bluuebunny/crossref_metadata_2025_split huggingface dataset:
Collagen Deposition in Diabetic Kidney Disease Boosts Intercellular Signaling: A Mathematical Model
Authors: Thomas Haryana Y. , Ford Versypt Ashlee N. 
Published: March 2021

ABSTRACTDiabetic kidney disease is a health burden that is becoming more prevalent in the US and worldwide. The limited options for treating and preventing diabetic kidney disease are in part due to gaps in our understanding of the progression of diabetic kidney damage and its impacts on cellular function. An important cellular function in the kidney glomerulus is intercellular communication via the release and uptake of soluble cytokines and growth factors. In diabetic kidney disease, excess collagen deposition alters the mesangial matrix properties, which, we hypothesize, diminishes the intercellular signaling between key glomerular cells. To test our hypothesis, we utilized established mathematical models of transport to study the impact of pathological deposition on the ability of cells to communicate via intercellular signaling. Our analysis reveals that pathological collagen deposition can enhance the signaling range of the glomerular cells rather than diminishing it.SIGNIFICANCEThe incidence of diabetes is expected to rise to over 600 million by the year 2040, one third of whom are expected to develop diabetic kidney disease. Our lack of understanding of how diabetic kidney disease progresses and affects cellular and tissue function has led to our inability to mitigate the rapidly rising burden of diabetic kidney disease. A hallmark of diabetic kidney damage is collagen deposition, yet its impact on cellular and tissue function is still not well understood. The elucidation of the impact of collagen deposition on cellular and tissue function will enable the identification of mechanisms that exacerbate the progression of diabetic kidney damage and thus provide novel avenues for preventing or slowing the progression of diabetic kidney damage.
The von Willebrand Factor stamps Plasmatic Extracellular Vesicles from Glioblastoma Patients
Authors: Sabbagh Quentin , André-Grégoire Gwennan , Alves-Nicolau Carolina , Bidère Nicolas , Jouglar Emmanuel , Guével Laëtitia , Frénel Jean-Sébastien , Gavard Julie 
Published: March 2021

AbstractGlioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness and resistance, as they carry and disseminate oncogenic material in the local tumor microenvironment and at distance. However, whether their quality and quantity reflect individual health status and changes in homeostasis is still not fully elucidated. Here, we separated EVs from plasma collected at different time points alongside with the clinical management of GBM patients. Our findings confirm that plasmatic EVs could be separated and characterized with standardized protocols, thereby ensuring the reliability of measuring vesiclemia,i.e. extracellular vesicle concentration in plasma. This unveils that vesiclemia is a dynamic parameter, which could be reflecting tumor burden and/or response to treatments. Further label-free liquid chromatography tandem mass spectrometry unmasks the von Willebrand Factor (VWF) as a selective protein hallmark for GBM-patient EVs. Our data thus support the notion that EVs from GBM patients showed differential protein cargos that can be further surveyed in circulating EVs, together with vesiclemia.
Target Capture Sequencing of SARS-CoV-2 Genomes Using the ONETest Coronaviruses Plus
Authors: Zhan Shing H. , Alamouti Sepideh M. , Kwok Brian S. , Lee Meng-Hsun , Khattra Jaswinder , Daneshpajouh Habib , Houck Herbert J. , Rand Kenneth H. 
Published: March 2021

ABSTRACTBackgroundGenomic sequencing is important to track and monitor genetic changes in SARS-CoV-2. We introduce a target capture next-generation sequencing methodology, the ONETest Coronaviruses Plus, to sequence SARS-CoV-2 genomes and select genes of other respiratory viruses simultaneously.MethodsWe applied the ONETest on 70 respiratory samples (collected in Florida, USA between May and July, 2020), in which SARS-CoV-2 had been detected by a qualitative PCR assay. For 48 (69%) of the samples, we also applied the ARTIC protocol for Illumina sequencing. All the libraries were sequenced as 2×150 nucleotide reads on an Illumina instrument. The ONETest data were analyzed using an in-house pipeline and the ARTIC data using a published pipeline to produce consensus SARS-CoV-2 genome sequences, to which lineages were assigned usingpangolin.ResultsOf the 70 ONETest libraries, 45 (64%) had a complete or near-complete SARS-CoV-2 genome sequence (> 29,000 bases and with > 90% of its bases covered by at least 10 reads). Of the 48 ARTIC libraries, 25 (52%) had a complete or near-complete SARS-CoV-2 genome sequence.In 24 out of 34 (71%) samples in which both the ONETest and ARTIC sequences were complete or near-complete and in which lineage could be assigned to both the ONETest and ARTIC sequences, the SARS-CoV-2 lineage identified was the same.ConclusionsThe ONETest can be used to sequence the SARS-CoV-2 genomes in archived samples and thereby enable detection of circulating and emerging SARS-CoV-2 variants. Target capture approaches, such as the ONETest, are less prone to loss of sequence coverage probably due to amplicon dropouts encountered in amplicon approaches, such as ARTIC. With its added value of characterizing other major respiratory pathogens, although not assessed in this study, the ONETest can help to better understand the epidemiology of infectious respiratory disease in the post COVID-19 era.
Postural perturbation induced by electrical stimulation; A new approach to examine the mechanism of falling
Authors: Tahayori Behdad , Tahayori Bahman , Mehdizadeh Alireza , Koceja David M. 
Published: March 2021

AbstractBackgroundFalling is a major cause of disability and death among elderly people. Therefore, a clear understanding of fall mechanism is necessary for providing preventative and treatment methods. Several fall simulation protocols have been introduced to study lost of balance in a laboratory setting.New MethodWe have explained and examined a new method to induce a sudden perturbation on standing posture to provide an insight into the mechanism of falling. The method comprises eliciting an H-reflex protocol while subjects are standing which produces a contraction in soleus and gastrocnemius muscles. We have also defined analytical techniques to provide biomarkers of balance control during perturbation. The method is easy to implement and interpret. The H-reflex or M-wave can be elicited unilaterally or bilaterally causing a forward or sideway perturbation. The vector analysis and the Equilibrium Point calculations defined here can quantify the amplitude, direction, and evolution of the perturbation.ResultsWe tested this method on a group of healthy individuals and observed clear patterns of loss of balance due to stimulation. Direction and magnitude of deviation was manifested through the reconstructed vectors, with bilateral stimulation causing the largest perturbation.Comparison and conclusionThe resultant plantarflexion torque is reminiscent of tripping over an obstacle and triggers corrective reactions to restore balance. Therefore, it is more similar to an internal perturbation. Mechanical perturbations to the torso cause a displacement in center of mass (COM) and trigger a cascade of mechanisms. Our method, does not trigger the perturbation by the displacement of COM initially and therefore, triggers fewer mechanisms for regaining balance.
Characterizing nucleotide variation and expansion dynamics in human-specific variable number tandem repeats
Authors: Course Meredith M. , Sulovari Arvis , Gudsnuk Kathryn , Eichler Evan E. , Valdmanis Paul N. 
Published: March 2021

AbstractThere are over 55,000 variable number tandem repeats (VNTRs) in the human genome, notable for both their striking polymorphism and mutability. Despite their role in human evolution and genomic variation, they have yet to be studied collectively and in detail, partially due to their large size, variability, and predominant location in non-coding regions. Here, we examine 467 VNTRs that are human-specific expansions, unique to one location in the genome, and not associated with retrotransposons. We leverage publicly available long-read genomes – including from the Human Genome Structural Variant Consortium – to ascertain the exact nucleotide composition of these VNTRs, and compare their composition of alleles. We then confirm repeat unit composition in over 3000 short-read samples from the 1000 Genomes Project. Our analysis reveals that these VNTRs contain remarkably structured repeat motif organization, modified by frequent deletion and duplication events. While overall VNTR compositions tend to remain similar between 1000 Genomes Project super-populations, we describe a notable exception with substantial differences in repeat composition (in PCBP3), as well as several VNTRs that are significantly different in length between super-populations (in ART1, PROP1, WDR60, and LOC102723906). We also observe that most of these VNTRs are expanded in archaic human genomes, yet remain stable in length between single generations. Collectively, our findings indicate that repeat motif variability, repeat composition, and repeat length are all informative modalities to consider when characterizing VNTRs and their contribution to genomic variation.
Brain endothelial cell tissue-nonspecific alkaline phosphatase (TNAP) activity promotes maintenance of barrier integrityviathe ROCK pathway
Authors: Nwafor Divine C. , Brichacek Allison L. , Wang Wei , Bidwai Nina , Lilly Christa L. , Luis Millán José , Brown Candice M. 
Published: March 2021

AbstractBlood-brain barrier (BBB) dysfunction is a key feature in many neuroinflammatory diseases. Yet, no therapies exist to effectively mitigate BBB dysfunction. A strategy to bridge this knowledge gap requires an examination of proteins localized to brain microvascular endothelial cells (BMECs) and evaluating their role in preserving barrier integrity. Tissue-nonspecific alkaline phosphatase (TNAP) is highly abundant in brain microvascular endothelial cells (BMECs); however, its function in BMECs remains unclear. We hypothesized that a loss or inhibition of TNAP activity on BMECs would impair barrier integrity through increased cytoskeletal remodeling driven by the Rho-associated protein kinase (ROCK) pathway. First, we examined barrier integrity in hCMEC/D3 cells treated with a TNAP inhibitor (TNAPi) and in primary BMECs (pBMECs)viathe conditional deletion of TNAP in endothelial cells. Our results showed that both pharmacological inhibition and genetic conditional loss of TNAP significantly worsened endothelial barrier integrity compared to controls. Next, we examined the mechanisms through which TNAP activity exerts a protective phenotype on BMECs. Our results showed that hCMEC/D3 cells treated with TNAPi displayed remarkable phalloidin and vimentin cytoskeletal remodeling compared to control. We then examined the role of ROCK, a key player in cytoskeletal remodeling. Our results showed that TNAPi increased the expression of ROCK 1/2. Furthermore, inhibition of ROCK 1/2 with fasudil mitigated TNAPi-induced and VE-cKO barrier dysfunction. Collectively, our results support a novel mechanism through which loss of TNAP activity results in cerebrovascular dysfunction, and selective modulation of TNAP activity in BMECs may be a therapeutic strategy to improve BBB function.
Hemodialysis Patients Show a Highly Diminished Antibody Response after COVID-19 mRNA Vaccination Compared to Healthy Controls
Authors: Simon Benedikt , Rubey Harald , Treipl Andreas , Gromann Martin , Hemedi Boris , Zehetmayer Sonja , Kirsch Bernhard 
Published: March 2021

1.Abstract1.1Background and ObjectivesHemodialysis patients are prone to infection with SARS-COV2 and show a high probability of a severe course of disease and high mortality when infected. In many countries hemodialysis patients are prioritised in vaccination programs to protect this vulnerable community. However, no hemodialysis patients were included in efficacy trials of SARS CoV-2 vaccines and therefore efficacy and safety data for this patient group are lacking. These data would be critical, since hemodialysis patients showed decreased responses against various other vaccines and this could mean decreased response to SARS CoV-2 vaccines.1.2Design, setting, participants, and measurementsWe conducted a prospective cohort study consisting of a group of 81 hemodialysis patients and 80 healthy controls who were vaccinated with mRNA vaccine BNT162b2 (BionTech/Pfizer, 2 doses with an interval of 21 days). Anti-SARS-COV-2 S antibody response in all participants was measured 21 days after the second dose. The groups were compared with univariate quantile regressions and a multiple analysis. Adverse events (AEs) of the vaccination were assessed with a standardized questionnaire. We also performed a correlation of HBs-Antibody response with the SARS-COV-2 antibody response in the hemodialysis patients.1.3ResultsDialysis patients had significantly lower Anti-SARS-COV-2 S antibody titres than healthy control patients 21 days after vaccination with BNT162b2 (median dialysis Patients 171 U/ml versus median controls 2500 U/ml). Age also had a significant but less pronounced influence on antibody titres. Dialysis patients showed less AEs than the control group. No significant correlation was found for Hepatitis B vaccine antibody response and SARS CoV-2 vaccine antibody response.1.4ConclusionsHemodialysis patients exhibit highly diminished SARS-COV-2 S antibody titres compared to a cohort of controls. Therefore these patients could be much less protected by SARS CoV-2 mRNA vaccination than expected. Alternative vaccination schemes must be considered and preventive measures must be maintained after vaccination.
Why COVID-19 is not so spread in Africa: How does Ivermectin affect it?
Authors: Tanioka Hisaya , Tanioka Sayaka , Kaga Kimitaka 
Published: March 2021

AbstractBackgroundScientists have so far been unable to determine the reason for the low number of COVID-19 cases in Africa.ObjectiveTo evaluate the impact of ivermectin interventions for onchocerciasis on the morbidity, mortality, recovery, and fatality rates caused by COVID-19.MethodA retrospective statistical analysis study of the impact of ivermectin against COVID-19 between the 31 onchocerciasis-endemic countries using the community-directed treatment with ivermectin (CDTI) and the non-endemic 22 countries in Africa. The morbidity, mortality, recovery rate, and fatality rate caused by COVID-19 were calculated from the WHO situation report in Africa. We investigated the onchocerciasis endemic 31 countries and the non-endemic 22 countries. Statistical comparisons used by the Welch test of them in the two groups were made.ResultsThe morbidity and mortality were statistically significantly less in the 31 countries using CDTI. The recovery and fatality rates were not statistically significant difference. The average life expectancy was statistically significantly higher in the non-endemic countries.ConclusionsThe morbidity and mortality in the onchocerciasis endemic countries are lesser than those in the non-endemic ones. The community-directed onchocerciasis treatment with ivermectin is the most reasonable explanation for the decrease in morbidity and fatality rate in Africa. In areas where ivermectin is distributed to and used by the entire population, it leads to a significant reduction in mortality.
COVID-19 Vaccine’s Gender Paradox
Authors: Galasso Vincenzo , Profeta Paola , Foucault Martial , Pons Vincent 
Published: March 2021

SummaryWomen die less than men of COVID-19, but have been more concerned about its health consequences and more compliant with the public health rules imposed during the pandemic. Since return to normal life depends on vaccination, but delays in acceptance or outright refusals of vaccination are already evident, we investigate gender differences in attitudes and expected behaviors regarding COVID-19 vaccination. Using original data from a survey conducted in December 2020 in ten developed countries (N=13,326), we discover aCOVID-19 Vaccine’s gender paradox. Being more concerned about COVID-19 and more likely to believe to be infected and consequently to become seriously ill, women could be expected to be more supportive of vaccination than men. Instead, our findings show that women agree less than men to be vaccinated and to make vaccination compulsory. Our evidence suggests that their vaccine hesitance is partly due skepticism, since women are less likely to believe that vaccination is the only solution to COVID-19 and more likely to believe that COVID-19 was created by large corporations. Using a survey experiment performed in these ten countries, we show that information provision on the role of vaccination to become immune to COVID-19 is effective in reducing vaccine hesitance.
Snapshots of actin and tubulin folding inside the TRiC chaperonin
Authors: Kelly John J. , Tranter Dale , Pardon Els , Chi Gamma , Kramer Holger , Knee Kelly M. , Janz Jay M. , Steyaert Jan , Bulawa Christine , Paavilainen Ville O. , Huiskonen Juha T. , Yue Wyatt W. 
Published: March 2021

AbstractThe integrity of a cell’s proteome depends on correct folding of polypeptides by chaperonins. The TCP-1 ring chaperonin (TRiC) acts as obligate folder for >10% of cytosolic proteins, including cytoskeletal proteins actin and tubulin. While its architecture and how it recognises folding substrates is emerging from structural studies, the subsequent fate of substrates inside the TRiC chamber is not defined. We trapped endogenous human TRiC with substrates (actin, tubulin) and co-chaperone (PhLP2A) at different folding stages, for structure determination by cryogenic electron microscopy. The already-folded regions of client proteins are anchored at the chamber wall, positioning unstructured regions towards the central space to achieve their folding. Substrates engage with different sections of the chamber during the folding cycle, coupled to TRiC open-and-close transitions. Furthermore, the cochaperone PhLP2A modulates folding, acting as a molecular strut between substrate and TRiC chamber. Our structural snapshots piece together an emerging atomistic model of client protein folding through TRiC.
Gene-gene relationships in an Escherichia coli accessory genome are linked to function and mobility
Authors: Hall Rebecca J. , Whelan Fiona J. , Cummins Elizabeth A. , Connor Christopher , McNally Alan , McInerney James O. 
Published: March 2021

AbstractThe pangenome contains all genes encoded by a species, with the core genome present in all strains and the accessory genome in only a subset. Coincident gene relationships are expected within the accessory genome, where the presence or absence of one gene is influenced by the presence or absence of another. Here, we analysed the accessory genome of an Escherichia coli pangenome consisting of 400 genomes from 20 sequence types to identify genes that display significant co-occurrence or avoidance patterns with one another. We present a complex network of genes that are either found together or that avoid one another more often than would be expected by chance, and show that these relationships vary by lineage. We demonstrate that genes co-occur by function, and that several highly connected gene relationships are linked to mobile genetic elements. We find that genes are more likely to co-occur with, rather than avoid, another gene, suggesting that cooperation is more common than conflict in the accessory genome. This work furthers our understanding of the dynamic nature of prokaryote pangenomes and implicates both function and mobility as drivers of gene relationships.Data summaryAll Supplementary Data files and the Python scripts used in the analyses are available at doi.org/10.17639/nott.7103.Impact statementThe pangenome of a species encompasses the core genes encoded by all genomes, as well as the accessory genes found in only a subset. Much remains to be understood about the relationships and interactions between accessory genes; in particular, what drives pairs of genes to appear together in the same genome, or what prevents them from being in the same genome together, more often than expected by chance. How these co-occurrence and avoidance relationships develop, and what effect they have on the dynamics and evolution of the pangenome as a whole, is largely unknown. Here, we present a springboard for understanding prokaryote pangenome evolution by uncovering significant gene relationships in a model Escherichia coli pangenome. We identify mobile genetic elements and the sharing of common function as possible driving forces behind the co-occurrence of accessory genes. Furthermore, this work offers an extensive dataset from which gene relationships could be identified for any gene of interest in this E. coli accessory genome, providing a rich resource for the community.
Adaptive finite element analysis of free vibration of elastic membranes via element energy projection technique
Authors: Sun Haohan , Yuan Si 
Published: March 2021

Purpose
A general strategy is developed for adaptive finite element (FE) analysis of free vibration of elastic membranes based on the element energy projection (EEP) technique.

Design/methodology/approach
By linearizing the free vibration problem of elastic membranes into a series of linear equivalent problems, reliable a posteriori point-wise error estimator is constructed via EEP super-convergent technique. Hierarchical local mesh refinement is incorporated to better deal with tough problems.

Findings
Several classical examples were analyzed, confirming the effectiveness of the EEP-based error estimation and overall adaptive procedure equipped with a local mesh refinement scheme. The computational results show that the adaptively-generated meshes reasonably catch the difficulties inherent in the problems and the procedure yields both eigenvalues with required accuracy and mode functions satisfying user-preset error tolerance in maximum norm.

Originality/value
By reasonable linearization, the linear-problem-based EEP technique is successfully transferred to two-dimensional eigenproblems with local mesh refinement incorporated to effectively and flexibly deal with singularity problems. The corresponding adaptive strategy can produce both eigenvalues with required accuracy and mode functions satisfying user-preset error tolerance in maximum norm and thus can be expected to apply to other types of eigenproblems.