bluuebunny/crossref_metadata_2025 huggingface dataset:
LRLoop: Feedback loops as a design principle of cell-cell communication
Authors: Xin Ying , Lyu Pin , Jiang Junyao , Zhou Fengquan , Wang Jie , Blackshaw Seth , Qian Jiang
Published: February 2022

Genome-wide gene expression profiling, and single-cell RNA-seq in particular, allows the predictions of molecular mechanisms regulating cell-cell communication based on the expression of known ligand-receptor pairs. Currently available techniques for predicting ligand-receptor interactions are one-directional from sender to receiver cells. Here we describe LRLoop, a new method for analyzing cell-cell communication that is based on bi-directional ligand-receptor interactions, where two pairs of ligand-receptor interactions are identified that are responsive to each other, and thereby form a closed feedback loop. We assessed LRLoop using both bulk and single-cell datasets and found our method significantly reduces the false positive rate seen with existing methods. Finally, we applied LRLoop to the single-cell datasets obtained from retinal development and discovered many new bi-directional ligand-receptor interactions among individual cell types that potentially control proliferation, neurogenesis and/or cell fate specification.
SpatialCorr: Identifying Gene Sets with Spatially Varying Correlation Structure
Authors: Bernstein Matthew N. , Ni Zijian , Prasad Aman , Brown Jared , Mohanty Chitrasen , Stewart Ron , Newton Michael A. , Kendziorski Christina
Published: February 2022

Recent advances in spatially resolved transcriptomics technologies enable both the measurement of genome-wide gene expression profiles and their mapping to spatial locations within a tissue. A first step in spatial transcriptomics data analysis is identifying genes with expression that varies spatially, and robust statistical methods exist to address this challenge. While useful, these methods do not detect spatial changes in the coordinated expression within a group of genes. To this end, we present SpatialCorr, a method for identifying sets of genes with spatially varying correlation structure. Given a collection of gene sets pre-defined by a user, SpatialCorr tests for spatially induced differences in the correlation of each gene set within tissue regions, as well as between and among regions. An application to cutaneous squamous cell carcinoma demonstrates the power of the approach for revealing biological insights not identified using existing methods.
Time-Optimal Adaptation in Metabolic Network Models
Authors: Köbis Markus A. , Bockmayr Alexander , Steuer Ralf
Published: February 2022

Analysis of metabolic models using constraint-based optimization has emerged as an important computational technique to elucidate and eventually predict cellular metabolism and growth. In this work, we introduce time-optimal adaptation (TOA), a new constraint-based modeling approach that allows us to evaluate the fastest possible adaptation to a pre-defined cellular state while fulfilling a given set of dynamic and static constraints. TOA falls into the mathematical problem class of time-optimal control problems, and, in its general form, can be applied in a broad sense and thereby extends most existing constraint-based modeling frameworks. Specifically, We introduce a general mathematical framework that captures many existing constraint-based methods and define TOA within this framework. We then exemplify TOA using a coarse-grained self-replicator model and demonstrate that TOA allows us to explain several well known experimental phenomena that are difficult to explore using existing constraint-based analysis methods. We show that TOA can explain accumulation of storage compounds in constant environments, as well as overshoot uptake metabolism after a period of nutrient scarcity. TOA reveals that organisms with internal temporal degrees of freedom, such as storage, can in most environments outperform organisms with a static intracellular composition. Furthermore, TOA shows that organisms adapted to better growth conditions than present in the environment (“optimists”) typically outperform organisms adapted to poorer growth conditions (“pessimists”).
Impacts of climate change on California’s rangeland production: sensitivity and future projection
Authors: Liu Han , Jin Yufang , Roche Leslie M. , O’Geen Anthony T. , Dahlgren Randy A.
Published: February 2022

Rangelands support many important ecosystem services and are highly sensitive to climate change. Understanding temporal dynamics in rangeland gross primary production (GPP) and how it may change under projected climate change, including more frequent and severe droughts, is critical for ranching communities to cope with future changes. Covering ~10% of California’s climatologically and topographically diverse landscapes, annual rangelands express varying sensitivity to precipitation fluctuation and warming. Herein, we examined how climate regulates temporal dynamics of annual GPP in California’s annual rangeland across scales, based on 20 years of satellite record derived GPP at 500-meter resolution since 2001. We built gradient boosted regression tree models for 23 ecoregion subsections in our study area, relating annual GPP with 30 climatic variables and disentangling the partial dependence of GPP on each climate variable. Our analysis showed that GPP was most sensitive to growing season precipitation amount; GPP decrease as much as 200 g C/m2/yr when growing season precipitation decreased from 400 to 100 mm/yr in one of the driest subsections. We also found that years with more evenly distributed growing season precipitation had higher GPP. Warmer winter minimum air temperature enhanced GPP in approximately two-thirds of the subsections. In contrast, average growing season mean and maximum air temperatures showed a negative relationship with annual GPP. When forced by downscaled future climate projections, changes in future rangeland productivity at the ecoregion subsection scale were more remarkable than at the state level; this suggests rangeland productivity responses to climate change will be highly variable at the local level. Further, we found large uncertainty in precipitation projections among the four climate models used in this study. Specifically, drier models predicted a larger degree of reduction in GPP, especially in drier subsections. Our machine learning-based analysis highlights key regional differences in GPP vulnerability to climate and provides insights into the intertwining and potentially counteracting effects of seasonal temperature and precipitation regimes. This work demonstrates the potential of using remote sensing to enhance field-based rangeland monitoring and, combined with machine learning, to inform adaptive management and conservation within the context of weather extremes and climate change.
Fate tracing reveals differences between Reelin+ HSCs and Desmin+ HSCs in activation, migration, and proliferation activities
Authors: Chen Ning , Liu Shenghui , Qin Dan , Guan Dian , Chen Yaqing , Hou Chenjiao , Zheng Songyun , Wang Liqiang , Chen Xiangmei , Zhang Lisheng
Published: February 2022

The activation of hepatic stellate cells (HSCs) which comprise distinct clusters, is the main cause of liver fibrogenesis in response to different etiologies of chronic liver injuries. In this study, we constructed a novel ReelinCreERT2 transgenic mouse in which cells expressing Reelin were fully marked and demonstrated that about 50% HSCs were labeled. These ReelinCreERT2-labeled HSCs displayed distinct characteristics in migration, activation and proliferation compared to Desmin+ HSCs (total HSCs) in cholestatic (bile duct ligation; BDL) or hepatotoxic (carbon tetrachloride; CCl4) liver injuries. In BDL-induced fibrotic livers, Desmin+ HSCs were activated with increased proliferation and accumulation activities around the portal triad, but mGFP+ HSCs did not show proliferation or accumulation activity around the portal triad, and only a small part was activated. In CCl4-induced fibrotic livers, most of Desmin+ and mGFP+ HSCs were activated along with proliferation and accumulation potential around the central vein, however fewer mGFP+ HSCs were activated compared to Desmin+ HSCs. Moreover, in the regression of CCl4-induced fibrosis, mGFP+ HSCs were apoptosed whereas Desmin+ HSCs recovered to normal state. Besides, we didn’t find evidence that mGFP+ HSCs transdifferentiated into hepatocytes or cholangiocytes through mesenchymal-epithelial transition (MET).
Deuterium metabolic imaging and hyperpolarized13C-MRI of the normal human brain at clinical field strength reveals differential cerebral metabolism
Authors: Kaggie Joshua D , Khan Alixander S , Matys Tomasz , Schulte Rolf F , Locke Matthew J , Grimmer Ashley , Frary Amy , Graves Martin J , McLean Mary A , Gallagher Ferdia A
Published: February 2022

Deuterium metabolic imaging (DMI) and hyperpolarized13C-pyruvate MRI (13C-HPMRI) are two emerging methods for non-invasive and non-ionizing imaging of tissue metabolism. Imaging cerebral metabolism has potential applications for cancer, neurodegeneration, multiple sclerosis, traumatic brain injury, stroke, and inborn errors of metabolism. Here we directly compare these two non-invasive methods at 3 T for the first time in humans, and how they simultaneously probe both glycolytic and oxidative metabolism. DMI was undertaken 1-2 hours after oral administration of [6,6’-2H2]glucose, and13C-MRI was performed immediately following intravenous injection of hyperpolarized [1-13C]pyruvate in ten and nine normal volunteers within each arm. DMI provided maps of deuterium-labelled water, glucose, lactate, and glutamate/glutamine.13C-HPMRI generated maps of hyperpolarized carbon-13 labelled pyruvate, lactate, and bicarbonate. There was clear spectral separation in the spectroscopic imaging data with both DMI and13C-HPMRI at 3 T. The ratio of13C-lactate/13C-bicarbonate (mean = 3.7 ± 1.2) acquired with13C-HPMRI was higher than the equivalent2H-lactate/2H-Glx ratio (mean = 0.18 ± 0.09) acquired with DMI. These differences can be explained by the route of administering each probe, the timing of imaging after ingestion or injection, as well as the biological differences in cerebral uptake and cellular physiology between the two molecules. The results demonstrate these two metabolic imaging methods provide different yet complementary readouts of oxidative and glycolytic metabolism within a clinically feasible timescale. Furthermore, as DMI was undertaken at a clinical field strength within a ten-minute scan time, it demonstrates its potential as a routine clinical tool in the future.
Evaluating Fomite Risk of Brown Paper Bags Storing Personal Protective Equipment Exposed to SARS-CoV-2: A Quasi-Experimental Study
Authors: Unger Kyirsty , Dietz Leslie , Horve Patrick , Van Den Wymelenberg Kevin , Lin Amber , Kinney Erin , Kea Bory
Published: February 2022

Introduction

Literature is lacking on the safety of storing contaminated PPE in paper bags for reuse, potentially increasing exposure to frontline healthcare workers (HCW) and patients.

Objectives

To evaluate the effectiveness of paper bags as a barrier for fomite transmission of SARS-CoV-2 by storing limited reusable face masks, respirators, and face shields.

Methods

This quasi-experimental study evaluated the presence of SARS-CoV-2 on the interior and exterior surfaces of paper bags containing PPE that had aerosolized exposures in clinical and simulated settings. Between May and October 2020, 30 unique PPE items were collected from critical and intermediate care COVID-19 units at two urban hospitals. Exposed PPE, worn by either an infected patient or HCW during a SARS-CoV-2 aerosolizing event, were placed into an unused brown paper bag. Samples were tested at 30-minute and 12-hour intervals.

Results

A total of 177 swabs were processed from 30 PPE samples. We found a (12/177 total) 6.8% positivity rate among all samples across both collection sites. Highest positivity rates were associated with ventilator disconnection (1/6 samples, 16.7% positivity) and exposure to respiratory droplets from coughing (2/24 samples, 8.3% positivity), compared to exposure to high-flow nasal cannula (8/129 samples, 6.2% positivity) or tracheostomy surgery (1/18 samples, 5.6% positivity). Positivity rates differed between hospital units. Total positivity rates were similar between 30-minute (6.7%) and 12-hour (6.9%) sample testing time intervals. Control samples exposed to inactivated SARS-CoV-2 droplets had higher total viral counts than samples exposed to nebulized aerosols.

Conclusions

Data suggests paper bags are not a significant fomite risk for SARS-CoV-2 transmission. However, controls demonstrated a risk with droplet exposure. Data can inform guidelines for storing and re-using PPE in situations of limited supplies during future pandemics.
Clinical outcomes in hospitalized vaccine-breakthrough COVID-19 cases compared with contemporary unvaccinated hospitalized adults
Authors: Wolff Marcelo , Gilabert Margarita , Hernández Rodrigo
Published: February 2022

The inactivated SARS-CoV-2 vaccine (CoronaVac®) has been the principal vaccine used in Chile’s pre-booster immunization campaign. We compared major outcomes in 260 hospitalized vaccinated vs 507 unvaccinated adults with COVID-19 (mid-2021). The vaccinated group was much older, required less critical care, had lower hospital mortality (adjusted by age), and had shorter hospitalization than the unvaccinated. Benefits were most pronounced in those older than 59 years

Objective

To compare major outcomes in fully vaccinated and unvaccinated adult persons hospitalized for COVID-19 in a general private hospital in Santiago, Chile during mid2021.
History of SARS-CoV-2 infection, anti-spike IgG antibody kinetics and neutralization capacities following the second and third dose of BNT162b2 vaccine in nursing home residents
Authors: Jeulin H. , Labat C. , Duarte K. , Toupance S. , Nadin G. , Craus D. , Georgiopoulos I. , Gantois I. , Goehringer F. , Benetos A.
Published: February 2022

Importance

Duration of post-vaccination protection against COVID-19 in individuals is a critical issue, especially in nursing home (NH) residents, i.e. one of the most vulnerable populations.

Objective

To estimate the duration of the IgG(S) response to the mRNA BNT162b2 vaccine in NH residents with (COV-Yes) or without (COV-No) history of natural infection with SARS-CoV-2.

Design, setting and participants

IgG(S) quantification was carried out at 3 different time periods following administration of the Pfizer BioNtech vaccine: three then seven months after the 2nd dose and one month after the 3rd dose. 574 COV-Yes and COV-No NH residents were included in 2 cohorts: Main (n=115, mean age 84 years) or Confirmatory (n=459, mean age 88 years).

Exposure

All subjects received the BNT162b2 vaccine.

Main outcomes and measurements

IgG(S) antibodies and seroneutralization capacity.

Results

Neutralization capacity was strongly correlated with IgG(S) levels (R2:76%) without any difference between COV-Yes and COV-No groups for the same levels of IgG(S). COV-Yes, compared to the COV-No subjects showed 5-fold and 15-fold higher IgG(S) titers 3 and 7 months after the 2nd dose, but less than 2-fold higher IgG(S) after the 3rd dose, due to a more pronounced effect of the 3rd dose in the COV-No group. These results were similar in both cohorts. After the 2nd dose, duration of assumed robust protection (IgG(S) >264 BAU/ml) was 2-fold higher in the COV-Yes vs. COV-No group: 12.60 (10.69-14.44) vs 5.76 (3.91-8.64) months, and this advantage was mainly due to the higher IgG(S) titers after the 2nd dose and secondary to a slower decay over time. After the 3rd dose, duration (months) of robust protection was estimated at 11.87 (9.88-14.87) (COV-Yes) and 8.95 (6.85-11.04) (COV-No).

Conclusions and relevance

In old subjects living in NH, history of SARS-CoV-2 infection provides a clear advantage in the magnitude and duration of high IgG(S) titers following the 2nd dose. Importantly, the 3rd dose induces a much more pronounced IgG(S) response than the 2nd dose in COV-No subjects, the effect of which should be able to ensure in these subjects a prolonged protection against severe forms of COVID-19.
Can you hear me now? Clinical applications of audio recordings
Authors: Kumar Anish , Jaquenoud Theo , Becker Jacqueline Helcer , Cho Dayeon , Mindt Monica Rivera , Federman Alex , Pandey Gaurav
Published: February 2022

Audio and speech have several implicit characteristics that have the potential for the identification and quantification of clinical disorders. This PRISMA-guided review is designed to provide an overview of the landscape of automated clinical audio processing to build data-driven predictive models and infer phenotypes of a variety of neuropsychiatric, cardiac, respiratory and other disorders. We detail the important components of this processing workflow, specifically data acquisition and processing, algorithms used and their customization for clinical applications, commonly used tools and software, and benchmarking and evaluation methodologies. Finally, we discuss important open challenges for the field, and potential strategies for addressing them.
Trends in Racial and Ethnic Disparities in Barriers to Timely Medical Care Among US Adults, 1999 to 2018
Authors: Caraballo César , Ndumele Chima D. , Roy Brita , Lu Yuan , Riley Carley , Herrin Jeph , Krumholz Harlan M.
Published: February 2022

Background

Racial and ethnic disparities in delayed medical care due to reasons not related to cost of care remain understudied. We aimed to describe recent 20-year trends in such disparities.

Methods

The study used data from the National Health Interview Survey from 1999–2018 and included individuals ≥18 years of age. Respondents were categorized by their sex, income, and self-reported race and ethnicity. The main outcomes were trends in disparities in any of 5 specific barriers to timely medical care: inability to get through by phone, no appointment available soon enough, long waiting times, inconvenient doctor’s office/clinic hours, or lack of transportation.

Results

The study included 590,603 adults (mean age 46.0 [SE, 0.07] years; 51.9% female). Of these, 4.7% were Asian, 11.8% Black, 13.8% Latino/Hispanic, and 69.7% White. In 1999, the proportion reporting any of the barriers to timely medical care was 7.3% among Asian, 6.9% among Black, 7.9% among Latino/Hispanic, and 7.0% among White individuals (P >0.05 for each difference with White individuals). From 1999 to 2018, this proportion increased across all 4 race/ethnicity groups (P<0.001 for each), slightly increasing the disparities between groups. In 2018, compared with White individuals, the proportion reporting any barrier was 2.1 and 3.1 percentage points higher among Black and Latino/Hispanic individuals (P=0.03 and P=0.001, respectively). The racial/ethnic disparities increased mostly among males and were attenuated when stratified by income level.

Conclusions

From 1999 to 2018, barriers to timely medical care increased for all populations with increasing disparities between racial/ethnic groups.
Five years follow-up of patients with non-melanoma skin cancer treated with HeberFERON
Authors: Duncan-Roberts Y , Garcia-Vega Y , Collazo-Caballero S , Rodriguez-Garcia M , Zalazar-Sedano M , Rodríguez-Rojas JL , Tuero-Iglesias A , Valenzuela-Silva C , Raices-Cruz I , Castro-Basart N , Garcia-Iglesias E , Pereda-Lamela L , Hernández-Rodríguez R , Arteaga-Hernandez E , Muzio-Gonzalez V , Bello-Rivero I
Published: February 2022

Introduction

Non-melanoma skin cancer is the most common tumor. The combination of IFN-alpha 2b and IFN-gamma has been used as a new therapeutic opportunity to treat basal cell carcinomas and cutaneous squamous cell carcinomas. The aim of this report is to record prospectively the recurrence and new lesions rates in patients participating in phase II clinical trials.

Methods

Phase II clinical trials (double-blind randomized one center study, InCarbacel-III, in patients with basal cell carcinoma; and open, non-randomized multicenter study, CECIN, in patients with cutaneous squamous cell carcinomas), with the use of the combination of IFN-alpha 2b and IFN-gamma were conducted to evaluate the efficacy, safety and the 5-year duration of clinical responses. Both studies were approved by institutional ethic committees and all the patients given their written informed consent. The investigational treatment was administered, peri- or intralesionally, three times per week, during 3 weeks. Clinical (RECIST 1.0) responses were evaluated three months after the end of treatment.

Results

The combination of IFNs in InCarbacel-III study showed the best clinical response (complete response of 64.3%, overall response of 85.7%) with the highest doses (10.5 MIU); without patient’s recurrence at 5 years follow-up (3.5 MUI and 10.5 MUI groups). The frequency of new lesions decreased in the treated patients 8 times. In the CECIN study 14 patients achieved complete response and 4 partial responses (overall response rate 67%). Up to the 5-year follow-up none of the patients with complete response had recurrence or new lesion. In both studies the cosmetic results were excellent and the reported adverse events were mostly of mild intensity.

Conclusions

The use of the combination of IFN-alpha 2b and IFN-gamma showed efficacy in basal cell carcinoma and cutaneous squamous cell carcinoma promoting a long term response for at least 5 years and decreasing the rate of new lesions, safely and with excellent cosmetic effects.
Genetic immune response and antibody repertoire of heterologous ChAdOx1-BNT162b2 vaccination in a Korean cohort
Authors: Lee Hye Kyung , Go Jinyoung , Sung Heungsup , Kim Seong Who , Walter Mary , Knabl Ludwig , Furth Priscilla , Hennighausen Lothar , Huh Jin Won
Published: February 2022

Heterologous ChAdOx1-BNT162b2 vaccination induces a stronger immune response than two doses of BNT162b2 or ChAdOx1. Yet, the molecular transcriptome, the germline allelic variants of immunoglobulin loci and anti-Omicron antibody levels induced by the heterologous vaccination have not been formally investigated. Moreover, there is a paucity of COVID vaccine studies including diverse genetic populations. Here, we show a robust molecular immune transcriptome and antibody repertoire in 51 office workers from the Republic of Korea after a heterologous ChAdOx1-BNT162b2 vaccination or a homologous ChAdOx1-ChAdOx1 vaccination. Anti-spike-specific IgG antibody levels in the heterologous group increased from 14,000 U/ml to 142,000 AU/ml within eight days after the BNT162b2 vaccination. In contrast, antibody levels in the homologous group increased two-fold after the second ChAdOx1 dose. Antibody titers against the Omicron spike protein as compared to the ancestral strain were reduced to a lesser extent in the heterologous group. RNA-seq conducted on immune cells demonstrated a stronger activation of interferon-induced genetic programs in the heterologous cohort. An increase of specific IGHV clonal transcripts encoding neutralizing antibodies was preferentially detected in the heterologous cohort. Enrichment of B cell and CD4+ T cell responses were observed following both heterologous and homologous vaccination using scRNA-seq, but clonally expanded memory B cells were relatively stronger in the ChAdOx1-BNT162b2 cohort. In summary, a heterologous vaccination with ChAdOx1 followed by BNT162b2 provides an innate and adaptive immune response exceeding that seen in homologous ChAdOx1 vaccinations but equivalent to that seen in homologous BNT162b2 vaccination.
Altered branched-chain α-keto acid metabolism is a feature of NAFLD in individuals with severe obesity
Authors: Grenier-Larouche Thomas , Kwee Lydia Coulter , Deleye Yann , Leon-Mimila Paola , Walejko Jacquelyn M. , McGarrah Robert W. , Marceau Simon , Trahan Sylvain , Racine Christine , Carpentier André C , Lusis Aldons J. , Ilkayeva Olga , Vohl Marie-Claude , Huertas-Vazquez Adriana , Tchernof André , Shah Svati H. , Newgard Christopher B , White Phillip J
Published: February 2022

Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). We aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-ketoacids (BCKAs) and hepatic BCKDK expression are associated with the presence and severity of non-alcoholic fatty liver disease (NAFLD).Eighty metabolites (3 BCKA, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 bariatric surgery patients with severe obesity (BMI > 35 kg/m2) with scored liver biopsy samples. Metabolite principal component analysis (PCA) factors, BCKA, branched-chain amino acids (BCAA), and the BCKA:BCAA ratio were tested for associations with steatosis grade and presence of non-alcoholic steatohepatitis (NASH). Of all analytes tested, only the valine-derived BCKA, α-ketoisovalerate, and the BCKA:BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from two independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowers BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.
Deploying wearable sensors for pandemic mitigation
Authors: Duarte Nathan , Arora Rahul K. , Bennett Graham , Wang Meng , Snyder Michael P. , Cooperstock Jeremy R. , Wagner Caroline E.
Published: February 2022

Wearable sensors can continuously and passively detect potential respiratory infections, before or absent symptoms. However, the population-level impact of deploying these devices during pandemics is unclear. We built a compartmental model of Canada’s second COVID-19 wave and simulated wearable sensor deployment scenarios, systematically varying detection algorithm accuracy, uptake, and adherence. With current detection algorithms and 4% uptake, we found that deploying wearable sensors could have averted 9% of second wave SARS-CoV-2 infections, though 29% of this reduction is attributed to incorrectly quarantining uninfected device users. Improving detection specificity and offering confirmatory rapid tests each minimized incorrect quarantines and associated costs. With a sufficiently low false positive rate, increasing uptake and adherence became effective strategies for scaling averted infections. We concluded that wearable sensor deployment can meaningfully contribute to pandemic mitigation; in the case of COVID-19, technology improvements or supporting measures are required to reduce social and economic costs to acceptable levels.
Both general- and central- obesity are causally associated with polycystic ovarian syndrome: Findings of a Mendelian randomization study
Authors: De Silva Kushan , Demmer Ryan T. , Jönsson Daniel , Mousa Aya , Teede Helena , Forbes Andrew , Enticott Joanne
Published: February 2022

Introduction

Obesity is observed in a majority of women with polycystic ovarian syndrome (PCOS). Using body mass index (BMI) as a proxy, previous Mendelian randomization studies revealed general obesity potentially causes PCOS. Central obesity frequently demonstrates a stronger association with PCOS, although evidence on its causality is sparse.

Objectives

To investigate causal effects of both central- and general- obesity on the development of PCOS via two-sample Mendelian randomization (2SMR).

Methods

Summary GWAS data of female-only, large-sample cohorts of European ancestry were retrieved for anthropometric markers of central obesity (waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR)) and general obesity (BMI and its constituent variables – weight and height), from the IEU Open GWAS Project. As the outcome data, we acquired summary data from a large-sample GWAS (96391 samples; 219 cases and 96172 controls) from the FinnGen cohort. Four 2SMR methods were applied: inverse variance weighted (IVW); MR Egger (MRE); weighted median (WME); weighted mode (WMO). Single SNP-, leave-one-out-, heterogeneity-, horizontal pleiotropy- and outlier- analyses were conducted. Genetic architectures underlying causal associations were explored.

Results

All SNPs selected as instrumental variables demonstrated no weak instrument bias (F > 10). Three anthropometric exposures, namely, BMI (OR: 5.55 – 7.24, WC (OR: 6.79 – 24.56), and HC (OR: 6.78 – 24.56), significantly causally associated with PCOS as per IVW, WME, and WMO models. Single SNP- and leave-one-out- sensitivity analysis results were indicative of robust causal estimates. No significant heterogeneity, horizontal pleiotropy, and outliers were observed. We observed a considerable degree of overlap (7 SNPs; 17 genes) across significant causal findings as well as a number of SNPs and genes that were not shared between causal associations.

Conclusions

This study revealed that both and general- and central obesity potentially cause PCOS. Findings underscore the importance of addressing obesity and adiposity for the prevention and management of PCOS.
Choroid plexus volume predicts expansion of chronic lesions and brain atrophy
Authors: Klistorner Samuel , Barnett Michael H , Graham Stuart L , Wang Chenyu , Klistorner Alexander
Published: February 2022

Background and Objectives

The expansion of long-standing multiple sclerosis (MS) lesions and an enlargement of choroid plexus are linked to chronic inflammation and microglial activation. In the current study, we investigated the association between plexus volume and subsequent lesion expansion in patients with relapsing remitting MS.

Methods

Pre- and post-gadolinium 3D-T1, 3D FLAIR and diffusion tensor images were acquired from 49 patients with relapsing-remitting MS. Choroid plexus volume and lesion activity were analysed between baseline and 48 months.

Results

Plexus volume remained stable during follow-up period. There was a strong correlation between baseline plexus volume and subsequent rate of chronic lesion expansion (r=0.77, p<0.001), which was stronger in close proximity to CSF. Furthermore, baseline plexus volume was also associated with change of Mean Diffusivity (MD) inside expanding area (r=0.55, p<0.001). There was, however, no correlation between baseline plexus volume and volume of new lesions. A cut-off of 98 × 10−5 plexus/TIV ratio predicted future lesion expansion with a sensitivity of 85% and specificity of 76%. Plexus volume larger than a cut-off was associated with >8-fold increased risk of chronic lesion expansion. Furthermore, baseline plexus volume significantly correlated with change of MD in lesional core during the study period (r=0.67, p<0.001) and with central brain atrophy (r=0.57, p<0.001).

Conclusion

Our data demonstrate that baseline plexus volume predicts subsequent expansion of chronic periventricular MS lesions and associated tissue damage.
Novel methodology for localizing and studying the insect dorsal rim area morphology in 2D and 3D
Authors: Jie Vun Wen , Miettinen Arttu , Baird Emily
Published: February 2022

1.

Polarized light-based navigation in insects is facilitated by a specialised polarisation-sensitive part of the eye known as the dorsal rim area (DRA). Existing methods to study the anatomy of the DRA are in most cases destructive and very time consuming. Here, we present a novel method that allows for DRA localization using 3D volumetric images acquired through micro-computed tomography in combination with 2D photographs. We used the method on size polymorphic buff-tailed bumblebees,Bombus terrestris. We found that the size of the DRA can be easily acquired from photographs of the dorsal part of the eye. An allometric analysis of the size of the DRA in relation to body size inB. terrestrisshowed that the DRA region increases with body size but not at the same rate. Using our method, we localised the DRA in a 3D volume rendering of the eye using 2D photos localization of an individual’s DRA onto the volumetric image stack of the head allowed for individual-level descriptions of the ommatidial structures (lens, crystalline cones, rhabdoms) to be performed on three different eye regions (DRA, non-DRA, proximate to DRA). The only feature distinctly unique to the DRA ommatidia was the smaller dimension of crystalline cones in comparison to other regions. Using our novel methodology we provide the first individual-level description of DRA ommatidial features and a comparison of how the DRA area varies with body size in bumblebees.
A transcription factor and a phosphatase regulate temperature-dependent morphogenesis in a fungal plant pathogen
Authors: Francisco Carolina Sardinha , McDonald Bruce A. , Palma-Guerrero Javier
Published: February 2022

Naturally fluctuating temperatures provide a constant environmental stress that requires adaptation. Some fungal pathogens respond to heat stress by producing new morphotypes that maximize their overall fitness. The fungal wheat pathogen Z. tritici responds to heat stress by switching from its yeast-like blastospore form to hyphae or chlamydospores. The regulatory mechanisms underlying this switch are unknown. Here, we demonstrate that a differential heat stress response is ubiquitous in Z. tritici populations around the world. We used QTL mapping to identify a single locus associated with the temperature-dependent morphogenesis and we found two genes, the transcription factor ZtMsr1 and the protein phosphatase ZtYvh1, regulating this mechanism. We find that ZtMsr1 regulates repression of hyphal growth and induces chlamydospore formation whereas ZtYvh1 is required for hyphal growth. We next pinpointed that chlamydospore formation is a response to the intracellular osmotic stress generated by the heat stress. This intracellular stress stimulates the CWI and HOG MAPK pathways resulting in hyphal growth. If cell wall integrity is however compromised, ZtMsr1 represses the hyphal development program and might induce the chlamydospore-inducing genes as a stress-response survival strategy. Taken together, these results suggest a novel mechanism through which morphological transitions are orchestrated in Z. tritici – a mechanism possibly also present in other pleomorphic fungi.

IMPORTANCE

Temperature is an environmental signal constantly monitored by pleomorphic fungi. Our experiments showed that yeast-to-hyphal or yeast-to-chlamydospore transitions are ubiquitous heat stress responses in Z. tritici. QTL mapping allowed us to identify a transcription factor and a protein phosphatase contributing to temperature-dependent morphogenesis. We showed that intracellular osmolarity is the pivotal signal inducing these transitions. We propose a regulatory network controlling Z. tritici morphogenesis, which may have broad implications for temperature sensing of fungal pathogens.
Anatomical connectivity profile development constrains medial-lateral topography in the dorsal prefrontal cortex
Authors: Li Wen , Shi Weiyang , Wang Haiyan , Li Jin , Cui Yue , Li Kaixin , Cheng Luqi , Lu Yuheng , Ma Liang , Chu Congying , Song Ming , Yang Zhengyi , Banaschewski Tobias , Bokde Arun L.W. , Desrivières Sylvane , Flor Herta , Grigis Antoine , Garavan Hugh , Gowland Penny , Walter Henrik , Brühl Rüdiger , Martinot Jean-Luc , Martinot Marie-Laure Paillère , Artiges Eric , Nees Frauke , Orfanos Dimitri Papadopoulos , Lemaitre Herve , Paus Tomáš , Poustka Luise , Hohmann Sarah , Millenet Sabina , Fröhner Juliane H. , Robinson Lauren , Smolka Michael N. , Winterer Jeanne , Whelan Robert , Schumann Gunter , Fan Lingzhong , Jiang Tianzi ,   IMAGEN Consortium
Published: February 2022

The prefrontal cortex (PFC) is a highly variable, evolutionarily expanded brain region that is engaged in multiple cognitive processes. The subregions of the PFC mature relatively late compared with other brain regions, and the maturation times vary between these subregions. Among these, the dorsomedial and dorsolateral prefrontal cortex (dmPFC and dlPFC) share a parallel topographic pattern of functional connectivity, while participating in different types of complex behaviors. However, the developmental trajectories of the two areas remain obscure. In this study, we uncovered differences in the developmental trends of the dmPFC and dlPFC. These differences were mainly caused by structural and functional changes in the medial area of the superior frontal gyrus (SFG). The developmentally different arealization patterns were verified using multiple parcellation approaches with multimodal data, including structural magnetic resonance imaging (sMRI), diffusion MRI (dMRI), resting state functional MRI (rfMRI), and a publicly available transcriptomic dataset. Human brain gene expression data was also used to perform downstream analyses, which could inform us about the potential biological mechanisms underlying the developmentally different arealizations. Furthermore, behavioral analyses hinted at the effects of regionalization on ontogeny. In brief, this study revealed a tendency toward a medial-lateral prefrontal division and can provide a fuller understanding of the potential underlying genetic underpinnings as well as of the potential effects on developmental behavior.
Functional substitutability of native herbivores by livestock for soil carbon depends on microbial decomposers
Authors: Roy Shamik , Naidu Dilip GT , Bagchi Sumanta
Published: February 2022

Grazing by large mammalian herbivores impacts climate as it can favor the size and stability of a large carbon (C) pool in soil. As native herbivores in the world’s grasslands, steppes, and savannas are progressively being displaced by livestock, it is important to ask whether livestock can emulate the functional roles of their native counterparts. While livestock and native herbivores can have remarkable similarity in their traits, they can differ greatly in their impacts on vegetation composition which can affect soil-C. It is uncertain how their similarities and differences impact soil-C via their influence on microbial decomposers. We test competing alternative hypotheses with a replicated, long-term, landscape-level, grazing-exclusion experiment to ask whether livestock in the Trans-Himalayan ecosystem of northern India can match decadal-scale (2005-2016) soil-C stocks under native herbivores. We evaluate multiple lines of evidence from 17 variables that influence soil-C (quantity and quality of C-input from plants, microbial biomass and metabolism, microbial community composition, veterinary antibiotics in soil), and asses their inter-relationships. Livestock and native herbivores differed in their effects on several soil microbial processes. Microbial carbon use efficiency (CUE) was 19% lower in soils under livestock. Compared to native herbivores, areas used by livestock contained 1.5 kg C m−2less soil-C. Structural equation models showed that alongside effects arising from plants, livestock alter soil microbial communities which is detrimental for CUE, and ultimately also for soil-C. Supporting evidence pointed toward a link between veterinary antibiotics used on livestock, microbial communities, and soil-C. Overcoming the challenges of sequestrating antibiotics to minimize their potential impacts on climate, alongside microbial rewilding under livestock, may reconcile the conflicting demands from food-security and ecosystem services. Conservation of native herbivores and better management of livestock is crucial for soil-C stewardship to envision and achieve natural climate solutions.
Pitfalls of machine learning models for protein-protein interactions
Authors: Lannelongue Loïc , Inouye Michael
Published: February 2022

Protein-protein interactions (PPIs) are essential to understanding biological pathways as well as their roles in development and disease. Computational tools, based on classic machine learning, have been successful at predicting PPIsin silico, but the lack of consistent and reliable frameworks for this task has led to network models that are difficult to compare and discrepancies between algorithms that remain unexplained. To better understand the underlying inference mechanisms that underpin these models, we designed an open-source framework for benchmarking that accounts for a range of biological and statistical pitfalls while facilitating reproducibility. We use it to shed light on the impact of network topology and how different algorithms deal with highly connected proteins. By studying functional genomics-based and sequence-based models on human PPIs, we show their complementarity as the former performs best on lone proteins while the latter specialises in interactions involving hubs. We also show that algorithm design has little impact on performance with functional genomic data. We replicate our results between both human andS. cerevisiaedata and demonstrate that models using functional genomics are better suited to PPI prediction across species. With rapidly increasing amounts of sequence and functional genomics data, our study provides a principled foundation for future construction, comparison and application of PPI networks.
A paternal bias in germline mutation is widespread in amniotes and can arise independently of cell divisions
Authors: de Manuel Marc , Wu Felix L. , Przeworski Molly
Published: February 2022

In humans and other mammals, germline mutations are more likely to arise in fathers than in mothers. Although this sex bias has long been attributed to DNA replication errors in spermatogenesis, recent evidence from humans points to the importance of mutagenic processes that do not depend on cell division, calling into question our understanding of this basic phenomenon. Here, we infer the ratio of paternal-to-maternal mutations, α, in 42 species of amniotes, from putatively neutral substitution rates of sex chromosomes and autosomes. Despite marked differences in gametogenesis, physiologies and environments across species, fathers consistently contribute more mutations than mothers in all the species examined, including mammals, birds and reptiles. In mammals, α is as high as 4 and correlates with generation times; in birds and snakes, α appears more stable around 2. These observations are consistent with a simple model, in which mutations accrue at equal rates in both sexes during early development and at a higher rate in the male germline after sexual differentiation, with a conserved paternal-to-maternal ratio across species. Thus, α may reflect the relative contributions of two or more developmental phases to total germline mutations, and is expected to depend on generation time even if mutations do not track cell divisions.
Boosting with Omicron-matched or historical mRNA vaccines increases neutralizing antibody responses and protection against B.1.1.529 infection in mice
Authors: Ying Baoling , Scheaffer Suzanne M. , Whitener Bradley , Liang Chieh-Yu , Dmytrenko Oleksandr , Mackin Samantha , Wu Kai , Lee Diana , Avena Laura E. , Chong Zhenlu , Case James Brett , Ma LingZhi , Kim Thu , Sein Caralyn , Woods Angela , Berrueta Daniela Montes , Carfi Andrea , Elbashir Sayda M. , Edwards Darin K. , Thackray Larissa B. , Diamond Michael S.
Published: February 2022

The B.1.1.529 Omicron variant jeopardizes vaccines designed with early pandemic spike antigens. Here, we evaluated in mice the protective activity of the Moderna mRNA-1273 vaccine against B.1.1.529 before or after boosting with preclinical mRNA-1273 or mRNA-1273.529, an Omicron-matched vaccine. Whereas two doses of mRNA-1273 vaccine induced high levels of serum neutralizing antibodies against historical WA1/2020 strains, levels were lower against B.1.1.529 and associated with infection and inflammation in the lung. A primary vaccination series with mRNA-1273.529 potently neutralized B.1.1.529 but showed limited inhibition of historical or other SARS-CoV-2 variants. However, boosting with mRNA-1273 or mRNA-1273.529 vaccines increased serum neutralizing titers and protection against B.1.1.529 infection. Nonetheless, the levels of inhibitory antibodies were higher, and viral burden and cytokines in the lung were slightly lower in mice given the Omicron-matched mRNA booster. Thus, in mice, boosting with mRNA-1273 or mRNA-1273.529 enhances protection against B.1.1.529 infection with limited differences in efficacy measured.
Spontaneous and ART-induced large offspring syndrome: similarities and differences in DNA methylome
Authors: Li Yahan , Lopes Jordana Sena , Fuster Pilar Coy , Rivera Rocío Melissa
Published: February 2022

Large/abnormal offspring syndrome (LOS/AOS) is a congenital overgrowth syndrome reported in ruminants produced by assisted reproduction (ART-LOS) which exhibit global disruption of the epigenome and transcriptome. LOS/AOS shares phenotypes and epigenotypes with the human congenital overgrowth condition Beckwith-Wiedemann syndrome. We have reported that LOS occurs spontaneously (SLOS), however, to date, no study has been conducted to determine if SLOS has the same methylome epimutations as ART-LOS. In this study, we performed whole genome bisulfite sequencing to examine global DNA methylation in SLOS and ART-LOS tissues. We observed unique patterns of global distribution of differentially methylated regions (DMRs) over different genomic contexts, such as promoters, CpG islands and surrounding regions, and repetitive sequences from different treatment groups. In addition, we identified hundreds of LOS-vulnerable DMRs across different cattle breeds when analyzing four idependent LOS experiments together. Specifically, there are 25 highly vulnerable DMRs that could potentially serve as molecular markers for the diagnosis of LOS, including at the promoters of DMRT2 and TBX18, at the imprinted gene bodies of IGF2R, PRDM8, and BLCAP/NNAT, and at multiple CpG islands. We also observed tissue-specific DNA methylation patterns between muscle and blood, and conservation of ART-induced DNA methylation changes between muscle and blood. We conclude that as in ART-LOS, alterations of the epigenome are involved in the etiology of SLOS. In addition, SLOS and ART-LOS share some similarities in methylome epimutations.
The evolution of novel biotic interactions at ecological margins in response to climate change involves alleles from across the geographical range of the UK Brown Argus butterfly
Authors: de Jong Maaike , van Rensburg Alexandra Jansen , Whiteford Samuel , Yung Carl J. , Beaumont Mark , Jiggins Chris , Bridle Jon
Published: February 2022

Understanding the rate and extent to which populations can adapt to novel environments at their ecological margins is fundamental to predicting the persistence of biological communities during ongoing and rapid global change. Recent range expansion in response to climate change in the UK butterfly Aricia agestis is associated with the evolution of novel interactions with a larval food plant, and the loss of its ability to use its ancestral larval host species. Using ddRAD analysis of 61210 variable SNPs from 261 females from throughout the UK range of this species, we identify genomic regions at multiple chromosomes that are associated with these evolutionary responses, and their association with demographic history and ecological variation. Gene flow appears widespread throughout the range, despite the apparently fragmented nature of the habitats used by this species. Patterns of haplotype variation between selected and neutral genomic regions suggest that evolution associated with climate adaptation is polygenic, resulting from the independent spread of existing alleles throughout the established range of this species, rather than the colonisation of pre-adapted genotypes from coastal populations. These data suggest that rapid responses to climate change do not depend on the availability of pre-adapted genotypes. Instead, the evolution of novel forms of biotic interaction in Aricia agestis has occurred during range expansion, through the assembly of novel genotypes from alleles from multiple localities.