bluuebunny/crossref_metadata_2025 huggingface dataset:
Olfactory detection and discrimination in domestic dogs (Canis lupus familiaris)
Authors: Ferrando Elodie , Dahl Christoph D.
Published: February 2022

The extraordinary olfactory capabilities in detection and rescue dogs are well-known. However, the olfactory performance varies by breed and search environment (Jezierski et al., 2014), as well as by the quantity of training (Horowitz et al., 2013). While detection of an olfactory cue inherently demands a judgment regarding the presence or absence of a cue at a given location, olfactory discrimination requires an assessment of quantity, a task demanding more attention and, hence, decreasing reliability as an informational source (Horowitz et al., 2013). This study aims at gaining more clarity on detection and discrimination of olfactory cues in untrained dogs and in a variety of dog breeds. Using a two-alternative forced choice (2AFC) paradigm, we assessed olfactory detection scores by presenting a varied quantity of food reward under one or the other hidden cup, and discrimination scores by presenting two varied quantities of food reward under both hidden cups. We found relatively reliable detection performances across all breeds and limited discrimination abilities, modulated by breed. We discuss our findings in relation to the cognitive demands imposed by the tasks and the cephalic index of the dog breeds.
Cell Type Composition Analysis: Comparison of statistical methods
Authors: Simmons Sean
Published: February 2022

Measuring changes in cell type composition between conditions (disease vs not, knockout vs wild type, treated vs not, etc) is fast becoming a standard step in single cell RNA-Seq analysis. Despite that, there is no agreement on the best approach for this type of analysis. As such, we decided to test numerous methods for cell type composition analysis, seeing how they performed in terms of false positive rate and power. Though there is not one clear winner, we do find two method (the propeller method with asin normalization and Dirichlet regression with the alternative parameterization) perform well in most situations. Most importantly, consistent with results in differential expression analysis, we see that it is important to take into account sample to sample (mouse to mouse, person to person, etc) variability to avoid high false positive rates. We also see evidence that aggregation (aka pseudobulk) based method slightly outperform the mixed model methods we tested.
Theta band-power shapes amyloid-driven longitudinal EEG changes in pre-clinical Alzheimer’s Disease
Authors: Spinelli Giuseppe , Bakardjian Hovagim , Schwartz Denis , Potier Marie-Claude , Habert Marie-Odile , Levy M. , Dubois Bruno , George Nathalie
Published: February 2022

Alzheimer’s Disease (AD) includes progressive symptoms spread along a continuum of pre-clinical (pre-AD) and clinical stages. Pre-AD refers to cognitively healthy individuals with presence of positive pathophysiological biomarkers of AD (i.e., markers of amyloidopathy and tauopathy). Although numerous studies uncovered the neuro-cognitive changes of AD, very little is known on the natural history of brain lesions and modifications of brain networks of pre-AD. To address this issue, we analysed resting-state EEG data of 318 cognitively healthy individuals with subjective memory complains from the INSIGHT-preAD cohort at the time of their first visit (M0) and two-years later (M24). Using 18F-florbetapir PET-scanner, subjects were stratified between amyloid positive (A-; n=230) and amyloid negative (A+; n=88) groups. Differences between A+ and A- individuals were estimated at source level in each band of the EEG power spectrum. At M0, we found an increase of theta-band power in the mid-frontal cortex in A+ compared to A-. No significant association was found between mid-frontal theta power and the individuals’ cognitive performance. While the very same effect was not replicated at M24, theta-band power increased in A+ relative to A- individuals in the posterior cingulate cortex and the pre-cuneus. Furthermore, alpha band revealed a peculiar decremental trend in posterior brain regions in the A+ relative to the A- group only at M24. These results provide the first source-level longitudinal evidence on the impact of brain amyloidosis on the EEG dynamics of a large-scale, monocentric cohort of pre-AD. Theta-band power increase over the mid-frontal and mid-posterior cortices suggests an hypoactivation of the default-mode network in individuals at-risk of AD and a non-linear longitudinal progression of the AD-spectrum.
Mutations of Omicron variant at the interface of the receptor domain motif and human angiotensin-converting enzyme-2
Authors: Adhikari Puja , Jawad Bahaa , Podgornik Rudolf , Ching Wai-Yim
Published: February 2022

The most recent Omicron variant of SARS-CoV-2 has caused global concern and anxiety. The only thing certain about this strain, with large number of mutations in the spike protein, is that it spreads quickly, seems to evade immune defense and mitigates the benefits of existing vaccines. Based on the ultra-large-scale ab initio computational modeling of the receptor binding motif (RBM) and human angiotensin-converting enzyme-2 (ACE2) interface we provide the details of the effect of Omicron mutations at the fundamental atomic scale level. In-depth analysis anchored in the novel concept of amino acid-amino acid bond pair units (AABPU), indicates that mutations in the Omicron variant are connected with (i) significant changes in the shape and structure of AABPU components, together with (ii) significant increase in the positive partial charge which facilitates the interaction with ACE2. The calculated bond order, based on AABPU, reveals that the Omicron mutations increase the binding strength of RBM to ACE2. Our findings correlate with and are instrumental to explain the current observations and can contribute to the prediction of next potential new variant of concern.
Schrödinger’s range-shifting cat: analytic predictions for the effect of asymmetric environmental performance on climate change responses
Authors: Terry J. Christopher D. , O’Sullivan Jacob D. , Rossberg A. G.
Published: February 2022

Analytic models for how species will respond to climate change can highlight key parameter dependencies. By mapping equations for population dynamics onto corresponding well-studied problems from quantum mechanics we derive analytical results for the frequently observed case of asymmetric environmental response curves. We derive expressions in terms of parameters representing climate velocity, dispersal rate, maximum growth rate, niche width, high-frequency climate variability and environmental performance curve skew for three key responses: 1) population persistence, 2) lag between range displacement and climate displacement, 3) location of maximum population sensitivity. Surprisingly, under our model assumptions, the direction of performance curve asymmetry does not strongly contribute to either persistence or lags. Conservation measures to support range-shifting populations may have most benefit near their environmental optimum or where the environmental dependence is shallow, irrespective of whether this is the ‘leading’ or ‘trailing’ edge. A metapopulation simulation corroborates our results.
PELP: accounting for missing data in neural time series by Periodic Estimation of Lost Packets
Authors: Dastin-van Rijn Evan M. , Provenza Nicole R. , Goodman Wayne K. , Harrison Matthew T. , Borton David. A.
Published: February 2022

Objective

Implanted electrical stimulators with sensing capabilities have enabled the development of closed-loop neuromodulation therapies capable of responding to patient needs in real-time. Through a combination of rechargeable technologies and wireless data transmission, it is now possible for researchers to acquire extensive neural recordings from human participants in naturalistic settings using these bidirectional devices. However, data losses during wireless transmission hamper processing and the identification of neural signals of interest, driving the need for methodologies to properly estimate the impact of data loss.

Approach

To accurately reconstruct the timing of data containing losses, we have developed a method called Periodic Estimation of Lost Packets (PELP) to precisely determine the number of samples lost from implanted recordings during active stimulation. PELP leverages a data-driven procedure for determining the period of stimulation and the knowledge that stimulation continues identically during periods where data are missing to accurately account for the number of samples lost.

Main results

Using simulated stimulation added to collected human EEG data, we show that PELP is robust to a range of stimulation waveforms and noise characteristics. Lastly, we successfully applied PELP to local field potential (LFP) recordings from an implanted, bidirectional device using data recorded in the clinic and the patient’s own home.

Significance

By effectively accounting for the timing of missing data, PELP enables the analysis of complex, naturalistic neural time series data from bidirectional implanted devices aiding in the development of novel therapeutic approaches. NCT04806516 (ClinicalTrials.gov).
SARS-CoV-2 infects, replicates, elevates angiotensin II and activates immune cells in human testes
Authors: Costa Guilherme M.J. , Lacerda Samyra M.S.N. , Figueiredo André F.A. , Wnuk Natália T. , Brener Marcos R. G. , Campolina-Silva Gabriel H. , Kauffmann-Zeh Andrea , Pacifico Lucila GG , Versiani Alice F. , Andrade Lídia M. , Antunes Maísa M. , Souza Fernanda R. , Cassali Geovanni D. , Caldeira-Brant André L. , Chiarini-Garcia Hélio , Costa Vivian V. , da Fonseca Flavio G. , Nogueira Maurício L. , Campos Guilherme R. F. , Kangussu Lucas M. , Martins Estefânia M. N. , Antonio Loudiana M. , Bittar Cintia , Rahal Paula , Aguiar Renato S. , Mendes Bárbara P. , Procópio Marcela S. , Furtado Thiago P. , Guimaraes Yuri L , Menezes Gustavo B , Martinez-Marchal Ana , Brieno-Enriquez Miguel , Orwig Kyle E. , Furtado Marcelo H.
Published: February 2022

Although much has been published since the first cases of COVID-19, there remain unanswered questions regarding SARS-CoV-2 impact on testes and the potential consequences for reproductive health. We investigated testicular alterations in deceased COVID-19-patients, the precise location of the virus, its replicative activity, and the molecules involved in the pathogenesis. We found that SARS-CoV-2 testicular tropism is higher than previously thought and that reliable viral detection in the testis requires sensitive nanosensoring or RT-qPCR using a specific methodology. Macrophages and spermatogonial cells are the main SARS-CoV-2 lodging sites and where new virions form inside the Endoplasmic Reticulum Golgi Intermediate Complex. Moreover, we showed infiltrative infected monocytes migrating into the testicular parenchyma. SARS-CoV-2 maintains its replicative and infective abilities long after the patient’s infection, suggesting that the testes may serve as a viral sanctuary. Further, infected testes show thickening of the tunica propria, germ cell apoptosis, Sertoli cell barrier loss, evident hemorrhage, angiogenesis, Leydig cell inhibition, inflammation, and fibrosis. Finally, our findings indicate that high angiotensin II levels and activation of mast cells and macrophages may be critical for testicular pathogenesis. Importantly, our data suggest that patients who become critically ill exhibit severe damages and may harbor the active virus in testes.
Single cell sequencing analysis uncovers genetics-influenced CD16+monocytes and memory CD8+T cells involved in severe COVID-19
Authors: Ma Yunlong , Qiu Fei , Deng Chunyu , Li Jingjing , Huang Yukuan , Wu Zeyi , Zhou Yijun , Zhang Yaru , Xiong Yichun , Yao Yinghao , Zhong Yigang , Qu Jia , Su Jianzhong
Published: February 2022

Background

Understanding the host genetic architecture and viral immunity contributes to the development of effective vaccines and therapeutics for controlling the COVID-19 pandemic. Alterations of immune responses in peripheral blood mononuclear cells play a crucial role in the detrimental progression of COVID-19. However, the effects of host genetic factors on immune responses for severe COVID-19 remain largely unknown.

Methods

We constructed a powerful computational framework to characterize the host genetics-influenced immune cell subpopulations for severe COVID-19 by integrating GWAS summary statistics (N = 969,689 samples) with four independent scRNA-seq datasets (N = 606,534 cells).

Results

We found that 34 risk genes were significantly associated with severe COVID-19, and the number of highly-expressed genetics-risk genes increased with the severity of COVID-19. Three cell-subtypes that are CD16+monocytes, megakaryocytes, and memory CD8+T cells were significantly enriched by COVID-19-related genetic association signals. Notably, three causal risk genes of CCR1, CXCR6, and ABO were specifically expressed in these three cell types, respectively. CCR1+CD16+monocytes and ABO+ megakaryocytes with significant up-regulated genes including S100A12, S100A8, S100A9, and IFITM1 confer higher risk to the cytokine storms among severe patients. CXCR6+ memory CD8+ T cells exhibit a notable polyfunctionality of multiple immunologic features, including elevation of proliferation, migration, and chemotaxis. Moreover, we observed a prominent increase in cell-cell interactions of both CCR1+ CD16+monocytes and CXCR6+ memory CD8+T cells in severe patients compared to normal controls among both PBMCs and lung tissues, and elevated interactions with epithelial cells could contribute to enhance the resident to lung airway for against COVID-19 infection.

Conclusions

We uncover a major genetics-modulated immunological shift between mild and severe infection, including an increase in up-regulated genetic-risk genes, excessive secreted inflammatory cytokines, and functional immune cell subsets contributing high risk to severity, which provides novel insights in parsing the host genetics-influenced immune cells for severe COVID-19.
A Bibliometric Analysis of Ophthalmology Resident Research Productivity in the United States
Authors: Huang Austin , Kim Sarah , Zhu Harrison , Pathare Nihar , Ooi Xin Yee , Kirby R. Parker , Yoon Stephen P. , Al-Mohtaseb Zaina
Published: February 2022

Purpose

To quantify scholarly activity of ophthalmology residents during residency and assess what factors may be associated with greater research productivity of these residents.

Methods

Ophthalmology residents who graduated in 2021 were identified from their respective program websites. Bibliometric data published by these residents between the beginning of their PGY-2 year (July 1st, 2018) until three months after graduation (September 30th, 2021) were captured through searches via PubMed, Scopus, and Google Scholar. The association of the following factors with greater research productivity numbers was analyzed: residency tier, medical school rank, sex, doctorate degree, type of medical degree, and international medical graduate status. Residency programs were sorted into five tiers by Doximity “reputation” and medical schools were stratified into US News Top 40 and non-Top 40 schools.

Results

We found 418 ophthalmology residents from 98 residency programs. These residents published a mean (±SD) number of 2.68±3.81 peer-reviewed publications, 2.39±3.40 ophthalmology-related publications, and 1.18±1.96 first-author publications each. The mean (±SD) h-index for this cohort was 0.79±1.17. Upon multivariate analysis, we discovered significant correlations between both residency tier and medical school rank and all bibliometric variables assessed. Pairwise comparisons revealed that residents from higher tier programs had greater research productivity numbers than those from lower tier programs.

Conclusions

We obtained bibliometric standards for ophthalmology residents on a national scale. Residents who graduated from higher-ranked residency programs and medical schools possessed higher h-indices and published more peer-reviewed publications, ophthalmology-related articles, and first author publications.
Improving estimates of social contact patterns for the airborne transmission of respiratory pathogens
Authors: McCreesh Nicky , Mohlamonyane Mbali , Edwards Anita , Olivier Stephen , Dikgale Keabetswe , Dayi Njabulo , Gareta Dickman , Wood Robin , Grant Alison D , White Richard G , Middelkoop Keren
Published: February 2022

Background

Data on social contact patterns are widely used to parameterise age-mixing matrices in mathematical models of infectious diseases designed to help understand transmission patterns or estimate intervention impacts. Despite this, little attention is given to how social contact data are collected and analysed, or how the types of contact most relevant for transmission may vary between different infections. In particular, the majority of studies focus on close contacts only – people spoken to face-to-face. This may be appropriate for infections spread primarily by droplet transmission, but it neglects the larger numbers of ‘shared air’ casual contacts who may be at risk from airborne transmission of pathogens such as Mycobacterium tuberculosis, measles, and SARS-CoV-2.

Methods

We conducted social contact surveys in communities in two provinces of South Africa in 2019 (KwaZulu-Natal and Western Cape). In line with most studies, we collected data on people spoken to (close contacts). We also collected data on places visited and people present, allowing casual contact patterns to be estimated. Using these data, we estimated age mixing patterns relevant for i) droplet and ii) non-saturating airborne transmission. We also estimated a third category of pattern relevant for the transmission of iii) Mycobacterium tuberculosis (Mtb), an airborne infection where saturation of household contacts plays an important role in transmission dynamics.

Results

Estimated contact patterns by age did not vary greatly between the three transmission routes/infections, in either setting. In both communities, relative to other adult age groups, overall contact intensities were lower in 50+ year olds when considering contact relevant for non-saturating airborne transmission or the transmission of Mycobacterium tuberculosis than when considering contact relevant for droplet transmission.

Conclusions

Our findings provide some reassurance that the widespread use of close contact data to parameterise age-mixing matrices for transmission models of airborne infections may not be resulting in major inaccuracies. The contribution of older age groups to transmission may be over-estimated, however. There is a need for future social contact surveys to collect data on casual contacts, to investigate whether our findings can be generalised to a wider range of settings, and to improve model predictions for infections with substantial airborne transmission.
First genotype-phenotype study in TBX4 syndrome: gain-of-function mutations causative for lung disease
Authors: Prapa Matina , Lago-Docampo Mauro , Swietlik Emilia M. , Montani David , Eyries Mélanie , Humbert Marc , Welch Carrie C.L. , Chung Wendy , Berger Rolf M.F. , Bogaard Ham Jan , Danhaive Olivier , Escribano-Subías Pilar , Gall Henning , Girerd Barbara , Hernandez-Gonzalez Ignacio , Holden Simon , Hunt David , Jansen Samara M.A. , Kerstjens-Frederikse Wilhelmina , Kiely David , Lapunzina Pablo , McDermott John , Moledina Shahin , Pepke-Zaba Joanna , Polwarth Gary J. , Schotte Gwen , Tenorio-Castaño Jair , Thompson A.A. Roger , Warton John , Wort Stephen J. ,   NIHR BioResource for Translational Research – Rare Diseases,   National Cohort Study of Idiopathic and Heritable PAH,   PAH Biobank Enrolling Centers’ Investigators, Megy Karyn , Mapeta Rutendo , Treacy Carmen M. , Martin Jennifer M , Li Wei , Swift Andrew J. , Upton Paul D. , Morrell Nicholas W. , Gräf Stefan , Valverde Diana
Published: February 2022

Rationale

Despite the increasing frequency ofTBX4-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights.

Methods

We assembled a multi-center cohort of 137 patients harboring monoallelicTBX4variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with PAH patients withBMPR2causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the NIHR BioResource - Rare Diseases (NBR).

Results

Functional assessment ofTBX4missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared to loss-of-function (p = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (p = 0.005) and increased incidence of interstitial lung disease (p = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (p = 0.022) although age had a significant effect in the hazard model (p = 0.0461). Carriers ofTBX4variants were diagnosed at a younger age (p < 0.001) and had worse baseline lung function (FEV1, FVC) (p = 0.009) compared to theBMPR2and no identified causal variant groups.

Conclusions

We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain-of-function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.
COVID-19 excess death rate in Eastern European countries associated with weaker regulation implementation and lower vaccination coverage
Authors: Ylli Alban , Burazeri Genc , Wu Yan Yan , Sentell Tetine
Published: February 2022

Aim

The objective of this analysis was to assess the association of excess COVID-19 mortality with regulation enforcement and vaccination rate in selected countries.

Methods

This analysis included 50 countries pertinent to the WHO European Region, in addition to USA and Canada. Excess mortality and vaccination data were retrieved from “Our World In Data” database, while regulation implementation was measured from a well-respected, standardized measure. Outpatient visits were also included in the analysis. Multiple linear regression was used to assess the independent association between excess mortality and each covariate.

Results

Excess mortality increased by 4.1/100 000 for every percent decrease in vaccination rate and with 6/100 000 for every decreased unit in the regulatory implementation score a country achieved in the Rule of Law Index.

Conclusion

Degree of regulation enforcement, likely including public health measure enforcement, may be an important factor in controlling COVID-19’s deleterious health impacts.
Inflammatory monocytes promote pyogranuloma formation to counteract Yersinia blockade of host defense
Authors: Sorobetea Daniel , Matsuda Rina , Peterson Stefan T. , Grayczyk James P. , Rao Indira , Krespan Elise , Lanza Matthew , Assenmacher Charles-Antoine , Beiting Daniel , Radaelli Enrico , Brodsky Igor
Published: February 2022

Granulomas are organized immune cell aggregates that form in response to chronic infection or antigen persistence. Yersinia pseudotuberculosis (Yp) blocks innate inflammatory signaling and phagocytosis, inducing formation of neutrophil-rich pyogranulomas within lymphoid tissues. Here, we uncover that Yp triggers pyogranuloma formation within the murine intestinal mucosa, a site not known to contain such structures. Mice lacking circulating monocytes fail to form defined pyogranulomas, have defects in neutrophil activation, and succumb to Yp infection. Yersinia lacking the virulence factors that block phagocytosis did not induce pyogranulomas, indicating that intestinal pyogranulomas form in response to Yp disruption of phagocytosis. Notably, mutation of a single anti-phagocytic virulence factor, YopH, restored pyogranuloma formation and control of Yp infection in monocyte-deficient mice, demonstrating that monocytes override YopH-dependent blockade of innate immune defense. This work reveals an unappreciated site of Yersinia intestinal invasion, and defines host and pathogen drivers of intestinal granuloma formation.
Designing a novel monitoring approach for the effects of space travel on astronauts’ health
Authors: Sakharkar Anurag , Yang Jian
Published: February 2022

Space exploration and extraterrestrial civilization have fascinated humankind since the earliest days of human history. However, it was only until last century that humankind finally began taking significant steps towards these goals by sending astronauts into space, landing on the moon, and building the International Space Station. However, space voyage is very challenging and dangerous, and astronauts are under constant space radiation and microgravity. It has been shown that astronauts are at a high risk of developing a broad range of diseases/disorders. Thus, it is critical to develop a rapid and effective assay to monitor astronauts’ health in space. In this study, gene expression and correlation patterns were analyzed for 10 astronauts (8 male and 2 female) using the publicly available microarray dataset E-GEOD-74708. We identified 218 differentially expressed genes between In-flight and Pre-flight and noticed that space travel decreased genome regulation and gene correlations across the entire genome, as well as individual signaling pathways. Furthermore, we rationally designed a rapid assay of 32 genes which could be used to monitor astronauts’ health during space travel. Further studies, including microgravity experiments, are warranted to optimize and validate the proposed assay.
Validating saliva as a biological sample for cost-effective, rapid and routine screening for SARS-CoV-2
Authors: Ansil B.R. , George Carolin Elizabeth , Chandrasingh Sindhulina , Viswanathan Ashwin , Thattai Mukund , Raghu Padinjat , Devadiga Santhosha , Harikumar Arun Geetha , Harsha Pulleri Kandi , Nair Indu , Ramakrishnan Uma , Mayor Satyajit
Published: February 2022

Purpose

Compared to nasopharyngeal/oropharyngeal swabs, non-invasive saliva samples have enormous potential for scalability and routine population screening of SARS-CoV-2. In this study, we are investigating the efficacy of saliva samples relative to nasopharyngeal/oropharyngeal swabs for use as a direct source for the RT-PCR based SARS-CoV-2 detection.

Methods

Paired nasopharyngeal/oropharyngeal swabs and saliva samples were collected from suspected positive SARS-CoV-2 patients and tested using RT-PCR. Generalised linear models were used to investigate factors that explain result agreement. Further, we used simulations to evaluate the effectiveness of saliva-based screening in restricting the spread of infection in a large campus such as an educational institution.

Results

We observed 75.4% overall result agreement. Prospective positive samples stored for three or more days showed a drastic reduction in the probability of result agreement. We observed 83% result agreement and 74.5% test sensitivity in samples processed and tested within two days of collection. Our simulations suggest that a test with 75% sensitivity, but high daily capacity can be very effective in limiting the size of infection clusters in a workspace. Guided by these results, we successfully implemented a saliva-based screening in the Bangalore Life Sciences Cluster (BLiSC) campus.

Conclusion

These results suggest that saliva may be a viable sample source for SARS-CoV-2 surveillance if samples are processed immediately. We strongly recommend the implementation of saliva-based screening strategies for large workplaces and in schools, as well as for population-level screening and routine surveillance as we learn to live with the SARS-CoV-2 virus.
Incidence and associated factors of elderly mortality following hip fracture in Brazil: a systematic review and meta-analysis
Authors: Peterle Viviane Cristina Uliana , Garbi Novaes Maria Rita Carvalho , Bezerra Junior Paulo Emiliano , Gomides Reis Ana Paula Monteiro , Geber Júnior João Carlos , de Souza Amanda Cristina , Alves Amanda Ribeiro , Silva de Albuquerque Natalia Mariana Diogenes , Mosquéra Júlia Milhomem , Peixoto Henry Maia
Published: February 2022

Introduction

Hip fractures are an important health problem worldwide, and several factors are associated with the mortality. This study aimed to investigate the factors associated with hip fractures in the elderly, based on studies on the population residing in Brazil, and the relationship of fractures with mortality.

Method

Prospective and retrospective primary observational studies including hospitalized men and/or women aged 60 or older presenting hip fracture due to bone fragility were selected on the Databases. Independent researchers conducted the study selection process and data extraction. A meta-analysis was performed to determine the hospital mortality rate at 90 days, six months, and one year. The Newcastle-Ottawa scale (NOS) was used to assess the quality of the included studies, and the meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Result

Twenty-five studies totalizing 3,949 patients were included in the systematic review. The population was mainly composed of women (2,680/67.86%). Most patients were in the age group of 70 to 80 years old. Meta-analysis findings: 1) hospital mortality (19 studies, n = 3,175), 10.22% (95% CI 7.27–14.17%; I2 88%); 2) 90-day mortality (3 studies, n = 543), 9.74% (95% CI 3.44–24.62%; I2 90%); 3) six-month mortality (3 studies, n = 205), 24.78% (95% CI 17.07–34.51%; I2 51%); 4) one-year mortality (13 studies, n = 2,790), 21.88% (95% CI 17.5–26.99%; I2 88%). The factors most related to mortality in the studies were: 1) demographic: Older age, male sex; 2) Attributed to clinical conditions: high scoring in preoperative risk scores, comorbidities, neurological/cognitive disorders, functional status; and 3) hospital factors: preoperative period and infections.

Conclusion

This review identified variables, including functional status and cognitive changes, related to hip fracture mortality. Knowing these predictors allows for early intervention and planning to adapt health systems to the growing demands of the elderly population.
Ruminococcus bromii enables the growth of proximal Bacteroides thetaiotaomicron by releasing glucose during starch degradation
Authors: Rangarajan Aathmaja Anandhi , Chia Hannah E. , Azaldegui Christopher A. , Olszewski Monica H. , Koropatkin Nicole M. , Biteen Julie S.
Published: February 2022

Complex carbohydrates shape the gut microbiota and the collective fermentation of resistant starch by gut microbes positively affects human health through enhanced butyrate production. The keystone species Ruminococcus bromii (Rb) is a specialist in degrading resistant starch; its degradation products are used by other bacteria including Bacteroides thetaiotaomicron (Bt). We analyzed the metabolic and spatial relationships between Rb and Bt during potato starch degradation and found that Bt utilizes glucose that is released from Rb upon degradation of resistant potato starch and soluble potato amylopectin. Additionally, we found that Rb produces a halo of glucose around it when grown on solid media containing potato amylopectin and that Bt cells deficient for growth on potato amylopectin (Δsus Bt) can grow within the halo. Furthermore, when these Δsus Bt cells grow within this glucose halo, they have an elongated cell morphology. This long-cell phenotype depends on the glucose concentration in the solid media: longer Bt cells are formed at higher glucose concentrations. Together, our results indicate that starch degradation by Rb cross-feeds other bacteria in the surrounding region by releasing glucose. Our results also elucidate the adaptive morphology of Bt cells under different nutrient and physiological conditions.

Impact Statement

Dietary intake of complex carbohydrates including resistant starch benefits human health by supporting the growth of keystone species that increase the microbiome diversity via cross-feeding. For instance, Ruminococcus bromii (Rb) is a specialist in degrading resistant starch, and the byproducts of this degradation process are used by bacterial species. In this study, we show that Bacteroides thetaiotaomicron (Bt) cross-feeds on the glucose released during potato starch degradation by Rb. We also show that proximity to Rb cells that are releasing sugars is important for the growth of the cross-fed Bt in solid media. Additionally, we find a longer phenotype for Bt cells grown on solid media in high glucose conditions, indicating that, like other bacteria, human gut bacteria undergo significant nutrient-dependent morphological adaptations.
Machine learning-based approach KEVOLVE efficiently identifies SARS-CoV-2 variant-specific genomic signatures
Authors: Lebatteux Dylan , Soudeyns Hugo , Boucoiran Isabelle , Gantt Soren , Diallo Abdoulaye Baniré
Published: February 2022

Machine learning was shown to be effective at identifying distinctive genomic signatures among viral sequences. These signatures are defined as pervasive motifs in the viral genome that allow discrimination between species or variants. In the context of SARS-CoV-2, the identification of these signatures can assist in taxonomic and phylogenetic studies, improve in the recognition and definition of emerging variants, and aid in the characterization of functional properties of polymorphic gene products. In this paper, we assess KEVOLVE, an approach based on a genetic algorithm with a machine-learning kernel, to identify multiple genomic signatures based on minimal sets ofk-mers. In a comparative study, in which we analyzed large SARS-CoV-2 genome dataset, KEVOLVE was more effective at identifying variant-discriminative signatures than several gold-standard statistical tools. Subsequently, these signatures were characterized using a new extension of KEVOLVE (KANALYZER) to highlight variations of the discriminative signatures among different classes of variants, their genomic location, and the mutations involved. The majority of identified signatures were associated with known mutations among the different variants, in terms of functional and pathological impact based on available literature. Here we showed that KEVOLVE is a robust machine learning approach to identify discriminative signatures among SARS-CoV-2 variants, which are frequently also biologically relevant, while bypassing multiple sequence alignments. The source code of the method and additional resources are available at:https://github.com/bioinfoUQAM/KEVOLVE.
Omicron BA.2 specifically evades broad sarbecovirus neutralizing antibodies
Authors: Cao Yunlong , Yisimayi Ayijiang , Jian Fanchong , Xiao Tianhe , Song Weiliang , Wang Jing , Du Shuo , Zhang Zhiying , Liu Pulan , Hao Xiaohua , Li Qianqian , Chen Xiaosu , Wang Lei , Wang Peng , An Ran , Wang Yao , Wang Jing , Yang Peng , Sun Haiyan , Zhao Lijuan , Zhang Wen , Zhao Dong , Zheng Jiang , Yu Lingling , Li Can , Zhang Na , Wang Rui , Niu Xiao , Yang Sijie , Song Xuetao , Zheng Linlin , Li Zhiqiang , Gu Qingqing , Shao Fei , Huang Weijin , Wang Youchun , Shen Zhongyang , Wang Xiangxi , Jin Ronghua , Xiao Junyu , Xie Xiaoliang Sunney
Published: February 2022

Omicron sub-lineage BA.2 has rapidly surged globally, accounting for over 60% of recent SARS-CoV-2 infections. Newly acquired RBD mutations and high transmission advantage over BA.1 urge the investigation of BA.2’s immune evasion capability. Here, we show that BA.2 causes strong neutralization resistance, comparable to BA.1, in vaccinated individuals’ plasma. However, BA.2 displays more severe antibody evasion in BA.1 convalescents, and most prominently, in vaccinated SARS convalescents’ plasma, suggesting a substantial antigenicity difference between BA.2 and BA.1. To specify, we determined the escaping mutation profiles1,2 of 714 SARS-CoV-2 RBD neutralizing antibodies, including 241 broad sarbecovirus neutralizing antibodies isolated from SARS convalescents, and measured their neutralization efficacy against BA.1, BA.1.1, BA.2. Importantly, BA.2 specifically induces large-scale escape of BA.1/BA.1.1-effective broad sarbecovirus neutralizing antibodies via novel mutations T376A, D405N, and R408S. These sites were highly conserved across sarbecoviruses, suggesting that Omicron BA.2 arose from immune pressure selection instead of zoonotic spillover. Moreover, BA.2 reduces the efficacy of S309 (Sotrovimab)3,4 and broad sarbecovirus neutralizing antibodies targeting the similar epitope region, including BD55-5840. Structural comparisons of BD55-5840 in complexes with BA.1 and BA.2 spike suggest that BA.2 could hinder antibody binding through S371F-induced N343-glycan displacement. Intriguingly, the absence of G446S mutation in BA.2 enabled a proportion of 440-449 linear epitope targeting antibodies to retain neutralizing efficacy, including COV2-2130 (Cilgavimab)5. Together, we showed that BA.2 exhibits distinct antigenicity compared to BA.1 and provided a comprehensive profile of SARS-CoV-2 antibody escaping mutations. Our study offers critical insights into the humoral immune evading mechanism of current and future variants.
DIP2 is a unique regulator of diacylglycerol lipid homeostasis in eukaryotes
Authors: Mondal Sudipta , Kinatukara Priyadarshan , Singh Shubham , Shambhavi Sakshi , Patil Gajanan S. , Dubey Noopur , Singh Salam Herojeet , Pal Biswajit , Chandra Shekar P , Kamat Siddhesh S. , Sankaranarayanan Rajan
Published: February 2022

Chain-length specific subsets of diacylglycerol (DAG) lipids are proposed to regulate differential physiological responses ranging from signal transduction to modulation of the membrane properties. However, the mechanism or molecular players regulating the subsets of DAG species remains unknown. Here, we uncover the role of a conserved eukaryotic protein family, DISCO-interacting protein 2 (DIP2) as a homeostatic regulator of a chemically distinct subset of DAGs using yeast, fly and mouse models. Genetic and chemical screens along with lipidomics analysis in yeast reveal that DIP2 prevents the toxic accumulation of specific DAGs in the logarithmic growth phase, which otherwise leads to endoplasmic reticulum stress. We also show that the fatty acyl-AMP ligase-like domains of DIP2 are essential for the redirection of the flux of DAG subspecies to storage lipid, triacylglycerols. Such modulation of selective DAG abundance by DIP2 is found to be crucial for optimal vacuole-membrane fusion and consequently osmoadaptation in yeast. Thus, the study illuminates an unprecedented DAG metabolism route and provides new insights on how cell fine-tunes DAG subspecies for cellular homeostasis and environmental adaptation.
Atypical and distinct microtubule radial symmetries in the centriole and the axoneme ofLecudina tuzetae
Authors: Bezler Alexandra , Woglar Alexander , Schneider Fabian , Douma Friso , Bürgy Léo , Busso Coralie , Gönczy Pierre
Published: February 2022

The centriole is a minute cylindrical organelle present in a wide range of eukaryotic species. Most centrioles have a signature 9-fold radial symmetry of microtubules that is imparted onto the axoneme of the cilia and flagella they template, with 9 centriolar microtubule doublets growing into 9 axonemal microtubule doublets. There are exceptions to the 9-fold symmetrical arrangement of axonemal microtubules, with lower or higher fold symmetries in some species. In the few cases where this has been examined, such alterations in axonemal symmetries are grounded in likewise alterations in centriolar symmetries. Here, we examine the question of microtubule number continuity between centriole and axoneme in flagellated gametes of the gregarineLecudina tuzetae, which have been reported to exhibit a 6-fold radial symmetry of axonemal microtubules. We used time-lapse differential interference microscopy to identify the stage at which flagellated gametes are present. Thereafter, using electron microscopy and ultrastructure-expansion microscopy coupled to STimulated Emission Depletion (STED) super-resolution imaging, we uncover that a 6- or 5-fold radial symmetry in the axoneme is accompanied by an 8-fold radial symmetry in the centriole. We conclude that there can be plasticity in the transition between centriolar and axonemal microtubules.
Comparative assessment of quantification methods for tumor tissue phosphoproteomics
Authors: Zhang Yang , Dreyer Benjamin , Govorukhina Natalia , Heberle Alexander M. , Končarević Saša , Krisp Christoph , Opitz Christiane A. , Pfänder Pauline , Bischoff Rainer , Schlüter Hartmut , Kwiatkowski Marcel , Thedieck Kathrin , Horvatovich Peter L.
Published: February 2022

With increasing sensitivity and accuracy in mass spectrometry, the tumor phosphoproteome is getting into reach. However, the selection of quantitation techniques best-suited to the biomedical question and diagnostic requirements remains a trial and error decision as no study has directly compared their performance for tumor tissue phosphoproteomics. We compared label-free quantification (LFQ), spike-in-SILAC (stable isotope labeling by amino acids in cell culture) and TMT isobaric tandem mass tags technology for quantitative phosphosite profiling in tumor tissue. TMT offered the lowest accuracy and the highest precision and robustness towards different phosphosite abundances and matrices. Spike-in-SILAC offered the best compromise between these features but suffered from a low phosphosite coverage. LFQ offered the lowest precision but the highest number of identifications. Both spike-in-SILAC and LFQ presented susceptibility to matrix effects. Match between run (MBR)-based analysis enhanced the phosphosite coverage across technical replicates in LFQ and spike-in-SILAC but further reduced the precision and robustness of quantification. The choice of quantitative methodology is critical for both study design such as sample size in sample groups and quantified phosphosites, and comparison of published cancer phosphoproteomes. Using ovarian cancer tissue as an example, our study builds a resource for the design and analysis of quantitative phosphoproteomic studies in cancer research and diagnostics.
Imputation of 3D genome structure by genetic-epigenetic interaction modeling in mice
Authors: Kuffler Lauren , Skelly Daniel A. , Czechanski Anne , Fortin Haley J. , Munger Steven C. , Baker Christopher L. , Reinholdt Laura G. , Carter Gregory W.
Published: February 2022

Gene expression is known to be affected by interactions between local genetic variation and DNA accessibility, with the latter organized into three-dimensional chromatin structures.

Analyses of these interactions has previously been limited, obscuring their regulatory context, and the extent to which they occur throughout the genome. Here we undertake a genome-scale analysis of these interactions in a genetically diverse population to systematically identify global genetic-epigenetic interaction, and reveal constraints imposed by chromatin structure. We establish the extent and structure of genotype-by-epigenotype interaction using embryonic stem cells derived from Diversity Outbred mice. This mouse population segregates millions of variants from eight inbred founders, enabling precision genetic mapping with extensive genotypic and phenotypic diversity. With 176 samples profiled for genotype, gene expression, and open chromatin, we used regression modeling to infer genetic-epigenetic interactions on a genome-wide scale. Our results demonstrate that statistical interactions between genetic variants and chromatin accessibility are common throughout the genome. We found that these interactions occur within the local area of the affected gene, and that this locality corresponds to topologically associated domains (TADs). The likelihood of interaction was most strongly defined by the three-dimensional (3D) domain structure rather than linear DNA sequence. We show that stable 3D genome structure is an effective tool to guide searches for regulatory elements and, conversely, that regulatory elements in genetically diverse populations provide a means to infer 3D genome structure. We confirmed this finding with CTCF ChIP-seq that revealed strain-specific binding in the inbred founder mice. In stem cells, open chromatin participating in the most significant regression models demonstrated an enrichment for developmental genes and the TAD-forming CTCF binding complex, providing an opportunity for statistical inference of shifting TAD boundaries operating during early development. These findings provide evidence that genetic and epigenetic factors operate within the context of three- dimensional chromatin structure.

Graphical Abstract
Reconstructing the 3D genome organization of Neanderthals reveals that chromatin folding shaped phenotypic and sequence divergence
Authors: McArthur Evonne , Rinker David C. , Gilbertson Erin N. , Fudenberg Geoff , Pittman Maureen , Keough Kathleen , Pollard Katherine S. , Capra John A.
Published: February 2022

Changes in gene regulation were a major driver of the divergence of archaic hominins (AHs)—Neanderthals and Denisovans—and modern humans (MHs). The three-dimensional (3D) folding of the genome is critical for regulating gene expression; however, its role in recent human evolution has not been explored because the degradation of ancient samples does not permit experimental determination of AH 3D genome folding. To fill this gap, we apply novel deep learning methods for inferring 3D genome organization from DNA sequence to Neanderthal, Denisovan, and diverse MH genomes. Using the resulting 3D contact maps across the genome, we identify 167 distinct regions with diverged 3D genome organization between AHs and MHs. We show that these 3D-diverged loci are enriched for genes related to the function and morphology of the eye, supra-orbital ridges, hair, lungs, immune response, and cognition. Despite these specific diverged loci, the 3D genome of AHs and MHs is more similar than expected based on sequence divergence, suggesting that the pressure to maintain 3D genome organization constrained hominin sequence evolution. We also find that 3D genome organization constrained the landscape of AH ancestry in MHs today: regions more tolerant of 3D variation are enriched for introgression in modern Eurasians. Finally, we identify loci where modern Eurasians have inherited novel 3D genome folding from AH ancestors, which provides a putative molecular mechanism for phenotypes associated with these introgressed haplotypes. In summary, our application of deep learning to predict archaic 3D genome organization illustrates the potential of inferring molecular phenotypes from ancient DNA to reveal previously unobservable biological differences.

1

Highlights

The 3D genome organization of archaic hominins can be inferred from sequence to facilitate comparisons to modern humans.

Loci with 3D genome folding divergence between humans and Neanderthals highlight functional differences in the eye, supra-orbital ridges, hair, lungs, immune response, and cognition.

3D genome organization constrained recent human evolution.

Tolerance to variation in 3D genome organization shaped the landscape of Neanderthal ancestry in modern humans.

Neanderthal introgression contributed novel 3D genome folding patterns to Eurasians.