bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of the burnout among medical residents before and during the pandemic
Authors: Küçükali Hüseyin , Türkoğlu Sezanur Nazlı , Hasanli Shams , Dayanir Çok Fatma Nur , Culpan Hazal Cansu , Hayran Osman
Published: May 2022

Objective

This study aims to compare the level of burnout syndrome in medical residents before and during the COVID-19 pandemic and identify potential risk factors.

Methods

This cross-sectional study was conducted on medical residents from three different university hospitals in Turkey in March 2021, one year after the pandemic hit Turkey. Burnout is measured by the Maslach Burnout Inventory which assesses three dimensions of it: emotional exhaustion, depersonalization, and personal accomplishment. Collected data were combined and compared with data from a previous study held in the same hospitals in December 2019, three months before the pandemic.

Results

412 medical residents from three universities participated. The mean age was 27.8±2.4 and half of them were female. Compared to pre-pandemic levels, no significant differences in emotional exhaustion (pre:19.0±7.6 post:18.8±7.8), depersonalization (pre:7.3±4.3 post:7.2±4.4), and personal accomplishment (pre:20.8±5.1 post:21.1±5) scores were observed one year after the pandemic. Adjusting for confounders, multiple linear regression models indicated that those who are female, are in a surgical speciality, have vulnerable cohabitants, and have more night shifts face higher emotional exhaustion. Depersonalisation is higher among those who spent more years in residency, have more night shifts, or have COVID-19 outpatient duty. Females and those who have vulnerable cohabitants have lower levels of Personal Achievement.

Conclusion

This study does not support the hypothesis that pandemic increases the burnout levels. Yet it identifies a couple of pandemic-related factors that are associated with burnout and confirms the association of several previously known factors.
Tixagevimab/Cilgavimab for Prevention of COVID-19 during the Omicron Surge: Retrospective Analysis of National VA Electronic Data
Authors: Young-Xu Yinong , Epstein Lauren , Marconi Vincent C , Davey Victoria , Zwain Gabrielle , Smith Jeremy , Korves Caroline , Cunningham Fran , Bonomo Robert , Ginde Adit A
Published: May 2022

Background

Little is known regarding the effectiveness of tixagevimab/cilgavimab in preventing SARS-CoV-2 infection in this population, particularly after the emergence of the Omicron variant.

Objective

To determine the effectiveness of tixagevimab/cilgavimab for prevention of SARS-CoV-2 infection and severe disease among immunocompromised patients.

Design

Retrospective cohort study with propensity matching and difference-in-difference analyses.

Setting

U.S. Department of Veterans Affairs (VA) healthcare system.

Participants

Veterans age ≥18 years as of January 1, 2022, receiving VA healthcare. We compared a cohort of 1,848 patients treated with at least one dose of intramuscular tixagevimab/cilgavimab to matched controls selected from 251,756 patients who were on immunocompromised or otherwise at high risk for COVID-19. Patients were followed through April 30, 2022, or until death, whichever occurred earlier.

Main Outcomes

Composite of SARS-CoV-2 infection, COVID-19-related hospitalization, and all-cause mortality. We used cox proportional hazards modelling to estimate the hazard ratios (HR) and 95% CI for the association between receipt of tixagevimab/cilgavimab and outcomes.

Results

Most (69%) tixagevimab/cilgavimab recipients were ≥65 years old, 92% were identified as immunocompromised in electronic data, and 73% had ≥3 mRNA vaccine doses or two doses of Ad26.COV2. Compared to propensity-matched controls, tixagevimab/cilgavimab-treated patients had a lower incidence of the composite COVID-19 outcome (17/1733 [1.0%] vs 206/6354 [3.2%]; HR 0.31; 95%CI, 0.18-0.53), and individually SARS-CoV-2 infection (HR 0.34; 95%CI, 0.13-0.87), COVID-19 hospitalization (HR 0.13; 95%CI, 0.02-0.99), and all-cause mortality (HR 0.36; 95%CI, 0.18-0.73).

Limitations

Confounding by indication and immortal time bias.

Conclusions

Using national real-world data from predominantly vaccinated, immunocompromised Veterans, administration of tixagevimab/cilgavimab was associated with lower rates of SARS-CoV-2 infection, COVID-19 hospitalization, and all-cause mortality during the Omicron surge.
The impact of antenatal balanced plate nutrition education for pregnant women on birth weight: a cluster randomised controlled trial in rural Bangladesh
Authors: Chowdhury Morseda , Raynes-Greenow Camille , Kelly Patrick J. , Alam Ashraful , Afsana Kaosar , Billah Sk Masum , Dibley Michael J.
Published: May 2022

Low birth weight (LBW) is a global public health problem with the highest prevalence in South Asia. It is strongly associated with maternal undernutrition. In South Asia, intra-household food distribution is inequitable, with lower dietary adequacy in women. Evidence that nutrition education improves diet during pregnancy and reduces LBW is weak. We assessed the impact of nutrition education for pregnant women on birth weight in rural Bangladesh. We conducted a parallel, two-arm, cluster-randomised controlled trial, with 36 clusters allocated equally to intervention (n=445) or standard care (n=448). From their first trimester until delivery, intervention participants received education about eating balanced meals to meet daily dietary requirements with diverse food groups. The primary outcome of mean birth weight was 127.5 g higher in the intervention compared to control women, and the intervention reduced the risk of LBW by 57%. Post hoc analyses showed a significantly higher birth weight and a greater reduction in LBW amongst adolescent mothers. The mean number of food groups consumed was significantly higher in the intervention from the third month of pregnancy than in the control. A community-based balanced plate nutrition education intervention effectively increased mean birth weight and reduced LBW, and improved dietary diversity in rural Bangladeshi women.
Keep Calm and Carry On: Projected Case Burden and Duration of the 2022 Monkeypox Outbreak in Non-endemic Countries
Authors: Bisanzio Donal , Reithinger Richard
Published: May 2022

We report the estimated size and duration of a monkeypox outbreak in a simulated population of 50 million people with socio-economic -and demographic characteristics typical of a high-income, European country. Seeding an individual-based model with 3, 30, 300 primary cases, we estimate that—without public health emergency interventions—this could lead to a median of 18, 118, and 402 of additional secondary cases, respectively; similarly, the median duration of these outbreaks for these three scenarios would be 23, 37, and 37 weeks, respectively. We also estimate that contact tracing and isolation of symptomatic cases, or contact tracing, isolation of symptomatic cases and ring vaccination of the primary case contacts would substantially reduce the median size of outbreaks by 66.1—88.6% and median duration by 60.8–75.6%.
Pooled Estimate of Risky Sexual Behavior among college and university students in sub-Saharan Africa: A Meta-Analysis
Authors: Lungu A. , Chella C. , Zambwe M. , Chipimo P.J.
Published: May 2022

Objective

To determine the pooled estimate of risky sexual behaviour among university students in sub Saharan Africa.

Methods

A meta analytic study conducted to identify predictors of risky sexual behavior among university students. Databases from PubMed, African Journals Online, Science Direct, Google Scholar were used to identify appropriate studies. The combined effect estimates for each outcome were computed in Meta XL using random effects.

Results

The estimated pooled prevalence of sexual activity among university students was 51.0% (95% CI: 43.0% - 59.0%). Pooled prevalence for multiple sexual partners was 36.0% (95% CI: 30.0% - 42.0%), inconsistent condom use, 53.0% (95% CI: 46% - 61.0%) and for at least one risky sexual behavior, 65.0% (48.0% - 81.0%). Males were 3.36 times [OR: 3.05; 95% CI: 2.59 - 4.37] more likely to have multiple sexual partners than females. This review also indicated that males were 2.99 times [OR: 2.99; 95% CI: 1.40 - 6.40] more likely to engage in at least one risky sexual behavior than females.

Conclusion

Inconsistent condom use and multiple sexual partners were the most rampant risky sexual behaviors in Universities in Sub-Saharan Africa. Sustained risk communication on Sexual and Reproductive Health and youth friendly programs are highly recommended.
Huntingtin gene CAG repeat size in patients with Lynch syndrome
Authors: Skarping Karin Dalene , Petersén Åsa , Gebre-Medhin Samuel
Published: May 2022

Patients with Lynch syndrome (LS) are prone to cancer due to heterozygous germline pathogenic variants in genes encoding DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. LS cancer cells exhibit deficient DNA mismatch repair and microsatellite instability due somatic inactivation of the second copy of the affected gene. To study microsatellite characteristics in non-neoplastic cells in LS we determined CAG repeat size in the huntingtin gene (HTT) microsatellite in lymphocyte DNA from LS patients with germline pathogenic variants in MLH1 (n = 11), MSH2 (n = 9), MSH6 (n = 7) and non-LS controls (n=19). Mean repeat size in LS was 19,55 CAG (MLH1), 19,39 CAG (MSH2), 18.07 CAG (MSH6), respectively compared to 18,42 CAG in controls. Standard deviation for CAG repeat size in LS was 4,183 CAG (MLH1), 5,089 CAG (MSH2), 3,075 CAG (MSH6), respectively, compared to 3,342 CAG in controls. Peak CAG repeat size in LS was 32 CAG (MLH1), 32 CAG (MSH2), 24 CAG (MSH6), respectively compared to 27 CAG in controls. Collectively, our data indicate that HTT CAG repeat size tends to be larger and more variable in individuals with LS caused by pathogenic variants in MLH1 and MSH2.
In Vivo and Phantom Repeatability of Diffusion-Weighted MRI Sequences on 1.5T MRI-Linear Accelerator (MR-Linac) and MR Simulator Devices for Head and Neck Cancers: Results from a Prospective R-IDEAL Stage 2a Evaluation of Tumor and Normal Tissue Apparent Diffusion Coefficients as Quantitative Imaging Biomarkers
Authors: McDonald Brigid A. , Salzillo Travis , Mulder Samuel , Ahmed Sara , Dresner Alex , Preston Kathryn , He Renjie , Christodouleas John , Mohamed Abdallah S. R. , Philippens Marielle , van Houdt Petra , Thorwarth Daniela , Wang Jihong , Dave Amita Shukla , Boss Michael , Fuller Clifton D.
Published: May 2022

Introduction

Diffusion-weighted imaging (DWI) on MRI-linear accelerator (MR-linac) systems can potentially be used for monitoring treatment response and adaptive radiotherapy in head and neck cancers (HNC) but requires extensive validation. We perform technical validation to compare six total DWI sequences on an MR-linac and MR simulator (MR sim) in patients, volunteers, and phantoms.

Methods

Ten human papillomavirus-positive oropharyngeal cancer patients and ten volunteers underwent DWI on a 1.5T MR-linac with three DWI sequences: echo planar imaging (EPI), split acquisition of fast spin echo signals (SPLICE), and turbo spin echo (TSE). Volunteers were also imaged on a 1.5T MR sim with three sequences: EPI, BLADE, and RESOLVE. Participants underwent two scan sessions per device and two repeats of each sequence per session. Repeatability and reproducibility within-subject coefficient of variation (wCV) of mean ADC were calculated for tumors and lymph nodes (patients) and parotid glands (volunteers). Differences in measured ADC values between sequences were quantified using Bland-Altman analysis. ADC bias, repeatability/reproducibility metrics, and SNR were quantified using a phantom.

Results

In vivo repeatability/reproducibility wCV of mean ADC for parotids were 5.41%/6.72%, 3.83%/8.80%, 5.66%/10.03%, 3.44%/5.70%, 5.04%/5.66%, 4.23%/7.36% for EPIMR-linac, SPLICE, TSE, EPIMR sim, BLADE, RESOLVE. Repeatability/reproducibility wCV for EPIMR-linac, SPLICE, TSE were 9.64%/10.28%, 7.84%/8.96%, 7.60%/11.68% for tumors and 7.80%/9.95%, 7.23%/8.48%, 10.82%/10.44% for nodes. Bland-Altman analysis revealed significant differences between all sequence pairs except BLADE-EPIMR-linac and RESOLVE-SPLICE. All sequences except TSE had phantom ADC biases within ±0.1×10−3 mm2/s for most vials. MR-linac sequences had inconsistent ADC values between different vials with the same known ADC value, indicating spatial inhomogeneities. SNR of b=0 images was 87.3, 180.5, 161.3, 171.0, 171.9, 130.2 for EPIMR-linac, SPLICE, TSE, EPIMR sim, BLADE, RESOLVE.

Conclusion

MR-linac DWI sequences demonstrate near-comparable performance to MR sim sequences and warrant further clinical validation for treatment response assessment in HNC.
Membrane-Localized Mutations Predict the Efficacy of Cancer Immunotherapy
Authors: Briquez Priscilla S. , Hauert Sylvie , Goldberger Zoe , Kurtanich Trevin , Alpar Aaron T. , Repond Grégoire , Wang Yue , Gomes Suzana , Siddarth Prabha , Swartz Melody A. , Hubbell Jeffrey A.
Published: May 2022

Due to their genetic instability, tumor cells bear mutations that can effectively be recognized by the immune system. In the clinic, immune checkpoint immunotherapy (ICI) can re-activate immune reactions against mutated proteins, known as neoantigens, leading to remarkable remission in cancer patients. Nevertheless, only a minority of patients are responsive to ICI, and approaches for prediction of responsiveness remain elusive yet are needed to improve the success of cancer treatments. While the tumor mutational burden (TMB) correlates positively with responsiveness and survival of patients undergoing ICI therapy, the influence of the subcellular localizations of the mutated proteins within the tumor cell has not been elucidated. Here, we hypothesized that the immune reactions are modulated by the localization of the mutated proteins and, therefore, that some subcellular localizations could favor responsiveness to ICI. We show in both a mouse melanoma model and human clinical datasets of 1722 ICI-treated patients that high membrane-localized tumor mutational burden (mTMB), particularly at the plasma membrane, correlate with responsiveness to ICI therapy and improved overall survival across multiple cancer types. We further highlight that mutations in the genes encoding for the membrane proteins NOTCH3, RNF43, NTRK3 and NOTCH1, among others, may serve as potent biomarkers to predict extended survival upon ICI in certain cancer types. We anticipate that our results will improve the predictability of cancer patient response to ICI and therefore may have important implications to establish future clinical guidelines to direct the choice of treatment toward ICI.
Weakly supervised learning for poorly differentiated adenocarcinoma classification in gastric endoscopic submucosal dissection whole slide images
Authors: Tsuneki Masayuki , Kanavati Fahdi
Published: May 2022

The endoscopic submucosal dissection (ESD) is the preferred technique for treating early gastric cancers including poorly differentiated adenocarcinoma without ulcerative findings. The histopathological classification of poorly differentiated adenocarcinoma including signet ring cell carcinoma is of pivotal importance for determining further optimum cancer treatment(s) and clinical outcomes. Because conventional diagnosis by pathologists using microscopes is time-consuming and limited in terms of human resources, it is very important to develop computer-aided techniques that can rapidly and accurately inspect large numbers of histopathological specimen whole-slide images (WSIs). Computational pathology applications which can assist pathologists in detecting and classifying gastric poorly differentiated adenocarcinoma from ESD WSIs would be of great benefit for routine histopathological diagnostic workflow. In this study, we trained the deep learning model to classify poorly differentiated adenocarcinoma in ESD WSIs by transfer and weakly supervised learning approaches. We evaluated the model on ESD, endoscopic biopsy, and surgical specimen WSI test sets, achieving and ROC-AUC up to 0.975 in gastric ESD test sets for poorly differentiated adenocarcinoma. The deep learning model developed in this study demonstrates the high promising potential of deployment in a routine practical gastric ESD histopathological diagnostic workflow as a computer-aided diagnosis system.
Hypoglycemic Events in Diabetic Patients under Non-insulin Regimens During Ramadan: A Frequentist Network Meta-Analysis
Authors: Kacimi Salah Eddine O. , Sukaina Mahnoor , Elgenidy Anas , Farahat Ramadan Abdelmoez , Cheema Huzaifa A. , Benmelouka Amira Y. , Awad Dina M. , Belaouni Hadj Ahmed , Abdelli Moustafa K.E , Tidjane Anisse , Mesli Nabil Smain , Shah Jaffer , Setti Mounir Ould , Afifi Ahmed M. , Ghozy Sherief ,   the Ramadan Diabetes Research Group (RDRG) Collaborators
Published: May 2022

Background

Diabetic Muslims who choose to fast during Ramadan encounter major risks such as hyperglycemia, hypoglycemia, diabetic ketoacidosis, and dehydration. Recently, newer antidiabetic agents have been found to be less likely to cause hypoglycemic emergencies. This meta-analysis aimed to present collective and conclusive results from major randomized controlled trials (RCTs) to determine the risk of hypoglycemia among patients taking oral antidiabetics during Ramadan.

Methods

We searched PubMed, Web of Science, and Google Scholar for RCTs. We performed a frequentist network meta-analysis using the “netmeta” package of R software version 4.1.1 to investigate the risk of developing hypoglycemia after taking oral antidiabetic drugs during Ramadan.

Results

Nine RCTs with a total of 3464 patients were included in the final analysis. In the comparison of all antidiabetic drug classes with sulfonylureas, SGLT-2 inhibitors were associated with the lowest hypoglycemic risk (RR, 0.18; 95% CI, 0.04-0.78; P-score, 0.909), followed by GLP-1 agonists (RR, 0.31; 95% CI, 0.17-0.56; P-score, 0.799), and DDP-4 inhibitors (RR, 0.57; 95% CI, 0.43-0.75; P-score, 0.483). When comparing individual drugs, dapagliflozin was associated with the lowest hypoglycemic risk (RR, 0.18; 95% CI, 0.04-0.78; P-score, 0.874), followed by lixisenatide (RR, 0.25; 95% CI, 0.09-0.71; P-score, 0.813), liraglutide (RR, 0.34; 95% CI, 0.17-0.69; P-score, 0.715), and sitagliptin (RR. 0.51; 95% CI, 0.37-0.71; P-score, 0.515).

Conclusion

SGLT-2 inhibitors are associated with the least documented hypoglycemic events and adverse outcomes compared with other oral hypoglycemic drugs. These findings could have considerable public health and clinical implications when extrapolated to the global Muslim population with a similar clinical background.

Abstract Figure
Melt Electrowriting of Scaffolds with a Porosity Gradient to Mimic the Matrix Structure of the Human Trabecular Meshwork
Authors: Włodarczyk-Biegun Małgorzata K. , Villiou Maria , Koch Marcus , Muth Christina , Wang Peixi , Ott Jenna , Campo Aranzazu del
Published: May 2022

The permeability of the Human Trabecular Meshwork (HTM) regulates eye pressure via a porosity gradient across its thickness modulated by stacked layers of matrix fibrils and cells. Changes in HTM porosity are associated with increases in intraocular pressure and the progress of diseases like glaucoma. Engineered HTMs could help to understand the structure-function relation in natural tissues, and lead to new regenerative solutions. Here, melt electrowriting (MEW) is explored as a biofabrication technique to produce fibrillar, porous scaffolds that mimic the multilayer, gradient structure of native HTM. Poly(caprolactone) constructs with a height of 125-500 μm and fiber diameters of 10-12 μm are printed. Scaffolds with a tensile modulus between 5.6 and 13 MPa, and a static compression modulus in the range of 6-360 kPa are obtained by varying the scaffolds design, i.e., density and orientation of the fibers and number of stacked layers. Primary HTM cells attach to the scaffolds, proliferate, and form a confluent layer within 8-14 days, depending on the scaffold design. High cell viability and cell morphology close to that in the native tissue are observed. The present work demonstrates the utility of MEW to reconstruct complex morphological features of natural tissues.
Female reproductive dormancy in Drosophila melanogaster is regulated by DH31-producing neurons projecting into the corpus allatum
Authors: Kurogi Yoshitomo , Imura Eisuke , Mizuno Yosuke , Hoshino Ryo , Nouzova Marcela , Matsuyama Shigeru , Mizoguchi Akira , Kondo Shu , Tanimoto Hiromu , Noriega Fernando G. , Niwa Ryusuke
Published: May 2022

Female reproductive dormancy in insects is a process that drastically suppresses oogenesis to conserve energy under adverse environments. In many insects, including the fruit fly, Drosophila melanogaster, reproductive dormancy is induced under low-temperature and short-day conditions by the downregulation of juvenile hormone (JH) biosynthesis by the corpus allatum (CA). Previous studies have suggested that brain neurons that project directly to the CA are important for the regulation of reproductive dormancy. However, the role of CA-projecting neurons in JH-mediated reproductive dormancy has not yet been confirmed by molecular genetic studies. In this study, we report that, in adult D. melanogaster, the neuropeptide diuretic hormone 31 (DH31) is produced by brain neurons that project into the CA. DH31-producing-CA-projecting neurons are connected downstream with a subset of circadian clock neurons, such as s-LNvs, which are known to be involved in reproductive dormancy regulation. The CA expresses the gene encoding the DH31 receptor, which is required for DH31-triggered elevation of intracellular cAMP in the CA. Knocking down Dh31 in these CA-projecting neurons or DH31 receptor in the CA leads to a failure in the decrease of the JH titer, normally observed under dormancy-inducing conditions, leading to abnormal yolk accumulation in the ovaries. Our findings provide the first molecular genetic evidence demonstrating that CA-projecting peptidergic neurons play an essential role in regulating reproductive dormancy by suppressing JH biosynthesis.

Significance Statement

Dormancy is an adaptive physiological response to environmental changes that are unsuitable for survival. Adult females of many insect species undergo reproductive dormancy in which oogenesis is drastically arrested; it is induced by a decrease in juvenile hormone (JH) titers. However, we are yet to fully understand the molecular mechanisms underlying the control of JH biosynthesis under dormancy-inducing conditions. In this study using the fruit fly, we demonstrated that brain neurons projecting directly to the JH-producing organ, corpus allatum, play an essential role in regulating reproductive dormancy via the neuropeptide DH31. As the morphologically-similar neurons have previously been suggested to be involved in reproductive dormancy regulation, this study provides a fundamental molecular and neuronal basis for reproductive dormancy in insects.
Rescue of the first Alphanucleorhabdovirus entirely from cloned complementary DNA: an efficient vector for systemic expression of foreign genes in maize and insect vectors
Authors: Kanakala Surapathrudu , Xavier Cesar Augusto Diniz , Martin Kathleen M. , Tran Hong Hanh , Redinbaugh Margaret G. , Whitfield Anna E.
Published: May 2022

Recent reverse genetics technologies have enabled genetic manipulation of plant negative-strand RNA virus (NSR) genomes. Here, we report construction of an infectious clone for the maize-infectingAlphanucleorhabdovirus maydis, the first efficient NSR vector for maize. The full-length infectious clone was established using agrobacterium-mediated delivery of full-length maize mosaic virus (MMV) antigenomic RNA and the viral core proteins (nucleoprotein N, phosphoprotein P, and RNA-directed RNA polymerase L) required for viral transcription and replication intoNicotiana benthamiana. Insertion of intron 2ST-LS1into the viral L gene increased stability of the infectious clone inEscherichia coliandAgrobacterium tumefaciens. To monitor virus infectionin vivo, a GFP gene was inserted in between the N and P gene junctions to generate recombinant MMV-GFP. cDNA clones of MMV-WT and MMV-GFP replicated in single cells of agroinfiltratedN. benthamiana. Uniform systemic infection and high GFP expression were observed in maize inoculated with extracts of the infiltratedN. benthamianaleaves. Insect vectors supported virus infection when inoculated via feeding on infected maize or microinjection. Both MMV-WT and MMV-GFP were efficiently transmitted to maize by planthopper vectors. The GFP reporter gene was stable in the virus genome and expression remained high over three cycles of transmission in plants and insects. The MMV infectious clone will be a versatile tool for expression of proteins of interest in maize and cross-kingdom studies of virus replication in plant and insect hosts.
IDPConformerGenerator: A Flexible Software Suite for Sampling Conformational Space of Disordered Protein States
Authors: Teixeira João M.C. , Liu Zi Hao , Namini Ashley , Li Jie , Vernon Robert M. , Krzeminski Mickaël , Shamandy Alaa A. , Zhang Oufan , Haghighatlari Mojtaba , Yu Lei , Head-Gordon Teresa , Forman-Kay Julie D.
Published: May 2022

The power of structural information for informing biological mechanism is clear for stable folded macromolecules, but similar structure-function insight is more difficult to obtain for highly dynamic systems such as intrinsically disordered proteins (IDPs) which must be described as structural ensembles. Here we present IDPConformerGenerator, a flexible, modular open source software platform for generating large and diverse ensembles of disordered protein states that builds conformers that obey geometric, steric and other physical restraints on the input sequence. IDPConformerGenerator samples backbone phi (φ), psi (ψ), and omega (ω) torsion angles of relevant sequence fragments from loops and secondary structure elements extracted from folded protein structures in the RCSB Protein Data Bank, and builds side chains from robust Monte Carlo algorithms using expanded rotamer libraries. IDPConformerGenerator has many user-defined options enabling variable fractional sampling of secondary structures, supports Bayesian models for assessing agreement of IDP ensembles for consistency with experimental data, and introduces a machine learning approach to transform between internal to Cartesian coordinates with reduced error. IDPConformerGenerator will facilitate the characterization of disordered proteins to ultimately provide structural insights into these states that have key biological functions.
Inferring gene expression models from snapshot RNA data
Authors: Moyer Camille , Kilic Zeliha , Schweiger Max , Shepherd Douglas , Pressé Steve
Published: May 2022

1

Gene networks, key toward understanding a cell’s regulatory response, underlie experimental observations of single cell transcriptional dynamics. While information on the gene network is encoded in RNA expression data, existing computational frameworks cannot currently infer gene networks from such data. Rather, gene networks—composed of gene states, their connectivities, and associated parameters—are currently deduced by pre-specifying gene state numbers and connectivity prior to learning associated rate parameters. As such, the correctness of gene networks cannot be independently assessed which can lead to strong biases. By contrast, here we propose a method to learn full distributions over gene states, state connectivities, and associated rate parameters, simultaneously and self-consistently from single molecule level RNA counts. Notably, our method propagates noise originating from fluctuating RNA counts over networks warranted by the data by treating networks themselves as random variables. We achieve this by operating within a Bayesian nonparametric paradigm. We demonstrate our method on thelacZpathway inEscherichia colicells, theSTL1pathway inSaccharomyces cerevisiaeyeast cells, and verify its robustness on synthetic data.
SNV-FEAST: microbial source tracking with single nucleotide variants
Authors: Briscoe Leah , Halperin Eran , Garud Nandita R.
Published: May 2022

Elucidating the sources of a microbiome can provide insight into the ecological dynamics responsible for the formation of these communities. “Source tracking” approaches to date leverage species abundance information, however, single nucleotide variants (SNVs) may be more informative because of their high specificity to certain sources. To overcome the computational burden of utilizing all SNVs for a given sample, we introduce a novel method to identify signature SNVs for source tracking. We show that signature SNVs used as input into a previously designed source tracking algorithm, FEAST, can more accurately estimate contributions than species and provide novel insights, demonstrated in three case studies.
Not just the sum of its parts: geographic variation and non-additive effects of pyrazines in the chemical defence of an aposematic moth
Authors: Ottocento Cristina , Winters Anne E. , Rojas Bibiana , Mappes Johanna , Burdfield-Steel Emily
Published: May 2022

Chemical defences often vary within and between populations both in quantity and quality, which is puzzling if prey survival is dependent on the strength of the defence. We investigated the within-and between-population variability in chemical defence of the wood tiger moth (Arctia plantaginis). The major components of its defences, SBMP (2-sec-butyl-3-methoxypyrazine) and IBMP (2-isobutyl-3-methoxypyrazine) are volatiles that deter bird attacks. We expected the variation to reflect populations’ predation pressures and early-life conditions. To understand the role of the methoxypyrazines, we experimentally manipulated synthetic SBMP and IBMP and tested the birds’ reactions. We found a considerable variation in methoxypyrazine amounts and composition, both from wild-caught and laboratory-raised male moths. In agreement with the “cost of defence” hypothesis, the moths raised in the laboratory had a higher amount of pyrazines. We found that SBMP is more effective at higher concentrations and that IBMP is more effective only in combination with SBMP and at lower concentrations. Our results fit findings from the wild: the amount of SBMP was higher in the populations with higher predation pressure. Altogether, this suggests that, regarding pyrazine concentration, more is not always better, and highlights the importance of testing the efficacy of chemical defence and its components with relevant predators, rather than relying only on results from chemical analyses.
Multi-dimensional structure of C. elegans thermal learning
Authors: Roman Ahmed , Palanski Konstantine , Nemenman Ilya , Ryu William S
Published: May 2022

Quantitative models of associative learning that explain behavior of real animals with high precision have turned out very difficult to construct. We do this in the context of the dynamics of the thermal preference of C. elegans. For this, we quantify C. elegans thermotaxis in response to various conditioning parameters, genetic perturbations, and operant behavior using a fast, high-throughput microfluidic droplet assay. We then model this data comprehensively, within a new, biologically interpretable, multi-modal framework. We discover that the dynamics of thermal preference are described by two independent contributions and require a model with at least four dynamical variables. One pathway positively associates the experienced temperature independently of food and the other negatively associates to the temperature when food is absent.
Trade-offs in telemetry tag programming for deep-diving cetaceans: data longevity, resolution, and continuity
Authors: Cioffi William R , Quick Nicola J , Swaim Zachary T , Foley Heather J , Waples Danielle M , Webster Daniel L , Baird Robin W , Southall Brandon L , Nowacek Douglas P , Read Andrew J
Published: May 2022

Background

Animal-borne telemetry instruments (tags) have greatly advanced our understanding of species that are challenging to observe. Recently, non-recoverable instruments attached to cetaceans have increased in use, but these devices have limitations in data transmission bandwidth. We analyze trade-offs in the longevity, resolution, and continuity of data records from non-recoverable satellite-linked tags on deep-diving Ziphius cavirostris in the context of a behavioral response study of acute noise exposure. We present a strategic data collection programming scheme that balances resolution and continuity against longevity to address specific questions about the behavioral responses of animals to noise exposure in experimental contexts. We compare accuracy and precision between two programming regimes on a commercially available satellite-linked tag: (1) dive behavior summary defined by conductivity thresholds and (2) depth time-series at various temporal resolutions.

Results

We found that time-series data could faithfully replicate the more precisely defined dives from a dive summary record data stream to an acceptable error range for our application. We determined a 5-minute time-series data stream collected for 14 days balanced resolution with longevity, achieving complete or nearly complete diving records in 6 out of 8 deployments. We increased our data reception rate several fold by employing a boat based data capture system. Finally, a tag deployed in a group concurrently with a high resolution depth recorder showed high depth concordance.

Conclusions

We present the conceptual framework and iterative process for matching telemetry tag programming to research questions that we used and which should be applicable to a wide range of studies. Although designing new hardware for our specific questions was not feasible at the time, we were able to optimize the sampling regime of a commercially available instrument to meet the needs of our research questions and proposed analyses. Nevertheless, for other study species or designs, the complicated intersection between animal behavior and bandwidth of telemetry systems can often create a severe mismatch among research questions, data collection, and analysis tools. More flexible programming and purpose built instruments will increase the efficacy of these studies and increase the scientific yield relative to the inherently higher risk of invasive studies.
Parallel adaptation to lower altitudes is associated with enhanced plasticity in Heliosperma pusillum (Caryophyllaceae)
Authors: Szukala Aglaia , Bertel Clara , Frajman Božo , Schönswetter Peter , Paun Ovidiu
Published: May 2022

High levels of phenotypic plasticity are thought to be inherently costly in stable or extreme environments, but enhanced plasticity may evolve as a response to novel environments and foster adaptation. Heliosperma pusillum forms pubescent montane and glabrous alpine ecotypes that diverged recurrently and polytopically (parallel evolution). The specific montane and alpine localities are characterized by distinct temperature conditions, available moisture and light. To disentangle the relative contribution of constitutive versus plastic gene expression to altitudinal divergence, we analyze the transcriptomic profiles of two parallely evolved ecotype pairs, grown in reciprocal transplantations at native altitudinal sites. In both ecotype pairs, only a minor proportion of genes appear constitutively differentially expressed between the ecotypes regardless of the growing environment. Both derived, montane populations bear comparatively higher plasticity of gene expression than the alpine populations that can be considered in this system as ‘ancestor-proxies’. Genes that change expression plastically and constitutively underlie similar ecologically relevant pathways, related to response to drought and trichome formation. Other relevant processes, such as photosynthesis, seem to rely mainly on plastic changes. The enhanced plasticity consistently observed in the montane ecotype likely evolved as a response to the newly colonized niche. Our findings confirm that directional changes in gene expression plasticity can shape initial stages of phenotypic evolution, likely fostering adaptation to novel environments.

Significance Statement

Understanding the importance of phenotypic plasticity for fast adaptation to stress is very timely for breeding and current environmental challenges. Our study of an alpine plant in the carnation family evidences an increased level of expression plasticity in early stages of adaptation to hotter and drier habitats.
PHYSIOLOGICAL CHARACTERISTICS OF BACTERIAL DROPLETS INDICATE A CATASTROPHIC CONSEQUENCE WITH AN INCREASE IN IMPACT VELOCITY
Authors: Hariharan Vishnu , Chowdhury Atish Roy , Rao S Srinivas , Chakravortty Dipshikha , Basu Saptarshi
Published: May 2022

Droplet impacts on various surfaces play a profound role in different bio-physiological processes and engineering applications. The current study opens a new realm that investigates the plausible effect of impact velocities on bacteria-laden droplets against a solid surface. We unveiled the alarming consequences of Salmonella Typhimurium (STM) laden drop, carrying out the in vitro and intracellular viability of STM to the impact Weber numbers ranging from 100-750. The specified Weber number range mimics the velocity range occurring during the respiratory processes, especially the airborne dispersion of drops during cough. A thick ring of bacterial deposition was observed in all cases irrespective of impacting velocity and the nutrient content of the bacterial medium. The mechanical properties of the bacterial deposit examined using Atomic Force Microscopy reveals the deformation of bacterial morphology, cushioning effect and adhesion energy to determine the cell-cell interactions. The impact velocity induces the shear stress onto the cell walls of STM, thereby deteriorating the in vitro viability. However, we found that even with compromised in vitro viability, Salmonella retrieved from deposited patterns impacted at higher velocity revealed an increased expression of phoP (the response regulator of the PhopQ two-component system) and uninterrupted intracellular proliferation in macrophages. The inability of STM ΔphoP growth in nutrient-rich dried droplets to the subjected impact velocities signifies the predominant role of phoP in maintaining the virulence of Salmonella during desiccation stress. Our findings open a promising avenue for understating the effect of bacteria-laden drop impact and its role in disease spread.

Abstract Figure
Joint Instability Causes Catabolic Enzyme Production in Chondrocytes prior to Synovial Cells in Novel Non-Invasive ACL ruptured Mouse Model
Authors: Takahata Kei , Arakawa Kohei , Enomoto Saaya , Usami Yuna , Nogi Koyo , Saitou Riku , Ozone Kaichi , Takahashi Haruna , Yoneno Moe , Kokubun Takanori
Published: May 2022

Objective

The ACL-deficient model helps to clarify the mechanism of knee OA; however, the conventional ACL injury model could have included concurrent onset factors such as direct compression stress to cartilage and subchondral bone. In this study, we established a novel Non-invasive ACL-Ruptured mouse model without concurrent injuries and elucidated the relationship between OA progression and joint instability.

Design

We induced the ACL-Rupture non-invasively in twelve-week-old C57BL/6 male mice and evaluated histological, macroscopical, and morphological analysis at 0 days. Next, we created the ACL-R, controlled abnormal tibial translation (CATT), and Sham groups. Then, the joint stability and OA pathophysiology were analyzed at 2, 4, and 8 weeks.

Results

No intra-articular injuries, except for ACL rupture, were observed in the ACL-R model. ACL-R mice increased anterior tibial displacement compared to the Sham group (p<0.001, 95% CI [-1.509 to -0.966]) and CATT group (p<0.001, 95% CI [-0.841 to -0.298]) at 8 weeks. All mice in the ACL-R group caused cartilage degeneration. The degree of cartilage degeneration in the ACL-R group was higher than in the CATT group (p=0.006) at 8 weeks. The MMP-3-positive cell rate of chondrocytes increased in the ACL-R group than CATT group from 4 weeks (p=0.043; 95% CI [-28.32 to -0.364]) while that of synovial cells increased at 8 weeks (p=0.031; 95% CI [-23.398 to -1.021]).

Conclusion

We successfully established a Non-invasive ACL-R model without intra-articular damage. Our model revealed that chondrocytes might react to abnormal mechanical stress prior to synovial cells while the knee OA onset.
Single-cell perspectives on the function and development of deep-sea mussel bacteriocytes
Authors: Chen Hao , Li Mengna , Wang Minxiao , Zhong Zhaoshan , Lian Chao , Zhou Li , Zhang Huan , Wang Hao , Cao Lei , Li Chaolun
Published: May 2022

The authors have withdrawn their manuscript because the authors need to re-organize the data and writing, meanwhile more experimental evidence from more RNA-seq replications, immunofluorescence assay andin vivoknock-down assays will be added to support the viewpoints. In this preprint, only one individual of decolonized mussel was employed for transcriptome sequencing while combined data from single cell transcriptomics with in situ hybridization is not enough convincing to draw some of the conclusion. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
An autoactive NB-LRR gene causes Rht13 dwarfism in wheat
Authors: Borrill Philippa , Mago Rohit , Xu Tianyuan , Ford Brett , Williams Simon J , Derkx Adinda , Bovill William D , Hyles Jessica , Bhatt Dhara , Xia Xiaodi , MacMillan Colleen , White Rosemary , Buss Wolfram , Molnár István , Walkowiak Sean , Olsen Odd-Arne , Doležel Jaroslav , Pozniak Curtis J , Spielmeyer Wolfgang
Published: May 2022

Semidwarfing genes have greatly increased wheat yields globally, yet the widely used gibberellin (GA) insensitive genes Rht-B1b and Rht-D1b have disadvantages for seedling emergence. Use of the GA sensitive semidwarfing gene Rht13 avoids this pleiotropic effect. Here we show that Rht13 encodes a nucleotide-binding site/leucine-rich repeat (NB-LRR) gene. A point mutation in the semidwarf Rht-B13b allele autoactivates the NB-LRR gene and causes a height reduction comparable to Rht-B1b and Rht-D1b in diverse genetic backgrounds. The autoactive Rht-B13b allele leads to transcriptional upregulation of pathogenesis-related genes including class III peroxidases associated with cell wall remodelling. Rht13 represents a new class of reduced height (Rht) gene, unlike other Rht genes which encode components of the GA signalling or metabolic pathways. This discovery opens new avenues to use autoactive NB-LRR genes as semidwarfing genes in a range of crop species, and to apply Rht13 in wheat breeding programmes using a perfect genetic marker.
A Diabetic Mice Model For Studying Skin Wound Healing
Authors: Poblete Jara Carlos , Nogueira Guilherme , Morari Joseane , Paulino do Prado Thaís , de Medeiros Bezerra Renan , Bombassaro Bruna , Velloso Lício A. , Velander William , de Araújo Eliana Pereira
Published: May 2022

Advances in wound treatment depend on the availability of suitable animal models. All animal models try to reflect human wound healing problems. For acute wounds, it is easier to obtain adequate animal models, however, for chronic wounds such as those found in individuals with diabetic foot ulcer, approximations of the clinical picture become a challenge. Nowadays, the key points of wound healing processes are better understood, and therefore, therapeutic strategies can be developed to manipulate wound repair. Research efforts involves the development of therapies to aid in the treatment of impaired wound healing and, to improving normal wound healing to drive a process close to regenerative. To achieve a better animal model that is more appropriate for studying wound healing, six-week- old male C57BL/6 mice were separated into groups fed a Chow and High-Fat Diet for 0.5, 3, and 6 months, when part of the animals were induced to diabetes by streptozotocin. Then, mice were submitted to metabolic, molecular, and morphological analyses. We show that this model results in a severe metabolic phenotype with insulin resistance, reduced insulin expression, and glucose intolerance associated with obesity and, more importantly, skin changes. Furthermore, the skin phenotype, both structurally and transcriptionally, overlapped with conditions found in elderly patients with DM that reproduce the phenotype of most patients who develop diabetic foot ulcers.
scMinerva: an Unsupervised Graph Learning Framework with Label-efficient Fine-tuning for Single-cell Multi-omics Integrated Analysis
Authors: Yu Tingyang , Zong Yongshuo , Wang Yixuan , Wang Xuesong , Li Yu
Published: May 2022

Single-cell multi-omics is a rapidly growing field in biomedicine, where multiple biological contents, such as the epigenome, genome, and transcriptome, can be measured simultaneously. Despite its potential, the integrated analysis and prediction of cellular states based on this complex multi-omics data pose significant challenges due to data sparsity, high noise, and computational overhead. To address these challenges, we developedscMinerva, an unsupervised framework for single-cell multi-omics integrated analysis. The learned embeddings from the multi-omics data enable accurate integrated classification of cell types and stages. Specifically, we construct a heterogeneous graph from multiple omics and propose a novel biased random walk algorithmomics2vec, which can learn the heterogeneous biological graph in a way that balances both local and global network structures. scMinerva successfully outperforms existing unsupervised methods on various simulated and real-world datasets when fine-tuned by very few labels. Additionally, scMinerva demonstrates strong label efficiency, is robust to fluctuation in data quality, allows one omics to compensate for weakness in others and could effectively classify cells with different annotation granularities. Furthermore, we showcase scMinerva’s ability to accurately provide prospective biomarkers and predict cell differentiation trends for COVID-19-infected cells, through the joint analysis of multi-omics data.
Dityrosine cross-links are present in Alzheimer’s disease-derived tau oligomers and paired helical filaments (PHF) which promotes the stability of the PHF-core tau (297-391) in vitro
Authors: Maina Mahmoud B. , Al-Hilaly Youssra K. , Oakley Sebastian , Burra Gunashekar , Khanon Tahmida , Biasetti Luca , Mengham Kurtis , Marshall Karen , Rickard Janet E. , Harrington Charles R. , Wischik Claude M. , Serpell Louise C.
Published: May 2022

A characteristic hallmark of Alzheimer’s Disease (AD) is the pathological aggregation and deposition of tau into paired helical filaments (PHF) in neurofibrillary tangles (NFTs). Oxidative stress is an early event during AD pathogenesis and is associated with tau-mediated AD pathology. Oxidative environments can result in the formation of covalent dityrosine crosslinks that can increase protein stability and insolubility. Dityrosine cross-linking has been shown to occur in vivo in Aβ plaques and α-synuclein aggregates in Lewy bodies, and this modification may increase the insolubility of these aggregates and their resistance to degradation. Using the PHF-core tau fragment (residues 297 – 391) as a model, we have previously demonstrated that dityrosine formation traps tau assemblies to reduce further elongation. However, it is unknown whether dityrosine crosslinks are found in tau deposits in vivo in AD and its relevance to disease mechanism is unclear. Here, using transmission electron microscope (TEM) double immunogold-labelling, we reveal that neurofibrillary NFTs in AD are heavily decorated with dityrosine crosslinks alongside tau. Single immunogold-labelling TEM and fluorescence spectroscopy revealed the presence of dityrosine on AD brain-derived tau oligomers and fibrils. Using the tau (297-391) PHF-core fragment as a model, we further showed that prefibrillar tau species are more amenable to dityrosine crosslinking than tau fibrils. Dityrosine formation results in heat and SDS stability of oxidised prefibrillar and fibrillar tau assemblies. This finding has implications for understanding the mechanism governing the insolubility and toxicity of tau assemblies in vivo.