bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of hypertension as an existing comorbidity on mortality rate in patients with COVID-19 A systematic review and meta-analysis
Authors: Whiteman Elena
Published: November 2020

Introduction

Coronavirus has spread throughout the world rapidly, and there is a growing need to identify host risk factors to identify those most at risk. There is a growing body of evidence suggesting a close link exists between an increased risk of infection and an increased severity of lung injury and mortality, in patients infected with COVID-19 who have existing hypertension. This is thought to be due to the possible involvement of the virus target receptor, ACE2, in the renin-angiotensin-aldosterone blood pressure management system.

Objective

To investigate the association between hypertension as an existing comorbidity and mortality in hospitalized patients with confirmed coronavirus disease 2019 (COVID-19).

Methods

A systematic literature search in several databases was performed to identify studies that comment on hypertension as an existing comorbidity, and its effect on mortality in hospitalized patients with confirmed COVID-19 infection. The results of these studies were then pooled, and a meta-analysis was peformed to assess the overall effect of hypertension as an existing comorbidity on risk of mortality in hospitalized COVID-19 positive patients.

Results

A total of 12243 hospitalised patients were pooled from 19 studies. All studies demonstrated a higher fatality rate in hypertensive COVID-19 patients when compared to non-hypertensive patients. Meta-analysis of the pooled studies also demonstrated that hypertension was associated with increased mortality in hospitalized patients with confirmed COVID-19 infection (risk ratio (RR) 2.57 (95% confidence interval (CI) 2.10, 3.14), p < 0.001;I2=74.98%).

Conclusion

Hypertension is associated with 157% increased risk of mortality in hospitalized COVID-19 positive patients. These results have not been adjusted for age, and a meta-regression of covariates including age is required to make these findings more conclusive.

Risk of mortality is considerably higher in hospitalised COVID-19 patients who have hypertension as an existing comorbidity prior to admission.
Designing Efficient Contact Tracing Through Risk-Based Quarantining
Authors: Perrault Andrew , Charpignon Marie , Gruber Jonathan , Tambe Milind , Majumder Maimuna S.
Published: November 2020

Contact tracing for COVID-19 is especially challenging because transmission often occurs in the absence of symptoms and because a purported 20% of cases cause 80% of infections, resulting in a small risk of infection for some contacts and a high risk for others. Here, we introduce risk-based quarantine, a system for contact tracing where each cluster (a group of individuals with a common source of exposure) is observed for symptoms when tracing begins, and clusters that do not display them are released from quarantine. We show that, under our assumptions, risk-based quarantine reduces the amount of quarantine time served by more than 30%, while achieving a reduction in transmission similar to standard contact tracing policies where all contacts are quarantined for two weeks. We compare our proposed risk-based quarantine approach against test-driven release policies, which fail to achieve a comparable level of transmission reduction due to the inability of tests to detect exposed people who are not yet infectious but will eventually become so. Additionally, test-based release policies are expensive, limiting their effectiveness in low-resource environments, whereas the costs imposed by risk-based quarantine are primarily in terms of labor and organization.
Risk factors for fecal carriage of multidrug-resistantEscherichia coliin a college community: a penalized regression model
Authors: Hu Yuan , Rubin Julia , Mussio Kaitlyn , Riley Lee W.
Published: November 2020

Background

Bacterial antimicrobial resistance is a serious global public health threat. Intestinal commensal drug-resistant bacteria have been suggested as an important reservoir of antimicrobial resistant genes (ARGs), which may be acquired via food. We aimed to identify risk factors associated with fecal carriage of drug-resistant commensalEscherichia coli (E. coli)among healthy adults focused on their dietary habit.

Methods

We conducted a cross-sectional study targeting healthy adult volunteers in a college community. Fecal samples and questionnaires were obtained from 113 volunteers. We conducted backward elimination logistic regression and least absolute shrinkage and selection (LASSO) methods to identify risk factors.

Results

We analyzed responses from 81 of 113 volunteers who completed the questionnaire. The logistic regression and LASSO methods identified red meat consumption to be associated with increased risk (OR = 6.13 [1.83-24.2] and 1.82, respectively) and fish consumption with reduced risk (OR = 0.27 [0.08-0.85] and 0.82) for the carriage of multidrug-resistantE. coli, adjusted for gender, employment status, frequently-used supermarket, and previous travel.

Conclusions

Dietary habits are associated with the risk of fecal carriage of multidrug-resistantE. coli. This study supports the growing evidence that food may be an important source of ARGs present in human commensalE. coli.
The total number and mass of SARS-CoV-2 virions
Authors: Sender Ron , Bar-On Yinon M. , Gleizer Shmuel , Bernsthein Biana , Flamholz Avi , Phillips Rob , Milo Ron
Published: November 2020

Quantitatively describing the time course of the SARS-CoV-2 infection within an infected individual is important for understanding the current global pandemic and possible ways to combat it. Here we integrate the best current knowledge about the typical viral load of SARS-CoV-2 in bodily fluids and host tissues to estimate the total number and mass of SARS-CoV-2 virions in an infected person. We estimate that each infected person carries 109-1011virions during peak infection, with a total mass in the range of 1-100 μg, which curiously implies that all SARS-CoV-2 virions currently circulating within human hosts have a collective mass of only 0.1-10 kg. We combine our estimates with the available literature on host immune response and viral mutation rates to demonstrate how antibodies markedly outnumber the spike proteins and the genetic diversity of virions in an infected host covers all possible single nucleotide substitutions.

Significance

Knowing the absolute numbers of virions in an infection promotes better understanding of the disease dynamics and the response of the immune system. Here we use the best current knowledge on the concentrations of virions in infected individuals to estimate the total number and mass of SARS-CoV-2 virions in an infected person. Although each infected person carries an estimated 1-100 billion virions during peak infection, their total mass is no more than 0.1 mg. This curiously implies that all SARS-CoV-2 virions currently in all human hosts have a mass of between 100 gram and 10 kilogram. Combining the known mutation rate and our estimate of the number of infectious virions we quantify the formation rate of genetic variants.
Spatiotemporal analysis of surveillance data enables climate-based forecasting of Lassa fever
Authors: Redding David W. , Gibb Rory , Dan-Nwafor Chioma C. , Ilori Elsie A. , Usman Yashe Rimamdeyati , Saliu Oladele H. , Michael Amedu O. , Akanimo Iniobong , Ipadeola Oladipupo B. , Enright Lauren , Donnelly Christl A. , Abubakar Ibrahim , Jones Kate E. , Ihekweazu Chikwe
Published: November 2020

Lassa fever (LF) is an acute rodent-borne viral haemorrhagic fever that is a longstanding public health concern in West Africa and increasingly a global health priority. Recent molecular studies1,2have confirmed the fundamental role of the rodent host (Mastomys natalensis) in driving human infections, but LF control and prevention efforts remain hampered by a limited baseline understanding of the disease’s true incidence, geographical distribution and underlying drivers3. Here, through analysing 8 years of weekly case reports (2012-2019) from 774 local government authorities (LGAs) across Nigeria, we identify the socioecological correlates of LF incidence that together drive predictable, seasonal surges in cases. At the LGA-level, the spatial endemic area of LF is dictated by a combination of rainfall, poverty, agriculture, urbanisation and housing effects, although LF’s patchy distribution is also strongly impacted by reporting effort, suggesting that many infections are still going undetected. We show that spatial patterns of LF incidence within the endemic area, are principally dictated by housing quality, with poor-quality housing areas seeing more cases than expected. When examining the seasonal and inter-annual variation in incidence within known LF hotspots, climate dynamics and reporting effort together explain observed trends effectively (with 98% of observations falling within the 95% predictive interval), including the sharp uptick in 2018-19. Our models show the potential for forecasting LF incidence surges 1-2 months in advance, and provide a framework for developing an early-warning system for public health planning.
Maternal perception of child weight and concern about child overweight mediates the relationship between child weight and non-responsive feeding practices
Authors: Wang Jian , Zhu Daqiao , Cheng Xuwen , LiuZhou Yicong , Zhu Bingqian , Montgomery Scott , Cao Yang
Published: November 2020

We aimed to examine the mediating effects of maternal perception of child weight (weight perception) and concern about overweight (weight concern) on the paths between child weight and non-responsive feeding practices. We recruited a convenience sample of 1164 mothers who were primary caregivers of preschool children. Child body mass index (BMI) Z-score was calculated to assess child weight. The Chinese version of the Child Feeding Questionnaire (C-CFQ) was used to measure four common non-responsive feeding practices, weight perception and weight concern. Structural equation modeling (SEM) was used to examine the associations between child BMI Z-scores, maternal feeding practices, and other covariates. Sixty percent of the mothers perceived their overweight/obese children as normal weight or even underweight. The disagreement between actual child weight and maternal weight perception was statistically significant (Kappa = 0.212,P< 0.001). SEM indicated that weight perception fully mediated the relationship between child BMI Z-scores and pressure to eat. Weight concern fully mediated the relationships between child BMI Z-scores and the other three feeding practices. The serial mediating effects of weight perception and concern were statistically significant for the paths between child BMI Z-score and monitoring (β = 0.035,P< 0.001), restriction (β = 0.022,P< 0.001), and food as a reward (β = -0.017,P< 0.05).

Conclusion

Child weight may influence maternal feeding practices through weight perception and concern. Thus, interventions are needed to increase the accuracy of weight perception, which may influence several maternal feeding practices and thereby contribute to child health.

What is Known

Non-responsive feeding practices may contribute to childhood obesity or eating disorders.

Relationships between maternal weight perception and concern, child weight, and feeding practices have been mixed.

What is New

Child weight may influence maternal non-responsive feeding practices through maternal weight perception and concern.

Interventions are needed to increase the accuracy of caregivers’ perception of child weight which may influence maternal feeding practices and thereby contribute to child health.
Phenotyping of Indian Polycystic Ovarian Syndrome on the basis of Biochemical Parameters: A retrospective analysis via Hierarchical Cluster Classification
Authors: Moorthy Janani Dakshina , Ayyappan Rajapriya , Usha B
Published: November 2020

Objective

We aimed to phenotype the Indian PCOS population based on their etiology for an effective treatment regimen.

Design

Retrospective analysis of biochemical data.

Setting

PCOS clinics in Tamil Nadu, India

Population or Sample

Girls and women in age group 18 to 30 diagnosed as PCOS by RC.

Method

The statistical analysis was done using two-way cluster analysis function of SPSS v.22 to identify the phenotypes and the resolving biochemical parameter. Also, the population was segregated into three cohorts based on their age for further analysis.

Main outcome measure

Endocrine parameters like LH, FSH, estradiol, testosterone and thyroid profile. Biochemical parameters like complete lipid profile, blood glucose and insulin fasting. Body Mass Index (BMI).

Results

The statistical analysis reported two phenotypes among the Indian PCOS population, segregated based on their LH: FSH ratio. The phenotype with LH: FSH >2, had a hormonal imbalance and may have its etiology from Hypothalamus – Pituitary - Ovarian axis. The phenotype with LH: FSH < 2 had significant markers indicating the incidence of metabolic syndrome and may follow an insulin – dependent pathway for PCOS manifestation.

Conclusion

The PCOS population needs a comprehensive screening before deciding on a treatment regimen. All the PCOS patients need to be recommended to follow an active lifestyle since 80% of them are predisposed to a metabolic syndrome in their later ages.
Celda: A Bayesian model to perform co-clustering of genes into modules and cells into subpopulations using single-cell RNA-seq data
Authors: Wang Zhe , Yang Shiyi , Koga Yusuke , Corbett Sean E. , Johnson W. Evan , Yajima Masanao , Campbell Joshua D.
Published: November 2020

Single-cell RNA-seq (scRNA-seq) has emerged as a powerful technique to quantify gene expression in individual cells and elucidate the molecular and cellular building blocks of complex tissues. We developed a novel Bayesian hierarchical model called Cellular Latent Dirichlet Allocation (Celda) to perform simultaneous co-clustering of genes into transcriptional modules and cells into subpopulations. Celda can quantify the probabilistic contribution of each gene to each module, each module to each cell population, and each cell population to each sample. We used Celda to identify transcriptional modules and cell subpopulations in a publicly available peripheral blood mononuclear cell (PBMC) dataset. Celda identified a population of proliferating T cells and a single plasma cell which were missed by two other clustering methods. Celda identified transcriptional modules that highlighted unique and shared biological programs across cell types. Celda also outperformed a PCA-based approach for gene clustering on simulated data. Overall, Celda presents a novel statistically principled approach towards characterizing transcriptional programs and cellular heterogeneity in single-cell RNA-seq data.
Molecular evidence indicates the existence of multiple lineages ofSperata speciesin Indian Rivers
Authors: Yadav Prabhaker , Kumar Ajit , Yadav Neha , Bisht Mansi , Hussain Syed Ainul , Gupta Sandeep Kumar
Published: November 2020

Sperata seenghala(Giant river-catfish) andSperata aor(Long-whiskered catfish) are commercially important freshwater catfishes of India, belongs to family Bagridae. Due to high nutritional significance and the low number of intramuscular bones, both fishes have considerable demand in South Asian countries. Both of theSperataspecies are morphologically close and well adapted to the same habitat. In this study, we have assessed the level of genetic diversity and differentiation ofS. seenghalaandS. aorin the Ganga River based on the mitochondrial DNA (mtDNA) control region and compared with the other major Indian rivers. We found high haplotypes diversity for both the species in the Ganga. However, it was comparatively low forS. seenghalain Mahanadi and Brahmaputra populations. The phylogenetic and median-joining network strongly indicated the presence of two distinct maternal lineages ofS. seenghalafrom the Ganga river. Interestingly, the genetic differentiation betweenS. seenghalaof Ganga-Brahmaputra was much higher (~25.3%) than theS. seenghalaandS. aor(~17%), whereas it was comparatively low between Ganges-Mahanadi (~8.0%). Our finding provided evidence that all the three rivers: Ganga, Mahanadi, and the Brahmaputra sustain a highly diverse and genetically distinct stock of giant river catfish; therefore, all populations should be considered as a different management unit for the protection of stocks. Our findings indicated that Brahmaputra lineages qualify the species level variations. This study can be further used as a reference database for proper lineage identification ofS. seenghalaandS. aorthat could formulate the appropriate conservation and management plans.
Looking for the needle in a downsized haystack: Whole-exome sequencing unravels how selection and gene flow have shaped climatic adaptation in Douglas-fir (Pseudotsuga menziesii)
Authors: George Jan-Peter , Schueler Silvio , Grabner Michael , Karanitsch-Ackerl Sandra , Mayer Konrad , Stierschneider Michael , Weissenbacher Lambert , van Loo Marcela
Published: November 2020

The widespread Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) occurs along a steep gradient of diverse climates throughout its natural range, which is expected to result in spatially varying selection to local climate conditions. However, phenotypic signals of climatic adaptation can often be confounded, because unraveled clines covary with signals caused by neutral evolutionary processes such as gene flow and genetic drift. Here, we present phenotypic and genotypic data from a common garden experiment showing a putative signal of adaptation to climate after trees have been growing for 40 years in a common environment. Sixteen Douglas-fir provenances originating from a North-to-South gradient of approx. 1,000 km were analyzed and genomic information was obtained from exome capture, which resulted in an initial genomic dataset of >90,000 single nucleotide polymorphisms. We used a restrictive and conservative filtering approach which permitted us to include only SNPs and individuals in environmental association analysis (EAA) that were free of potentially confounding effects (LD, relatedness among trees, heterozygosity deficiency and deviations from Hardy-Weinberg proportions). We used four conceptually different genome scan methods based on FSToutlier detection and gene-environment association in order to disentangle truly adaptive SNPs from neutral SNPs and found that a relatively small proportion of the exome showed a truely adaptive signal (0.01-0.17%) when population substructuring and multiple testing was accounted for. Nevertheless, the unraveled SNP candidates showed significant relationship with climate at provenance origins which strongly suggests that they have most likely featured adaption in Douglas-fir across a steep climatic gradient. Two SNPs were independently found by three of the employed algorithms and one could be assigned with high probability to aPicea abieshomolog gene involved in circadian clock control as was also found inPopulus balsamifera.
N2O-respiring bacteria in biogas digestates for reduced agricultural emissions
Authors: Jonassen Kjell Rune , Hagen Live H. , Vick Silas H.W. , Arntzen Magnus Ø. , Eijsink Vincent G.H. , Frostegård Åsa , Lycus Pawel , Molstad Lars , Pope Phillip B. , Bakken Lars R.
Published: November 2020

Inoculating agricultural soils with N2O-respiring bacteria (NRB) can reduce N2O-emissions, but would be impractical as a standalone operation. Here we demonstrate that digestates obtained after biogas production are suitable substrates and vectors for NRB. We show that indigenous NRB in digestates grew to high abundance during anaerobic enrichment under N2O. Gas-kinetics and meta-omic analyses showed that these NRB's, recovered as metagenome-assembled genomes (MAGs), grew by harvesting fermentation intermediates of the methanogenic consortium. Three NRB's were isolated, one of which matched the recovered MAG of a Dechloromonas, deemed by proteomics to be the dominant producer of N2O-reductase in the enrichment. While the isolates harbored genes required for a full denitrification pathway and could thus both produce and sequester N2O, their regulatory traits predicted that they act as N2O sinks in soil, which was confirmed experimentally. The isolates were grown by aerobic respiration in digestates, and fertilization with these NRB-enriched digestates reduced N2O emissions from soil. Our use of digestates for low-cost and large-scale inoculation with NRB in soil can be taken as a blueprint for future applications of this powerful instrument to engineer the soil microbiome, be it for enhancing plant growth, bioremediation, or any other desirable function.
Protein turnover dynamics suggest a diffusion to capture mechanism for peri-basal body recruitment and retention of intraflagellar transport proteins
Authors: Hibbard Jaime V.K. , Vazquez Neftali , Satija Rohit , Wallingford John B.
Published: November 2020

Intraflagellar transport (IFT) is essential for construction and maintenance of cilia. IFT proteins concentrate at the basal body, where they are thought to assemble into trains and bind cargoes for transport. To study the mechanisms of IFT recruitment to this peri-basal body pool, we quantified protein dynamics of eight IFT proteins, as well as five other basal body localizing proteins, using fluorescence recovery after photobleaching in vertebrate multiciliated cells. We found that members of the IFT-A and IFT-B protein complexes show distinct turnover kinetics from other basal body components. Additionally, known IFT sub-complexes displayed shared dynamics, and these dynamics were not altered during cilia regeneration as compared to homeostasis. Finally, we evaluated the mechanisms of basal body recruitment by depolymerizing cytosolic MTs, which suggested that IFT proteins are recruited to basal bodies through a diffusion-to-capture mechanism. Our survey of IFT protein dynamics provides new insights into IFT recruitment to basal bodies, a crucial step in ciliogenesis.
Region-specific and state-dependent astrocyte Ca2+dynamics during the sleep-wake cycle in mice
Authors: Tsunematsu Tomomi , Sakata Shuzo , Sanagi Tomomi , Tanaka Kenji F. , Matsui Ko
Published: November 2020

Neural activity is diverse, and varies depending on brain regions and sleep/wakefulness states. However, whether astrocyte activity differs between sleep/wakefulness states, and whether there are differences in astrocyte activity among brain regions remain poorly understood. In this study, we recorded astrocyte intracellular calcium (Ca2+) concentrations of mice during sleep/wakefulness states in the cortex, hippocampus, hypothalamus, cerebellum, and pons using fiber photometry. For this purpose, male transgenic mice in which their astrocytes specifically express the genetically encoded ratiometric Ca2+sensor YCnano50 were used. We demonstrated that Ca2+levels in astrocytes significantly decrease during Rapid Eye Movement (REM) sleep and increase after the onset of wakefulness. In contrast, differences in Ca2+levels during non-Rapid Eye Movement (NREM) sleep were observed among different brain regions, and no significant decrease was observed in the hypothalamus and pons. Further analyses focusing on the transition between sleep/wakefulness states and correlation analysis with episode duration of REM showed that Ca2+dynamics differed among brain regions, suggesting the existence of several clusters. To quantify region-specific Ca2+dynamics, principal component analysis was performed to uncover three clusters; i.e., the first comprised the cortex and hippocampus, the second comprised the cerebellum, and the third comprised the hypothalamus and pons. Our study demonstrated that astrocyte Ca2+levels change substantially according to sleep/wakefulness states. These changes were generally consistent, unlike neural activity. However, we also clarified that Ca2+dynamics varies depending on the brain region, implying that astrocytes may play various physiological roles in sleep.

Significance statement

Sleep is an instinctive behavior of many organisms. In the previous five decades, the mechanism of the neural circuits controlling sleep/wakefulness states and the neural activities associated with sleep/wakefulness states in various brain regions have been elucidated. However, whether astrocytes, which are a type of glial cell, change their activity during different sleep/wakefulness states is poorly understood. Here, we demonstrated that dynamic changes in intracellular Ca2+concentrations occur in the cortex, hippocampus, hypothalamus, cerebellum, and pons of genetically modified mice during natural sleep. Further analyses demonstrated that Ca2+dynamics slightly differ among different brain regions, implying that the physiological roles of astrocytes in sleep/wakefulness might vary depending on the brain region.
Community prevalence of antibodies to SARS-CoV-2 and correlates of protective immunity in an Indian metropolitan city
Authors: Ghose Aurnab , Bhattacharya Sankar , Karthikeyan Arun S. , Kudale Abhay , Monteiro Joy M. , Joshi Aparna , Medigeshi Guruprasad , Kang Gagandeep , Bal Vineeta , Rath Satyajit , Shashidhara L. S. , John Jacob , Chaudhuri Susmita , Nagarkar Aarti
Published: November 2020

Objectives

To assess seroprevalence of anti-SARS-CoV-2 antibodies in a densely populated urban Indian settings and its implications for disease trends and protective immunity.

Design

Cross-sectional sero-epidemiological survey linked with administrative reporting of COVID-19 testing data.

Settings

Pune city in western India

Main outcome measure

Prevalence of anti-SARS-CoV-2 spike protein antibodies were estimated and along with correlates of virus neutralisation and other immune and inflammatory markers.

Results

Seropositivity was extensive (51·3%; 95%CI 39·9 to 62·4) but varied widely in the five localities tested, ranging from 35·8% to 66·4%. Seropositivity was higher in crowded living conditions in the slums (OR 1·91), and was lower in those 65 years or older (OR 0·59). The infection-fatality ratio was estimated at 0.21%. Post survey, COVID-19 incidence was lower in areas noted to have higher seroprevalence. Substantial virus-neutralising activity was observed in seropositive individuals, but with considerable heterogeneity in the immune response and possible age-dependent diversity in the antibody repertoire.

Conclusion

Despite crowded living conditions having facilitated widespread transmission, the variability in seroprevalence in localities that are in geographical proximity indicates a heterogenous spread of infection. Declining infection rates in areas with high seropositivity suggest population-level protection. It is also supported by substantial neutralising activity in asymptomatically infected individuals. This is the first report of a significantly high proportion of protective immune response among asymptomatic individuals in the population. The heterogeneity in antibody levels and neutralisation capacity indicates the existence of immunological sub-groups of functional interest.

Trial registration

Registered with the Clinical Trials Registry of India (CTRI/2020/07/026509)
Hilbert-Envelope Features for Cardiac Disease Classification from Noisy Phonocardiograms
Authors: Nizam Nusrat Binta , Khan Nuhash Shoyad Ibn Sabur , Hasan Taufiq
Published: November 2020

Cardiovascular disease (CVD) is considered a significant public health concern around the world. Automated early diagnostic tools for CVDs can provide substantial benefits, especially in low-resource countries. In this study, we propose a time-domain Hilbert envelope feature (HEF) extraction scheme that can effectively distinguish among different cardiac anomalies from heart sounds even in highly noisy recordings. The method is motivated by how a cardiologist listens to the heart murmur configuration, e.g., the intensity of the heart sound envelope over a cardiac cycle. The proposed feature is invariant to the heart rate, the position of the first and second heart sounds, and robust in extracting the murmur configuration pattern in the presence of respiratory noise. Experimental evaluations are performed compared to two different state-of-the-art methods in the presence of respiratory noise with signal-to-noise ratio (SNR) values ranging from 0-15dB. The proposed HEF, fused with standard acoustic and Resnet features, yields an average accuracy, sensitivity, specificity, and F1-score of, 94.78%(±2.63), 87.48%(±6.07), 96.87%(±1.51) and 87.47%(±5.94), respectively, while using a random forest (RF) classifier. Compared to the best-performing baseline model, this feature-fusion scheme provides a significant performance improvement (p <0.05), notably achieving an absolute improvement of 6.16% in averaged sensitivity. In the case of 0dB SNR, the proposed feature alone provides a 9.2% absolute improvement in sensitivity compared to the top baseline system demonstrating the robustness of the HEF. The developed methods can significantly impact computer-aided auscultation (CAA) systems when deployed in noisy conditions, especially in low-resource settings.
Knockout ofmyocreveals the role of myocilin in zebrafish sex determination associated with Wnt signalling downregulation
Authors: Atienzar-Aroca Raquel , Aroca-Aguilar José-Daniel , Alexandre-Moreno Susana , Ferre-Fernández Jesús-José , Bonet-Fernández Juan-Manuel , Cabañero-Varela María-José , Escribano Julio
Published: November 2020

Myocilin is a secreted glycoprotein with a poorly understood biological function and it is mainly known for its association with glaucoma. To explore the normal role of this proteinin vivowe developed amyocknockout (KO) zebrafish line using CRISPR/Cas9 genome editing. This line carries a homozygous variant (c.236_239delinsAAAGGGGAAGGGGA) that is predicted to result in a loss-of-function of the protein because of a premature termination codon p.(V75EfsX60) that resulted in a significant reduction ofmyocmRNA levels. Immunohistochemistry showed the presence of myocilin in wild-type embryonic (96 hours post-fertilization) anterior segment eye structures and caudal muscles. The protein was also detected in different adult ocular and non-ocular tissues. No gross macroscopic or microscopic alterations were identified in the KO zebrafish, but remarkably, we observed absence of females among the adult KO animals and apoptosis in the immature juvenile gonad (28 dpf) of these animals, which is characteristic of male development. Transcriptomic analysis showed that adult KO males overexpressed key genes involved in male sex determination and presented differentially expressed Wnt signalling genes. These results show that myocilin is required for ovary differentiation in zebrafish and providein vivosupport for the role of myocilin as a Wnt signalling pathway modulator. In summary, thismyocKO zebrafish line can be useful to investigate the elusive function of this protein, and it provides evidence for the unexpected function of myocilin as a key factor in zebrafish sex determination.
Viral-structured models of dividing cells shows cell-virus coexistence via viral load partitioning between cell progeny
Authors: Ford Hugh Z.
Published: November 2020

The present study develops and analyses a system of partial differential equations that model a single population of dividing cells infected by lytic viruses in a closed system. This mean-field model stratifies cells by cell size (continuous) and number of virus particles per cell (discrete) to couple the cell cycle and the lytic cycle under mass conservation. We present numerical solutions to the mean-field model and an equivalent stochastic model for parameter values representative ofEscherichia Coliand lytic bacteriophages such as Escherichia virus T4. This analysis suggests that dividing cells and lytic virus populations in isolation can coexist in the absence of evolutionary, ecological and biochemical processes. Coexistence emerges because viral load dilution via cell growth and viral load partitioning via cell division both counteract viral load growth via viral synthesis and hence cell death by lysis. Furthermore, we analytically determine the quasi-steady state solution of the mean-field model in the continuum limit with respect to viral loads. From this solution we derive a condition for cell-virus coexistence through viral load partitioning: that the product of the viral synthesis rate, cell lysis rate and the time between cell divisions must be less than the product of log(2) and the cell growth rate. Overall, the present study provides a theoretical argument for a stable relationship between cells and lytic viruses simply by virtue of cell growth and division.
GSAP regulates mitochondrial function through the Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease
Authors: Xu Peng , Chang Jerry C. , Zhou Xiaopu , Wang Wei , Bamkole Michael , Wong Eitan , Bettayeb Karima , Jiang Lu-Lin , Huang Timothy , Luo Wenjie , Xu Huaxi , Nairn Angus C. , Flajolet Marc , Ip Nancy , Li Yue-Ming , Greengard Paul
Published: November 2020

Biochemical, pathogenic and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer’s disease (AD) and Down syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNA-seq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with Fe65:APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization, and lowering GSAP expression reduces pathological effects associated with AD.
An Engineered Antibody with Broad Protective Efficacy in Murine Models of SARS and COVID-19
Authors: Rappazzo C. Garrett , Tse Longping V. , Kaku Chengzi I. , Wrapp Daniel , Sakharkar Mrunal , Huang Deli , Deveau Laura M. , Yockachonis Thomas J. , Herbert Andrew S. , Battles Michael B. , O’Brien Cecilia M. , Brown Michael E. , Geoghegan James C. , Belk Jonathan , Peng Linghang , Yang Linlin , Scobey Trevor D. , Burton Dennis R. , Nemazee David , Dye John M. , Voss James E. , Gunn Bronwyn M. , McLellan Jason S. , Baric Ralph S. , Gralinski Lisa E. , Walker Laura M.
Published: November 2020

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. Here, we employed a directed evolution approach to engineer three SARS-CoV-2 antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains (RBDs) and neutralizes representative epidemic sarbecoviruses with remarkable potency. Structural and biochemical studies demonstrate that ADG-2 employs a unique angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In murine models of SARS-CoV and SARS-CoV-2 infection, passive transfer of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate for the treatment and prevention of SARS-CoV-2 and future emerging SARS-like CoVs.
Thiol-ene cross-linked alginate hydrogel encapsulation modulates the extracellular matrix of kidney organoids by reducing abnormal type 1a1 collagen deposition
Authors: Geuens Thomas , Ruiter Floor A.A. , Schumacher Anika , Morgan Francis L. C. , Rademakers Timo , Wiersma Loes E. , van den Berg Cathelijne W. , Rabelink Ton J. , Baker Matthew B. , LaPointe Vanessa L.S.
Published: November 2020

Differentiated kidney organoids from induced pluripotent stem cells hold promise as a treatment for patients with kidney diseases. Before these organoids can be translated to the clinic, shortcomings regarding their cellular, extracellular compositions and developmental plateau needs to be overcome. We performed a proteomic analysis on kidney organoids cultured for a prolonged culture time and we found a specific change in the extracellular matrix composition with increased expression of types 1a1, 2 and 6a1 collagen. Such an excessive accumulation of specific collagen types is a hallmark of renal fibrosis that causes a life-threatening pathological condition by compromising key functions of the human kidney. Here we hypothesized the need for a three-dimensional environment to grow the kidney organoids, which could better mimic the in vivo surroundings of the developing kidney than standard culture on a transwell filter. Encapsulating organoids for four days in a soft, thiol-ene cross-linked alginate hydrogel resulted in decreased type 1a1 collagen expression. Furthermore, the encapsulation did not result in any changes of organoid structural morphology. Using a biomaterial to modulate collagen expression allows for a prolonged kidney organoid culture in vitro and a reduction of abnormal type 1a1 collagen expression bringing kidney organoids closer to clinical application.

HIGHLIGHTS

Prolonging kidney organoid culture results in a developmental plateau instead of improvedin vitromaturation.

Proteomic analyses point to an increased expression of specific collagen subtypes associated with renal fibrosis.

Encapsulating kidney organoids using a soft thiol-ene cross-linked alginate hydrogel reduces collagen type 1a1 and αSMA deposition.
In exogenous attention, time is the clue: brain and heart interactions to survive threatening stimuli
Authors: Ruiz-Padial Elisabeth , Mercado Francisco
Published: November 2020

The capture of exogenous attention by negative stimuli has been interpreted as adaptive for survival in a diverse and changing environment. In the present paper, we investigate the neural responses towards two discrete negative emotions with different biological meanings, disgust and fear, and its potential relationships with heart rate variability (HRV) as an index of emotional regulation. With that aim, 30 participants performed a digit categorization task while fear, disgust and neutral distractor pictures were presented. Resting HRV at baseline, behavioral responses, and event-related potentials were recorded. Whereas P1 amplitudes were highest to fear distractors, the disgust stimulation led to augmented P2 amplitudes compared to the rest of distractors. Interestingly, increased N2 amplitudes were also found to disgust distractors, but only in high HRV participants. Neural source estimation data point to the involvement of the insula in this exogenous attentional response to disgust. Additionally, disgust distractors provoked longer reaction times than fear and neutral distractors in the high HRV group. Present findings are interpreted in evolutionary terms suggesting that exogenous attention is captured by negative stimuli following a different time course for fear and disgust. Possible HRV influences on neural mechanisms underlying exogenous attention are discussed considering the potential important role of this variable in emotional regulation processes.
A generalised mechano-kinetic model for use in multiscale simulation protocols
Authors: Hanson Benjamin S. , Dougan Lorna , Harlen Oliver G. , Harris Sarah A. , Read Daniel J.
Published: November 2020

Many biophysical systems and proteins undergo mesoscopic conformational changes in order to perform their biological function. However, these conformational changes often result from a cascade of atomistic interactions within a much larger overall object. For simulations of such systems, the computational cost of retaining high-resolution structural and dynamical information whilst at the same time observing large scale motions over long times is high. Furthermore, this cost is only going to increase as ever larger biological objects are observed experimentally at high resolution.

We derive a generalised mechano-kinetic simulation framework which aims to compensate for these disparate time scales, capable of dynamically exploring a defined mechanical energy landscape whilst at the same time performing kinetic transitions between discretely defined states. With insight from the theory of Markov state models and transition state theory, the framework models continuous dynamical motion at coarse-grained length scales whilst simultaneously including fine-detail, chemical reactions or conformational changes implicitly using a kinetic model. The kinetic model is coupled to the dynamic model in a highly generalised manner, such that kinetic transition rates are continuously modulated by the dynamic simulation. Further, it can be applied to any defined continuous energy landscape, and hence, any existing dynamic simulation framework. We present a series of analytical examples to validate the framework, and showcase its capabilities for studying more complex systems by simulating protein unfolding via single-molecule force spectroscopy on an atomic force microscope.

Author summary

Our intention with this work is to provide a generalised, highly coarse-grained model to allow kinetic processes (conformational changes, protein unfolding, chemical reactions etc) to occur within the context of a dynamic simulation. Performing computationally intensive dynamic simulations to obtain kinetic information can be unjustifiably costly and scientifically inefficient, and so we instead want to emphasise that experimentally available kinetic information can be used to infer the underlying dynamics they result from. We hope our work can begin a discussion on the topic of computationally efficient science, and continue the drive towards collaborative science between theory and experimentation.
LRP1 and SORL1 regulate tau internalization and degradation and enhance tau seeding
Authors: Cooper Joanna M. , Lathuiliere Aurelien , Migliorini Mary , Arai Allison L. , Wani Mashhood M. , Dujardin Simon , Muratoglu Selen C. , Hyman Bradley T. , Strickland Dudley K.
Published: November 2020

The identification of the apoE receptor, LRP1, as an endocytic receptor for tau raises several questions about LRP1s’ role in tauopathies. Is internalized tau, like other LRP1 ligands, delivered to lysosomes for degradation? Does LRP1 internalize pathological tau leading to cytosolic seeding? Do other, related receptors participate in these processes? We confirm that LRP1 rapidly internalizes tau, leading to efficient lysosomal degradation. Employing brain homogenates from human Alzheimer brain, we find that LRP1 also mediates cytosolic tau seeding. We additionally found that another apoE receptor,SORL1, a gene implicated in AD risk, also mediates tau endocytosis, degradation, and release into the cytoplasm of seed competent species. These data suggest a role for these apoE receptors in tau uptake, as well as the competing processes of degradation and release to the cytoplasm. The balance of these processes may be fundamental to spread of neuropathology across the brain in Alzheimer disease.
Meera Nair at PhoenixWay: Which Way to Go?
Authors: Premapuri Priyanka , Gupta Vishal
Published: November 2020

The case describes the dilemma faced by Meera Nair, chief manager at PhoenixWay – a consultancy firm that has successfully grown over the years. There is a silent conflict in the personalities, work styles and attitude of Meera Nair and Mohit Dubey, her contemporary looking after client relationships. Nair finds inconsistencies in the words and actions of Dubey that have started to impact the work and motivation of her team. Her unsuccessful attempts to draw the attention of their boss Shekhar Sinha to these variances have left her unsure and demotivated. Sinha overlooks Dubey's fallacies and shows no signs of paying attention to the discrepancies and contradictions.
Localized automation solutions in response to the first wave of COVID-19: a story from Vietnam
Authors: Cao Hoang-Long , Nguyen Huynh Anh Duy , Luu Trong Hieu , Vu Huong Thi Thu , Pham Diep , Vu Van Thi Ngoc , Le Hoang Hai , Nguyen Duy Xuan Bach , Truong Trong Toai , Nguyen Hoang-Dung , Nguyen Chi-Ngon
Published: November 2020

Purpose

COVID-19 hits every country’s health-care system and economy. There is a trend toward using automation technology in response to the COVID-19 crisis not only in developed countries but also in those with lower levels of technology development. However, current studies mainly focus on the world level, and only a few ones report deployments at the country level. The purpose of this paper is to investigate the use of automation solutions in Vietnam with locally available materials mainly in the first wave from January to July 2020.

Design/methodology/approach

The authors collected COVID-related automation solutions during the first wave of COVID-19 in Vietnam from January to July 2020 through a search process. The analysis and insights of a panel consisting of various disciplines (i.e. academia, health care, government, entrepreneur and media) aim at providing a clear picture of how and to what extent these solutions have been deployed.

Findings

The authors found seven groups of solutions from low to high research and development (R&D) levels deployed across the country with various funding sources. Low R&D solutions were widely spread owing to simplicity and affordability. High R&D solutions were mainly deployed in big cities. Most of the solutions were deployed during the first phases when international supply chains were limited with a significant contribution of the media. Higher R&D solutions have opportunities to be deployed in the reopening phase. However, challenges can be listed as limited interdisciplinary research teams, market demand, the local supporting industry, end-user validation and social-ethical issues.

Originality/value

To the authors’ best knowledge, this is the first study analyzing the use of automation technology in response to COVID-19 in Vietnam and also in a country in Southeast Asia. Lessons learned from these current deployments are useful for future emerging infectious diseases. The reality of Vietnam’s automation solutions in response to COVID-19 might be a reference for other developing countries with similar social-economic circumstances and contributes to the global picture of how different countries adopt technology to combat COVID-19.