aaro , Laitinen Ville , Havulinna Aki , Meric Guillaume , Cheng Susan , Perola Markus , Valsta Liisa , Alfthan Georg , Inouye Michael , Watrous Jeramie D. , Long Tao , Salido Rodolfo , Sanders Karenina , Brennan Caitriona , Humphrey Gregory C. , Sanders Jon G. , Jain Mohit , Jousilahti Pekka , Salomaa Veikko , Knight Rob , Lahti Leo , Niiranen Teemu
Published: January 2020

The collection of fecal material and developments in sequencing technologies have enabled cost-efficient, standardized, and non-invasive gut microbiome profiling. As a result, microbiome composition data from several large cohorts have been cross-sectionally linked to various lifestyle factors and diseases.1–5 In spite of these advances, prospective associations between microbiome composition and health have remained uncharacterized due to the lack of sufficiently large and representative population cohorts with comprehensive follow-up data.6–8 Here, we analyse the long-term association between gut microbiome variation and mortality in a large, well-phenotyped, and representative population cohort (n = 7211, FINRISK 2002; Finland).9 We report specific taxonomic and functional signatures related to the Enterobacteriaceae family in the human gut microbiome that predict mortality during a 15-year follow-up. These associations can be observed both in the Eastern and Western Finns who have differing genetic backgrounds, lifestyles, and mortality rates.10,11 Our results supplement previously reported cross-sectional associations,1–4,12 and help to establish a methodological and conceptual basis for examining long-term associations between human gut microbiome composition, incident outcomes, and general health status. These findings could serve as a solid framework for microbiome profiling in clinical risk prediction, paving the way towards clinical applications of human microbiome sequencing aimed at prediction, prevention, and treatment of disease.
Human Tau Isoform Aggregation and Selective Detection of Misfolded Tau from Post-Mortem Alzheimer’s Disease Brains
Authors: Wu Ling , Wang Zerui , Ladd Shradha , Dougharty Darren T. , Madhavan Sidharth S. , Marcus Madeleine , Henderson Frances , Ray W. Keith , Tan Christopher , Siedlak Sandra , Li Jianyong , Helm Richard F. , Zhu Xiongwei , Bloom George S. , Zou Wen-Quan , Xu Bin
Published: January 2020

Tau aggregates are present in a large number of neurodegenerative diseases known as “tauopathies”, including Alzheimer’s disease (AD). As there are six human tau isoforms in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions, we tested whether tau isoforms behave differently in aggregation. We discovered that all six tau isoforms are capable of forming PHF-tau like filaments and the 3R tau isoforms aggregate significantly faster than their 4R counterparts. We further mapped key segments of tau isoforms that contribute to their aggregation kinetics, where it was determined that microtubule binding domains R2 and R3 were the major contributors to tau aggregation. To evaluate the feasibility of using the six recombinant tau isoforms as substrates to amplify misfolded tau, we demonstrated that full-length human tau isoforms can seed and detect misfolded tau from the post-mortem AD brain tissues with high specificity by an ultrasensitive technology termed real-time quaking-induced conversion (RT-QuIC). Mass spectrometric analysis of PHF-tau samples extracted from AD brains identified peptides corresponding to all major forms of human brain tau isoforms along with a consensus hyperphosphorylated peptide near the C-terminus. Together, our findings not only reveal new aggregation kinetic properties of human tau isoforms, support the development of methods to quantitatively measure misfolded human tau isoforms in AD brains, but also uncover the capability of full-length human tau isoforms as substrates for “prion-like” tau seeding by RT-QuIC assays that may be used for new biomarker development for AD and other tauopathy diagnosis.
Weekend light shifts evoke persistentDrosophilacircadian neural network desynchrony
Authors: Nave Ceazar , Roberts Logan , Hwu Patrick , Estrella Jerson D. , Vo Thanh C , Nguyen Thanh H , Pervolarakis Nicholas , Shaw Paul J. , Leise Tanya L. , Holmes Todd C.
Published: January 2020

Billions of people subject themselves to phase-shifting light signals on a weekly basis by remaining active later at night and sleeping in later on weekends relative to weekday for up to a 3hr weekend light shift (WLS). Unnatural light signals disrupt circadian rhythms and physiology and behavior. Real-time light responses of mammalian suprachiasmatic nucleus are unmeasurable at single cell resolution. We comparedDrosophilawhole-circadian circuit responses between unshifted daytime/nighttime schedule and a 3hr WLS schedule at the single-cell resolution in cultured adultDrosophilabrains using real-time bioluminescence imaging of the PERIOD protein for 11 days to determine how light shifts alter biological clock entrainment and stability. We find that circadian circuits show highly synchronous oscillations across all major circadian neuronal subgroups in unshifted light schedules. In contrast, circadian circuits exposed to a WLS schedule show significantly dampened oscillator synchrony and rhythmicity in most circadian neurons during, and after exposure. The WLS schedule first desynchronizes lateral ventral neuron (LNv) oscillations and the LNv are the last to resynchronize upon returning to a simulated weekday schedule. Surprisingly, one circadian subgroup, the dorsal neuron group-3 (DN3s), robustly increase their within-group synchrony in response to WLS exposure. Intact adult flies exposed to the WLS schedule show post-WLS transient defects in sleep stability, learning, and memory. Our findings suggest that WLS schedules disrupt circuit-wide circadian neuronal oscillator synchrony for much of the week, thus leading to observed behavioral defects in sleep, learning, and memory.

Significance Statement

The circadian clock controls numerous aspects of daily animal physiology, metabolism and behavior. Shift work in humans is harmful. Our understanding of circadian circuit-level oscillations stem fromex vivoimaging of mammalian suprachiasmatic nucleus (SCN) brain slices. However, our knowledge is limited to investigations without direct interrogation of phase-shifting light signals. We measured circuit-level circadian responses to a WLS protocol in light sensitiveex vivo Drosophilawhole-brain preparation and find robust sub-circuit-specific oscillator desynchrony/resynchrony responses to light. These circuit-level behaviors correspond to our observed functional defects in learning and memory, and sleep pattern disruptionin vivo. Our results reflect that WLS cause circadian-circuit desynchronization and correlate with disrupted cognitive and sleep performance.
The predictive power of the microbiome exceeds that of genome-wide association studies in the discrimination of complex human disease
Authors: Tierney Braden T , He Yixuan , Church George M , Segal Eran , Kostic Aleksandar D , Patel Chirag J
Published: January 2020

Over the past decade, studies of the human genome and microbiome have deepened our understanding of the connections between human genes, environments, microbes, and disease. For example, the sheer number of indicators of the microbiome and human genetic common variants associated with disease has been immense, but clinical utility has been elusive. Here, we compared the predictive capabilities of the human microbiome versus human genomic common variants across 13 common diseases. We concluded that microbiomic indicators outperform human genetics in predicting host phenotype (overall Microbiome-Association-Study [MAS] area under the curve [AUC] = 0.79 [SE = 0.03], overall Genome-Wide-Association-Study [GWAS] AUC = 0.67 [SE = 0.02]). Our results, while preliminary and focused on a subset of the totality of disease, demonstrate the relative predictive ability of the microbiome, indicating that it may outperform human genetics in discriminating human disease cases and controls. They additionally motivate the need for population-level microbiome sequencing resources, akin to the UK Biobank, to further improve and reproduce metagenomic models of disease.
Dual roles of the Sterol Recognition Region in Hedgehog protein modification
Authors: Purohit Rahul , Peng Daniel S. , Vielmas Erika , Ondrus Alison E.
Published: January 2020

Nature provides a number of mechanisms to encode dynamic information in biomolecules. In metazoans, there exist rare chemical modifications that occur through entirely unique mechanistic regimes. One such example occurs in the Hedgehog (Hh) morphogens, proteins singular across all domains of life for the nature of their covalent ligation to cholesterol. The isoform- and context-specific efficiency of the ligation reaction has profound impact on the activity of Hh morphogens and represents an unexplored aspect of Hh ligand-dependent cancers. To elucidate the chemical mechanism of this modification, we have defined roles of the uncharacterized sterol recognition region (SRR) in Hh proteins. We use a combination of sequence conservation, directed mutagenesis, and biochemical assays to specify residues of the SRR that are responsible for cellular and biochemical processes in Hh cholesterolysis. Our investigations offer the first functional template of this region, providing opportunities to identify parallel reactivity in nature and revealing new mechanisms that can be exploited as tools in chemical biology.
Molecular height measurement by cell surface optical profilometry (CSOP)
Authors: Son Sungmin , Takatori Sho C. , Belardi Brian , Podolski Marija , Bakalar Matthew H. , Fletcher Daniel A.
Published: January 2020

The physical dimensions of proteins and glycans on cell surfaces can critically affect cell function, for example by preventing close contact between cells and limiting receptor accessibility. However, high-resolution measurements of molecular heights on native cell membranes have been difficult to obtain. Here we present a simple and rapid method that achieves nanometer height resolution by localizing fluorophores at the tip and base of cell surface molecules and determining their separation by radially averaging across many molecules. We use this method, which we call cell surface optical profilometry (CSOP), to quantify height of key multi-domain proteins on a model macrophage and cancer cell, as well as to capture average protein and glycan heights on native cell membranes. We show that average height of a protein is significantly smaller than its contour length due to thermally driven bending and rotation on the membrane and that height strongly depends on local surface and solution conditions. We find that average height increases with cell surface molecular crowding, while it decreases with solution crowding by solutes, both of which we confirm with molecular dynamics simulations. We also use experiments and simulations to determine the height of an epitope based on the location of an antibody, which allows CSOP to profile various proteins and glycans on a native cell surface using antibodies and lectins. This versatile method for profiling cell surfaces has the potential to advance understanding of the molecular landscape of cells and its role in cell function.
Correlated Gene Modules Uncovered by Single-Cell Transcriptomics with High Detectability and Accuracy
Authors: Chapman Alec R. , Lee David F. , Cai Wenting , Ma Wenping , Li Xiang , Sun Wenjie , Xie X. Sunney
Published: January 2020

Single cell transcriptome sequencing has become extremely useful for cell typing. However, such differential expression data has shed little light on regulatory relationships among genes. Here, by examining pairwise correlations between mRNA levels of any two genes under steady-state conditions, we uncovered correlated gene modules (CGMs), clusters of intercorrelated genes that carry out certain biological functions together. We report a novel single-cell RNA-seq method called MALBAC-DT with higher detectability and accuracy, allowing determination of the covariance matrix of the expressed mRNAs for a homogenous cell population. We observed a prevalence of positive correlations between pairs of genes, with higher correlations corresponding to higher likelihoods of protein-protein interactions. Some CGMs, such as the p53 module in a cancer cell line, are cell type specific, while others, such as the protein synthesis CGM, are shared by different cell types. CGMs distinguished direct targets of p53 and exposed different modes of regulation of these genes in different cell types. Our covariance analyses of steady-state fluctuations provides a powerful way to advance our functional understanding of gene-to-gene interactions.
Improving protein alignment algorithms using amino-acid hydrophobicities - Applications of TMATCH, A new algorithms
Authors: Cavanaugh David P. , Chittur Krishnan K.
Published: January 2020

Motivation

Sequence database search and matching algorithms are an important tool when trying to understand the structure (and so the function) of proteins. Proteins with similar structure and function often have very similar primary structure. There are however many cases where proteins with similar structure have very different primary structures. Substitution matrices (PAM, BLOSUM, Gonnett) can be used to identify proteins of similar structure, but they fail when the sequence similarity falls below about 25%.

Results

We have described a new algorithm for examining the the primary structure of proteins against a database of known proteins with a new hydrophobicity index. In this paper, we examine the ability of TMATCH to identify proteins of similar structure using sequence matching with the hydrophobicity index. We compare results from TMATCH with those obtained using FASTA and PSI-BLAST. We show that by using similarity patterns spread across the entire length of two proteins we get a more robust indicator of remote relatedness than relying upon high similarity scoring pair regions.

Availability

The program TMATCH is available on request

Contact

chitturk@uah.edu
ATR expands embryonic stem cell fate potential in response to replication stress
Authors: Atashpaz Sina , Shams Sara Samadi , Gonzalez Javier Martin , Sebestyén Endre , Arghavanifard Negar , Gnocchi Andrea , Albers Eliene , Minardi Simone , Faga Giovanni , Soffientini Paolo , Allievi Elisa , Cancila Valeria , Bachi Angela , Fernandez-Capetillo Oscar , Tripodo Claudio , Ferrari Francesco , López-Contreras Andrés Joaquin , Costanzo Vincenzo
Published: January 2020

Unrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood.

Here, we uncovered an ATR- and CHK1-mediated transcriptional response to replication stress (RS) in ESCs that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated byDux,a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX triggers the transcription of 2C-like markers such as murine endogenous retrovirus-like elements (MERVL) andZscan4.This response can also be elicited by ETAA1-mediated ATR activation in the absence of RS. ATR-mediated activation of DUX requires GSRF1 dependent post-transcriptional regulation ofDuxmRNA. Strikingly, activation of ATR expands ESCs fate potential by extending their contribution to both embryonic and extra­embryonic tissues. These findings define a novel ATR dependent pathway involved in maintaining genome stability in developing embryos by controlling ESCs fate in response to RS.
Associative Learning and Motivation Differentially Requires Neuroligin-1 at Excitatory Synapses
Authors: Luo Jiaqi , Tan Jessica M , Nithianantharajah Jess
Published: January 2020

In a changing environment, a challenge for the brain is to flexibly guide adaptive behavior towards survival. Understanding how these decision-making processes and underlying neural computations are orchestrated by the structural components of the brain, from circuits to cells, and ultimately the signaling complex of proteins at synapses, is central to elucidating the mechanisms that shape normal and abnormal brain connectivity, plasticity and behavior. At excitatory synapses, neuroligin-1 (Nlgn1) a postsynaptic cell-adhesion molecule required for the formation of trans-synaptic complexes with presynaptic partners is critical for regulating synapse specification, function and plasticity. Extensive evidence shows Nlgn1 is essential for synaptic transmission and long-term plasticity, but how these signaling processes ultimately regulate components of cognitive behavior is much less understood. Here, employing a comprehensive battery of touchscreen-based cognitive assays, we measured two key decision problems: i) the ability to learn and exploit the associative structure of the environment and ii) the trade-off between potential rewards and costs, or positive and negative utilities associated with available actions. We found that mice lacking Nlgn1 have an intact capacity to acquire complex associative structures and adjust learned associations. However, loss of Nlgn1 alters motivation leading to areducedwillingness to overcome response effort for reward and anincreasedwillingness to exert effort to escape an aversive situation. We suggest Nlgn1 may be important for balancing the weighting on positive and negative utilities in reward-cost trade-off. Our findings identify Nlgn1 is essential for regulating distinct cognitive processes underlying decision-making, providing evidence of a new model for dissociating the computations underlying learning and motivational processing.
BET bromodomain inhibitor HMBA synergizes with MEK inhibition in treatment of malignant glioma
Authors: Funck-Brentano Elisa , Vizlin-Hodzic Dzeneta , Nilsson Jonas A. , Nilsson Lisa M.
Published: January 2020

(1)

Background

BET bromodomain proteins regulate transcription by binding acetylated histones and attracting key factors for e.g. transcriptional elongation. BET inhibitors have been developed to block pathogenic processes such as cancer and inflammation. Despite having potent biological activities, BET inhibitors have still not made a breakthrough in clinical use for treating cancer. Multiple resistance mechanisms have been proposed but thus far no attempts to block this in glioma has been made.

(2)

Methods

Here, we have conducted a pharmacological synergy screen in glioma cells to search for possible combination treatments augmenting the apoptotic response to BET inhibitors. We first used HMBA, a compound that was developed as a differentiation therapy four decades ago but more recently was shown to primarily inhibit BET bromodomain proteins. Data was also generated using other BET inhibitors.

(3)

Results

In the synergy screen, we discovered that several MEK inhibitors can enhance apoptosis in response to HMBA in rat and human glioma cells in vitro as well as in vivo xenografts. The combination is not unique to HMBA but also other BET inhibitors such as JQ1 and I-BET-762 can synergize with MEK inhibitors.

(4)

Conclusions

Our findings validate a combination therapy previously demonstrated to exhibit anti-cancer activities in multiple other tumor types but which appears to have been lost in translation to the clinic.
Granular Transcriptomic Signatures Derived from Independent Component Analysis of Bulk Nervous Tissue for Studying Labile Brain Physiologies
Authors: Rusan Zeid M , Cary Michael P , Bainton Roland J
Published: January 2020

Multicellular organisms employ concurrent gene regulatory programs to control development and physiology of cells and tissues. TheDrosophila melanogastermodel system has a remarkable history of revealing the genes and mechanisms underlying fundamental biology yet much remains unclear. In particular, brain xenobiotic protection and endobiotic regulatory systems that require transcriptional coordination across different cell types, operating in parallel with the primary nervous system and metabolic functions of each cell type, are still poorly understood. Here we use the unsupervised machine learning method independent component analysis (ICA) on majority fresh-frozen, bulk tissue microarrays to define biologically pertinent gene expression signatures which are sparse, i.e. each involving only a fraction of all fly genes. We optimize the gene expression signature definitions partly through repeated application of a stochastic ICA algorithm to a compendium of 3,346 microarrays from 221 experiments provided by theDrosophilaresearch community. Our optimized ICA model of pan fly gene expression consists of 850 modules of co-regulated genes that map to tissue developmental stages, disease states, cell-autonomous pathways and presumably novel processes. Importantly, we show biologically relevant gene modules expressed at varying amplitudes in whole brain and isolated adult blood-brain barrier cell levels. Thus, whole tissue derived ICA transcriptional signatures that transcend single cell type boundaries provide a window into the transcriptional states of difficult to isolate cell ensembles maintaining delicate brain physiologies. We believe the fly ICA gene expression signatures set, by virtue of the success of ICA at inferring robust often low amplitude patterns across large datasets and the quality of the input samples, to be an important asset for analyzing compendium and newly generated microarray or RNA-seq expression datasets.
Exploring Mechanisms of Glucose Uptake Regulation and Dilution Resistance in Growing Cancer Cells
Authors: Tveit Daniel M. , Fjeld Gunhild , Drengstig Tormod , Filipp Fabian V. , Ruoff Peter , Thorsen Kristian
Published: January 2020

Most cancer cells rely on aerobic glycolysis and increased glucose uptake for the production of biosynthetic precursors needed to support rapid proliferation. Increased glucose uptake and glycolytic activity may result in intracellular acidosis and increase of osmotically active substances, leading to cell swelling. This causes dilution of cellular constituents, which can markedly influence cellular reactions and the function of proteins, and hence, control mechanisms used by cancer cells to maintain a highly glycolytic phenotype must be robust to dilution. In this paper, we review the literature on cancer cell metabolism and glucose uptake, and employ mathematical modeling to examine control mechanisms in cancer cell metabolism that show robust homeostatic control in the presence of dilution. Using differential gene expression data from the Expression Atlas database, we identify the key components of glucose uptake in cancer, in order to guide the construction of a mathematical model. By simulations of this model we show that while negative feedback from downstream glycolytic metabolites to glucose transporters is sufficient for homeostatic control of glycolysis in a constant cellular volume, it is necessary to control intermediate glycolytic enzymes in order to achieve homeostatic control during growth. With a focus on glucose uptake in cancer, we demonstrate a systems biology approach to the identification, reduction, and analysis of complex regulatory systems.

SIGNIFICANCE

Rapid proliferation and increased glycolytic activity in cancer cells lead to dilution of cellular constituents, which can markedly influence cellular reactions and the function of proteins. Therefore, control mechanisms used by cancer cells to maintain a highly glycolytic phenotype must be robust to dilution. We construct a mathematical model of glucose uptake in cancer, and using a systems biology approach to the analysis of regulatory networks, identify the presence of integral control motifs as a means for achieving dilution resistance. Furthermore, we show that while negative feedback from downstream glycolytic metabolites to glucose transporters is sufficient for homeostatic control of glycolysis in a constant cellular volume, it is necessary to control intermediate glycolytic enzymes to achieve homeostatic control during growth.
Genomic imprinting in plants—revisiting existing models
Authors: Batista Rita A. , Köhler Claudia
Published: January 2020

Genomic imprinting is an epigenetic phenomenon leading to parentally biased gene expression. Throughout the years, extensive efforts have been made to characterize the epigenetic marks underlying imprinting in animals and plants. As a result, DNA methylation asymmetries between parental genomes emerged as the primary factor controlling the imprinting status of many genes. Nevertheless, the data accumulated so far suggest that this process cannot solely explain the imprinting of all genes. In this review, we revisit the current models explaining imprinting regulation in plants, and discuss novel regulatory mechanisms that could function independently of parental DNA methylation asymmetries in the establishment of imprinting.
53BP1: a DSB escort
Authors: Mirman Zachary , de Lange Titia
Published: January 2020

53BP1 is an enigmatic DNA damage response factor that gained prominence because it determines the efficacy of PARP1 inhibitory drugs (PARPi) in BRCA1-deficient cancers. Recent studies have elevated 53BP1 from its modest status of (yet another) DNA damage factor to master regulator of double-strand break (DSB) repair pathway choice. Our review of the literature suggests an alternative view. We propose that 53BP1 has evolved to avoid mutagenic repair outcomes and does so by controlling the processing of DNA ends and the dynamics of DSBs. The consequences of 53BP1 deficiency, such as diminished PARPi efficacy in BRCA1-deficient cells and altered repair of damaged telomeres, can be explained from this viewpoint. We further propose that some of the fidelity functions of 53BP1 coevolved with class switch recombination (CSR) in the immune system. We speculate that, rather than being deterministic in DSB repair pathway choice, 53BP1 functions as a DSB escort that guards against illegitimate and potentially tumorigenic recombination.
Linking cancer transcriptional addictions by CDK7 to YAP/TAZ
Authors: Piccolo Stefano
Published: January 2020

Inhibition of CDK7 is a promising strategy for cancer therapy. CDK7 so far has been understood mainly in the context of Pol II-driven transcription. However, how are the roles of CDK7 in the “basal” transcriptional machinery reconciled with the function of CDK7 as inducer of specific transcriptional programs in tumor cells? In this issue of Genes & Development, Cho and colleagues (pp. 53–71) advance in this direction, demonstrating that attenuation of CDK7 fosters the oncogenic activity of the YAP/TAZ/Yki coactivators. CDK7 directly phosphorylates YAP/TAZ/Yki in the nucleus, protecting them from ubiquitination and degradation, in a manner independent from the Hippo cascade and independent from CDK7 basal transcriptional functions.
Intelligent compaction practice and development: a bibliometric analysis
Authors: Liu Donghai , Wang Youle , Chen Junjie , Zhang Yalin
Published: January 2020

Purpose

The purpose of this paper is to provide insights into the current practice, challenges and future development trends of intelligent compaction (IC) technology from a bibliometric perspective.

Design/methodology/approach

A bibliometric analysis on IC-relevant studies is presented. Through this quantitative manner, insights into the current IC research practice and development trends have been derived from the perspectives of publications and citations, spatial distribution, knowledge construction, structural variations, existing problems, and conclusions and recommendations.

Findings

Currently, IC applications are confronted with the issues of intelligent compaction measurement values (ICMVs) applicability, autonomous control, specifications and applications. To address the issues, three potential research directions are identified: a comprehensive ICMV measurement system that is designated for single layer analysis; autonomous control mechanisms with integrated management capabilities that can efficiently collaborate all stakeholders; and a standardized application workflow and the cost-benefit evaluation of IC in the context of the full life cycle.

Research limitations/implications

The literature used in this paper is collected from the Web of Science. Although the database covers almost all the important publications in IC field, studies not indexed by the database are not considered.

Originality/value

This research quantitatively analyzes the current IC practice and development trends from the perspectives of bibliometric analysis. It provides an overview of the knowledge construction and development of IC technology. The discussions about the problems and the suggested solutions can be useful for those interested in this field.
Apprenticeship for craftspeople in the construction industry: a state-of-the-art review
Authors: Daniel Emmanuel Itodo , Oshodi Olalekan Shamsideen , Gyoh Louis , Chinyio Ezekiel
Published: January 2020

Purpose

Apprenticeship programmes are designed to provide young trainees with essential broad-based skills. Through apprenticeships, different sectors that are underpopulated can fill up their skills gaps. Apprenticeships are particularly useful to the construction sector which has a high ageing workforce and associated lower labour productivity. However, the completion rates of apprenticeship training programmes in the construction sector remain low in several countries across the globe. Thus, the purpose of this paper is to review the published research on apprenticeship training that is specifically focused on the construction sector, to determine the current status quo and suggest a direction for future research.

Design/methodology/approach

A systematic review approach was adopted. Based on a comprehensive search using SCOPUS databases, 33 relevant journal articles were identified and analysed.

Findings

It was found that monitoring and control is the most mentioned factor responsible for improvements in the completion rates of apprenticeship training. In contrast, the length of time required for going through the full training is the most common factor responsible for low completion rates. Three research gaps were identified, among which is the dearth of studies that has focused on apprentices training in developing countries.

Research limitations/implications

The gaps identified in the current knowledge on apprenticeship training would serve as a justification for future investigations. However, the scope of the review is limited to papers published in academic journals and citable through SCOPUS.

Practical implications

The outcomes of the study provide researchers and other relevant stakeholders with a concise report on the findings of previous studies. It also provides insight into strategies for improving the completion rates of apprenticeship training in the construction sector.

Originality/value

A systematic evaluation of the extant literature draws on theoretical evidence and highlights the factors that are more likely to influence the outcomes of apprentice training for craftspeople in the construction sector.