bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACE2 Homo-dimerization, Human Genomic variants and Interaction of Host Proteins Explain High Population Specific Differences in Outcomes of COVID19
Authors: Sharma Swarkar , Singh Inderpal , Haider Shazia , Malik Md. Zubbair , Ponnusamy Kalaiarasan , Rai Ekta 
Published: April 2020

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive single-stranded RNA virus that causes a highly contagious Corona Virus Disease (COVID19). Entry of SARS-CoV-2 in human cells depends on binding of the viral spike (S) proteins to cellular receptor Angiotensin-converting enzyme 2 (ACE2) and on S-protein priming by host cell serine protease TMPRSS2. Recently, COVID19 has been declared pandemic by World Health Organization (WHO) yet high differences in disease outcomes across countries have been seen. We provide evidences to explain these population-level differences. One of the key factors of entry of the virus in host cells presumably is because of differential interaction of viral proteins with host cell proteins due to different genetic backgrounds. Based on our findings, we conclude that a higher expression ofACE2is facilitated by natural variations, acting as Expression quantitative trait loci (eQTLs), with different frequencies in different populations. We suggest that high expression of ACE2 results in homo-dimerization, proving disadvantageous for TMPRSS2 mediated cleavage of ACE2; whereas, the monomeric ACE2 has higher preferential binding with SARS-CoV-2 S-Protein vis-a-vis its dimerized counterpart. Further, eQTLs inTMPRSS2and natural structural variations in the gene may also result in differential outcomes towards priming of viral S-protein, a critical step for entry of the Virus in host cells. In addition, we suggest that several key host genes, likeSLC6A19, ADAM17, RPS6, HNRNPA1, SUMO1, NACA, BTF3and some other proteases as Cathepsins, might have a critical role. To conclude, understanding population specific differences in these genes may help in developing appropriate management strategies for COVID19 with better therapeutic interventions.
Kidney epithelial proliferation impairs cell viability via energy depletion
Authors: Galichon Pierre , Lannoy Morgane , Li Li , Vandermeersch Sophie , Legouis David , Valerius Michael T , Hadchouel Juliette , Bonventre Joseph V 
Published: April 2020

AbstractBoth proliferative and anti-proliferative pathways are induced after acute kidney injury. The consequences of proliferation on energy homeostasis and cell viability are unknown. We hypothesized that proliferation regulation is an important determinant of epithelial fate after acute kidney injury. We studied the relationship between proliferation and cell viability in kidney tubular cells. We then analyzed the effect of proliferation on the intracellular ATP/ADP ratio. Finally, we used transcriptomic data from transplanted kidneys to study the relationship between cell proliferation and energy production with different clinical evolutions. We found that proliferation is associated with decreased survival after toxic or energetic stresses in kidney proximal tubular cells.In vitro, we found that the ATP/ADP ratio oscillates reproducibly throughout the cell cycle, and that proliferation is instrumental to an overall decrease in intracellular ATP/ADP ratio.In vivo, in injured kidneys, we found that proliferation was strongly associated with a specific decrease in the expression of the mitochondria-encoded genes of the oxidative phosphorylation pathway as opposed to the nucleus-encoded ones. These observations suggest that mitochondrial function is the limiting factor for energy production in kidney cells proliferating after injury. The association of increased proliferation and decreased mitochondrial function was associated with poor renal outcomes. In summary, we show that proliferation is an energy demanding process impairing the cellular ability to cope with a toxic or ischemic injury, identifying the association of proliferative repair and metabolic recovery as indispensable and interdependent features for successful kidney repair.One Sentence SummaryProliferation decreases energy availability in kidney epithelial cells and is associated with enhanced cell death and chronic kidney disease in case of a superimposed metabolic stress.
Barbary ground squirrels do not have a sentinel system but instead synchronise vigilance
Authors: van der Marel Annemarie , Waterman Jane M. , López-Darias Marta 
Published: April 2020

AbstractCoordinated behavior, such as hunting in lions and coordinated vigilance as antipredator behavior, are examples of benefits of group-living. Instead of asynchronous vigilance, some social species synchronize their vigilance bouts or take turns acting as sentinels. To increase our knowledge on the evolution of vigilance behavior, we studied whether vigilance is coordinated in Barbary ground squirrels,Atlantoxerus getulus. We show that vigilance was synchronized instead of taking turns. Multiple non-mutually exclusive hypotheses could explain synchronization: Barbary ground squirrels may perch because 1) neighbors are perched (copying effect), 2) perch synchrony may be an emergent property of the ecology as all squirrels may be satiated at the same time (collective behavior), or 3) the benefits are large in terms of evading ambush predators and scanning effectiveness (watch each other’s back). Particularly, in habitats where the field of view is obstructed by man-made structures and multiple individuals may be necessary to watch for terrestrial predators, synchronized vigilance may have greater fitness benefits than sentinel behavior. We conclude that it is essential to test assumptions of coordination and, thus, to analyze coordination to describe sentinel systems.Significance StatementVigilance behavior can be vital to an animal’s survival. Taking turns acting as sentinels or synchronizing vigilance bouts reduces the cost of the trade-off between feeding and predation risk. A sentinel system assumes that sentinels are vigilant from raised positions, warn group members of danger, and alternate vigilance bouts. However, the assumption of alternating vigilance bouts remains poorly tested. We tested this assumption in invasive Barbary ground squirrels. We found that instead of alternating, individuals synchronized their vigilance bouts. Perch synchrony may be 1) a response to perching group members (copying effect), 2) an emergent property of the species’ ecology, and 3) an adaptation to anthropogenically altered habitats (watch each other’s back).
Mapping of Neuropeptide Y Expression inOctopusBrains
Authors: Winters Gabrielle C. , Polese Gianluca , Di Cosmo Anna , Moroz Leonid L. 
Published: April 2020

AbstractNeuropeptide Y (NPY) is an evolutionarily conserved neurosecretory molecule implicated in a diverse complement of functions across taxa and in regulating feeding behavior and reproductive maturation inOctopus. However, little is known about the precise molecular circuitry of NPY-mediated behaviors and physiological processes, which likely involve a complex interaction of multiple signal molecules in specific brain regions. Here we examined the expression of NPY throughout theOctopuscentral nervous system. The sequence analysis ofOctopusNPY precursor confirmed the presence of both signal peptide and putative active peptides, which are highly conserved across bilaterians.In situhybridization revealed distinct expression of NPY in specialized compartments, including potential “integration centers,” where visual, tactile, and other behavioral circuitries converge. These centers integrating separate circuits may maintain and modulate learning and memory or other behaviors not yet attributed to NPY-dependent modulation inOctopus. Extrasomatic localization of NPY mRNA in the neurites of specific neuron populations in the brain suggests a potential demand for immediate translation at synapses and a crucial temporal role for NPY in these cell populations. We also verified the presence of NPY mRNA in a small cell population in the olfactory lobe, which is a component of theOctopusfeeding and reproductive control centers. However, the molecular mapping of NPY expression only partially overlapped with that produced by immunohistochemistry in previous studies. Our study provides a precise molecular map of NPY mRNA expression that can be used to design and test future hypotheses about molecular signaling in variousOctopusbehaviors.Research Highlights/Graphical Abstract textNeuropeptide Y (NPY), an evolutionarily conserved neurosecretory molecule, is expressed in specialized regions of theOctopusbrain controlling feeding, reproduction, and visual and tactile memory circuits. Extrasomatic mRNAs were found in neurites, suggesting synaptic synthesis of NPY.
Modified Bacterial Lipids Which Alter Membrane Surface Charge Reduce Binding of Antimicrobial Peptides
Authors: Simcock Patrick W. , Bublitz Maike , Cipcigan Flaviu , Ryadnov Maxim G. , Crain Jason , Stansfeld Phillip J. , Sansom Mark S.P. 
Published: April 2020

ABSTRACTAntimicrobial peptides (AMPs) initiate killing of bacteria by binding to and destabilizing their membranes. The multiple peptide resistance factor (MprF) provides a defence mechanism for bacteria against a broad range of AMPs. MprF reduces the negative charge of both Gram-positive and Gram--negative bacterial membranes through enzymatic conversion of the anionic lipid phosphatidyl glycerol (PG) to either zwitterionic alanyl-phosphatidyl glycerol (Ala-PG) or cationic lysylphosphatidyl glycerol (Lys-PG). The resulting change in membrane charge is suggested to reduce AMP-membrane binding and hinder downstream AMP activity. Using molecular dynamics to investigate the effects of these modified lipids on AMP-binding to model membranes, we show that AMPs have substantially reduced affinity for model membranes containing Ala-PG or Lys-PG. A total of ~7000 simulations are used to define the relationship between bilayer composition and binding for 5 different membrane active peptides. The reduction of degree of interaction of a peptide with the membrane is shown to correlate with the change in membrane surface charge density. Free energy profile (potential of mean force) calculations reveal that these lipid modifications alter the energy barrier to peptide helix penetration of the bilayer. These results will enable us to guide design of novel peptides which address the issue of resistance via MprF-mediated membrane modification.
Effect of salinity on modulation by ATP, protein kinases and FXYD2 peptide of gill (Na+, K+)-ATPase activity in the swamp ghost crabUcides cordatus(Brachyura, Ocypodidae)
Authors: Leone Francisco A. , Lucena Malson N. , Fabri Leonardo M. , Garçon Daniela P. , Fontes Carlos F.L. , Faleiros Rogério O. , Moraes Cintya M. , McNamara John C. 
Published: April 2020

ABSTRACTThe gill (Na+, K+)-ATPase is the main enzyme that underpins osmoregulatory ability in crustaceans that occupy biotopes like mangroves, characterized by salinity variation. We evaluated osmotic and ionic regulatory ability in the semi-terrestrial mangrove crabUcides cordatusafter 10-days acclimation to different salinities. We also analyzed modulation by exogenous FXYD2 peptide and by endogenous protein kinases A and C, and Ca2+- calmodulin-dependent kinase of (Na+, K+)-ATPase activity. Hemolymph osmolality was strongly hyper-/hypo-regulated in crabs acclimated at 2 to 35 ‰S. Cl-was well hyper-/hypo- regulated although Na+much less so, becoming iso-natremic at high salinity. (Na+, K+)- ATPase activity was greatest in isosmotic crabs (26 ‰S), diminishing progressively from 18 and 8 ‰S (≈0.5 fold) to 2 ‰S (0.04-fold), and decreasing notably at 35 ‰S (0.07-fold). At low salinity, the (Na+, K+)-ATPase exhibited a low affinity ATP-binding site that showed Michaelis-Menten behavior. Above 18 ‰S, an additional, high affinity ATP-binding site, corresponding to 10-20% of total (Na+, K+)-ATPase activity appeared. Activity is stimulated by exogenous pig kidney FXYD2 peptide, while endogenous protein kinases A and C and Ca2+/calmodulin-dependent kinase all inhibit activity. This is the first demonstration of inhibitory phosphorylation of a crustacean (Na+, K+)-ATPase by Ca2+/calmodulin-dependent kinase. Curiously, hyper-osmoregulation inU. cordatusshows little dependence on gill (Na+, K+)-ATPase activity, suggesting a role for other ion transporters. These findings reveal that the salinity acclimation response inU. cordatusconsists of a suite of osmoregulatory and enzymatic adjustments that maintain its osmotic homeostasis in a challenging, mangrove forest environment.Graphical abstractHighlightsGill (Na+, K+)-ATPase activity is greatest in isosmotic crabs, diminishing in lower and higher salinities.A high affinity ATP-binding site (10-20% of total activity) is exposed above 18 ‰S.Exogenous FXYD2 peptide stimulates activity; endogenous PKA, PKC and CaMK inhibit activity.First demonstration of inhibitory phosphorylation of crustacean (Na+, K+)-ATPase by CaMK.Hyper-osmoregulation shows little dependence on (Na+, K+)-ATPase activity.
Tumor-infiltrating nerves create an electro-physiologically active microenvironment and contribute to treatment resistance
Authors: Kovacs Attila , Vermeer Daniel W. , Madeo Marianna , Reavis Hunter D. , Vermeer Samuel J. , Williamson Caitlin S. , Rickel Alex , Stamp Jillian , Lucido Christopher T. , Cain Jacob , Bell Maria , Morgan Mark , Yoon Ju-Yoon , Mitchell Marilyn A. , Tulina Natalia , Stuckelberger Sarah , Budina Anna , Omran Dalia K. , Jung Euihye , Schwartz Lauren E. , Eichwald Tuany , Hong Zhongkui , Weimer Jill , Hooper Jody E. , Godwin Andrew K. , Talbot Sebastien , Drapkin Ronny , Vermeer Paola D. 
Published: April 2020

ABSTRACTPatients with densely innervated tumors do poorly as compared to those with sparsely innervated disease. Why some tumors heavily recruit nerves while others do not, remains unknown as does the functional contribution of tumor-infiltrating nerves to cancer. Moreover, while patients receive chemotherapeutic treatment, whether these drugs affect nerve recruitment has not been tested. Using a murine model of ovarian cancer, we show that tumor-infiltrating sensory nerves potentiate tumor growth, decrease survival, and contribute to treatment resistance. Furthermore, matched patient samples show significantly increased tumor innervation following chemotherapy.In vitroanalysis of tumor-released extracellular vesicles (sEVs) shows they harbor neurite outgrowth activity. These data suggest that chemotherapy may alter sEV cargo, endowing it with robust nerve recruiting capacity.
Genetic differences between extreme and composite constitution types from whole exome sequences reveal actionable variations
Authors: Abbas Tahseen , Kutum Rintu , Pandey Rajesh , Dakle Pushkar , Narang Ankita , Manchanda Vijeta , Patil Rutuja , Aggarwal Dheeraj , Bansal Gourja , Sharma Pooja , Chaturvedi Gaura , Girase Bhushan , Srivastava Ankita , Juvekar Sanjay , Dash Debasis , Prasher Bhavana , Mukerji Mitali 
Published: April 2020

AbstractPersonalized medicine relies on successful identification of genome-wide variations that governs inter-individual differences in phenotypes and system level outcomes. In Ayurveda, assessment of composite constitution types “Prakriti”forms the basis for risk stratification, predicting health and disease trajectories and personalized recommendations. Here, we report a novel method for identifying pleiotropic genes and variants that associate with healthy individuals of three extreme and contrasting “Prakriti”constitutions through exome sequencing and state-of-the-art computational methods. Exome Seq of three extremePrakrititypes from 108 healthy individuals 54 each from genetically homogeneous populations of North India (NI, Discovery cohort) and Western India (VADU, Replication cohort) were evaluated. Fisher’s Exact Test was applied betweenPrakrititypes in both cohorts and further permutation based p-value was used for selection of exonic variants. To investigate the effect of sample size per genetic association test, we performed power analysis. Functional impact of differentiating genes and variations were inferred using diverse resources -Toppfun, GTEx, GWAS, PheWAS, UK Biobank and mouse knockdown/knockout phenotype (MGI). We also applied supervised machine learning approach to evaluate the association of exonic variants with multisystem phenotypes ofPrakriti. Our targeted investigation into exome sequencing from NI (discovery) and VADU (validation) cohorts datasets provide ~7,000 differentiating SNPs. Closer inspection further identified a subset of SNPs (2407 (NI) and 2393 (VADU)), that mapped to an overlapping set of 1181 genes. This set can robustly stratify the Prakriti groups into three distinct clusters with distinct gene ontological (GO) enrichments. Functional analysis further strengthens the potential pleiotropic effects of these differentiating genes/variants and multisystem phenotypic consequences. Replicated SNPs map to some very prominent genes likeFIG4, EDNRA, ANKLE1, BCKDHA, ATP5SL, EXOCS5,IFIT5, ZNF502, PNPLA3 and IL6R. Lastly, multivariate analysis using random forest uncovered rs7244213 within urea transporterSLC14A2, that associate with an ensemble of features linked to distinct constitutions. Our results reinforce the concept of integration of Prakriti based deep phenotypes for risk stratification of healthy individuals and provides markers for early actionable interventions.
Klf4 methylated by Prmt1 is required for lineage segregation of epiblast and primitive endoderm
Authors: Zuo Zhen-yu , Yang Guang-hui , Wang Hai-yu , Zhang Yan-jun , Cai Yun , Chen Fei , Xiao Yi , Cheng Mo-bin , Huang Yue , Zhang Ye 
Published: April 2020

AbstractThe second cell fate decision in the early stage of mammalian embryonic development is pivotal; however, the underlying molecular mechanism is largely unexplored. Here, we report that Prmt1 acts as an important regulator in primitive endoderm (PrE) formation. First, an embryonic chimeric assay showed that Prmt1 inhibition induces the integration of mouse embryonic stem cells (ESCs) into the PrE. Second, Prmt1 inhibition promotes Gata6 expression in both mouse blastocysts and ESCs. Single-cell RNA sequencing and flow cytometry assays demonstrated that Prmt1 depletion in ESCs contributes to an emerging cluster, where PrE genes are upregulated significantly. Furthermore, the efficiency of extraembryonic endoderm stem cell induction increased in Prmt1-depleted ESCs. Finally, we showed that the pluripotency factor Klf4 methylated at Arg396 by Prmt1 is required for recruitment of the repressive mSin3a/HDAC complex to silence PrE genes. Therefore, we reveal a regulatory mechanism for cell fate decisions centered on Prmt1-mediated Klf4 methylation.
Characterising a stable five-species microbial community for use in experimental evolution and ecology
Authors: Castledine Meaghan , Pennycook Joseph , Newbury Arthur , Lear Luke , Erdos Zoltan , Lewis Rai , Kay Suzanne , Sanders Dirk , Sünderhauf David , Buckling Angus , Hesse Elze , Padfield Daniel 
Published: April 2020

AbstractModel microbial communities are regularly used to test ecological and evolutionary theory as they are easy to manipulate and have fast generation times, allowing for large-scale, high throughput experiments. A key assumption for most model microbial communities is that they stably coexist, but this is rarely tested experimentally. Here we report the (dis)assembly of a five-species microbial community from a metacommunity of soil microbes that can be used for future experiments. Using reciprocal invasion from rare experiments we show that all species can coexist and we demonstrate that the community is stable for a long time (∼600 generations). Crucially for future work, we show that each species can be identified by their plate morphologies, even after >1 year in co-culture. We characterise pairwise species interactions and produce high-quality reference genomes for each species. This stable five-species community can be used to test key questions in microbial ecology and evolution.
CREB1 contributes colorectal cancer cell plasticity by regulating lncRNA CCAT1 and NF-κB pathways
Authors: Li Bin , Zheng Li-Si , Zhang Chen-Min , Huang Qiao-Juan , Guo Yan-Hua , Wang Lu-Qin , Yu Peng , Liu Shu-Rong , Lin Qiao , Luo Yu-Xia , Zhou Hui , Yang Jian-Hua , Qu Liang-Hu 
Published: April 2020

AbstractThe CREB1 gene encodes a pleiotropic transcription factor that frequently dysregulated in cancers. CREB1 can regulates tumour cell status of proliferation or migration, however, the molecular basis for this switch involvement in cell plasticity has not been fully understood. Here, we show that knocking out CREB1 triggered a remarkable effect of epithelial-mesenchymal transition (EMT) and led to the occurrence of inhibited proliferation and enhanced motility in cancer cells. Mechanistically, CREB1-knockout cells showed arrest in the G0/G1 phase as a result of impaired CREB1-dependent transcription of CCAT1 and E2F1. Interestingly, the competition between the coactivator CBP/p300 for CREB1 and p65 leads to the activation of the NF-κB pathway in cells with CREB1 disrupted, which induces an EMT phenotype and enhances motility. These studies identified previously unknown mechanisms of CREB1 in cell plasticity via its lncRNA and protein effector pathways, revealing an important feature that should be considered in CREB1-targeted tumour therapies.