bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex Differences in Solute and Water Handling in the Human Kidney: Modeling and Functional Implications
Authors: Hu Rui , McDonough Alicia A. , Layton Anita T. 
Published: February 2021

AbstractBesides the excretion of metabolic wastes, the kidneys regulate homeostasis of electrolytes, pH, metabolites, volume and blood pressure. Sex differences in kidney function and blood pressure have been widely described across many species. Immunoblot analysis has revealed that the kidney of a female rat is not simply a smaller version of a male kidney. Rather, male and female rat kidneys exhibit dimorphic patterns of transporter expression and salt handling, the functional implications of which have been analyzed in a series of previously published modeling studies of rat kidney function. In the present study, we extend the analysis to the human kidney: we developed sex-specific models of solute and water transport in the human kidney, and identified epithelial transport parameters, consistent with patterns found in male and female rats, that yield urine output and excretion rates consistent with known human values. The model predicts that the lower sodium hydrogen exchanger 3 (NHE3) activity in women reduces the fractional reabsorption of Na+, K+, Cl-, and water along the proximal tubule, compared to men, and that the larger load on the distal nephron can be handled by enhanced activities in key Na+transporter such as epithelial sodium channel (ENaC) and sodium chloride cotransporter (NCC) in women. Model simulations further indicate that the larger distal transport capacity and proximal transport reserve may better prepare women for elevated demands of pregnancy and lactation. The larger distal transport capacity may also contribute to reduced efficacy of angiotensin converting enzyme inhibitors to lower blood pressure in women.Author summaryThe kidneys maintain homeostasis by controlling the amount of water, ions, and other substances in the blood. That function is accomplished by the nephrons, which transform glomerular filtrate into urine by an exquisite transport process mediated by a number of membrane transporters. Recently, the distribution of renal transporters along the nephron has been shown to be markedly different between male and female rodents. We postulate that similar sexual dimorphism exists between men and women, and we seek to reveal its physiological implications. We hypothesize that the larger abundance of a renal Na+transport in the proximal tubules in females may also better prepare them for the fluid retention adaptations required during pregnancy and lactation, durint which renal and systemic hemodynamics are both drastically altered by the marked volume expansion and vasodilation. Also, kidneys play a key role in blood pressure regulation, and a popular class of anti-hypertensive medications, angiotensin converting enzymes (ACE) inhibitors, have been reported to be less effective in women. Model simulations suggest that the blunted natriuretic and diuretic effects of ACE inhibition in women can be attributed, in part, to their higher distal baseline transport capacity.
How public reaction to disease information across scales and the impacts of vector control methods influence disease prevalence and control efficacy
Authors: Jiao Jing , Suarez Gonzalo P. , Fefferman Nina H. 
Published: February 2021

AbstractWith the development of social media, the information about vector-borne disease incidence over broad spatial scales can cause demand for local vector control before local risk exists. Anticipatory intervention may still benefit local disease control efforts; however, infection risks are not the only focal concerns governing public demand for vector control. Concern for environmental contamination from pesticides and economic limitations on the frequency and magnitude of control measures also play key roles. Further, public concern may be focused more on ecological factors (i.e., controlling mosquito populations) or on epidemiological factors (i.e., controlling infection-carrying mosquitoes), which may lead to very different control outcomes. Here we introduced a generic Ross-MacDonald model, incorporating these factors under three spatial scales of disease information: local, regional, and global. We tailored and parameterized the model for Zika virus transmitted byAedes aegyptimosquito. We found that overreaction caused by larger-scale incidence information could decrease average human infections per patch breeding capacity, however, the associated increase in total control effort plays a larger role, which leads to an overall decrease in control efficacy. The shift of focal concerns from epidemiological to ecological risk could relax the negative effect of overreaction on control efficacy when mosquito breeding capacity populations are expected to be large. This work demonstrates that, depending on expected total mosquito breeding capacity population size, and weights of different focal concerns, large-scale disease information can reduce disease infections without lowering control efficacy. Our findings provide guidance for vector-control strategies by considering public reaction through social media.
The purine nucleoside phosphorylasepnp-1regulates epithelial cell resistance to infection inC. elegans
Authors: Tecle Eillen , Chhan Crystal B. , Franklin Latisha , Underwood Ryan S. , Hanna-Rose Wendy , Troemel Emily R. 
Published: February 2021

AbstractIntestinal epithelial cells are subject to attack by a diverse array of microbes, including intracellular as well as extracellular pathogens. While defense in epithelial cells can be triggered by pattern recognition receptor-mediated detection of microbe-associated molecular patterns, there is much to be learned about how they sense infection via perturbations of host physiology, which often occur during infection. A recently described host defense response in the nematodeC. eleganscalled the Intracellular Pathogen Response (IPR) can be triggered by infection with diverse natural intracellular pathogens, as well as by perturbations to protein homeostasis. From a forward genetic screen, we identified theC. elegansortholog of purine nucleoside phosphorylasepnp-1as a negative regulator of IPR gene expression, as well as a negative regulator of genes induced by extracellular pathogens. Accordingly,pnp-1mutants have resistance to both intracellular and extracellular pathogens. Metabolomics analysis indicates thatC. elegans pnp-1likely has enzymatic activity similar to its human ortholog, serving to convert purine nucleosides into free bases. Classic genetic studies have shown how mutations in human purine nucleoside phosphorylase cause immunodeficiency due to T-cell dysfunction. Here we show thatC. elegans pnp-1acts in intestinal epithelial cells to regulate defense. Altogether, these results indicate that perturbations in purine metabolism are likely monitored as a cue to promote defense against epithelial infection in the nematodeC. elegans.Author summaryAll life requires purine nucleotides. However, obligate intracellular pathogens are incapable of generating their own purine nucleotides and thus have evolved strategies to steal these nucleotides from host cells in order to support their growth and replication. Using the small roundwormC. elegans,we show that infection with natural obligate intracellular pathogens is impaired by loss ofpnp-1,theC. elegansortholog of the vertebrate purine nucleoside phosphorylase (PNP), which is an enzyme involved in salvaging purines. Loss ofpnp-1leads to altered levels of purine nucleotide precursors and increased expression of Intracellular Pathogen Response genes, which are induced by viral and fungal intracellular pathogens ofC. elegans.In addition, we find that loss ofpnp-1increases resistance to extracellular pathogen infection and increases expression of genes involved in extracellular pathogen defense. Interestingly, studies from 1975 found that mutations in human PNP impair T-cell immunity, whereas our findings here indicateC. elegans pnp-1regulates intestinal epithelial immunity. Overall, our work indicates that host purine homeostasis regulates resistance to both intracellular and extracellular pathogen infection.
Revisiting a GWAS peak inArabidopsis thalianareveals possible confounding by genetic heterogeneity
Authors: Sasaki Eriko , Köcher Thomas , Filiault Danièle L , Nordborg Magnus 
Published: February 2021

AbstractGenome-wide association studies (GWAS) have become a standard approach for exploring the genetic basis of phenotypic variation. However, correlation is not causation, and only a tiny fraction of all associations have been experimentally confirmed. One practical problem is that a peak of association does not always pinpoint a causal gene, but may instead be tagging multiple causal variants. In this study, we reanalyze a previously reported peak associated with flowering time traits in Swedish inArabidopsis thaliana. The peak appeared to pinpoint theAOP2/AOP3cluster of glucosinolate biosynthesis genes, which is known to be responsible for natural variation in herbivore resistance. Here we propose an alternative hypothesis, by demonstrating that theAOP2/AOP3flowering association can be wholly accounted for by allelic variation in two flanking genes with clear roles in regulating flowering:NDX1, a regulator of the main flowering time controllerFLC, andGA1, which plays a central role in gibberellin synthesis and is required for flowering under some conditions. In other words, we propose that theAOP2/AOP3flowering-time association is yet another example of a spurious, “synthetic” association, arising from trying to fit a single-locus model in the presence of two statistically associated causative loci.
Induction of exaggerated cytokine production in human peripheral blood mononuclear cells by a recombinant SARS-CoV-2 spike glycoprotein S1 and its inhibition by dexamethasone
Authors: Olajide Olumayokun A , Iwuanyanwu Victoria U , Lepiarz-Raba Izabela , Al-Hindawi Alaa A 
Published: February 2021

AbstractAn understanding of the pathological inflammatory mechanisms involved in SARS-CoV-2 virus infection is necessary in order to discover new molecular pharmacological targets for SARS-CoV-2 cytokine storm. In this study, the effects of a recombinant SARS-CoV-2 spike glycoprotein S1 was investigated in human peripheral blood mononuclear cells (PBMCs). Stimulation of PBMCs with spike glycoprotein S1 (100 ng/mL) resulted in significant elevation in the production of TNFα, IL-6, IL-1β and IL-8. However, pre-treatment with dexamethasone (100 nM) caused significant reduction in the release of these cytokines. Further experiments revealed that S1 stimulation of PBMCs increased phosphorylation of NF-κB p65 and IκBα, and IκBα degradation. DNA binding of NF-κB p65 was also significantly increased following stimulation with spike glycoprotein S1. Treatment of PBMCs with dexamethasone (100 nM) or BAY11-7082 (1 µM) resulted in inhibition of spike glycoprotein S1-induced NF-κB activation. Activation of p38 MAPK by S1 was blocked in the presence of dexamethasone and SKF 86002. CRID3, but not dexamethasone pre-treatment produced significant inhibition of S1-induced activation of NLRP3/caspase-1. Further experiments revealed that S1-induced increase in the production of TNFα, IL-6, IL-1β and IL-8 was reduced in the presence of BAY11-7082 and SKF 86002, while CRID3 pre-treatment resulted in the reduction of IL-1β production. These results suggest that SARS-CoV-2 spike glycoprotein S1 stimulated PBMCs to release pro-inflammatory cytokines through mechanisms involving activation of NF-κB, p38 MAPK and NLRP3 inflammasome. It is proposed that the clinical benefits of dexamethasone in COVID-19 is possibly due to its anti-inflammatory activity in reducing SARS-CoV-2 cytokine storm.
MSX2 safeguards syncytiotrophoblast fate of human trophoblast stem cells
Authors: Hornbachner Ruth , Lackner Andreas , Haider Sandra , Knöfler Martin , Mechtler Karl , Latos Paulina A. 
Published: February 2021

AbstractThe majority of placental pathologies are associated with failures in trophoblast differentiation, yet the underlying transcriptional regulation is poorly understood. Here, we use human trophoblast stem cells to elucidate the function of the transcription factor MSX2 in trophoblast specification. We show that depletion of MSX2 de-represses the syncytiotrophoblast program, while forced expression of MSX2 blocks it. We demonstrate that a large proportion of the affected genes are directly bound and regulated by MSX2 and identify components of the SWI/SNF complex as its strong interactors. Our findings uncover the pivotal role of MSX2 in cell fate decisions that govern human placental development and function.
Identifying nearshore nursery habitats for sharks in the Eastern Tropical Pacific from fisheries landings and interviews
Authors: López-Angarita Juliana , Villate Melany , Díaz Juan Manuel , Cubillos Juan C. , Tilley Alexander 
Published: February 2021

AbstractThe Eastern Tropical Pacific (ETP) comprising the coasts of Costa Rica, Panama, Colombia and Ecuador, represents an area of high marine biodiversity that supports productive fisheries and acts as an important migratory corridor for many marine species. Despite its biological importance, the ETP is understudied and lacks sufficient data for science-based fisheries management and conservation decision-making. This study aims to consolidate understanding of the current and historical distribution of sharks and mobulid rays in the ETP. We used interviews of coastal community stakeholders to document traditional knowledge of shark and mobulid ray species and distributions. We also analysed small-scale fisheries landings data, where available, to quantify local exploitation patterns and the importance of sharks and rays in small-scale fisheries catches. All shark species landed in the dominant nearshore gillnet fishery show very low mean individuals weights (<5 kg), indicating that the fisheries are dominated by juveniles, captured. Aside from smooth-hounds (Mustelusspp.), the scalloped hammerhead shark,Sphyrna lewini, is the most frequently landed shark species in the region by weight and number, with peaks in abundance between April - July. From 132 interviews in 51 communities across the three countries, and landings data from two small-scale fisheries sites, we identified 41 sites in 12 broad geographical zones as important shark nursery habitats. Of these sites, 68% were associated closely with large mangrove systems of the ETP, highlighting the importance of this habitat for shark life history. No patterns were seen in the occurrence or distribution of mobulid rays in coastal areas. Marine protected areas and responsible fishing zones cover 37% of identified nursery habitats in the ETP, 30% in Costa Rica, 48% in Panama and 30% in Colombia. These findings provide an important benchmark of the conservation status of sharks in the ETP and allow for the prioritisation of research and policy-making.
In vivoidentification and validation of novel potential predictors for human cardiovascular diseases
Authors: Hammouda Omar T. , Wu Meng Yue , Kaul Verena , Gierten Jakob , Thumberger Thomas , Wittbrodt Joachim 
Published: February 2021

AbstractGenetics crucially contributes to cardiovascular diseases (CVDs), the global leading cause of death. Since the majority of CVDs can be prevented by early intervention there is a high demand for predictive markers. While genome wide association studies (GWAS) correlate genes and CVDs after diagnosis and provide a valuable resource for such markers, preferentially those with previously known or suspected function are addressed further. To tackle the unaddressed blind spot of understudied genes, we particularly focused on the validation of heart GWAS candidates with little or no apparent connection to cardiac function. Building on the high conservation of basic heart function and underlying genetics from fish to human we combined CRISPR/Cas9 genome editing of the orthologs of human GWAS candidates in isogenic medaka with automated high-throughput heart rate analysis. Our functional analyses of understudied human candidates uncovered a prominent fraction of heart rate associated genes from adult human patients displaying a heart rate effect in embryonic medaka already in the injected generation. Following this pipeline, we identified 16 GWAS candidates with potential diagnostic and predictive power for human CVDs.
Global spread and evolutionary history of HCV subtype 3a
Authors: lin Shang-kuan , De Maio Nicola , Pedergnana Vincent , Wu Chieh-Hsi , Thézé Julien , Barnes Ellie , Ansari M. Azim 
Published: February 2021

AbstractStudies have shown that HCV subtype 3a had likely been circulating in South Asia before its global spread. However, the time and route of this dissemination remain unclear. For the first time, we generated host and virus genome-wide data for more than 500 patients infected with HCV subtype 3a from the UK, North America, Australia and New Zealand. We used the host genomic data to infer the ancestry of the patients and used this information to investigate the epidemic history of HCV subtype 3a. We observed that viruses from hosts of South Asian ancestry clustered together near the root of the tree, irrespective of the sampling country and that they were more diverse than viruses from other host ancestries. We also inferred that three independent transmission events resulted in the spread of the virus from South Asia to the UK, North America and the Australian continent. This initial spread happened during or soon after the end of the second world war. This was followed by an exponential growth in the effective population size of HCV subtype 3a worldwide and many independent transmissions between the UK, North America and Australian continent. Using both host and virus genomic information can be highly informative in studying the virus epidemic history especially in the context of chronic infections.
PIGNON: A protein-protein interaction-guided functional enrichment analysis for quantitative proteomics
Authors: Nadeau Rachel , Byvsheva Anastasiia , Lavallée-Adam Mathieu 
Published: February 2021

AbstractBackgroundQuantitative proteomics studies are often used to detect proteins that are differentially expressed across different experimental conditions. Functional enrichment analyses are then typically used to detect annotations, such as biological processes that are significantly enriched among such differentially expressed proteins to provide insights into the molecular impacts of the studied conditions. While common, this analytical pipeline heavily relies on arbitrary thresholds of significance. Indeed, a functional annotation may be dysregulated in a given experimental condition, while none or very few of its proteins may be individually considered to be significantly differentially expressed. Such an annotation would therefore be missed by standard approaches.ResultsHerein, we propose a novel graph theory-based method, PIGNON, for the detection of differentially expressed functional annotations in different conditions. PIGNON does not assess the statistical significance of individual genes, but rather maps protein differential expression levels onto a protein-protein interaction network and measures the clustering of proteins from a given functional annotation within the network. This process allows the detection of functional annotations for which the proteins are differentially expressed and grouped in the network. A Monte-Carlo sampling approach is used to assess the clustering of proteins in an expression-weighted network. When applied to a quantitative proteomics analysis of different molecular subtypes of breast cancer, PIGNON detects Gene Ontology terms that are both significantly clustered in a protein-protein interaction network and differentially expressed across two breast cancer subtypes. PIGNON identified 168 breast cancer pathways dysregulated and clustered within the network between the HER2+ and triple negative subtypes, 203 breast cancer pathways shared by HER2+ and hormone receptor positive subtypes, 19 breast cancer pathways shared by hormone receptor positive and triple negative breast that are not detected by standard approaches. PIGNON identifies functional annotations that have been previously associated with specific breast cancer subtypes as well as novel annotations that may be implicated in the diseases.ConclusionPIGNON provides an alternative to functional enrichment analyses and a more comprehensive characterization of quantitative datasets. Hence, it contributes to yielding a better understanding of dysregulated functions and processes in biological samples under different conditions.
Artificial Intelligence Approaches to Assessing Primary Cilia
Authors: Bansal Ruchi , Engle Staci E. , Kamba Tisianna K. , Brewer Kathryn , Lewis Wesley R. , Berbari Nicolas F. 
Published: February 2021

ABSTRACTCilia are microtubule based cellular appendages that function as signaling centers for a diversity of signaling pathways in many mammalian cell types. Cilia length is highly conserved, tightly regulated, and varies between different cell types and tissues and has been implicated in directly impacting their signaling capacity. For example, cilia have been shown to alter their lengths in response to activation of ciliary G protein-coupled receptors. However, accurately and reproducibly measuring the lengths of numerous cilia is a time-consuming and labor-intensive procedure. Current approaches are also error and bias prone. Artificial intelligence (Ai) programs can be utilized to overcome many of these challenges due to capabilities that permit assimilation, manipulation, and optimization of extensive data sets. Here, we demonstrate that an Ai module can be trained to recognize cilia in images from bothin vivoandin vitrosamples. After using the trained Ai to identify cilia, we are able to design and rapidly utilize applications that analyze hundreds of cilia in a single sample for length, fluorescence intensity and colocalization. This unbiased approach increased our confidence and rigor when comparing samples from different primary neuronal prepsin vitroas well as across different brain regions within an animal and between animals. Moreover, this technique can be used to reliably analyze cilia dynamics from any cell type and tissue in a high-throughput manner across multiple samples and treatment groups. Ultimately, Ai-based approaches will likely become standard as most fields move toward less biased and more reproducible approaches for image acquisition and analysis.SUMMARYThe use of Artificial Intelligence (Ai) to analyze images is emerging as a powerful, less biased, and rapid approach compared with commonly used methods. Here we trained Ai to recognize a cellular organelle, primary cilia, and analyze properties such as length and staining intensity in a rigorous and reproducible manner.