bluuebunny/crossref_metadata_2025 huggingface dataset:
Trade-Offs Between Hepatic Host Defense and Metabolic Programs Underlie Sex-Biased Diseases
Authors: Nikkanen Joni , Leong Yew Ann , Krause William C. , Dermadi Denis , Maschek J. Alan , Van Ry Tyler , Cox James E. , Weiss Ethan J. , Gokcumen Omer , Chawla Ajay , Ingraham Holly A.
Published: January 2022

Current concepts in evolutionary medicine propose that trade-offs and mismatches with a shifting environment increase disease risk. While biological sex also impacts disease prevalence, contributions of environmental pressures to sex-biased diseases remain unexplored. Here, we show that sex-dependent hepatic programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor BCL6, which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 comes at a cost following dietary excess, resulting in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male fitness during infection, thus establishing a sex-dependent tradeoff between host defense and metabolic systems. We suggest that these tradeoffs, coupled with current environmental pressures, drive metabolic disease in males.
EstimatingPanevolutionary history from nucleotide site patterns
Authors: Brand Colin M. , White Frances J. , Rogers Alan R. , Webster Timothy H.
Published: January 2022

Introgression appears increasingly ubiquitous in the evolutionary history of various taxa, including humans. However, accurately estimating introgression is difficult, particularly when 1) there are many parameters, 2) multiple models fit the data well, and 3) parameters are not simultaneously estimated. Here, we use the software Legofit to investigate the evolutionary history of bonobos (Pan paniscus) and chimpanzees (P. troglodytes) using whole genome sequences. This approach 1) ignores within-population variation, reducing the number of parameters requiring estimation, 2) allows for model selection, and 3) simultaneously estimates all parameters. We tabulated site patterns from the autosomes of 71 bonobos and chimpanzees representing all five extantPanlineages. We then compared previously proposed demographic models and estimated parameters using a deterministic approach. We further considered sex bias inPanevolutionary history by analyzing the site patterns from the X chromosome. Introgression from bonobos into the ancestor of eastern and central chimpanzees and from western into eastern chimpanzees best explained the autosomal site patterns. This second event was substantial with an estimated 0.21 admixture proportion. Estimates of effective population size and most divergence dates are consistent with previous findings; however, we observe a deeper divergence within chimpanzees at 987 ka. Finally, we identify male-biased reproduction inPanevolutionary history and suggest that western to eastern chimpanzee introgression was driven by western males mating with eastern females.
Single-Cell Proteomics Study of Immune Cell Diversity by Quantitating 465 Proteins
Authors: Yang Liwei , Liu Jesse , Reddy Revanth , Wang Jun
Published: January 2022

The identification and characterization of T cell subpopulations is critical to reveal cell development throughout life and immune responses to environmental factors. Next-generation sequencing technologies have dramatically advanced the single-cell genomics and transcriptomics for T cell classification. However, gene expression is often not correlated with protein expression, and immunotyping is mostly accepted in the protein format. Current single-cell proteomics technologies are either limited in multiplex capacity or not sensitive enough to detect the critical functional proteins. Herein we present a cyclic multiplex in situ tagging (Cyclic MIST) technology to simultaneously measure 465 proteins, a scale of >10 times than similar technologies, in single cells. Such a high multiplexity is achieved by reiterative staining of the single cells coupled with a MIST array for detection. This technology has been thoroughly validated through comparison with flow cytometry and fluorescence immunostaining techniques. Both THP1 and CD4+ T cells are analyzed by the Cyclic MIST technology, and over 300 surface markers have been profiled to classify the subpopulations. This represents the most comprehensive mapping of the diversity of immune cells at the protein level. With additional information from intracellular proteins of the same single cells, our technology can potentially facilitate mechanistic studies of immune responses, particularly cytokine storm that results in sepsis.
RNA-sequencing of human post-mortem hypothalamus and nucleus accumbens identifies expression profiles associated with obesity
Authors: Wake Christian , Schneider Julie A. , Stein Thor D. , Bregu Joli , Labadorf Adam , McKee Ann , De Jager Philip L. , Bennett David A. , Seshadri Sudha , Myers Richard H. , DeStefano Anita L.
Published: January 2022

Obesity, the accumulation of body fat to excess, may cause serious negative health effects, including increased risk of heart disease, type 2 diabetes, stroke and certain cancers. The biology of obesity is complex and not well understood, involving both environmental and genetic factors and affecting metabolic and endocrine mechanisms in tissues of the gut, adipose, and brain. Previous RNA sequencing studies have identified transcripts associated with obesity and body mass index in blood and fat, often using animal models, but RNA sequencing studies in human brain tissue related to obesity have not been previously undertaken. We conducted both large and small RNA sequencing of hypothalamus (207 samples) and nucleus accumbens (276 samples) from individuals defined as consistently obese (124 samples), consistently normal weight as controls (148 samples) or selected without respect to BMI and falling within neither case nor control definition (211 samples), based on longitudinal BMI measures. The samples were provided by three cohort studies with brain donation programs; the Framingham Heart Study (FHS), the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). For each brain region and large/small RNA sequencing set, differential expression of obesity, BMI, brain region and sex was performed. Analyses were done transcriptome-wide as well as with a priori defined sets of obesity or BMI-associated mRNAs and microRNAs (miRNAs). There are sixteen mRNAs and five microRNAs that are differentially expressed (adjusted p < 0.05) by obesity or BMI in these tissues, several of which were validated with qPCR data. The results include many that are BMI-associated, such as APOBR and CES1, as well as many associated with the immune system and some with addiction, such as the gene sets “cytokine signaling in immune system” and “opioid signaling”. In spite of the relatively large number of samples, our study was likely under-powered to detect other transcripts or miRNA with relevant but smaller effects.
Withdrawal from repeated nicotine vapor exposure increases somatic signs of physical dependence, anxiety-like behavior, and brain reward thresholds in adult male rats
Authors: Martinez Michelle , Uribe Kevin , Garcia Valeria , Lira Omar , Matos-Ocasio Felix , Negishi Kenichiro , Khan Arshad M. , O’Dell Laura E. , Mendez Ian A.
Published: January 2022

In recent years, there has been a dramatic increase in nicotine vapor consumption via electronic nicotine delivery systems (i.e., e-cigarettes), particularly in adolescents. While recent work has focused on the health effects of nicotine vapor exposure, its effects on the brain and behavior remain unclear. In this study, we assessed the effects that cessation from repeated nicotine vapor exposure had on behavioral and neuronal measures of withdrawal. For Experiment 1, fifty-six adult male rats were tested for plasma cotinine levels, somatic withdrawal signs, and anxiety-like behavior in the elevated plus maze, immediately following precipitated withdrawal from repeated exposure to 12 or 24 mg/mL nicotine vapor. In Experiment 2, twelve adult male rats were tested for intracranial self-stimulation (ICSS) across 14 days of exposure to 24 mg/mL nicotine vapor and across the 14 days immediately following nicotine exposure. Results revealed that plasma cotinine, somatic signs, anxiety-like behavior, and ICSS stimulation thresholds were all observed to be elevated during withdrawal in the 24 mg/mL nicotine group, when compared to vehicle controls (50/50 vegetable glycerin/propylene glycol). The data suggest that cessation from repeated nicotine vapor exposure using our preclinical model leads to nicotine dependence and withdrawal, and demonstrates that the vapor system described in these experiments is a viable pre-clinical model of e-cigarette use in humans. Further characterization of the mechanisms driving nicotine vapor abuse and dependence is needed to improve policies and educational campaigns related to e-cigarette use.

Highlights

A rodent model of nicotine e-cigarette vapor use was utilized to assess effects of cessation from repeated nicotine vapor exposure on behavioral and neuronal measures of drug withdrawal.

Cessation of repeated nicotine vapor exposure resulted in increased plasma cotinine levels, somatic withdrawal signs, and anxiety-like behavior.

Cessation of repeated nicotine vapor exposure resulted in elevations of ICSS reward threshold.

Electrode implantations for ICSS were mapped by location and threshold to a standardized reference atlas of the rat brain to facilitate comparisons with the published literature.
COVID-19 Time of Intubation Mortality Evaluation (C-TIME): A System for Predicting Mortality of Patients with COVID-19 Pneumonia at the Time They Require Mechanical Ventilation
Authors: Raschke Robert A , Rangan Pooja , Agarwal Sumit , Uppalapu Suresh , Sher Nehan , Curry Steven C , Heise C. William
Published: January 2022

Background

An accurate system to predict mortality in patients requiring intubation for COVID-19 could help to inform consent, frame family expectations and assist end-of-life decisions.

Research objective

To develop and validate a mortality prediction system called C-TIME (COVID-19 Time of Intubation Mortality Evaluation) using variables available before intubation, determine its discriminant accuracy, and compare it to APACHE IVa and SOFA.

Methods

A retrospective cohort was set in 18 medical-surgical ICUs, enrolling consecutive adults, positive by SARS-CoV 2 RNA by reverse transcriptase polymerase chain reaction or positive rapid antigen test, and undergoing endotracheal intubation. All were followed until hospital discharge or death. The combined outcome was hospital mortality or terminal extubation with hospice discharge. Twenty-five clinical and laboratory variables available 48 hours prior to intubation were entered into multiple logistic regression (MLR) and the resulting model was used to predict mortality of validation cohort patients. AUROC was calculated for C-TIME, APACHE IVa and SOFA.

Results

The median age of the 2,440 study patients was 66 years; 61.6 percent were men, and 50.5 percent were Hispanic, Native American or African American. Age, gender, COPD, minimum mean arterial pressure, Glasgow Coma scale score, and PaO2/FiO2 ratio, maximum creatinine and bilirubin, receiving factor Xa inhibitors, days receiving non-invasive respiratory support and days receiving corticosteroids prior to intubation were significantly associated with the outcome variable. The validation cohort comprised 1,179 patients. C-TIME had the highest AUROC of 0.75 (95%CI 0.72-0.79), vs 0.67 (0.64-0.71) and 0.59 (0.55-0.62) for APACHE and SOFA, respectively (Chi2 P<0.0001).

Conclusions

C-TIME is the only mortality prediction score specifically developed and validated for COVID-19 patients who require mechanical ventilation. It has acceptable discriminant accuracy and goodness-of-fit to assist decision-making just prior to intubation. The C-TIME mortality prediction calculator can be freely accessed on-line at https://phoenixmed.arizona.edu/ctime.
HIF-1α Contributes to the Progression of Chronic Obstructive Pulmonary Disease
Authors: Zhang Kedong , Zhou Feng , Zhu Caixia , Yuan Liang , Li Defu , Wang Jian , Lu Wenju
Published: January 2022

Background

Hypoxia-inducible factor-1α (HIF-1α) plays an important regulatory role in inflammatory and hypoxic diseases. Higher HIF-1α level was found in lungs of chronic obstructive pulmonary disease (COPD) patients, however, its role in cigarette smoke (CS)-induced COPD has not been fully studied. Digoxin has been showed to inhibit HIF-1α translation and block HIF-1α activity and thus is often used as the HIF-1α inhibitor. Therefore, in the present study, we chose digoxin as the inhibitor to investigate whether HIF-1α contributes to the progression of COPD and possible mechanism.

Methods

CS-exposed mice were intragastrically treated with different doses of digoxin, and COPD-associated phenotypes such as pathological changes in lungs, inflammation, lung function and mucus secretion in airways were evaluated. Meanwhile, CSE-treated A549 cells were administrated with digoxin or S7959. Moreover, EMT-associated markers together with HIF-1α\TGF-β1\Smad3 signaling pathway were detected both in vivo and in vitro.

Results

The level of HIF-1α was significantly increased in lungs of COPD mice and CSE-exposed A549 cells, which was markedly suppressed by digoxin. Moreover, digoxin inhibited CS-induced inflammatory responses, lung function decline, and mucus hyper-secretion in COPD mouse model. In in vitro studies, digoxin decreased CSE-induced pro-inflammatory cytokine release. Importantly, CS-induced or CSE-induced EMT and up-regulation of HIF-1α/TGF-β1/Smad pathway was inhibited by digoxin. Additionally, S7959 mitigated CSE-induced EMT in A549 cells.

Conclusions

Digoxin can protect CS-induced COPD and prevent CS-induced EMT possibly through HIF-1α/TGF-β1/Smad3 signaling pathway. This study suggests HIF1-α could be a potential intervention target for COPD prevention and treatment, especially for EMT in CS-induced COPD.
Quantitative Assessment of 3D Printed Blood Vessels Produced with J750™ Digital Anatomy™ for Suture Simulation
Authors: Marconi Stefania , Mauri Valeria , Negrello Erika , Pugliese Luigi , Pietrabissa Andrea , Auricchio Ferdinando
Published: January 2022

Blood vessels anastomosis is one of the most challenging and delicate tasks to learn in many surgical specialties, especially for vascular and abdominal surgeons. Such a critical skill implies a learning curve that goes beyond technical execution. The surgeon needs to gain proficiency in adapting gestures and the amount of force expressed according to the type of tissue he/she is dealing with. In this context, surgical simulation is gaining a pivotal role in the training of surgeons, but currently available simulators can provide only standard or simplified anatomies, without the chance of presenting specific pathological conditions and rare cases.

3D printing technology, allowing the manufacturing of extremely complex geometries, find a perfect application in the production of realistic replica of patient-specific anatomies. According to available technologies and materials, morphological aspects can be easily handled, while the reproduction of tissues mechanical properties still poses major problems, especially when dealing with soft tissues.

The present work focuses on blood vessels, with the aim of identifying – by means of both qualitative and quantitative tests - materials combinations able to best mimic the behavior of the biological tissue during anastomoses, by means of J750™ Digital Anatomy™ technology and commercial photopolymers from Stratasys. Puncture tests and stitch traction tests are used to quantify the performance of the various formulations. Surgical simulations involving anastomoses are performed on selected clinical cases by surgeons to validate the results.

A total of 37 experimental materials were tested and 2 formulations were identified as the most promising solutions to be used for anastomoses simulation. Clinical applicative tests, specifically selected to challenge the new materials, raised additional issues on the performance of the materials to be considered for future developments.
Examining historical rates of leafcutting bee cell pathogens to establish baseline infectivity rates for alfalfa seed growers
Authors: Clements Justin , Haylett Maggie , Nelson Brenda , Walsh Doug
Published: January 2022

The alfalfa leafcutting bee (Megachile rotundata) is one of the primary pollinators for the alfalfa seed industry. The alfalfa leafcutting bee is a solitary cavity nesting bee. Female Megachile rotundata bees will construct and provision individual brood cells lined with cut leaves (cocoon) and will gather nectar and pollen to place within the constructed cocoon. The female bee will lay a single egg within the constructed cocoon and leave the egg to undergo larval stage development and pupation into the adult stage. During this time multiple pathogens and parasitoids can prey on the developing larvae, resulting in the loss of the future adult bee. A major concern for commercial alfalfa seed growers is the presence of invertebrate pests and fugal pathogens. In the present study, we used historical data from the Parma Cocoon Diagnostic Laboratory to determine baseline rates of pathogen and parasite infection of Megachile rotundata cells and used this analysis to determine historical infection rates and cutoffs for management practices. Additionally, using a Faxitron (X-ray) analysis for Megachile rotundata cell obtained in 2020, we compared the presence of chalkbrood, pathogens, and parasitoids in samples collected from both growers’ stocks and newly purchased Canada bees. The results of the investigation demonstrate historical averages of the presence of chalkbrood, pathogens, and parasitoids. We also show a significant increase in chalkbrood and predators in 2007-2011 and a significant difference in chalkbrood and predators between bee samples obtained from Canada and grower stocks.
Multiplex PCR reveals unique trends in pathogen and parasitoid infestations of alfalfa leafcutting brood cells
Authors: Clements Justin , Haylett Maggie , Nelson Brenda , Shumate Silas , Young Nicole , Bradford Benjamin , Walsh Doug , Lamour Kurt
Published: January 2022

The alfalfa leafcutting bee Megachile rotundata Fabricius (HYMENOPTERA: Megachilidae) is an important pollinator for multiple agricultural seed commodities in the United States. Megachile rotundata is a solitary bee that forms brood cocoons where its larvae can develop. During the developmental stages of growth, broods can be preyed upon by multiple different fungal and bacterial pathogens and insect predators and parasitoids, resulting in the loss of the developing larvae. Larval loss is a major concern for alfalfa (Medicago sativa L.) seed producers because they rely on pollinator services provided by Megachile rotundata and reduced pollination rates result in lower yields and increased production costs. In the present study, we examined the taxonomic composition of organisms found within M. rotundata brood cells using a multiplex PCR assay which was developed for the detection of the most common bacterial, fungal, and invertebrate pests and pathogens of M. rotundata larvae. Known pests of M. rotundata were detected, including members of the fungal genus Ascosphaera, the causative agent of chalkbrood. Co-infection of single brood cells by multiple Ascosphaera species was confirmed, with potential implications for chalkbrood disease management. The multiplex assay also identified DNA from more than 2,400 total species including multiple new predators and pathogenetic species not previously documented in associated with M. rotundata brood cells.
Increased resolution in the face of conflict: phylogenomics of the Neotropical bellflowers (Campanulaceae: Lobelioideae), a rapid plant radiation
Authors: Lagomarsino Laura P. , Frankel Lauren , Uribe-Convers Simon , Antonelli Alexandre , Muchhala Nathan
Published: January 2022

Background and Aims

The centropogonid clade (Lobelioideae: Campanulaceae) is an Andean-centered rapid radiation characterized by repeated convergent evolution of morphological traits, including fruit type and pollination syndromes. While previous studies have resolved relationships of lineages with fleshy fruits into subclades, relationships among capsular species remain unresolved, particularly along the phylogenetic backbone. This lack of resolution has impeded reclassification of non-monophyletic genera, whose current taxonomy relies heavily on traits that have evolved multiple times within the clade.

Methods

Targeted sequence capture using a probeset recently developed for the centropogonid clade was used to obtain phylogenomic data from DNA extracted from both silica-dried and herbarium leaf tissue. These data were used to infer relationships among species using concatenated and partitioned species tree methods, as well as to quantify gene tree discordance.

Key Results

While silica-dried leaf tissue resulted in generally more and longer sequence data, the inclusion of herbarium samples improved phylogenetic reconstruction. Relationships among baccate lineages are similar to those inferred by previous studies, though they differ within and among capsular lineages. We improve resolution of Siphocampylus, which forms ten groups of closely related species to which we provide informal names that largely do not correspond to current infrageneric taxonomy. Two subclades of Siphocampylus and two individual species are rogue taxa whose placement differs widely across analyses. Gene tree discordance is high.

Conclusions

The first phylogenomic study of the centropogonid clade considerably improves our understanding of relationships in this rapid radiation. Differences across analyses and the possibility of additional lineage discoveries still hamper a solid and stable reclassification. Rapid morphological innovation corresponds with a high degree of phylogenomic complexity, including cytonuclear discordance, nuclear gene tree conflict, and well-supported differences between analyses based on different nuclear loci. Taken together, these results point to a potential role of hemiplasy underlying repeated convergent evolution. This hallmark of rapid radiations is likely present in many other species-rich Andean plant radiations.
ATm4sf1-Marked Subpopulation of Endothelial Stem/Progenitor Cells Identified by Lung Single-Cell Omics of Pulmonary Arterial Hypertension
Authors: Hong Jason , Wong Brenda , Huynh Caroline , Tang Brian , Umar Soban , Yang Xia , Eghbali Mansoureh
Published: January 2022

Rationale

The identification and role of endothelial progenitor cells (EPCs) in pulmonary arterial hypertension (PAH) remains controversial. Single-cell omics analysis can shed light on EPCs and their potential contribution to PAH pathobiology.

Objectives

We aim to identify EPCs in rat lungs and assess their relevance to preclinical and human PAH.

Methods

Differential expression, gene set enrichment, cell-cell communication, and trajectory reconstruction analyses were performed on lung endothelial cells from single-cell RNA-seq of Sugen-hypoxia, monocrotaline, and control rats. Relevance to human PAH was assessed in multiple independent blood and lung transcriptomic datasets.

Measurements and Main Results

A subpopulation of endothelial cells (EA2) marked byTm4sf1, a gene strongly implicated in cancer, harbored a distinct transcriptomic signature includingBmpr2downregulation that was enriched for pathways such as inflammation and angiogenesis. Cell-to-cell communication networks specific to EA2 were activated in PAH such as CXCL12 signaling. Trajectory analysis demonstrated EA2 has a stem/progenitor cell phenotype. Analysis of independent datasets revealedTm4sf1is a marker for hematopoietic stem cells and is upregulated in PAH peripheral blood, particularly in patients with worse WHO functional class. EA2 signature genes includingProcrandSulf1were found to be differentially regulated in the lungs of PAH patients and in PAH modelsin vitro, such as BMPR2 knockdown.

Conclusions

Our study uncovered a novelTm4sf1-marked stem/progenitor subpopulation of rat lung endothelial cells and demonstrated its relevance to preclinical and human PAH. Future experimental studies are warranted to further elucidate the pathogenic role and therapeutic potential of targeting EA2 andTm4sf1in PAH.
Frequent co-regulation of splicing and polyadenylation by RNA-binding proteins inferred with MAPP
Authors: Bak Maciej , van Nimwegen Erik , Schmidt Ralf , Zavolan Mihaela , Gruber Andreas J.
Published: January 2022

Maturation of eukaryotic pre-mRNAs via splicing, 3’ end cleavage and polyadenylation is modulated across cell types and conditions by a variety of RNA-binding proteins (RBPs). Although over 1’500 proteins are associated with RNAs in human cells, their binding motifs, targets and functions still remain to be elucidated, especially in the complex environment of human tissues and in the context of diseases. To overcome the lack of methods for systematic and automated detection of sequence motif-guided changes in pre-mRNA processing based on RNA sequencing (RNA-seq) data we have developed MAPP (Motif Activity on Pre-mRNA Processing). We demonstrate MAPP’s functionality by applying it to RNA-seq data from 284 RBP knock-down experiments in the ENCODE project, from which MAPP not only infers position-dependent impact profiles of known regulators, but also reveals RBPs that modulate both the inclusion of cassette exons and the poly(A) site choice. Among these, the Polypyrimidine Tract Binding Protein 1 (PTBP1) has a similar activity in glioblastoma samples. This highlights the ability of MAPP to unveil global regulators of mRNA processing under physiological and pathological conditions.
Patterns of Structural Variation Define Prostate Cancer Across Disease States
Authors: Zhou Meng , Ko Minjeong , Hoge Anna C. , Luu Kelsey , Liu Yuzhen , Russell Magdalena L. , Hannon William W. , Zhang Zhenwei , Carrot-Zhang Jian , Beroukhim Rameen , Van Allen Eliezer M. , Choudhury Atish D. , Nelson Peter S. , Freedman Matthew L. , Taplin Mary-Ellen , Meyerson Matthew , Viswanathan Srinivas R. , Ha Gavin
Published: January 2022

The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation shapes the genomic landscape of this disease across disease states. We uniformly characterized structural alterations across 278 localized and 143 metastatic prostate cancers profiled by whole genome and transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes enriched in mCRPC and TMPRSS2-ERG rearrangements enriched in localized prostate cancer. We defined nine subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.
SARS-CoV-2 risk taxation model and validation based on large scale Dutch test-events
Authors: Kolen Bas , Znidarsic Laurens , Voss Andreas , Donders Simon , Kamphorst Iris , van Rijn Maarten , Bonthuis Dimitri , Cloquet Merit , Schram Maarten , Scharloo Rutger , Boersma Tim , Stobernack Tim , van Gelder Pieter
Published: January 2022

In response to the outbreak of SARS-CoV-2 many governments decided in 2020 to impose lockdowns on societies. Although the package of measures which constitute such lockdowns differs between countries, it is a general rule that contacts between people, and especially in large groups of people, are avoided or prohibited. The main reasoning behind these measures is preventing that healthcare systems become overloaded. As of 2021 vaccines against SARS-CoV-are available, but these do not guarantee 100% risk reduction and it will take a while for the world to reach a sufficient immune status. This raises the question whether and under which conditions events like theater shows, conferences, professional sports events, concerts and festivals can be organized. The current paper presents a COVID-19 Risk taxation method for (large scale) events. This method can be applied to events to define an alternative package of measures replacing generic social distancing.
Machine Learning Prediction of Progression in FEV1in the COPDGene Study
Authors: Boueiz Adel , Xu Zhonghui , Chang Yale , Masoomi Aria , Gregory Andrew , Lutz Sharon M. , Qiao Dandi , Crapo James D. , Dy Jennifer G. , Silverman Edwin K. , Castaldi Peter J. ,   for the COPDGene investigators
Published: January 2022

Background

The heterogeneous nature of COPD complicates the identification of the predictors of disease progression and consequently the development of effective therapies. We aimed to improve the prediction of disease progression in COPD by using machine learning and incorporating a rich dataset of phenotypic features.

Methods

We included 4,496 smokers with available data from their enrollment and 5-year follow-up visits in the Genetic Epidemiology of COPD (COPDGene) study. We constructed supervised random forest models to predict 5-year progression in FEV1from 46 baseline demographic, clinical, physiologic, and imaging features. Using cross-validation, we randomly partitioned participants into training and testing samples. We also validated the results in the COPDGene 10-year follow-up visit.

Results

Predicting the change in FEV1over time is more challenging than simply predicting the future absolute FEV1level. Nevertheless, the area under the ROC curves for the prediction of subjects in the top quartile of observed disease progression was 0.70 in the 10-year follow-up data. The model performance accuracy was best for GOLD1-2 subjects and it was harder to achieve accurate prediction in advanced stages of the disease. Predictive variables differed in their relative importance as well as for the predictions by GOLD grade.

Conclusion

This state-of-the art approach along with deep phenotyping predicts FEV1progression with reasonable accuracy. There is significant room for improvement in future models. This prediction model facilitates the identification of smokers at increased risk for rapid disease progression. Such findings may be useful in the selection of patient populations for targeted clinical trials.
Factors influencing the motivation of maternal health workers in conflict setting of Mogadishu, Somalia
Authors: Sheikh Naima Said , Gele Abdi
Published: January 2022

Background

Motivated health workers play an important role in delivering high-quality maternal health services, especially in low-income countries where maternal mortality rates are high, and shortages of human resource for health is prevalent. The aim of this study is to investigate maternal health workers’ motivation in three tertiary hospitals in Mogadishu Somalia.

Method

To investigate health worker motivation in Somalia, we used a semi-structured questionnaire that was validated and widely used in Sub-Saharan Africa. Data were collected from 220 health workers across three tertiary hospitals in Mogadishu between February and April 2020. Health worker motivation was measured using seven constructs: general motivation, burnout, job satisfaction, intrinsic job satisfaction, organizational commitment, conscientiousness, timeliness and attendance. A multivariate regression analysis was performed to determine the predictors of health worker motivation.

Results

The study found that male health workers have a higher work motivation, with a mean score of 92.75 (SD 21.31) versus 90.43 (SD 21.61) in women. A significant correlation was found between health workers’ motivation and being an assistant, nurse, physician, pediatric-assistant, midwife, supervisor and pharmacist. Unexpectedly, the gynecologists and midwives were the least motivated groups among the different professions, with mean scores of 83.63, (SD: 27.41) and 86.95 (SD: 21.08), respectively. Of the aforementioned seven motivation constructs, the highest mean motivation scores (from 1-5) were observed in conscientiousness and intrinsic job satisfaction.

Conclusion

The results highlight the importance of targeted interventions that increase female health workers’ motivation, particularly gynecologists and midwives in Somalia. This can be done by providing non-financial incentives, in addition to encouraging their participation in the decision-making process. Further research is needed to investigate the effect of a lack of motivation among gynecologists and midwives on maternal health in Somalia.
Development of tool for assessment of performance motivation and job satisfaction among the Community Health Workers of Central India
Authors: Revadi G , Joshi Ankur , Pakhare Abhijit P
Published: January 2022

Introduction

Among the various factors influencing the performance of Community health workers, motivation and job satisfaction serves as a potential drive to perform better. Hence, this study aimed at constructing a motivation and job satisfaction tool in a systematic method that would serve as a potential tool for further research considering the heterogeneity in the study population.

Objective

To develop a tool to measure how well the CHWs are motivated and satisfied pertaining to individual, community and health system determinants.

Methods

This cross-sectional study from rural block of Madhya Pradesh in Central India included relatively high performing and low performing CHWs based on their annual performance-based incentives for the year (April 2017-March 2018). The CHWs were administered a self-reported questionnaire that contained a 5-point Likert scale with individual, health system and community determinants of motivation and job satisfaction.

Results

The performance motivation scale with 18 items and job satisfaction scale with 15 items were administered to the 92 CHWs. Their item content validity index was 0.66 and 0.83 respectively. The finalized tool consisted of 11 items in motivation scale and all the 15 items in job satisfaction scale following the Explanatory factor analysis. All the individual constructs in both the scales showed good internal consistency with Cronbachs alpha ranging from 0.62-0.88. The overall median (IQR) score of both RLP and RHP CHWs were 4(4–5) in both the questionnaires.

Conclusion

The CHWs in our study were intrinsically motivated and were satisfied with their performance as voluntary village health workers. Further research would be planned to validate the constructs using confirmatory factor analysis.
Estimating the cost of antibiotic use on future collateral resistance: a retrospective comparison of cefuroxime versus cefazolin and amoxicillin/clavulanate
Authors: Chowers Michal , Zehavi Tamir , Gottesman Bat-Sheva , Baraz Avi , Nevo Daniel , Obolski Uri
Published: January 2022

Background

Quantitative estimates of collateral resistance induced by antibiotic use are scarce. This study compared the effects of treatment with amoxicillin/clavulanate or cefazolin, compared to cefuroxime, on future resistance to ceftazidime among hospitalized patients.

Methods

A retrospective analysis of patients with positive bacterial cultures hospitalized in an Israeli hospital during 2016-2019 was conducted. Patients were restricted to those treated with either amoxicillin/clavulanate, cefazolin, or cefuroxime and re-hospitalized with a positive bacterial culture during the following year. A 1:1 matching was performed for each patient in the amoxicillin/clavulanate and cefazolin groups, to a single patient from the cefuroxime group, yielding 185:185 and 298:298 matched patients. Logistic regression and g-formula (standardization) were used to estimate the odds ratio (OR), risk difference (RD), and number needed to harm (NNH).

Results

Cefuroxime induced significantly higher resistance to ceftazidime than amoxicillin/clavulanate or cefazolin: the marginal OR was 1.76)95%CI 1.16-2.83) compared to amoxicillin/clavulanate, and 1.98 (95%CI 1.41-2.8) compared to cefazolin; The RD was 0.118 (95%CI 0.031-0.215) compared to amoxicillin/clavulanate, and 0.131 (95%CI 0.058-0.197) compared to cefazolin. We also estimated the NNH: replacing amoxicillin/clavulanate or cefazolin with cefuroxime would yield ceftazidime-resistance in one more patient for every 8.5 (95% CI 4.66-32.14) or 7.6 (95% CI 5.1-17.3) patients re-hospitalized in the following year.

Conclusions

Our results indicate that treatment with amoxicillin/clavulanate or cefazolin is preferable to cefuroxime, in terms of future collateral resistance. The results presented here are a first step towards quantitative estimations of the ecological damage caused by different antibiotics.

Key points

We performed a retrospective study estimating collateral resistance of treatment with cefuroxime relative to amoxicillin/clavulanate or cefazolin. Application of novel analytical methods allowed us to estimate the number needed to harm and hence ecological damage of the different treatments.
Infectious viral load in unvaccinated and vaccinated patients infected with SARS-CoV-2 WT, Delta and Omicron
Authors: Puhach Olha , Adea Kenneth , Hulo Nicolas , Sattonnet Pascale , Genecand Camille , Iten Anne , Bausch Frédérique Jacquérioz , Kaiser Laurent , Vetter Pauline , Eckerle Isabella , Meyer Benjamin
Published: January 2022

Background

Viral load (VL) is one determinant of secondary transmission of SARS-CoV-2. Emergence of variants of concerns (VOC) Alpha and Delta was ascribed, at least partly, to higher VL. Furthermore, with parts of the population vaccinated, knowledge on VL in vaccine-breakthrough infections is crucial. As RNA VL is only a weak proxy for infectiousness, studies on infectious virus presence by cell culture isolation are of importance.

Methods

We assessed nasopharyngeal swabs of COVID-19 patients for quantitative infectious viral titres (IVT) by focus-forming assay and compared to overall virus isolation success and RNA genome copies. We assessed IVTs during the first 5 symptomatic days in a total of 384 patients: unvaccinated individuals infected with pre-VOC SARS-CoV-2 (n= 118) or Delta (n= 127) and vaccine breakthrough infections with Delta (n= 121) or Omicron (n=18).

Findings

Correlation between RNA copy number and IVT was low for all groups. No correlation between IVTs and age or sex was seen. We observed higher RNA genome copies in pre-VOC SARS-CoV-2 compared to Delta, but significantly higher IVTs in Delta infected individuals. Vaccinated Delta infected individuals had significantly lower RNA genome copies and IVTs compared to unvaccinated subjects and cleared virus faster. In addition, vaccinated individuals with Omicron infection had comparable IVTs to Delta breakthrough infections.

Interpretation

Quantitative IVTs can give detailed insights into virus shedding kinetics. Vaccination was associated with lower infectious titres and faster clearance for Delta, showing that vaccination would also lower transmission risk. Omicron vaccine-breakthrough infections did not show elevated IVTs compared to Delta, suggesting that other mechanisms than increase VL contribute to the high infectiousness of Omicron.

Funding

This work was supported by the Swiss National Science Foundation 196644, 196383, NRP (National Research Program) 78 Covid-19 Grant 198412, the Fondation Ancrage Bienfaisance du Groupe Pictet and the Fondation Privée des Hôpitaux Universitaires de Genève.
Molnupiravir combined with different repurposed drugs further inhibits SARS-CoV-2 infection in human nasal epithelium in vitro
Authors: Jonsdottir Hulda R. , Siegrist Denise , Julien Thomas , Padey Blandine , Bouveret Mendy , Terrier Olivier , Pizzorno Andres , Huang Song , Samby Kirandeep , Wells Timothy N.C. , Boda Bernadett , Rosa-Calatrava Manuel , Engler Olivier B. , Constant Samuel
Published: January 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first identified in late 2019, has caused a worldwide pandemic with unprecedented economic and societal impact. Currently, several vaccines are available, and multitudes of antiviral treatments have been proposed and tested. Although many of the vaccines show high clinical efficacy, they are not equally accessible worldwide. Additionally, due to the continuous emergence of new virus variants, and generally short duration of immunity, the development of safe and effective antiviral treatments remains of the utmost importance. Since the emergence of SARS-CoV-2, substantial efforts have been undertaken to repurpose existing and approved drugs for accelerated clinical testing and potential emergency use authorizations. However, drug-repurposing using high throughput screenings in cellular assays, often identify hits that later prove ineffective in clinical studies. Our approach was to evaluate the activity of compounds that have either been tested clinically or already undergone extensive preclinical profiling, using a standardized in vitro model of human nasal epithelium. Secondly, we evaluated drug combinations using sub-maximal doses of each active single compound. Here, we report the antiviral effects of 95 single compounds and 30 combinations. The data show that selected drug combinations including 10 μM of molnupiravir, a viral RNA-dependent RNA polymerase (RdRp) inhibitor, effectively inhibit SARS-CoV-2 replication. This indicates that such combinations are worthy of further evaluation as potential treatment strategies against coronavirus disease 2019 (COVID-19).
Exploring high-resolution cryo-ET and subtomogram averaging capabilities of contemporary DEDs
Authors: Obr Martin , Hagen Wim JH , Dick Robert A , Yu Lingbo , Kotecha Abhay , Schur Florian KM
Published: January 2022

The potential of energy filtering and direct electron detection for cryo-electron microscopy (cryo-EM) image processing has been well documented for single particle analysis (SPA). Here, we assess the performance of recently introduced hardware for cryo-electron tomography (cryo-ET) and subtomogram averaging (STA), an increasingly popular structural determination method for complex 3D specimens. We acquired cryo-ET datasets of EIAV virus-like particles (VLPs) on two contemporary cryo-EM systems equipped with different energy filters and direct electron detectors (DED), specifically a Krios G4, equipped with a cold field emission gun (CFEG), Thermo Fisher Scientific Selectris X energy filter, and a Falcon 4 DED; and a Krios G3i, with a Schottky field emission gun (XFEG), a Gatan Bioquantum energy filter, and a K3 DED. We performed constrained cross-correlation-based STA on equally sized datasets acquired on the respective systems. The resulting EIAV CA hexamer reconstructions show that both systems perform comparably in the 4-6 Å resolution range. In addition, by employing a recently introduced multiparticle refinement approach, we obtained a reconstruction of the EIAV CA hexamer at 2.9 Å. Our results demonstrate the potential of the new generation of energy filters and DEDs for STA, and the effects of using different processing pipelines on their STA outcomes.
The genomic landscape of contemporary western Remote Oceanians
Authors: Arauna Lara R. , Bergstedt Jacob , Choin Jeremy , Mendoza-Revilla Javier , Harmant Christine , Roux Maguelonne , Mas-Sandoval Alex , Lémée Laure , Colleran Heidi , François Alexandre , Valentin Frédérique , Cassar Olivier , Gessain Antoine , Quintana-Murci Lluis , Patin Etienne
Published: January 2022

The Vanuatu archipelago served as a gateway to Remote Oceania during one of the most extensive human migrations to uninhabited lands, ~3,000 years ago. Ancient DNA studies suggest an initial settlement by East Asian-related peoples that was quickly followed by the arrival of Papuan-related populations, leading to a major population turnover. Yet, there is uncertainty over the population processes and the sociocultural factors that have shaped the genomic diversity of ni-Vanuatu, who present nowadays among the world’s highest linguistic and cultural diversity. Here, we report new genome-wide data for 1,433 contemporary ni-Vanuatu from 29 different islands, including 287 couples. We find that ni-Vanuatu derive their East Asian- and Papuan-related ancestry from the same source populations and descend from relatively synchronous, sex-biased admixture events that occurred ~1,700-2,300 years ago, indicating a peopling history common to all the archipelago. However, East Asian-related ancestry proportions differ markedly across islands, suggesting that the Papuan-related population turnover was geographically uneven. Furthermore, we detect Polynesian ancestry arriving ~600-1,000 years ago to South Vanuatu in both Polynesian- and non-Polynesian-speaking populations. Lastly, we provide evidence for a tendency of spouses to carry similar genetic ancestry, when accounting for relatedness avoidance. The signal is not driven by strong genetic effects of specific loci or trait-associated variants, suggesting that it results instead from social assortative mating. Altogether, our findings provide insight into both the genetic history of ni-Vanuatu populations and how sociocultural processes have shaped the diversity of their genomes.
Active site geometry stabilization of a presenilin homolog by the lipid bilayer promotes intramembrane proteolysis
Authors: Feilen Lukas P. , Chen Shu-Yu , Fukumori Akio , Feederle Regina , Zacharias Martin , Steiner Harald
Published: January 2022

Cleavage of membrane proteins in the lipid bilayer by intramembrane proteases is crucial for health and disease. Although different lipid environments can potently modulate their activity, how this is linked to their structural dynamics is unclear. Here we show that the carboxy-peptidase-like activity of the archaeal intramembrane protease PSH, a homolog of the Alzheimeŕs disease-associated presenilin/γ-secretase is impaired in micelles and promoted in a lipid bilayer. Comparative molecular dynamics simulations revealed that important elements for substrate binding such as transmembrane domain 6a of PSH are more labile in micelles and stabilized in the lipid bilayer. Moreover, consistent with an enhanced interaction of PSH with a transition- state analog inhibitor, the bilayer promoted the formation of the enzymés catalytic active site geometry. Our data indicate that the lipid environment of an intramembrane protease plays a critical role in structural stabilization and active site arrangement of the enzyme-substrate complex thereby promoting intramembrane proteolysis.