bluuebunny/crossref_metadata_2025 huggingface dataset:
Monocytic Subsets and Their Signature Genes Differentially Impact Cortex and Cognition in First-Episode Schizophrenia
Authors: Chen Song , Chithanathan Keerthana , Fan Fengmei , Xiu Meihong , Fan Hongzhen , Cui Yimin , Zhang Ping , Yu Ting , Yang Fude , Tian Baopeng , Hong L. Elliot , Tan Yunlong , Tian Li
Published: September 2021

Accumulating evidence supports involvement of innate immunity in the pathophysiology of schizophrenia. Monocytes are a highly heterogeneous population, subcategorized into classical (CD14++CD16−), intermediate (CD14++CD16+) and nonclassical subsets (CD14+CD16++). How monocytic subsets may shape brain structures and functions remains unclear. The primary goal of this cross-sectional study was to investigate the inter-relationships among monocytic subsets and their specific transcriptomic profiles, cerebral cortical thickness, and cognitive functions in first-episode schizophrenia (FES) patients. We performed whole-blood RNA sequencing (RNAseq) in 128 FES patients and 111 healthy controls (HCs) along with MATRICS Consensus Cognitive Battery (MCCB) measurement, as well as neuroimaging and flow cytometry among partial participants. RNAseq revealed significantly changed expressions of 54 monocytic signature genes in FES patients compared to HCs, especially for intermediate and nonclassical monocytic subsets, with the most outstanding alterations being downregulated S100 Calcium Binding Protein A (S100A) and upregulated Interferon Induced Transmembrane Protein (IFITM) family members, respectively. The percentage of nonclassical monocytes was decreased in FES patients. Cortical thicknesses and MCCB performance were expectantly reduced in FES patients too. Interestingly, negative inter-relationships of monocytic signature genes with both cortical thicknesses and cognition were found in HCs, which were weakened or even reversed in FES patients. Furthermore, the lateral occipital cortex fully mediated the negative effect of a classical monocytic gene Ribonuclease A Family Member 2 (RNASE2) on visual learning in patient group. This study suggests that monocytic dysfunctions play an essential role in cognitive deficit of schizophrenia, and their subtypes should be considered in future research.

One Sentence Summary

Dysfunctions of monocytic subsets play an essential role in cortex and cognitive deficit of schizophrenia
Should the family have a role in deceased organ donation decision-making? A systematic review of public knowledge and attitudes towards organ procurement policies in Europe
Authors: Molina-Pérez Alberto , Delgado Janet , Frunza Michaela , Morgan Myfanwy , Randhawa Gurch , Reiger-Van de Wijdeven Jeantine , Schicktanz Silke , Schiks Eline , Wöhlke Sabine , Rodríguez-Arias David
Published: September 2021

Goal

To assess public knowledge and attitudes towards the role of the family in deceased organ donation in Europe.

Methods

A systematic search was conducted in CINHAL, MEDLINE, PAIS Index, Scopus, PsycINFO, and Web of Science. These databases were last searched on December 15th, 2017. Eligibility criteria were empirical studies conducted in Europe from 2008 to 2017 and addressing either knowledge or attitudes by the public towards the consent system, including the involvement of the family in the decision-making process, for post-mortem organ retrieval. Each record was screened by two or more independent reviewers in three phases. Data collection from each report was performed by two or more independent reviewers.

Results

Of the 1,482 results, 467 reports were assessed in full-text form, and 33 were included in this synthesis. Studies show that a majority of the public support the family’s involvement in organ retrieval decision-making and, in particular, their role as surrogate decision-maker when the deceased has expressed no preference.

Conclusions

A common conceptual framework and validated well-designed questionnaires are needed to address the role of the family in future studies. The findings should be considered in the development of Government policy and guidance regarding the role of families in deceased organ donation.
The role of social support in achieving weight loss in adults in the Caribbean aiming to achieve remission of type 2 diabetes: A cross-case analysis
Authors: Bartholomew Latoya , Unwin Nigel , Guell Cornelia , Bynoe Karen , Murphy Madhuvanti M.
Published: September 2021

Background

Remission of type 2 diabetes through weight loss is possible in a high proportion of persons with a recent diagnosis, but a major challenge is achieving sufficient weight loss.

Objectives

In the first study of this type in the Caribbean, we investigated factors associated with successful weight loss in adults in a diabetes remission intervention. We hypothesized that differences in social support may have influenced differences in weight loss achieved by participants in the Barbados Diabetes Reversal Study (BDRS).

Methods

A comparative case study was conducted. Quantitative data for the primary outcome measure of weight reduction (the participants’ baseline and 8-month weights) were assessed to identify the 6 participants with the highest and 6 participants with the lowest weight loss. The 8-week (low-calorie diet phase) and 8-month (weight maintenance phase) interview transcripts for each participant were then analysed via qualitative thematic analysis to explore factors related to social support.

Results

Informal and formal support were identified for both categories of participants. Cases were similar with respect to their sources of support however dissimilarities were found in (1) the depth of support received; (2) access to supportive environments and (3) diversity of social supportive networks. Participants in the top weight loss group reported consistency in the levels of support received over the low-calorie diet and weight maintenance phases of the study while the converse was true for those of the bottom weight loss group.

Conclusion

Study findings suggest that individuals aiming at type 2 diabetes remission benefit from strong social support networks. These networks provide tangible assistance and facilitate the sharing and discussion of strategies for weight reduction. Future studies should facilitate in-depth understanding of how formal and informal supportive networks can aid sustained dietary diabetes remission and long-term weight maintenance.
The immunogenetics of viral antigen response is associated with sub-type specific glioma risk and survival
Authors: Guerra Geno , Kachuri Linda , Wendt George , Hansen Helen M. , Mack Steven J. , Molinaro Annette M. , Rice Terri , Bracci Paige , Wiencke John K. , Kasahara Nori , Eckel-Passow Jeanette E , Jenkins Robert B. , Wrensch Margaret , Francis Stephen S.
Published: September 2021

Glioma is a highly fatal cancer with prognostically significant molecular subtypes and few known risk factors. Multiple studies have implicated infections in glioma susceptibility, but evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. In this study we leveraged genetic predictors of antibody response to 10 viral antigens to investigate the relationship with glioma risk and survival.

Genetic reactivity scores (GRS) for each antigen were derived from genome-wide significant (p<5×10−8) variants associated with immunoglobulin G antibody response in the UK Biobank cohort. We conducted parallel analyses of glioma risk and survival for each GRS and HLA alleles imputed at two-field resolution using data from 3418 glioma patients subtyped by somatic mutations and 8156 controls.

Genetic reactivity scores to Epstein-Barr virus (EBV) ZEBRA and EBNA antigens and Merkel cell polyomavirus (MCV) VP1 antigen were associated with glioma risk and survival (Bonferroni-corrected p<0.01). GRSZEBRA and GRSMCV were associated in opposite directions with risk of IDH wild type gliomas (ORZEBRA=0.91, p=0.0099 / ORMCV=1.11, p=0.0054). GRSEBNA was associated with both increased risk for IDH mutated gliomas (OR=1.09, p=0.040) and improved survival (HR=0.86, p=0.010). HLA-DQA1*03:01 was significantly associated with decreased risk of glioma overall (OR=0.85, p=3.96×10−4) after multiple testing adjustment.

This first systematic investigation of the role of genetic determinants of viral antigen reactivity in glioma risk and survival provides insight into complex immunogenomic mechanisms of glioma pathogenesis. These results may inform applications of antiviral based therapies in glioma treatment.
Live wildlife trade in markets – a scoping review to inform risk assessment of emerging infectious diseases
Authors: Brookes V.J. , Wismandanu O. , Sudarnika E. , Roby J.A. , Hayes L. , Ward M.P. , Basri C. , Wibawa H. , Davis J. , Indrawan D. , Manyweathers J. , Nugroho W.S. , Windria S. , Hernandez-Jover M.
Published: September 2021

Wet markets are important for food security in many regions worldwide but have come under scrutiny due to their potential role in the emergence of infectious diseases. The sale of live wildlife has been highlighted as a particular risk, and the World Health Organisation has called for the banning of live, wild-caught mammalian species in markets unless risk assessment and effective regulations are in place. Following PRISMA guidelines, we conducted a global scoping review of peer-reviewed information about the sale of live, terrestrial wildlife in markets that are likely to sell fresh food, and collated data about the characteristics of such markets, activities involving live wildlife, the species sold, their purpose, and animal, human, and environmental health risks that were identified. Of the 59 peer-reviewed records within scope, only 25% (n = 14) focussed on disease risks; the rest focused on the impact of wildlife sale on conservation. Although there were some global patterns (for example, the types of markets and purpose of sale of wildlife), there was wide diversity and huge epistemic uncertainty in all aspects associated with live, terrestrial wildlife sale in markets such that the feasibility of accurate assessment of the risk of emerging infectious disease associated with live wildlife trade in markets is limited. Given the value of both wet markets and wildlife trade and the need to support food affordability and accessibility, conservation, public health, and the social and economic aspects of livelihoods of often vulnerable people, there are major information gaps that need to be addressed to develop evidence-based policy in this environment. This review identifies these gaps and provides a foundation from which information for risk assessments can be collected.
Association between work attendance when experiencing fever or cold symptoms and company characteristics and socioeconomic status in the COVID-19 pandemic in Japanese workers: a cross-sectional study
Authors: Mizuki Kazuyoshi , Okawara Makoto , Hino Ayako , Ando Hajime , Nagata Tomohisa , Tateishi Seiichiro , Tsuji Mayumi , Matsuda Shinya , Fujino Yoshihisa ,   for the CORoNaWork project
Published: September 2021

Objective

This study investigated the association between attending work while experiencing fever or cold symptoms and workers’ socioeconomic background and company characteristics during the COVID-19 pandemic.

Methods

A cross-sectional online survey was performed. Of a total of 33,302 participants, 3,676 workers who experienced fever or cold symptoms after April 2020 were included. The odds ratios (ORs) of attending work while sick associated with workers’ socioeconomic background and company characteristics were evaluated using a multilevel logistic model.

Results

The OR of attending work while sick associated with a lack of policy prohibiting workers from working when ill was 2.75 (95%CI: 2.28–3.20, P<0.001).

Conclusion

This study suggests that clear company policies on work and illness can be effective for preventing employees from attending work while sick.
'Like brushing teeth' - Implementation experiences with opt-in, at-home screening for SARS-CoV-2 among schoolchildren in Germany
Authors: Wachinger Jonas , Schirmer Maximilian , Taeuber Nicole , McMahon Shannon A , Denkinger Claudia M
Published: September 2021

Background: Over the course of the pandemic, many countries have repeatedly closed schools and shifted students to remote learning. However, evidence for negative mental and physiological health consequences of such measures for students is increasing, highlighting the need for evidence-based recommendations on how to safely reopen schools. This study presents experiences when implementing opt-in, at-home SARS-CoV-2 screening using rapid diagnostic tests (RDTs) to facilitate safe face-to-face-teaching during a pandemic.

Methods: We present data form a prospective study implementing an RDT-based screening program at a primary school in southwest Germany. We conducted qualitative in-depth interviews with participating children, parents, and school stakeholders to elicit implementation experiences and screening perception.

Results: The screening intervention was highly accepted and appreciated among participants; no positive RDT was reported over the duration of the study. Self-testing at home before coming to school was feasible, but more positive consequences of screening participation (e.g., easing of mask mandates) besides a personal feeling of safety would be appreciated. Participants preferred home-based RDTs over some other measures, particularly mask mandates. Despite the RDTs being licensed as self-tests in Germany, additional training can help avoid mistakes, and ensuring intervention ownership and improving pre-implementation communication can facilitate buy-in.

Conclusions: Ag-RDT-based SARS-CoV-2 screening programs relying on self-testing at home proved feasible and accepted among primary school students, parents, and school staff who participated in this study.
Factors Influencing The First and Second Peak of COVID-19 Global Cases: A Survival Analysis
Authors: Oshan Yesar Ahmed , Zainab Begum , Bandyopadhyay Dipankar , Rahaman Khan Md Hasinur
Published: September 2021

Objectives

The number of reported cases continues to increase everyday, since the first case of COVID-19 was detected in Wuhan, China in December 2019. Using the global COVID-19 data of 188 countries extracted from the Our World in Data between January 22, 2020–January 18, 2021, this study attempts to explore the potential determinants of the number of days to reach the first and second peak of COVID-19 cases for all 188 countries.

Methods

A semi-parametric Cox proportional hazard (PH) model has been used to explore the covariates that are associated with the number of days to reach the first and second peak of global COVID-19 cases.

Results

As of January 18, 2021, the first and second peak were found in 175 and 59 countries, out of 188 countries, respectively. The median number of days to hit the first peak was 60 days for countries which have median age above 40 while the median number of days to hit the second peak was 267 days for countries which have population density above 500 per square kilometer. Countries having population density between 250 and 500 were 2.25 times more likely to experience the first peak of COVID-19 cases (95% CI: 1.15-4.45, P < 0.05) than countries which have population density below 25. Countries having population density between 100 and 250 were 67% less likely to get the second peak (95% CI: 0.119-0.908, P < 0.05) compared to countries which have population density below 25. Countries having cardiovascular death rates above 350 were 2.94 times more likely to get the first peak (95% CI: 1.59-5.43, P < 0.001). In contrast, countries having diabetes prevalence rate 3 to 12 were 85% less likely to experience the second peak of COVID-19 cases (95% CI: 0.036-0.680, P < 0.05) than countries which have diabetes prevalence rate below 3. Besides, highly significant difference is found in the Kaplan-Meier plots of the number of days to reach both peaks across different categories of the country’s Human Development Index.

Conclusions

The number of days to the first peak was considerably small in Asian & European countries but that to the second peak in the countries where diabetes prevalence was very higher. Country’s life expectancy had a significant effect on determining the first peak and so was the case for two other variables–the cardiovascular death rate and hospital beds per thousand. A contrast result was found for Human Development Index factor under the second peak. Additionally, it was found that the second peak was more likely to occur in more densely populated countries.
Misdiagnosis prevents accurate monitoring of transmission and burden for sub-critical pathogens: a case study of Plasmodium knowlesi malaria
Authors: Huber John H.
Published: September 2021

Maintaining surveillance of emerging infectious diseases presents challenges for monitoring their transmission and burden. Incomplete observation of infections and imperfect diagnosis reduce the observed sizes of transmission chains relative to their true sizes. Previous studies have examined the effect of incomplete observation on estimates of pathogen transmission and burden. However, each study assumed that, if observed, each infection was correctly diagnosed. Here, I leveraged principles from branching process theory to examine how misdiagnosis could contribute to bias in estimates of transmission and burden for emerging infectious diseases. Using the zoonotic Plasmodium knowlesi malaria as a case study, I found that, even when assuming complete observation of infections, the number of misdiagnosed cases within a transmission chain for every correctly diagnosed case could range from 0 (0 – 4) when R0 was 0.1 to 86 (0 – 837) when R0 was 0.9. Data on transmission chain sizes obtained using an imperfect diagnostic could consistently lead to underestimates of R0, the basic reproduction number, and simulations revealed that such data on up to 1,000 observed transmission chains was not powered to detect changes in transmission. My results demonstrate that misdiagnosis may hinder effective monitoring of emerging infectious diseases and that sensitivity of diagnostics should be considered in evaluations of surveillance systems.
Multi-trait genome-wide association study of opioid addiction:OPRM1and Beyond
Authors: Gaddis Nathan , Mathur Ravi , Marks Jesse , Zhou Linran , Quach Bryan , Waldrop Alex , Levran Orna , Agrawal Arpana , Randesi Matthew , Adelson Miriam , Jeffries Paul W. , Johnson Emma C. , Martin Nicholas G. , Degenhardt Louisa , Montgomery Grant W , Wetherill Leah , Lai Dongbing , Bucholz Kathleen , Foroud Tatiana , Porjesz Bernice , Webb Bradley Todd , Crist Richard C. , Kranzler Henry R. , Zhou Hang , Hulse Gary , Wildenauer Dieter , Kelty Erin , Attia John , Holliday Elizabeth G. , McEvoy Mark , Scott Rodney J. , Schwab Sibylle G , Maher Brion S. , Gruza Richard , Kreek Mary-Jeanne , Nelson Elliot C. , Berrettini Wade H. , Gelernter Joel , Edenberg Howard , Bierut Laura , Hancock Dana B. , Johnson Eric O.
Published: September 2021

Opioid addiction (OA) has strong heritability, yet few genetic variant associations have been robustly identified. Only rs1799971, the A118G variant inOPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data and published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg> 0.9). We observed the strongest evidence to date forOPRM1: lead SNP rs9478500 (p=2.56×10−9). Gene-based analyses identified novel genome-wide significant associations withPPP6CandFURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.
Aging-related cell type-specific pathophysiologic immune responses that exacerbate disease severity in aged COVID-19 patients
Authors: Hou Yuan , Zhou Yadi , Gack Michaela U. , Luo Yuan , Jehi Lara , Chan Timothy , Yu Haiyuan , Eng Charis , Pieper Andrew A. , Cheng Feixiong
Published: September 2021

Coronavirus Disease 2019 (COVID-19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID-19 incidence and severity as a function of age. Our analysis leveraged age-specific COVID-19 mortality and laboratory testing from a large COVID-19 registry, along with epidemiological data of ∼3.4 million individuals, large-scale deep immune cell profiling data, and single-cell RNA-sequencing data from aged COVID-19 patients across diverse populations. To begin, we confirmed a significantly increased rate of severe outcomes in aged COVID-19 patients. Furthermore, we identified increased inflammatory markers (C-reactive protein, D-dimer, and neutrophil-lymphocyte ratio), viral entry factors in secretory cells, and TGFβ-mediated immune-epithelial cell interactions, as well as reduction in both naïve CD8 T cells and expression of interferon antiviral defense genes (i.e.,IFITM3andTRIM22), along with strong TGF-beta mediated immune-epithelial cell interactions (i.e., secretory - T regulatory cells), in aged severe COVID-19 patients. Taken together, our findings point to immuno-inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID-19 patients.
Maternal childhood trauma and perinatal distress predict the development of attention in infants from 6 to 18 months in a Swedish cohort study
Authors: Tu Hsing-Fen , Skalkidou Alkistis , Lindskog Marcus , Gredebäck Gustaf
Published: September 2021

Maternal distress is repeatedly reported to have negative impacts on the cognitive development in children. Studies examining the association between maternal distress and the development of attention in infancy are few. This study investigated the longitudinal relationships between maternal distress (depressive symptoms, anxiety symptoms, and exposure to childhood trauma) and the development of attention in infancy in 118 mother-infant dyads. We found that maternal exposure to non-interpersonal traumatic events in childhood and a large degree of anxiety during the 2nd trimester was associated with less attention of the infants to audio-visual stimuli at 6, 10, and 18 months. In addition, exposure to interpersonal traumatic events in childhood was identified as a moderator of the negative effect of maternal anxiety during the 2nd trimester on the development of attention in infants. We discuss the possible mechanisms accounting for these cross-generational effects. Our findings underscore the importance of maternal mental health to the development of attention in infancy and address the need for early screening of maternal mental health during pregnancy.
Functional group-dependent responses of forest bird communities to invasive predator control and habitat fragmentation
Authors: Morgan Shaun , Binks Nigel A. , Didham Raphael K. , Barnes Andrew D.
Published: September 2021

Aim

Mounting global pressure on bird populations from invasive predators and habitat loss has driven a rapid growth in restorative and protective conservation action around the world, yet the efficacy of such actions is still not well understood. We investigated the relative effects of invasive predator control and habitat fragmentation on the abundance of native birds and invasive mammalian predators in native forest fragments.

Location

Waikato region, New Zealand

Methods

We sampled invasive mammalian predator and native bird abundances using camera traps and bird counts at 26 sites in 15 forest fragments across New Zealand’s Waikato region. Fragment area, shape complexity, and surrounding land cover of exotic and native forest were determined in ArcMap. We further created two composite gradients reflecting predator control intensity and temporal distribution of control based on seven quantitative variables recorded in each of the five years preceding native bird data collection. Finally, we estimated the relative influence of these drivers on invasive mammals and functional groups of native birds using model averaging.

Results

Of the two invasive predator control variables, only control intensity significantly affected invasive predator abundance and was also a more important driver than landscape or fragment structure, but responses varied among invasive mammal species. In contrast, both invasive predator control intensity and fragment structure were similarly important drivers of native bird abundance, though bird community responses varied markedly between functional groups.

Main conclusions

Our findings suggest that spatial extent of invasive mammal control is important for controlling mammal numbers and enhancing bird abundance, especially for small insectivorous species, and that habitat fragmentation is less important for invasive mammals but at least as important for native bird communities. Consequently, both drivers should be given strong consideration when undertaking landscape-scale conservation and restoration of bird communities in human-altered landscapes threatened by invasive predators.
Network- and Enrichment-based Inference of Phenotypes and Targets from large-scale Disease Maps
Authors: Hoch Matti , Smita Suchi , Cesnulevicius Konstantin , Lescheid David , Schultz Myron , Wolkenhauer Olaf , Gupta Shailendra
Published: September 2021

Disease maps have emerged as computational knowledge bases for exploring and modeling diseasespecific molecular processes. By capturing molecular interactions, disease-associated processes, and phenotypes in standardized representations, disease maps provide a platform for applying bioinformatics and systems biology approaches. Applications range from simple map exploration to algorithm-driven target discovery and network perturbation. The web-based MINERVA environment for disease maps provides a platform to develop tools not only for mapping experimental data but also to identify, analyze and simulate disease-specific regulatory networks. We have developed a MINERVA plugin suite based on network topology and enrichment analyses that facilitate multi-omics data integration and enablein silicoperturbation experiments on disease maps. We demonstrate workflows by analyzing two RNA-seq datasets on the Atlas of Inflammation Resolution (AIR). Our approach improves usability and increases the functionality of disease maps by providing easy access to available data and integration of selfgenerated data. It supports efficient and intuitive analysis of omics data, with a focus on disease maps.
Behavioural analysis of swarming mosquitoes reveals higher hearing sensitivity than previously measured with electrophysiology methods
Authors: Feugère Lionel , Roux Olivier , Gibson Gabriella
Published: September 2021

Mosquitoes of many species mate in station-keeping swarms. Mating chases ensue as soon as a male detects the flight tones of a female with his auditory organs. Previous studies of hearing thresholds have mainly used electrophysiological methods that prevent the mosquito from flying naturally. The main aim of this study was to quantify behaviourally the sound-level threshold at which males can hear females. Free-flying male Anopheles coluzzii were released in a large arena (~2 m high × 2 m × 1 m) with a conspicuous object on the ground that stimulates swarming behaviour. Males were exposed to a range of natural and synthetic played-back sounds of female flight. We monitored the responses of males and their distance to the speaker by recording changes in their wingbeat frequency and angular speed. We show that the mean male behavioural threshold of particle-velocity hearing lies between 13-20 dB SVL (95%-CI). A conservative estimate of 20 dB SVL (i.e., < 0.5 μm/s particle velocity) is already 12 to 26 dB lower than most of the published electrophysiological measurements from the Johnston’s organ. In addition, we suggest that 1) the first harmonic of female flight-sound is sufficient for males to detect her presence, 2) males respond with a greater amplitude to single-female sounds than to the sound of a group of females and 3) the response of males to the playback of the flight sound of a live female is the same as that of a recorded sound of constant frequency and amplitude.
Local adaptation shapes metabolic diversity in the global population of Arabidopsis thaliana
Authors: Kooke Rik , Kruijer Willem , van Eekelen Henriette D.L.M. , Becker Frank F.M. , Wehrens Ron , Hall Robert D. , Mumm Roland , de Vos Ric C.H. , van Eeuwijk Fred A. , Keurentjes Joost J.B.
Published: September 2021

The biosynthesis, structure and accumulation of secondary metabolites in plants are largely controlled by genetic factors, which can vary substantially among genotypes within a species. Here we studied a global population of Arabidopsis thaliana accessions for qualitative and quantitative variation in volatile and non-volatile secondary metabolites using essentially untargeted metabolomics. Genome-wide association (GWA) mapping revealed that metabolic variation mainly traces back to genetic variation in dedicated biosynthesis genes. Effect sizes of genetic variants, estimated by a Bayesian procedure, indicate that most of the genetic variation in the accumulation of secondary metabolites is explained by large-effect genes and defined by multiple polymorphisms. The various genetic variants resulted from independent mutation events and combined into distinctive haplotypes, which are representative for specific geographical regions. A strong relationship between the effect-size of regulatory loci, their allele frequencies and fixation index indicates that selection forces discriminate between haplotypes, resulting in different phytochemical profiles. Finally, we demonstrate that haplotype frequencies deviate from neutral theory predictions, suggesting that metabolic profiles are shaped by local adaptation and co-evolution of independent loci.
Evolution of reproductive strategies in incipient multicellularity
Authors: Gao Yuanxiao , Pichugin Yuriy , Gokhale Chaitanya S. , Traulsen Arne
Published: September 2021

Multicellular organisms can potentially show a large degree of diversity in reproductive strategies, as they could reproduce offspring with varying sizes and compositions compared to their unicellular ancestors. In reality, only a few of these reproductive strategies are prevalent. To understand why this could be the case, we develop a stage-structured population model to probe the evolutionary growth advantages of reproductive strategies in incipient multicellular organisms. The performance of reproductive strategies is evaluated by the growth rates of corresponding populations. We identify the optimal reproductive strategy, which leads to the largest growth rate for a population. Considering the effects of organism size and cellular interaction, we found that distinct reproductive strategies could perform uniquely or equally well under different conditions. Only binary-splitting reproductive strategies can be uniquely optimal. Our results show that organism size and cellular interaction can play crucial roles in shaping reproductive strategies in nascent multicellularity. Our model sheds light on understanding the mechanism driving the evolution of reproductive strategies in incipient multicellularity. Meanwhile, beyond multicellularity, our results imply a crucial factor in the evolution of reproductive strategies of unicellular species - organism size.
XePhIR: The zebrafish Xenograft Phenotype Interactive Repository
Authors: Groenewoud A. , Forn-Cuní G. , Engel F.B. , Snaar-Jagalska B. E.
Published: September 2021

Zebrafish xenografts are an established model in cancer biology, with a steadily rising number of models and users. However, as of yet, there is no platform dedicated to standardizing protocols and sharing data regarding zebrafish xenograft phenotypes. Here, we present the Xenograft Phenotype Interactive Repository (XePhIR,www.xephir.org) as an independent data sharing platform to deposit, share and repurpose zebrafish xenograft data. Deposition of data and publication with XePhIR will be done after the acceptation of the original publication. This will enhance the reach of the original research article, enhance visibility, and does not interfere with publication or copyrights of the original article. With XePhIR, we strive to fulfill these objectives and reason that this resource will enhance reproducibility and showcase the appeal and applicability of the zebrafish xenograft model.
Identifying locations susceptible to micro-anatomical reentry using a spatial network representation of atrial fibre maps
Authors: Falkenberg Max , Coleman James A , Dobson Sam , Hickey David J , Terrill Louie , Ciacci Alberto , Thomas Belvin , Peters Nicholas S , Sau Arunashis , Ng Fu Siong , Zhao Jichao , Christensen Kim
Published: September 2021

Micro-anatomical reentry has been identified as a potential driver of atrial fibrillation (AF). In this paper, we introduce a novel computational method which aims to identify which atrial regions are most susceptible to micro-reentry. The approach, which considers the structural basis for micro-reentry only, is based on the premise that the accumulation of electrically insulating interstitial fibrosis can be modelled by simulating percolation-like phenomena on spatial networks. Our results suggest that at high coupling, where micro-reentry is rare, the micro-reentrant substrate is highly clustered in areas where the atrial walls are thin and have convex wall morphology. However, as transverse connections between fibres are removed, mimicking the accumulation of interstitial fibrosis, the substrate becomes less spatially clustered, and the bias to forming in thin, convex regions of the atria is reduced. Comparing our algorithm on image-based models with and without atrial fibre structure, we find that strong longitudinal fibre coupling can suppress the micro-reentrant substrate, whereas regions with disordered fibre orientations have an enhanced risk of micro-reentry. We suggest that with further development, these methods may have future potential for patient-specific risk stratification, taking a longitudinal view of the development of the micro-reentrant substrate.

Author summary

Atrial fibrillation (AF) is the most common abnormal heart rhythm, yet, despite extensive research, treatment success rates remain poor. In part, this is because there is an incomplete understanding of the mechanistic origin of AF. In this paper, we investigate one proposed mechanism of AF, the formation of “micro-reentrant circuits”, which can be thought of as a “short circuit”, forming when electrically insulating fibrosis (structural repair tissue) infiltrates the space between heart muscle cells. Previously, such circuits have been found in experimental hearts, but identifying these circuits clinically is difficult. Here, we aim to take a small step towards developing computational methods for identifying where in the atria these circuits are most likely to form, drawing on techniques from network science. Our approach indicates that a number of factors are key to determining where circuits form, most notably the thickness of the heart muscle, and the alignment of muscle fibres.
Ancient genomes redate the extinction of Sussemionus, a subgenus of Equus, to late Holocene
Authors: Cai Dawei , Zhu Siqi , Gong Mian , Zhang Naifan , Wen Jia , Liang Qiyao , Sun Weilu , Shao Xinyue , Guo Yaqi , Cai Yudong , Zheng Zhuqing , Zhang Wei , Hu Songmei , Wang Xiaoyang , Tian He , Li Youqian , Liu Wei , Yang Miaomiao , Yang Jian , Wu Duo , Orlando Ludovic , Jiang Yu
Published: September 2021

The exceptionally-rich fossil record available for the equid family has provided textbook examples of macroevolutionary changes. Horses, asses and zebras represent three extant subgenus of Equus lineage, while the Sussemionus subgenus is another remarkable Equus lineage ranging from North America to Ethiopia in Pleistocene. We sequenced 26 archaeological specimens from northern China in Holocene showing morphological features reminiscent of Equus ovodovi, a species representative of Sussemionus, and further confirmed them as this species by genetic analyses. Thus, we present the first high-quality complete genome of the Sussemionus that we sequenced to 12.0× depth-of-coverage and demonstrate that it survived until ∼3,500 years ago, despite the continued demographic collapse during the Last Glacial Maximum and the great human expansion in East Asia. We also confirmed the Equus phylogenetic tree, and found Sussemionus diverged from the ancestor of non-caballine equids ∼2.3-2.7 Million years ago and admixture events could have taken place between them. Our works suggest the small genetic diversity but not the enhanced inbreeding mainly limited the chances of survival of the species, and illustrates how ancient DNA can inform on extinction dynamics and the long-term resilience of species surviving in cryptic population pockets.
Longitudinal effects of using and discontinuing CNS medications on cognitive functioning
Authors: Koch Elise , Johnell Kristina , Kauppi Karolina
Published: September 2021

Purpose

To investigate the longitudinal effect of using and discontinuing central nervous system (CNS) medications on cognitive performance.

Methods

Using longitudinal cognitive data from healthy adults aged 25-100 years (N = 2,188) from four test waves five years apart, we investigated both the link between use of CNS medications (opioids, antidepressants, and anxiolytics, hypnotics and sedatives) on cognitive task performance (episodic memory, semantic memory, visuospatial ability) across 15 years, and the effect of discontinuing these medications in linear mixed effects models.

Results

We found that opioid use was associated with decline in visuospatial ability, whereas antidepressant use was associated with decline in semantic memory over 15 years. A link between drug discontinuation and cognitive improvement was seen for opioids, antidepressants as well as for anxiolytics, hypnotics and sedatives.

Conclusions

Although our results may be confounded by subjacent conditions, they suggest that long-term use of CNS medications may have domain-specific negative effects on cognitive performance over time, whereas the discontinuation of these medications may partly reverse these effects. These results open up for future studies that address subjacent conditions on cognition to develop a more complete understanding of the cognitive effects of CNS medications.

Key points

Opioid use was associated with decline in visuospatial ability, and individuals discontinuing using opioids showed improvement in visuospatial ability compared to individuals continuing using opioids.

Antidepressant use was associated with decline in semantic memory, and individuals discontinuing using antidepressants showed improvement in semantic memory compared to individuals continuing using antidepressants.

For anxiolytics, hypnotics and sedatives there was no difference between continued users and non-users, but drug discontinuation was associated with more positive cognitive development both in episodic memory and visuospatial ability.
Structural Disconnection of the Posterior Medial Frontal Cortex Reduces Speech Error Monitoring
Authors: McCall Joshua D. , Dickens J. Vivian , Mandal Ayan S. , DeMarco Andrew T. , Fama Mackenzie E. , Lacey Elizabeth H. , Kelkar Apoorva , Medaglia John D. , Turkeltaub Peter E.
Published: September 2021

Optimal performance in any task relies on the ability to detect and repair errors. The anterior cingulate cortex and the broader posterior medial frontal cortex (pMFC) are active during error processing. However, it is unclear whether damage to the pMFC impairs error monitoring. We hypothesized that successful error monitoring critically relies on connections between the pMFC and broader cortical networks involved in executive functions and the task being monitored. We tested this hypothesis in the context of speech error monitoring in people with post-stroke aphasia. Diffusion weighted images were collected in 51 adults with chronic left-hemisphere stroke and 37 age-matched control participants. Whole-brain connectomes were derived using constrained spherical deconvolution and anatomically-constrained probabilistic tractography. Support vector regressions identified white matter connections in which lost integrity in stroke survivors related to reduced error detection during confrontation naming. Lesioned connections to the bilateral pMFC were related to reduce error monitoring, including many connections to regions associated with speech production and executive function. We conclude that connections to the pMFC support error monitoring. Error monitoring in speech production is supported by the structural connectivity between the pMFC and regions involved in speech production and executive function. Interactions between pMFC and other taskrelevant processors may similarly be critical for error monitoring in other task contexts.
Orientation dependent proton transverse relaxation in the human brain white matter: The magic angle effect on a cylindrical helix
Authors: Pang Yuxi
Published: September 2021

Purpose

To overcome some limitations of prior orientation-dependent proton transverse relaxation formalisms in white matter (WM) with a novel framework based on the generalized magic angle effect function.

Methods

A cylindrical helix model was developed embracing anisotropic rotational and translational diffusion of restricted molecules in human brain WM, with the former characterized by an axially symmetric system. Transverse relaxation ratesR2andwere divided into isotropicand anisotropic parts,, withαdenoting an open angle andε0an orientation (Φ) offset from DTI-derived primary diffusivity direction. The proposed framework (Fit A) was compared with prior models withoutε0on previously published water and methylene proton transverse relaxation rates from developing, healthy, and pathological WM at 3T. Goodness of fit was represented by root-mean-square error (RMSE).F-test and linear correlation were used with statistical significance set toP≤ 0.05.

Results

Fit A significantly (P<0.01) outperformed prior models as demonstrated by reduced RMSEs, e.g., 0.349 vs. 0.724 in myelin water. Fittedε0was in good agreement with calculatedε0from directional diffusivities. Compared with those from healthy adult, the fitted, andαfrom neonates were substantially reduced butε0increased, consistent with incomplete myelination. Significant positiveand negative (αand) correlations were found with aging (demyelination) in elderly.

Conclusion

The developed framework can better characterize orientation dependences from a wide range of proton transverse relaxation measurements in human brain WM, shedding new light on myelin microstructural alterations at the molecular level.
Hydrogen sulfide release via the ACE inhibitor Zofenopril prevents intimal hyperplasia in human vein segments and in a mouse model of carotid artery stenosis
Authors: Macabrey Diane , Deslarzes-Dubuis Céline , Longchamp Alban , Lambelet Martine , Ozaki Charles K. , Corpataux Jean-Marc , Allagnat Florent , Déglise Sébastien
Published: September 2021

Objectives

Hypertension is a major risk factor for intimal hyperplasia (IH) and restenosis following vascular and endovascular interventions. Pre-clinical studies suggest that hydrogen sulfide (H2S), an endogenous gasotransmitter, limits restenosis. While there is no clinically available pure H2S releasing compound, the sulfhydryl-containing angiotensin-converting enzyme inhibitor Zofenopril is a source of H2S. Here, we hypothesized that Zofenopril, due to H2S release, would be superior to other non-sulfhydryl containing angiotensin converting enzyme inhibitor (ACEi), in reducing intimal hyperplasia.

Materials

Spontaneously hypertensive male Cx40 deleted mice (Cx40−/−) or WT littermates were randomly treated with Enalapril 20 mg (Mepha Pharma) or Zofenopril 30 mg (Mylan SA). Discarded human vein segments and primary human smooth muscle cells (SMC) were treated with the active compound Enalaprilat or Zofenoprilat.

Methods

IH was evaluated in mice 28 days after focal carotid artery stenosis surgery and in human vein segments cultured for 7 days ex vivo. Human primary smooth muscle cell (SMC) proliferation and migration were studied in vitro.

Results

Compared to control animals (intima/media thickness=2.3±0.33), Enalapril reduced IH in Cx40−/− hypertensive mice by 30% (1.7±0.35; p=0.037), while Zofenopril abrogated IH (0.4±0.16; p<.0015 vs. Ctrl and p>0.99 vs. sham-operated Cx40−/− mice). In WT normotensive mice, enalapril had no effect (0.9665±0.2 in control vs 1.140±0.27; p>.99), while Zofenopril also abrogated IH (0.1623±0.07, p<.008 vs. Ctrl and p>0.99 vs. sham-operated WT mice). Zofenoprilat, but not Enalaprilat, also prevented intimal hyperplasia in human veins segments ex vivo. The effect of Zofenopril on carotid and SMC correlated with reduced SMC proliferation and migration. Zofenoprilat inhibited the MAPK and mTOR pathways in SMC and human vein segments.

Conclusion

Zofenopril provides extra beneficial effects compared to non-sulfhydryl ACEi to reduce SMC proliferation and restenosis, even in normotensive animals. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases and hypertension.

Graphical Abstract

What this paper adds

The current strategies to reduce intimal hyperplasia (IH) principally rely on local drug delivery, in endovascular approach. The oral angiotensin converting enzyme inhibitor (ACEi) Zofenopril has additional effects compared to other non-sulfyhydrated ACEi to prevent intimal hyperplasia and restenosis. Given the number of patients treated with ACEi worldwide, these findings call for further prospective clinical trials to test the benefits of sulfhydrated ACEi over classic ACEi for the prevention of restenosis in hypertensive patients.
Social modulation of oogenesis and egg-laying inDrosophila melanogaster
Authors: Bailly Tiphaine P. M. , Kohlmeier Philip , Etienne Rampal S. , Wertheim Bregje , Billeter Jean-Christophe
Published: September 2021

Being part of a group facilitates cooperation between group members, but also creates competition for limited resources. This conundrum is problematic for gravid females who benefit from being in a group, but whose future offspring may struggle for access to nutrition in larger groups. Females should thus modulate their reproductive output depending on their social context. Although social-context dependent modulation of reproduction is documented in a broad range of species, its underlying mechanisms and functions are poorly understood. In the fruit flyDrosophila melanogaster,females actively attract conspecifics to lay eggs on the same resources, generating groups in which individuals may cooperate or compete. The tractability of the genetics of this species allows dissecting the mechanisms underlying physiological adaptation to their social context.

Here, we show that females produce eggs increasingly faster as group size increases. By laying eggs faster in group than alone, females appear to reduce competition between offspring and increase their likelihood of survival. In addition, females in a group lay their eggs during the light phase of the day, while isolated females lay them during the night. We show that responses to the presence of others are determined by vision through the motion detection pathway and that flies from any sex, mating status or species can trigger these responses. The mechanisms of this modulation of egg-laying by group is connected to a lifting of the inhibition of light on oogenesis and egg-laying by stimulating hormonal pathways involving juvenile hormone. Because modulation of reproduction by social context is a hallmark of animals with higher levels of sociality, our findings represent a protosocial mechanism in a species considered solitary that may have been the target of selection for the evolution of more complex social systems.