bluuebunny/crossref_metadata_2025 huggingface dataset:
High rate of increased level of plasma Angiotensin II and its gender difference in COVID-19: an analysis of 55 hospitalized patients with COVID-19 in a single hospital, WuHan, China
Authors: Liu Na , Hong Yan , Chen Ren-Gui , Zhu Heng-Mei
Published: May 2020

Background

2019 Novel coronavirus disease (COVID-19) is turning into a pandemic globally lately. Angiotensin-converting enzyme 2 (ACE2) is identified as an important functional receptor for SARS-Cov-2. ACE2 and ACE are homologues with inverse functions in the renin–angiotensin system. ACE converts angiotensin I into a vital vasoactive peptide called angiotensin II(AngII), whereas ACE2 hydrolyzes AngII into a series of vasodilators. There were few reports illustrated the expression of AngII in COVID-19. This study aimed to demonstrate the expression of angiotensin II in COVID-19 and how it correlated to the disease.

Methods

We enrolled 55 patients with COVID-19 admitted to renmin Hospital of Wuhan University from January 21st to February 21st, 2020. Demographic data were collected upon admission. COVID-19 nuclear acid, plasma AngII, Renin and aldosterone in the lying position without sodium restriction, and other laboratory indicators were together measured by the laboratory department of our hospital.

Findings

Of the 55 patients with COVID-19, 34(61.8%) had an increased level of AngII. The severity of COVID-19 and male is positively related with the level of AngII. The level of blood lymphocyte, PCT, ALT, and AST were remarkably severe with those of normal level of AngII (P < 0.05). CD4/CD8 cells ratio was significantly higher whereas CD3+CD8+ cells amount, CD3+CD8+ cells proportion, CD56+CD16+CD3- cells amount and CD19+CD3- cells amount were considerably lower than those of normal level of AngII (P < 0.05). Abnormal rates of blood lymphocyte and PCT were significantly higher in Patients with elevated AngII level. The results of binary logistic regression analysis showed that the severity of COVID-19 (OR=4.123) and CD4/CD8 ratio(OR=4.050) were the co-directional impact factor while female(OR=0.146) was inverse impact factor of elevated AngII level.

Interpretation

High rate of increased level of AngII was detected in COVID-19 patients. Patients with elevated AngII level were more likely to be critically ill with COVID-19. Considering the gender differences in ACE2 expression and no gender differences in angiotensin expression, the gender differences in AngII level might indicate less loss of ACE2 in female patients. Elevated AngII level was correlated with CD4/CD8 ratio, suggesting it might involve in immune disorder.
Favipiravir for treating novel coronavirus (COVID-19) patients: protocol for a systematic review and meta-analysis of controlled trials
Authors: Arab-zozani Morteza , Hassanipour Soheil , Ghoddoosi-Nejad Djavad
Published: May 2020

Introduction

An outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was reported in Wuhan, China in mid-December 2019, and declared a pandemic by the World Health Organization (WHO) on March 11, 2020. Due to the unknown nature of the disease and the lack of specific drugs, several potential treatments were used for patients. This systematic review and meta-analysis will evaluate studies of the effects of Favipiravir in COVID-19 pneumonia.

Methods and analysis

We will search electronic databases including LitCovid hub, PubMed, Scopus, ISI web of Sciences, Cochrane, and Embase using keywords related to COVID-19 and Favipiravir. We will search the reference lists of all included studies and reviews. We will also search for clinical trial registries, such as clinicaltrial.gov for the ongoing clinical trials. Two investigators (MAZ and SH) will independently screen titles, abstracts, and full-text of included studies based on eligibility criteria. These investigators will also independently extract data and appraise the quality of studies. All potential discrepancies will be resolved through consultation with the third reviewer. Data synthesis will be conducted using the Review Manager software (version 5.3) or CMA (version 2). Statistical heterogeneity will be assessed using a standard I2 test. A funnel plot, Egger’s test, and Begg’s test will be used for asymmetry to explore possible publication bias.

Ethics and dissemination

The findings of this systematic review with proportional meta-analysis will help to identify the safety and efficacy of Favipiravir for COVID-19 patients. Knowledge gained from this research will also assist physicians in selecting better treatment options and developing a guideline in this field.

Strengths and limitations of this study

In the protocol, all stage of study conducted by two reviewers independently and supervised by a third reviewer.

This systematic review may produce the first meta-analysis that provides evidence regarding the safety and effectiveness of favipiravir on COVID-19 patients.

The small number of studies published in this field when writing a protocol can be one of the most important limitations.

PROSPERO registration number: CRD42020180032
Empirical evidence for safety of mechanical ventilation during simulated cardiopulmonary resuscitation on a physical model
Authors: de Andrade Neumamm Leonardo Bugarin , Jardim-Neto Alcendino Cândido , Motta-Ribeiro Gabriel Casulari da
Published: May 2020

Background

Cardiac arrest is a critical event requiring adequate and timely response in order to increase patient’s chance of survival. In patients mechanically ventilated with advance airways cardiopulmonary resuscitation (CPR) maneuver may be simplified by keeping the ventilator on. This work assessed the response of a intensive care mechanical ventilator to CPR using a patient manikin ventilated in three conventional modes.

Methods

Volume controlled (VCV), pressure controlled (PCV) and pressure regulated volume controlled (PRVC) ventilation were applied in a thorax physical model with or without chest compressions. The mechanical ventilator was set with inspiratory time of 1.0 s, ventilation rate of 10 breaths/minute, positive end-expiratory pressure of 0 cmH2O, FiO2 of 1.0, target tidal volume of 600 ml and trigger level of -20 cmH2O. Airway opening pressure and ventilatory flow signals were continuously recorded..

Results

Chest compression resulted in increased airway peak pressure in all ventilation modes (p<0.001), specially with VCV (137% in VCV, 83% in PCV, 80% in PRVC). However, these pressures were limited to levels similar to release valves in manual resuscitators (∼60 cmH2O). In pressure controlled modes tidal/minute volumes decreased (PRVC=11%, p=0.027 and PCV=12%, p<0.001), while still within the variability observed during bag-valve-mask ventilation. During VCV, variation in tidal/minute volumes were not significant (p=0.140). Respiratory rates were constant with and without chest compression.

Conclusions

A intensive care mechanical ventilator could provide adequate ventilation during compressions in a manikin model while using conventional ventilation modes.
Cuticular hydrocarbon biosynthesis in malaria vectors: insights from the adult oenocyte transcriptome
Authors: Grigoraki Linda , Grau-Bove Xavier , Carrington-Yates Henrietta , Lycett Gareth J , Ranson Hilary
Published: May 2020

The surface of insects is coated in cuticular hydrocarbons (CHCs); variations in the composition of this layer affect a range of traits including adaptation to arid environments and defence against pathogens and toxins. In the African malaria vector,Anopheles gambiaequantitative and qualitative variance in CHC composition have been associated with speciation, ecological habitat and insecticide resistance. Understanding how these modifications arise will inform us of how mosquitoes are responding to climate change and vector control interventions. CHCs are synthesised in sub-epidermal cells called oenocytes that are very difficult to isolate from surrounding tissue. Here we utilise a transgenic line with fluorescent oenocytes to purify these cells for the first time. Comparative transcriptomics revealed the enrichment of biological processes related to long chain fatty acyl-CoA biosynthesis and elongation of mono-, poly-unsaturated and saturated fatty acids and enabled us to delineate, and partially validate, the hydrocarbon biosynthetic pathway inAn gambiae.
COVID-19 in people living with human immunodeficiency virus: A case series of 33 patients
Authors: Härter Georg , Spinner Christoph D. , Roider Julia , Bickel Markus , Krznaric Ivanka , Grunwald Stephan , Schabaz Farhad , Gillor Daniel , Postel Nils , Mueller Matthias C. , Müller Markus , Römer Katja , Schewe Knud , Hoffmann Christian
Published: May 2020

Data on people living with human immunodeficiency virus (PLWH) in the current SARS-CoV-2 pandemic is still scarce. This case series of 33 PLWH patients with COVID-19 reveals symptoms and outcome in this special population. Three out of 32 patients with documented outcome died (9%). However, 91% of the patients recovered and 76% have been classified as mild cases, indicating that there is no excess morbidity and mortality among PLWH with symptomatic COVID-19. All patients were on antiretroviral treatment, of them 22 on tenofovir-containing regimen, and 4 on the protease inhibitor darunavir.
Cohort profile: Preliminary experience of 500 COVID-19 postive cases at a South West London District General Hospital
Authors: Field R.E , Afzal I. , Dixon J. , Patel V.R , Sarkar P , Marsh J.E
Published: May 2020

This retrospective cohort analysis, reports the demographic data and early outcome of the first 500 patients who were admitted to a District General Hospital in South West London, UK and tested positive to COVID-19. The patients were admitted between 10 January and 10 April 2020; with the first COVID-19 positive diagnosis on 6 March. A surge in admissions started around the 15 March and peaked at the beginning of April.

56.8% of the admissions were male and 43.2% were female. The average age of the 500 admissions was 69.32 years (SD 19.23 years, range 1 week to 99.21 years). By the morning of 14 April 2020, 199 patients had been discharged (Female 89, Male 111), 163 patients had died (female 61, male 102) and 131 remained as in-patients (female 66, male 71).

Fewer than one in twenty deaths occurred in patients below the age of 50 years, in either gender. Mortality rose dramatically, for both genders, after the age of sixty with males being almost twice as vulnerable to dying, as females, during the 7th decade. Males older than their mid-fifties were more likely to die than leave hospital. The same applied to females beyond their mid seventies. We did not see any evidence of a poorer outcome associated with a lower decile for Index of Multiple Deprivation or convincing evidence that any Ethnic minority groups were more likely to die than the White subgroups. When compared to the equivalent medical conditions, normally treated in the early spring, COVID-19 has an increased mortality, adversely affecting more men and an older population.

The mean duration from admission to discharge was 11.29 days (SD 11.50 days). For admission to death, the mean interval was 11.72 days (SD 11.05 days). 62 of the 500 admissions required ventilator support. Of this subgroup, 71% were male and 29% were female. By the morning of the 14 April, no female over the age of 60 had left the intensive care unit alive and no male over the age of 50 had left the intensive care unit alive. At this time-point, 1.2% of the 500 admitted patients had returned alive from the intensive care units, following a period of ventilator support. This figure will rise if prolonged ventilator and renal support proves effective.

While only providing a snapshot of a relatively small number of patients, reviewed over a short time period, from a small geographic area, the data supports the view that the younger members of society are less vulnerable to the adverse sequelae of COVID-19 infection and that any return to normal work and social activities should be considered initially for the individuals who are less than 40-50 years of age. There is an ongoing need for analyses on larger patient cohorts using both demographic and detailed clinical data.
Potential spreading risks and disinfection challenges of medical wastewater by the presence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral RNA in septic tanks of fangcang hospital
Authors: Zhang Dayi , Ling Haibo , Huang Xia , Li Jing , Li Weiwei , Yi Chuan , Zhang Ting , Jiang Yongzhong , He Yuning , Deng Songqiang , Zhang Xian , Liu Yi , Li Guanghe , Qu Jiuhui
Published: May 2020

The outbreak of coronavirus infectious disease-2019 (COVID-19) pneumonia raises the concerns of effective deactivation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in medical wastewater by disinfectants. In this study, we evaluated the presence of SARS-CoV-2 viral RNA in septic tanks of Wuchang Fangcang Hospital and found their unexpected occurrence after disinfection with sodium hypochlorite. Embedded viruses in faeces particles might be released in septic tanks, behaving as a source of SARS-CoV-2 and potentially contributing to its spread through drainage pipelines. Current recommended disinfection strategy (free chlorine above 6.5 mg/L after 1.5-hour contact) needs to be reevaluated to completely remove SARS-CoV-2 viral RNA in non-centralized disinfection system and effectively deactivate SARS-CoV-2. The effluents showed negative results for SARS-CoV-2 viral RNA when overdosed with sodium hypochlorite but had high a level of disinfection by-product residuals, possessing significant ecological risks.
Network Analysis Prioritizes DEWAX and ICE1 as the Candidate Genes for Major eQTL Hotspots in Seed Germination
Authors: Hartanto Margi , Joosen Ronny V. L. , Snoek Basten L. , Willems Leo A. J. , Sterken Mark G. , de Ridder Dick , Hilhorst Henk W. M. , Ligterink Wilco , Nijveen Harm
Published: May 2020

Seed germination is characterized by a constant change of gene expression across different time points. These changes are related to specific processes, which eventually determine the onset of seed germination. To get a better understanding on the regulation of gene expression during seed germination, we performed a quantitative trait locus mapping of gene expression (eQTL) at four important seed germination stages (primary dormant, after-ripened, six-hour after imbibition, and radicle protrusion stage) usingArabidopsis thalianaBay x Sha recombinant inbred lines (RILs). The mapping displayed the distinctness of the eQTL landscape for each stage. We found several eQTL hotspots across stages associated with the regulation of expression of a large number of genes. Interestingly, an eQTL hotspot on chromosome five collocates with hotspots for phenotypic and metabolic QTLs in the same population. Finally, we constructed a gene co-expression network to prioritize the regulatory genes for two major eQTL hotspots. The network analysis prioritizes transcription factors DEWAX and ICE1 as the most likely regulatory genes for the hotspot. Together, we have revealed that the genetic regulation of gene expression is dynamic along the course of seed germination.

One-sentence summary

Two transcription factors, DEWAX and ICE1, may be important regulators of gene expression during seed germination, based on network analysis of eQTL hotspots.
Specificity of Gβ and γ subunits to the SNARE complex both at rest and after α2aadrenergic receptor stimulation
Authors: Yim Yun Young , McDonald W. Hayes , Betke Katherine M. , Kaya Ali , Hyde Karren , Erreger Kevin , Gilsbach Ralf , Hein Lutz , Hamm Heidi E.
Published: May 2020

Though much is known about the various physiological functions of each GPCR and the specificity of Gα subunits, the specificity of Gβγ activated by a given GPCR and activating each effector in vivo is not known. Previously, we identified different Gβ and Gγ subunits interacting specifically with α2a-adrenergic receptors (α2aAR). In this study, we examined its in vivo specificity to the soluble NSF attachment proteins (SNARE) complex in adrenergic (auto-α2aAR) and non-adrenergic (hetero-α2aAR) neurons. We applied a quantitative targeted multiple reaction monitoring proteomic analysis of Gβ and Gγ subunits bound to the SNARE complex, and found only a subset of Gβ and Gγ bound. Without stimulation of auto-α2aAR, Gβ1and Gγ3interacted with the SNARE complex. When auto-α2aAR were activated, Gβ1, Gβ2, and Gγ3were found. Further understanding of in vivo Gβγ specificity to its effectors provides new insights into the multiplicity of genes for Gβ and Gγ.

Specific Gβγ dimers interact with the SNARE complex following presynaptic α2aAR activation in both adrenergic and non-adrenergic neurons.
Rapid invisible frequency tagging reveals nonlinear integration of auditory and visual information
Authors: Drijvers Linda , Jensen Ole , Spaak Eelke
Published: May 2020

During communication in real-life settings, the brain integrates information from auditory and visual modalities to form a unified percept of our environment. In the current magnetoencephalography (MEG) study, we used rapid invisible frequency tagging (RIFT) to generate steady-state evoked fields and investigated the integration of audiovisual information in a semantic context. We presented participants with videos of an actress uttering action verbs (auditory; tagged at 61 Hz) accompanied by a gesture (visual; tagged at 68 Hz, using a projector with a 1440 Hz refresh rate). Integration difficulty was manipulated by lower-order auditory factors (clear/degraded speech) and higher-order visual factors (congruent/incongruent gesture). We identified MEG spectral peaks at the individual (61/68 Hz) tagging frequencies. We furthermore observed a peak at the intermodulation frequency of the auditory and visually tagged signals (fvisual- fauditory= 7 Hz), specifically when lower-order integration was easiest because signal quality was optimal. This intermodulation peak is a signature of nonlinear audiovisual integration, and was strongest in left inferior frontal gyrus and left temporal regions; areas known to be involved in speech-gesture integration. The enhanced power at the intermodulation frequency thus reflects the ease of lower-order audiovisual integration and demonstrates that speech-gesture information interacts in higher-order language areas. Furthermore, we provide a proof-of-principle of the use of RIFT to study the integration of audiovisual stimuli, in relation to, for instance, semantic context.
Maintenance of species differences in closely related tetraploid parasiticEuphrasia(Orobanchaceae) on an isolated island
Authors: Becher Hannes , Brown Max R. , Powell Gavin , Metherell Chris , Riddiford Nick J. , Twyford Alex D.
Published: May 2020

Polyploidy is pervasive in angiosperm evolution and plays important roles in adaptation and speciation. However, polyploid groups are understudied due to complex sequence homology, challenging genome assembly, and taxonomic complexity. Here we study adaptive divergence in taxonomically complex eyebrights (Euphrasia), where recent divergence, phenotypic plasticity and hybridisation blur species boundaries. We focus on three closely-related tetraploid species with contrasting ecological preferences, and which are sympatric on Fair Isle, a small isolated island in the British Isles. Using a common garden experiment, we show a genetic component to the morphological differences present between these species. Using whole genome sequencing and a novelk-mer approach, we demonstrate an allopolyploid origin, with sub-genome divergence of approximately 5%. Using ~2 million SNPs we show sub-genome homology across species consistent with a common origin, with very low sequence divergence characteristic of recent speciation. This genetic variation is broadly structured by species, with clear divergence of Fair Isle heathlandE. micrantha,while grasslandE. arcticaand coastalE. foulaensisare more closely related. Overall, we show tetraploidEuphrasiais an allopolyploid system characterised by postglacial species divergence, where adaptation to novel environments may be conferred by old variants rearranged into new genetic lineages.
DietaryS. maltophiliapromotes fat storage by enhancing lipogenesis and ER-LD contacts inC. elegans
Authors: Xie Kang , Liu Yangli , Li Xixia , Zhang Hong , Zhang Shuyan , Mak Ho Yi , Liu Pingsheng
Published: May 2020

Dietary and symbiotic bacteria can exert powerful influence on metazoan lipid metabolism. Here, we demonstrate that feedingCaenorhabditis elegans (C. elegans)with the opportunistic pathogenic bacteriaStenotrophomonas maltophilia (S. maltophilia)retards growth and promotes excessive fat storage. Gene expression analysis reveals that dietaryS. maltophiliainduces a lipogenic transcriptional response that includes the SREBP ortholog SBP-1, and fatty acid desaturases FAT-6 and FAT-7. Live imaging and ultrastructural analysis suggest that excess fat is stored in greatly expanded lipid droplets (LDs), as a result of enhanced endoplasmic reticulum-LD interaction. We also report that loss of function mutations incyp-35B1ordpy-9inC. elegansconfers resistance toS. maltophilia.Our work delineates a new model for understanding microbial regulation of metazoan physiology.
Proteomic and functional mapping of cardiac NaV1.5 channel phosphorylation reveals multisite regulation of surface expression and gating
Authors: Lorenzini Maxime , Burel Sophie , Lesage Adrien , Wagner Emily , Charrière Camille , Chevillard Pierre-Marie , Evrard Bérangère , Maloney Dan , Ruff Kiersten M. , Pappu Rohit V. , Wagner Stefan , Nerbonne Jeanne M. , Silva Jonathan R. , Townsend R. Reid , Maier Lars S. , Marionneau Céline
Published: May 2020

Phosphorylation of NaV1.5 channels regulates cardiac excitability, yet the phosphorylation sites regulating channel function and the underlying mechanisms remain largely unknown. Using a systematic quantitative phosphoproteomic approach, we analyzed NaV1.5 channel complexes purified from non-failing and failing mouse left ventricles, and we identified 42 phosphorylation sites on NaV1.5. Most sites are clustered, and three of these clusters are highly phosphorylated. Analyses of phosphosilent and phosphomimetic NaV1.5 mutants revealed the roles of three phosphosites in regulating NaV1.5 channel expression and gating. The phosphorylated serines-664 and -667 regulate the voltage-dependence of channel activation in a cumulative manner, whereas phosphorylation of the nearby serine-671, which is increased in failing hearts, decreases cell surface NaV1.5 expression and peak Na+current. No additional roles could be assigned to the other clusters of phosphosites. Taken together, the results demonstrate that ventricular NaV1.5 is highly phosphorylated, and that the phosphorylation-dependent regulation of NaV1.5-encoded channels is highly complex, site-specific and dynamic.

Abbreviations

A, alanine; E, glutamate; HEK-293, Human Embryonic Kidney 293 cells; INa, peak Na+current; INaL, late Na+current; IP, immunoprecipitation; mαNaVPAN, anti-NaVchannel subunit mouse monoclonal antibody; MS, Mass Spectrometry; MS1, mass spectrum of peptide precursors; MS2 or MS/MS, fragmentation mass spectrum of peptides selected in narrow mass range (2 Da) from MS1 scan; NaV, voltage-gated Na+channel; pS, phosphoserine; pT, phosphothreonine; S, serine; T, threonine; TAC, Transverse Aortic Constriction; TMT, Tandem Mass Tag.
Hypoxia Depletes Contaminating CD45+Hematopoietic Cells from Bone Marrow Stromal Cell (BMSC) Cultures: Methods for BMSC Culture Purification
Authors: Guo Wendi , Spiller Kassandra V. , Tang Jackie , Karner Courtney M. , Hilton Matthew J. , Wu Colleen
Published: May 2020

Culture expanded bone marrow stromal cells (BMSCs) are easily isolated, can be grown rapidlyen masse,and contain both skeletal stem cells (SSCs) and multipotent mesenchymal progenitors (MMPs). Despite this functional heterogeneity, BMSC cultures continue to be utilized for many applications due to the lack of definitive and universally accepted markers to prospectively identify and purify SSCs. Isolation of BMSCs is widely based on their adherence to tissue culture plastic; however, this method poses unique challenges when working with murine models. In particular, hematopoietic cell contamination is a significant impediment during the isolation or murine BMSCs. Several strategies to reduce hematopoietic contamination have been developed with varying levels of success. In this study, we found that up to 60% of cells isolated in standard BMSC cultures expressed the hematopoietic marker CD45. Remarkably, when cultured at a physiological oxygen tension of 1% O2, there was a 10-fold reduction in hematopoietic cells associated with a concomitant increase in PDGFRα+expressing stromal cells. This finding was due, in part, to a differential response of the two populations to low oxygen tension, or hypoxia. Specifically, in standard tissue culture conditions of 21% O2, CD45+hematopoietic cells showed increased proliferation coupled with no observable changes in cell death when compared to their counterparts grown at 1% O2. In contrast, PDGFRα+stromal cells responded to hypoxia by increasing proliferation and exhibiting a 10-fold decrease in cell death. In summary, we describe a simple and reliable method exploiting the divergent biological response of hematopoietic and stromal cells to hypoxia to significantly increase the PDGFRα+stromal cell population in murine BMSC cultures.
Roosting ecology of the southernmost bats,Myotis chiloensisandHistiotus magellanicus, in southern Tierra del Fuego, Chile
Authors: Ossa Gonzalo , Lilley Thomas M. , Waag Austin G. , Meierhofer Melissa B. , Johnson Joseph S.
Published: May 2020

There are few studies of day-roosting ecology of bats inhabiting the southernmost forests of South America, where cool summer temperatures and land management practices pose several challenges. The goal of the present study was to describe day-roosting habitats and patterns of thermoregulation in two bat species occurring on Tierra del Fuego,Myotis chiloensis(Chilean myotis) andHistiotus magellanicus(southern big-eared brown bat), during late spring. To do so, we tagged 17 bats with temperature-sensitive radio-transmitters, located 17 day-roosts, and collected 81 days of skin temperature data. We concurrently recorded ambient air temperature to determine its effect on torpor use. Both species were found roosting in large diameter (77.8 ± 6 cm), typically live,Nothofagus pumiliotrees (lenga) located on the edges of forest gaps or within stands primarily composed of smaller, younger trees. Bats of both species frequently used torpor, with skin temperatures dropping below a torpor threshold on 89% of days (n= 72) and daily minimum skin temperatures averaging 16.5 °C over the course of our study. Average daily air temperature was a significant predictor of torpor use, with lower skin temperatures and more time spent in torpor observed on colder days. Minimum skin temperature and time spent torpid did not vary between bat species, nor did the characteristics of day-roosts. These data show that spring temperatures in Tierra del Fuego pose an energetic challenge that bats meet through frequent use of torpor, and likely, habitat selection. We recommend local conservation efforts keep these thermal challenges in mind by retaining large trees, which may provide warmer microclimates or room for social groups.
Calcium ions promote membrane fusion by forming negative-curvature inducing clusters on specific anionic lipids
Authors: Allolio Christoph , Harries Daniel
Published: May 2020

Vesicles enriched in certain negatively charged lipids, such as phosphatidylserine and PIP2, are known to undergo fusion in the presence of calcium ions without assistance from protein assemblies. Other lipids do not exhibit this propensity, even if they are negatively charged. Using our recently developed methodology, we extract elastic properties of a representative set of lipids. This allows us to trace the origin of lipid-calcium selectivity in membrane fusion to the formation of lipid clusters with long-range correlations that induce negative curvature on the membrane surface. Furthermore, the clusters generate lateral tension in the headgroup region at the membrane surface, concomitantly increasing its Gaussian bending modulus. Finally, calcium binding also reduces the orientational polarization of water around the membrane headgroups, potentially reducing the hydration force acting between membranes. Binding calcium only weakly increases membrane bending rigidity and tilt moduli, in agreement with experiments. We show how the combined effects of calcium binding to membranes lower the barriers along the fusion pathway that lead to the formation of the fusion stalk as well as the fusion pore.
Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT
Authors: Jia Wen , Tripathi Shubham , Chakraborty Priyanka , Chedere Adithya , Rangarajan Annapoorni , Levine Herbert , Jolly Mohit Kumar
Published: May 2020

Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are central to metastatic aggressiveness and therapy resistance in solid tumors. While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies. Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals. While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging. Here, we identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division. Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, we use mechanistic mathematical models to show how GRHL2 can be involved in both the abovementioned processes, thus driving an irreversible MET. Our study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.
Bacterial diets differentially alter lifespan and healthspan trajectories inC. elegans
Authors: Stuhr Nicole L. , Curran Sean P.
Published: May 2020

Diet is one of the more variable aspects in life due to the variety of options that organisms are exposed to in their natural habitats. In the laboratory,C. elegansare raised on bacterial monocultures, traditionally theE. coli Bstrain OP50, and spontaneously occurring microbial contaminants are removed to limit experimental variability because diet - including the presence of contaminants, can exert a potent influence over animal physiology. In order to diversify the menu available to cultureC. elegansin the lab, we have isolated and cultured three such microbes:Methylobacterium, Xanthomonas, andSphingomonas.The nutritional composition of these bacterial foods is unique, and when fed toC. elegans, can differentially alter multiple life history traits including development, reproduction, and metabolism. In light of the influence each food source has on specific physiological attributes, we comprehensively assessed the impact of these bacteria on animal health and devised a blueprint for utilizing different food combinations over the lifespan, in order to promote longevity. The expansion of the bacterial food options to use in the laboratory will provide a critical tool to better understand the complexities of bacterial diets and subsequent changes in physiology and gene expression.
Molecular basis for the ATPase-powered substrate translocation by the Lon AAA+ protease
Authors: Li Shanshan , Hsieh Kan-Yen , Su Shih-Chieh , Pintilie Grigore D. , Zhang Kaiming , Chang Chung-I
Published: May 2020

The Lon AAA+ (adenosine triphosphatases associated with diverse cellular activities) protease (LonA) converts ATP-fuelled conformational changes into sufficient mechanical force to drive translocation of the substrate into a hexameric proteolytic chamber. To understand the structural basis for the substrate translocation process, we have determined the cryo-electron microscopy (cryo-EM) structure ofMeiothermus taiwanensisLonA (MtaLonA) at 3.6 Å resolution in a substrate-engaged state. Substrate interactions are mediated by the dual pore-loops of the ATPase domains, organized in spiral staircase arrangement from four consecutive protomers in different ATP-binding and hydrolysis states; a closed AAA+ ring is nevertheless maintained by two disengaged ADP-bound protomers transiting between the lowest and highest position. The structure reveals a processive rotary translocation mechanism mediated by LonA-specific nucleotide-dependent allosteric coordination among the ATPase domains, which is induced by substrate binding.
Prediction and characterization of transcription factors involved in drought stress response
Authors: Gupta Chirag , Ramegowda Venkategowda , Basu Supratim , Pereira Andy
Published: May 2020

Transcription factors (TFs) play a central role in regulating molecular level responses of plants to external stresses such as water limiting conditions, but identification of such TFs in the genome remains a challenge. Here, we describe a network-based supervised machine learning framework that accurately predicts and ranks all TFs in the genome according to their potential association with drought tolerance. We show that top ranked regulators fall mainly into two ‘age’ groups; genes that appeared first in land plants and genes that emerged later in theOryzaclade. TFs predicted to be high in the ranking belong to specific gene families, have relatively simple intron/exon and protein structures, and functionally converge to regulate primary and secondary metabolism pathways. Repeated trials of nested cross-validation tests showed that models trained only on regulatory network patterns, inferred from large transcriptome datasets, outperform models trained on heterogenous genomic features in the prediction of known drought response regulators. A new R/Shiny based web application, called the DroughtApp, provides a primer for generation of new testable hypotheses related to regulation of drought stress response. Furthermore, to test the system we experimentally validated predictions on the functional role of the rice transcription factorOsbHLH148, using RNA sequencing of knockout mutants in response to drought stress and protein-DNA interaction assays. Our study exemplifies the integration of domain knowledge for prioritization of regulatory genes in biological pathways of well-studied agricultural traits.

One Sentence Summary

Network-based supervised machine learning accurately predicts transcription factors involved in drought tolerance.
Determinants of Adenine-mutagenesis in Diversity-Generating Retroelements
Authors: Handa Sumit , Reyna Andres , Wiryaman Timothy , Ghosh Partho
Published: May 2020

Diversity-generating retroelements (DGRs) vary protein sequences to the greatest extent known in the natural world. These elements are encoded by constituents of the human microbiome and the microbial ‘dark matter’. Variation occurs through adenine-mutagenesis, in which genetic information in RNA is reverse transcribed faithfully to cDNA for all template bases but adenine. We investigated the determinants of adenine-mutagenesis in the prototypicalBordetellabacteriophage DGR through anin vitrosystem composed of the reverse transcriptase bRT, Avd protein, and a specific RNA. We found that the catalytic efficiency for correct incorporation during reverse transcription by the bRT-Avd complex was strikingly low for all template bases, with the lowest occurring for adenine. Misincorporation across a template adenine was only somewhat lower in efficiency than correct incorporation. We found that the C6, but not the N1 or C2, purine substituent was a key determinant of adenine-mutagenesis. bRT-Avd was insensitive to the C6 amine of adenine but recognized the C6 carbonyl of guanine. We also identified two bRT amino acids predicted to nonspecifically contact incoming dNTPs, R74 and I181, as promoters of adenine-mutagenesis. Our results suggest that the overall low catalytic efficiency of bRT-Avd is intimately tied to its ability to carry out adenine-mutagenesis.
Optoacoustic imaging of GLP-1 Receptor with a near-infrared exendin-4 analog
Authors: Roberts Sheryl , Khera Eshita , Choi Crystal , Navaratna Tejas , Grimm Jan , Thurber Greg M. , Reiner Thomas
Published: May 2020

Limitations in current imaging tools have long challenged the imaging of small pancreatic islets in animal models. Here, we report the first development and in vivo validation testing of a broad spectrum and high absorbance near infrared optoacoustic contrast agent, E4x12-Cy7. Our near infrared tracer (E4x12-Cy7) is based on the amino acid sequence of exendin-4 and targets the glucagon-like peptide-1 receptor (GLP-1R). Cell assays confirmed that E4x12-Cy7 has a high binding affinity (IC50= 4.6 ± 0.8 nM). Using the multi-spectral optoacoustic tomography (MSOT), we imaged E4x12-Cy7 and optoacoustically visualized ß-cell insulinoma xenograftsin vivofor the first time. In the future, similar optoacoustic tracers that are specific for ß-cells and combines optoacoustic and fluorescence imaging modalities could prove to be important tools for monitoring the pancreas for the progression of diabetes.
Suicidal Thoughts, Behaviors, and Event-Related Potentials: A Systematic Review and Meta-Analysis
Authors: Gallyer Austin J. , Dougherty Sean P. , Burani Kreshnik , Albanese Brian J. , Joiner Thomas E. , Hajcak Greg
Published: May 2020

Background

Suicidal thoughts and behaviors (STBs) are thought to result from, at least in part, abnormalities in various neural systems. Event-related potentials (ERPs) are a useful method for studying neural activity and can be leveraged to study neural deficits related to STBs; however, it is unknown how effective ERPs are at differentiating various STB groups. The present meta-analysis examined how well ERPs can differentiate (a) those with and without suicidal ideation, (b) those with and without suicide attempts, (c) those with different levels of suicide risk, and (d) differences between those with suicide attempts versus those with suicidal ideation only.

Method

This meta-analysis included 208 effect sizes from 2,517 participants from 27 studies. We used a random-effects meta-analysis using a restricted maximum likelihood estimator with robust variance estimation. We meta-analyzed ERP-STB combinations that had at least three effect sizes across two or more studies.

Results

A qualitative review found that for each ERP and STB combination, the literature is highly mixed. Our meta-analyses largely did not find significant relationships between STBs and ERPs. We also found that the literature is likely severely underpowered, with most studies only being sufficiently powered to detect unrealistically large effect sizes.

Conclusions

Our results provided little-to-no support for a reliable relationship between the ERPs assessed and STBs. However, the current literature is severely underpowered, and there are many methodological weaknesses that must be resolved before making this determination. We recommend large-scale collaboration and improvements in measurement practices to combat the issues in this literature.
Sniff-synchronized, gradient-guided olfactory search by freely moving mice
Authors: Findley Teresa M , Wyrick David G , Cramer Jennifer L , Brown Morgan A , Holcomb Blake , Attey Robin , Yeh Dorian , Monasevitch Eric , Nouboussi Nelly , Cullen Isabelle , Songco Jeremea , King Jared F , Ahmadian Yashar , Smear Matthew C
Published: May 2020

For many organisms, searching for relevant targets such as food or mates entails active, strategic sampling of the environment. Finding odorous targets may be the most ancient search problem that motile organisms evolved to solve. While chemosensory navigation has been well characterized in micro-organisms and invertebrates, spatial olfaction in vertebrates is poorly understood. We have established an olfactory search assay in which freely-moving mice navigate noisy concentration gradients of airborne odor. Mice solve this task using concentration gradient cues and do not require stereo olfaction for performance. During task performance, respiration and nose movement are synchronized with tens of milliseconds precision. This synchrony is present during trials and largely absent during inter-trial intervals, suggesting that sniff-synchronized nose movement is a strategic behavioral state rather than simply a constant accompaniment to fast breathing. To investigate the spatiotemporal structure of these active sensing movements, we used machine learning methods to parse motion trajectories into elementary movement motifs. Motifs fall into two clusters, which correspond to investigation and approach states. Investigation motifs lock precisely to sniffing, such that the individual motifs preferentially occur at specific phases of the sniff cycle. This work clarifies sensorimotor strategies for mouse olfactory search and guides ongoing work into the underlying neural mechanisms.
VIL1, a Polycomb-associated protein, modulates high ambient temperature response via H3K27me3 and H2A.Z inArabidopsis thaliana
Authors: Bordiya Yogendra , Kim Junghyun , Xi Yanpeng , Kim Dong-Hwan , Pyo Youngjae , Zhao Bo , Zong Wei , Ricci William A. , Zhang Xiaoyu , Sung Sibum
Published: May 2020

Adapting to the everchanging environment is key to a successful life for an organism. Eukaryotes reprogram their transcriptome in order to adapt to an unfavorable environment. To achieve this reprogramming, plants and animals employ multiple responses including epigenetic regulation. In the search for mutations compromised in high ambient temperature response, we found that VIL1, a PHD finger protein displays aberrant development at high temperature. RNA-seq analysis shows thatvil1fails to downregulate heat suppressed genes. H2A.Z ChIP-seq showed that unlike wild type,vil1fails to evict H2A.Z from heat responsive genes. We also found thatvil1suppresses constitutive thermo-morphogenic phenotype ofarp6. Supporting this phenotype, RNA-seq analysis revealed that constitutive heat responsive transcriptome ofarp6reverted back to the wild-type levels inarp6vil1. This observation suggests an antagonistic relationship between VIL1 and ARP6. We found that this antagonism can be explained in part by interaction between H3K27me3 and H2A.Z.
Single-Molecule Imaging and Microfluidic Platform Reveal Molecular Mechanisms of Leukemic Cell Rolling
Authors: Alwan Bader Al , AbuZineh Karmen , Nozue Shuho , Rakhmatulina Aigerim , Aldehaiman Mansour , Al-Amoodi Asma S. , Serag Maged F. , Aleisa Fajr A. , Merzaban Jasmeen S. , Habuchi Satoshi
Published: May 2020

Hematopoietic stem/progenitor cell (HSPC) and leukemic cell homing is an important biological phenomenon that occurs through key interactions between adhesion molecules. Tethering and rolling of the cells on endothelium, the crucial initial step of the adhesion cascade, is mediated by interactions between selectins expressed on endothelium to their ligands expressed on HSPCs/leukemic cells in flow. Although multiple factors that affect the rolling behavior of the cells have been identified, molecular mechanisms that enable the essential slow and stable cell rolling remain elusive. To investigate the molecular mechanisms of cell rolling, an experimental platform that enables molecular level characterization of the adhesion molecules in the context of space, time, and force is required. Here, using a microfluidics-based single-molecule live cell fluorescence imaging, we reveal that unique spatiotemporal dynamics of selectin ligands on the membrane tethers and slings, which are distinct from that on the cell body, play an essential role in the rolling of the cell. Our results suggest that the spatial confinement of the selectin ligands to the tethers and slings together with the rapid scanning of a large area by the selectin ligands, increases the efficiency of selectin-ligand interactions during cell rolling, resulting in slow and stable rolling of the cell on the selectins. Our findings provide novel insights and contribute significantly to the molecular-level understanding of the initial and essential step of the homing process.
Ectopic expression of pericentric HSATII RNA results in nuclear RNA accumulation, MeCP2 recruitment, and cell division defects
Authors: Landers Catherine C. , Rabeler Christina A. , Ferrari Emily K. , D’Alessandro Lia R. , Kang Diana D. , Malisa Jessica , Bashir Safia M. , Carone Dawn M.
Published: May 2020

Within the pericentric regions of human chromosomes reside large arrays of tandemly repeated satellite sequences. Expression of the human pericentric satellite HSATII is prevented by extensive heterochromatin silencing in normal cells, yet in many cancer cells, HSATII RNA is aberrantly expressed and accumulates in large nuclear fociin cis. Expression and aggregation of HSATII RNA in cancer cells is concomitant with recruitment of key chromatin regulatory proteins including methyl-CpG binding protein 2 (MeCP2). While HSATII expression has been observed in a wide variety of cancer cell lines and tissues, the effect of its expression is unknown. We tested the effect of stable expression of HSATII RNA within cells that do not normally express HSATII. Ectopic HSATII expression in HeLa and primary fibroblast cells leads to focal accumulation of HSATII RNAin cisand triggers the accumulation of MeCP2 onto nuclear HSATII RNA bodies. Further, long-term expression of HSATII RNA leads to cell division defects including lagging chromosomes, chromatin bridges, and other chromatin defects. Thus, expression of HSATII RNA in normal cells phenocopies its nuclear accumulation in cancer cells and allows for the characterization of the cellular events triggered by aberrant expression of pericentric satellite RNA.