bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of the Risk Assessment and Management Programme for hypertension (RAMP-HT) in reducing complications and service utilization after 5 years: A population-based matched cohort study
Authors: Yu Esther YT , Wan Eric YF , Mak Ivy L , Chao David VK , Ko Welchie WK , Leung Maria , Li Yim Chu , Liang Jun , Wan Luk , Wong Michelle MY , Kwok Ruby LP , Chan Anca KC , Fong Daniel YT , Lam Cindy LK
Published: September 2022

Background

The Risk Assessment and Management Programme for Hypertension (RAMP-HT) is a multi-component team-based intervention implemented in public primary care clinics across Hong Kong since 2011. After 12 months, significantly greater proportion of RAMP-HT participants achieved target blood pressure (Odd Ratio (OR) 1.18, P<0.001) and low-density lipoprotein-Cholesterol levels (OR 1.13, P<0.001) compared to usual care patients. This study evaluated the effectiveness of RAMP-HT for reducing hypertension-related complications and health service utilization among patients with hypertension relative to usual care after 5 years.

Methods and Findings

Design

Population-based prospective matched cohort study

Setting

All 73 public primary care clinics in Hong Kong

Participants

212,707 adults with uncomplicated hypertension managed in public primary care clinics in Hong Kong between 2011 and 2013 were included. 108,045 RAMP-HT participants were matched to 104,662 patients receiving usual care using propensity score fine stratification weightings.

Main outcome measures

Hypertension-related complications (cardiovascular diseases (CVD), end-stage renal disease (ESRD)), all-cause mortality, public health service utilization (overnight hospitalization, attendances at accident and emergency department (AED), specialist outpatient clinic (SOPC) and general outpatient clinic (GOPC).

Results

After a median follow-up of 5.4 years, RAMP-HT participants had 8.0%, 1.6% and 10.0% lower absolute risks for CVD events, ESRD and all-cause mortality, respectively, compared to patients receiving usual care. After adjusting for all baseline covariates, the RAMP-HT group was associated with a 38% (Hazard Ratio (HR) 0.62, (95% CI 0.61 to 0.64)), 46% (HR 0.54, (95% CI 0.50 to 0.59)), and 48% (HR 0.52, (95% CI 0.50 to 0.54)) lower risk of CVD, ESRD, and all-cause mortality respectively, compared to the usual care group. The number-needed-to-treat was 16 to prevent one CVD event, 106 for ESRD and 17 for all-cause mortality. RAMP-HT participants also had significantly lower incidences for overnight hospitalization, AED, and SOPC attendances (Incidence Rate Ratio (IRR) 0.60, 0.70 and 0.87, respectively) but more GOPC attendances (IRR 1.06) compared to usual care patients.

Conclusions

RAMP-HT was associated with significant and clinically important reductions in all-cause mortality and hypertension-related complications for patients with hypertension in the naturalistic primary care setting after 5 years.

Trial registration

NCT02219958
The epidemiology of long COVID in US adults two years after the start of the US SARS-CoV-2 pandemic
Authors: Robertson McKaylee M , Qasmieh Saba A , Kulkarni Sarah G , Teasdale Chloe A , Jones Heidi , McNairy Margaret , Borrell Luisa N. , Nash Denis
Published: September 2022

Objectives

To characterize prevalence and impact of long COVID.

Methods

We conducted a population-representative survey, June 30-July 2, 2022, of a random sample of 3,042 United States adults. Using questions developed by the United Kingdom’s Office of National Statistics, we estimated the prevalence by sociodemographics, adjusting for gender and age.

Results

An estimated 7.3% (95% CI: 6.1-8.5%) of all respondents reported long COVID, approximately 18,533,864 adults. One-quarter (25.3% [18.2-32.4%]) of respondents with long COVID reported their day-to-day activities were impacted ‘a lot’ and 28.9% had SARS-CoV-2 infection >12 months ago. The prevalence of long COVID was higher among respondents who were female (aPR: 1.84 [1.40-2.42]), had comorbidities (aPR: 1.55 [1.19-2.00]) or were not (versus were) boosted (aPR: 1.67 [1.19-2.34]) or not vaccinated (versus boosted) (aPR: 1.41 (1.05-1.91)).

Conclusions

We observed a high burden of long COVID and substantial variability in prevalence of SARS-CoV-2. Population-based surveys are an important surveillance tool and supplement to ongoing efforts to monitor long COVID.
The intergenerational effects of parental physical activity on offspring brain and neurocognition in humans: a scoping review
Authors: Valkenborghs Sarah R. , Dent Paige C. , Stillman Chelsea M.
Published: September 2022

Animal models suggest physical activity (PA) has intergenerational effects on brain health and neurocognition. This scoping review compiles the human literature in this area, identifies knowledge gaps, and makes recommendations for future research.

We systematically searched for experimental or observational studies conducted in humans, published in English, and reporting parental PA exposure (preconception or prenatal) and subsequent offspring brain and neurocognition. Two reviewers independently screened studies according to predetermined inclusion criteria.

Fourteen articles were included (four experimental and 10 observational). All studies reported maternal characteristics, whereas only one (7%) study reported paternal characteristics (but not paternal PA). Prenatal maternal PA exposure was examined in 10 (71%) studies, while preconceptionandprenatal PA exposure was examined in four (29%) studies. Maternal PA exposure was positively related to offspring brain and neurocognitive development in most studies.

Little is known about the intergenerational effects of parental PA on offspring brain and neurocognition in humans, particularly paternal preconception PA. More experimental studies with longer offspring follow-up and more objective and/or mechanistic assessments are required.

HIGHLIGHTS

Animal models suggest physical activity has intergenerational neurobiological effects

All observational human studies report a positive relationship between maternal physical activity and offspring brain and neurocognition

Most experimental human studies report no effects of maternal physical activity on offspring brain and neurocognition
Expanding the repertoire of human tandem repeat RNA-binding proteins
Authors: Ormazábal Agustín , Carletti Matías Sebastián , Saldaño Tadeo Enrique , Gonzalez-Buitron Martín , Marchetti Julia , Palopoli Nicolas , Bateman Alex
Published: September 2022

Protein regions consisting of arrays of tandem repeats are known to bind other molecular partners, including nucleic acid molecules. Although the interactions between repeat proteins and DNA are already widely explored, studies characterising tandem repeat RNA-binding proteins are lacking. We performed a large-scale analysis of human proteins devoted to expanding the knowledge about tandem repeat proteins experimentally reported as RNA-binding molecules. This work is timely because of the release of a full set of accurate structural models for the human proteome amenable to repeat detection using structural methods. We identified 219 tandem repeat proteins that bind RNA molecules and characterised the overlap between repeat regions and RNA-binding regions as a first step towards assessing their functional relationship. Our results showed that the combination of sequence and structural methods finds more tandem repeat proteins than either method alone. We observed differences in the characteristics of regions predicted as repetitive by sequence-based or structure-based computational methods in terms of their sequence composition, their functions and their protein domains.
Fast bioluminescent nucleic acid detection using one-pot isothermal amplification and dCas9-based split luciferase complementation
Authors: van der Veer Harmen J. , van Aalen Eva A. , Michielsen Claire M. S. , Hanckmann Eva T. L. , Deckers Jeroen , van Borren Marcel M. G. J. , Flipse Jacky , Loonen Anne J. M. , Schoeber Joost P. H. , Merkx Maarten
Published: September 2022

Nucleic acid detection methods based on isothermal amplification techniques show great potential for point-of-care diagnostic applications. However, most current methods rely on fluorescent or lateral flow assay readout, requiring external excitation or post-amplification reaction transfer. Here, we developed a bioluminescent nucleic acid sensor (LUNAS) platform in which target dsDNA is sequence-specifically detected by a pair of dCas9-based probes mediating split NanoLuc luciferase complementation. Whereas LUNAS itself features a detection limit of ∼1 pM for dsDNA targets, the LUNAS platform is easily integrated with recombinase polymerase amplification (RPA), providing attomolar sensitivity in a single-pot assay. We designed a one-pot RT-RPA-LUNAS assay for detecting SARS-CoV-2 RNA without the need for RNA isolation and demonstrated the diagnostic performance for COVID-19 patient nasopharyngeal swab samples using a digital camera to record the ratiometric signal. Detection of SARS-CoV-2 from samples with viral RNA loads of ∼200 cp/μL was achieved within ∼20 minutes, showing that RPA-LUNAS is attractive for point-of-care diagnostic applications.
grandR: a comprehensive package for nucleotide conversion sequencing data analysis
Authors: Rummel Teresa , Sakellaridi Lygeri , Erhard Florian
Published: September 2022

Metabolic labeling of RNA is a powerful technique for studying the temporal dynamics of gene expression. Nucleotide conversion approaches greatly facilitate the generation of data but introduce challenges for their analysis. We here present grandR, a comprehensive package for quality control, differential gene expression analysis, kinetic modeling, and visualization of such data. We compare several existing methods for inference of RNA synthesis rates and half-lives using progressive labeling time courses. We demonstrate the need for recalibration of effective labeling times and introduce a Bayesian approach to study the temporal dynamics of RNA using snapshot experiments.
Haplotype resolved DNA methylome of African cassava genome
Authors: Zhong Zhenhui , Feng Suhua , Mansfeld Ben N. , Ke Yunqing , Qi Weihong , Lim Yi-Wen , Gruissem Wilhelm , Bart Rebecca S. , Jacobsen Steven E.
Published: September 2022

Cytosine DNA methylation is involved in biological processes such as transposable element (TE) silencing, imprinting, and X chromosome inactivation. Plant methylation is mediated by MET1 (mammalian DNMT1), DRM2 (mammalian DNMT3), and two plant-specific DNA methyltransferases, CMT2 and CMT3 (Law and Jacobsen, 2010). De novo DNA methylation in plants is established by DRM2 via the plant specific RNA-directed DNA methylation (RdDM) pathway that depends on two DNA-dependent RNA polymerases, Pol IV and Pol V (Gallego-Bartolome et al., 2019; Law and Jacobsen, 2010; Stroud et al., 2013). The DNA methylome of cassava has been previously documented based on its haploid collapsed genome (Wang et al., 2015). Since the cassava genome is highly heterozygous, DNA methylome analysis of the haplotype-collapsed genome misses many features of the methylome. With the development of long read sequencing and chromosomal conformation capture techniques, haplotype resolved genomes are available for highly heterozygous genomes (Mansfeld et al., 2021; Qi et al., 2022; Zhou et al., 2020), which provides high-quality reference genomes facilitating studies of haplotype resolved DNA methylomes.
Modulation effect of non-invasive transcranial ultrasound stimulation in an ADHD rat model
Authors: Wang Mengran , Wang Teng , Ji Hui , Yan Jiaqing , Wang Xingran , Zhang Xiangjian , Li Xin , Yuan Yi
Published: September 2022

Previous studies have demonstrated that transcranial ultrasound stimulation (TUS) with noninvasive high penetration and high spatial resolution has an effective neuromodulatory effect on neurological diseases. Attention deficit hyperactivity disorder (ADHD) is a persistent neurodevelopmental disorder that severely affects child health. However, the neuromodulatory effects of TUS on ADHD have not been reported to date. To reveal the neuromodulatory effects, TUS was performed in ADHD model rats for 2 consecutive weeks, and the behavioral improvement of ADHD, neural activity of ADHD from neurons and neural oscillation levels, and the plasma membrane dopamine transporter (DAT) and brain-derived neurotrophic factor (BDNF) in the brains of ADHD rats were evaluated. The results showed that TUS can improve cognitive behavior in ADHD rats, and that TUS altered neuronal firing patterns and modulated the relative power and sample entropy of local field potentials in an ADHD rat model. In addition, TUS can also enhance BDNF expression in the brain tissue of the ADHD rat model. In conclusion, TUS has an effective neuromodulatory effect on ADHD and thus has the potential to clinically improve cognitive dysfunction in ADHD.
Pyro-Velocity: Probabilistic RNA Velocity inference from single-cell data
Authors: Qin Qian , Bingham Eli , La Manno Gioele , Langenau David M. , Pinello Luca
Published: September 2022

Single-cell RNA Velocity has dramatically advanced our ability to model cellular differentiation and cell fate decisions. However, current preprocessing choices and model assumptions often lead to errors in assigning developmental trajectories. Here, we develop, Pyro-Velocity, a Bayesian, generative, and multivariate RNA Velocity model to estimate the uncertainty of cell future states. This approach models raw sequencing counts with the synchronized cell time across all expressed genes to provide quantifiable and improved information on cell fate choices and developmental trajectory dynamics.
Negative regulation of C. elegans innate immunity by orphan nuclear receptor NHR-42
Authors: Goswamy Debanjan , Labed Sid A. , Gonzalez Xavier , Irazoqui Javier E.
Published: September 2022

Positive and negative regulators of innate immunity work together to maintain immune homeostasis. We previously discovered that HLH-30/TFEB is a critical transcription factor that positively regulates host defense genes upon S. aureus infection in C. elegans. However, repression of host defense genes and negative regulation of immunity remain poorly understood. In this study, we identified nhr-42 as a negative regulator of host defense genes functioning downstream of HLH-30/TFEB, with major implications in host survival and metabolism after infection. nhr-42 expression is induced in an HLH-30/TFEB dependent manner mostly in the pharynx upon infection. We find that animals lacking nhr-42 have higher expression of host defense genes, which enables enhanced survival after infection. Antimicrobials expressed in the pharynx such as abf-2, function downstream of nhr-42 to confer resistance to infection by mitigating pathogen burden. Furthermore, nhr-42 deficient animals are defective in lipid mobilization, having higher lipid stores compared to wild type animals after infection. nhr-42 therefore enables C. elegans to limit the host defense response and reallocate energy resources through lipid mobilization after infection. To our knowledge, this is the first report of a transcription factor that represses host defense genes in C. elegans.
Prognostic refinement of NSMP high-risk endometrial cancers using oestrogen receptor immunohistochemistry
Authors: Vermij Lisa , Jobsen Jan J. , León-Castillo Alicia , Brinkhuis Mariel , Roothaan Suzan , Powell Melanie E. , de Boer Stephanie M. , Khaw Pearly , Mileshkin Linda R. , Fyles Anthony , Leary Alexandra , Genestie Catherine , Jürgenliemk-Schulz Ina M. , Crosbie Emma J. , Mackay Helen J. , Nijman Hans. W. , Nout Remi A. , Smit Vincent T.H.B.M. , Creutzberg Carien L. , Horeweg Nanda , Bosse Tjalling ,   TransPORTEC consortium
Published: September 2022

Background

Risk-assessment of endometrial cancer (EC) is based on clinicopathological factors and molecular subgroup. It is unclear whether adding hormone receptor expression, L1CAM expression or CTNNB1 status yields prognostic refinement.

Methods

Paraffin-embedded tumour samples of women with high-risk EC (HR-EC) from the PORTEC-3 trial (n=424), and a Dutch prospective clinical cohort called MST (n=256), were used. All cases were molecularly classified. Expression of L1CAM, ER and PR were analysed by whole-slide immunohistochemistry and CTNNB1 mutations were assessed with a next-generation sequencing. Kaplan-Meier method, log-rank tests and Cox’s proportional hazard models were used for survival analysis.

Results

In total, 649 HR-EC were included. No independent prognostic value of ER, PR, L1CAM and CTNNB1 was found, while age, stage, and adjuvant chemotherapy had an independent impact on risk of recurrence. Subgroup-analysis showed that only in NSMP HR-EC, ER-positivity was independently associated with a reduced risk of recurrence (HR 0.33, 95%CI 0.15-0.75).

Conclusions

ER-positivity is a strong favourable prognostic factor in NSMP HR-EC and identifies a homogeneous subgroup of NSMP tumours. ER-positive NSMP EC may be regarded as a novel fifth molecular subgroup. Assessment of ER status in high-risk NSMP EC is feasible in clinical practice and could improve risk stratification and treatment.
Excess mortality in the general population versus Veterans Healthcare System during the first year of the COVID-19 pandemic in the United States
Authors: Weinberger Daniel M. , Rose Liam , Rentsch Christopher , Asch Steven M. , Columbo Jesse , King Joseph , Korves Caroline , Lucas Brian P. , Taub Cynthia , Young-Xu Yinong , Vashi Anita , Davies Louise , Justice Amy C.
Published: September 2022

Importance

The COVID-19 pandemic had a substantial impact on the overall rate of death in the United States during the first year. It is unclear whether access to comprehensive medical care, such as through the VA healthcare system, altered death rates compared to the US population.

Objective

Quantify the increase in death rates during the first year of the COVID-19 pandemic in the general US population and among individuals who receive comprehensive medical care through the Department of Veterans Affairs (VA).

Design

Analysis of changes in all-cause death rates by quarter, stratified by age, sex race/ethnicity, and region, based on individual-level data. Hierarchical regression models were fit in a Bayesian setting. Standardized rates were used for comparison between populations.

Setting and participants

General population of the United States, enrollees in the VA, and active users of VA healthcare.

Exposure and main outcome

Changes in rates of death from any cause during the COVID-19 pandemic in 2020 compared to previous years.

Results

Sharp increases were apparent across all of the adult age groups (25 years and older) in both the general US population and the VA populations. Across all of 2020, the relative increase in death rates was similar in the general US population (RR: 1.20 (95% CI: 1.17, 1.22)), VA enrollees (RR: 1.20 (95% CI: 1.14, 1.29)), and VA active users (RR: 1.19 (95% CI: 1.14, 1.26)). Because the pre-pandemic standardized mortality rates were higher in the VA populations prior to the pandemic, the absolute rates of excess mortality were higher in the VA populations.

Conclusions and Relevance

Despite access to comprehensive medical care, active users of the VA had similar relative mortality increases from all causes compared with the general US population. Factors that influenced baseline rates of death and that mitigated viral transmission in the community are more likely to have influenced the impact of the pandemic.
Sexual risk-taking behavior amongst emerging adults in Africa: a systematic review and meta-analysis
Authors: Chea Stevenson K. , Kagonya Vincent A. , Abdullahi Osman , Abubakar Amina A. , Abbeddou Souheila , Michielsen Kristien , Hassan Amin S.
Published: September 2022

Background

Incidence of HIV and other sexually transmitted infections (STIs) among emerging adults (EmA) is high in some African settings. Estimates on sexual risk-taking behavior (SRTB) among EmA is varied in literature, which presents a challenge when designing targeted interventions. We aimed to review and summarize literature on prevalence and risk factors of SRTB among EmA in Africa.

Methods

A search for studies published in PubMed, Embase and Psych Info involving EmA (18 – 25 years), conducted in Africa and reporting one or more SRTB was done. Pooled prevalence estimates were summarized using forest plots. Heterogeneity in SRTB was explored by sex, geographic region, year of publication and outcome definition. Risk factors were synthesized using a modified socio-ecological model.

Results

Overall, 117 studies were analyzed. Non-condom use had the highest pooled prevalence (46.0% [95% CI: 14.0-51.0]), followed by study-defined SRTB (37.0% [95% CI: 23.0 -51.0]), concurrency (35.0% [95% CI: 19.0-53.0]), multiple sex partnerships (30.0% [95% CI: 24.0-37.0]), younger age at sexual debut (25.0% [95% CI: 19.0-31.0]), age disparate relationships (24.0% [95% CI: 17.0-32.0]) and transactional sex (17.0% [95% CI: 11.0-24.0]). In four of the seven outcomes, heterogeneity was partially explained by sex, with female participants having higher pooled prevalence estimates compared to their male counterparts. In four of the seven outcomes, alcohol/drug use was the most common risk factor.

Conclusions

SRTB was common among EmA and differentially higher in emerging female adults. Non-condom use had the highest pooled prevalence, which may contribute to the propagation of HIV and other STIs in this population. Interventions targeting emerging female adults and alcohol/drug use may reduce SRTB, which may in-turn mitigate propagation of HIV and other STIs among EmA in Africa.
Top-down specific preparatory activations for Selective Attention and Perceptual Expectations
Authors: Peñalver José M. G. , López-García David , González-García Carlos , Aguado-López Blanca , Górriz Juan M. , Ruz María
Published: September 2022

Proactive cognition brain models are mainstream nowadays. Within these, preparation is understood as an endogenous, top-down function that takes place prior to the actual perception of a stimulus and improves subsequent behavior. Neuroimaging has shown the existence of such preparatory activity separately in different cognitive domains, however no research to date has sought to uncover their potential similarities and differences. Two of these, often confounded in the literature, are Selective Attention (information relevance) and Perceptual Expectation (information probability). We used EEG to characterize the mechanisms that pre-activate specific contents in Attention and Expectation. In different blocks, participants were cued to therelevanceor to theprobabilityof target categories, faces vs. names, in a gender discrimination task. Multivariate Pattern (MVPA) and Representational Similarity Analyses (RSA) during the preparation window showed that both manipulations led to a significant, ramping-up prediction of the relevant or expected target category. However, classifiers trained on data from one condition did not generalize to the other, indicating the existence of unique anticipatory neural patterns. In addition, a Canonical Template Tracking procedure showed that there was stronger anticipatory perceptual reinstatement for relevance than for expectation blocks. Overall, results indicate that preparation during attention and expectation acts through distinguishable neural mechanisms. These findings have important implications for current models of brain functioning, as they are a first step towards characterizing and dissociating the neural mechanisms involved in top-down anticipatory processing.
Spatially resolved transcriptomic profiling of degraded and challenging fresh frozen samples
Authors: Mirzazadeh Reza , Andrusivova Zaneta , Larsson Ludvig , Newton Phillip T. , Galicia Leire Alonso , Abalo Xesús M. , Avijgan Mahtab , Kvastad Linda , Denadai-Souza Alexandre , Stakenborg Nathalie , Firsova Alexandra B. , Shamikh Alia , Jurek Aleksandra , Schultz Niklas , Nistér Monica , Samakovlis Christos , Boeckxstaens Guy , Lundeberg Joakim
Published: September 2022

Spatially resolved transcriptomics (SRT) has enabled precise genome-wide mRNA expression profiling within tissue sections. The performance of unbiased SRT methods targeting the polyA tail of mRNA, relies on the availability of specimens with high RNA quality. Moreover, the high cost of currently available SRT assays requires a careful sample screening process to increase the chance of obtaining high-quality data. Indeed, the upfront analysis of RNA quality can show considerable variability due to sample handling, storage, and/or intrinsic factors. We present RNA-Rescue Spatial Transcriptomics (RRST), an SRT workflow designed to improve mRNA recovery from fresh frozen (FF) specimens with moderate to low RNA quality. First, we provide a benchmark of RRST against the standard Visium spatial gene expression protocol on high RNA quality samples represented by mouse brain and prostate cancer samples. Then, we demonstrate the RRST protocol on tissue sections collected from 5 challenging tissue types, including: human lung, colon, small intestine, pediatric brain tumor, and mouse bone/cartilage. In total, we analyzed 52 tissue sections and our results demonstrate that RRST is a versatile, powerful, and reproducible protocol for FF specimens of different qualities and origins.
Elucidating polymorphs of crystal structures with intensity-based hierarchical clustering analysis on multiple diffraction datasets
Authors: Matsuura Hiroaki , Sakai Naoki , Toma-Fukai Sachiko , Muraki Norifumi , Hayama Koki , Kamikubo Hironari , Aono Shigetoshi , Kawano Yoshiaki , Yamamoto Masaki , Hirata Kunio
Published: September 2022

In macromolecular structure determination using X-ray diffraction from multiple crystals, the presence of different structures (structural polymorphs) necessitates the classification of diffraction data for appropriate structural analysis. Hierarchical clustering analysis (HCA) is a promising technique that has so far been used to extract isomorphous data, mainly for single structure determination. Although in principle the use of HCA can be extended to detect polymorphs, the absence of a reference for defining a threshold used for grouping the isomorphous datasets (‘isomorphic threshold’) poses a challenge. Here, we have applied unit cell-based and intensity-based HCAs to the datasets of apo-trypsin and inhibitor-bound trypsin that were mixed post-data acquisition to investigate how effective HCA is in classifying polymorphous datasets. Single-step intensity-based HCA successfully classified polymorphs with a certain ‘isomorphic threshold’. In datasets of several samples containing an unknown degree of structural heterogeneity, polymorphs could be identified by intensity-based HCA using the suggested ‘isomorphic threshold’. Polymorphs were also detected in single crystals using the data collected by the continuous helical scheme. These findings are expected to facilitate the determination of multiple structural snapshots by exploiting automated data collection and analysis.

Synopsis

Single-step intensity-based hierarchical clustering is demonstrated to allow the detection of structural polymorphs in the diffraction datasets obtained from multiple crystals. By splitting the datasets collected by continuous helical scheme into several chunks, both inter and intra-crystal polymorphs can be successfully analyzed.
Diffusible fraction of niche BMP ligand safeguards stem-cell differentiation
Authors: Ridwan Sharif M. , Twillie Autumn , Poursaeid Samaneh , Beard Emma Kristine , Bener Muhammed Burak , Antel Matthew , Cowan Ann E. , Matsuda Shinya , Inaba Mayu
Published: September 2022

Drosophilamale germline stem cells (GSCs) reside at the tip of the testis and surround a cluster of niche cells. It has been believed that the niche-derived Decapentaplegic (Dpp) has a role in maintaining stem cells in close proximity but has no role in the differentiating cells spaced one-cell layer away. However, the range of Dpp diffusion has never been tested. Here, using genetically encoded nanobodies called Morphotrap, we physically block Dpp diffusion without interfering with niche-stem cell signaling and find that diffusible fraction of Dpp is required to ensure differentiation of GSC daughter cells, opposite of its role in maintenance of GSC in the niche. Our work provides an example in which a soluble niche ligand induces opposed cellular responses in stem cells and in differentiating descendants so that the niche can tightly restrict its space. This may be a common mechanism to regulate tissue homeostasis.

One sentence summary

BMP ligand diffuses from the niche and has dual, and opposite roles on stem cells and differentiating daughter cells.
Detecting changes in population trends in infection surveillance using community SARS-CoV-2 prevalence as an exemplar
Authors: Pritchard Emma , Vihta Karina-Doris , Eyre David W. , Hopkins Susan , Peto Tim EA , Matthews Philippa C. , Stoesser Nicole , Studley Ruth , Rourke Emma , Diamond Ian , Pouwels Koen B. , Walker Ann Sarah ,   the COVID-19 Infection Survey Team
Published: September 2022

Background

Monitoring infection trends is vital to informing public health strategy. Detecting and quantifying changes in growth rates can inform policymakers’ rationale for implementing or continuing interventions aimed at reducing impact. Substantial changes in SARS-CoV-2 prevalence with emergence of variants provides opportunity to investigate different methods to do this.

Methods

We included PCR results from all participants in the UK’s COVID-19 Infection Survey between 1 August 2020-30 June 2022. Change-points for growth rates were identified using iterative sequential regression (ISR) and second derivatives of generalised additive models (GAMs).

Consistency between methods and timeliness of detection were compared.

Findings

Of 8,799,079 visits, 147,278 (1·7%) were PCR-positive. Over the time period, change-points associated with emergence of major variants were estimated to occur a median 4 days earlier (IQR 0-8) in GAMs versus ISR, with only 2/48 change-points identified by only one method. Estimating recent change-points using successive data periods, four change-points (4/96) identified by GAMs were not found when adding later data or by ISR; 77% (74/96) of change-points identified by successive GAMs were identified by ISR. Change-points were detected 3-5 weeks after they occurred in both methods but could be detected earlier within specific subgroups.

Interpretation

Change-points in growth rates of SARS-CoV-2 can be detected in near real-time using ISR and second derivatives of GAMs. To increase certainty about changes in epidemic trajectories both methods could be run in parallel. Running either method in near real-time on different infection surveillance data streams could provide timely warnings of changing underlying epidemiology.

Funding

UK Health Security Agency, Department of Health and Social Care (UK), Welsh Government, Department of Health (on behalf of the Northern Ireland Government), Scottish Government, National Institute for Health Research.
Structure-Function analysis of Lactiplantibacillus plantarum DltE reveals D-alanylated lipoteichoic acids as direct symbiotic cues supporting Drosophila juvenile growth
Authors: Nikolopoulos Nikos , Matos Renata C. , Ravaud Stéphanie , Courtin Pascal , Akherraz Houssam , Palussière Simon , Gueguen-Chaignon Virginie , Salomon-Mallet Marie , Guillot Alain , Guerardel Yann , Chapot-Chartier Marie-Pierre , Grangeasse Christophe , Leulier François
Published: September 2022

Metazoans establish mutually beneficial interactions with their resident microorganisms. However, our understanding of the microbial cues contributing to host physiology remains elusive. Previously, we identified a bacterial machinery encoded by the dlt operon involved in Drosophila melanogaster’s juvenile growth promotion by Lactiplantibacillus plantarum. Here, using crystallography combined with biochemical and cellular approaches, we investigate the physiological role of an uncharacterized protein (DltE) encoded by this operon. We show that LTAs but not WTAs are D-alanylated in Lactiplantibacillus plantarumNC8 cell envelope and demonstrate that DltE is a D-Ala carboxyesterase removing D-Ala from LTA. Using the mutualistic association of L. plantarumNC8 and Drosophila melanogaster as a symbiosis model, we establish that D-Ala-LTAs are direct symbiotic cues supporting intestinal peptidase expression and juvenile growth in Drosophila. Our results pave the way to probing the contribution of D-Ala-LTA to host physiology in other symbiotic models.
Pseudocontact shift NMR data obtained from a non-canonical amino acid-linked lanthanide tag improves integral membrane protein structure prediction
Authors: Ledwitch Kaitlyn V. , Künze Georg , Larochelle Katherine , Okwei Elleansar , Pankewitz Lisa , Ganguly Soumya , Darling Heather L. , Coin Irene , Meiler Jens
Published: September 2022

A single experimental method alone often fails to provide the resolution, accuracy, and coverage needed to model integral membrane proteins (IMPs). Integrating computation with experimental data is a powerful approach to supplement missing structural information with atomic detail. We combine RosettaNMR with experimentally-derived paramagnetic NMR restraints to guide membrane protein structure prediction. We demonstrate this approach using the disulfide bond formation protein B (DsbB), an α-helical IMP. We attached a cyclen-based paramagnetic lanthanide tag to an engineered noncanonical amino acid (ncAA) using a copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry reaction. Using this tagging strategy, we collected 203 backbone HN pseudocontact shifts (PCSs) for three different labeling sites and used these as input to guide de novo membrane protein structure prediction protocols in Rosetta. We find that this sparse PCS dataset combined with 44 long-range NOEs as restraints in our calculations improves structure prediction of DsbB by enhancements in model accuracy, sampling, and scoring. The most accurate DsbB models generated in this case gave Cα-RMSD values over the transmembrane region of 2.11 Å (best-RMSD) and 3.23 Å (best-scoring).
Functional comparison of full-length palladin to isolated actin binding domain
Authors: Albraiki Sharifah , Klausmeyer Rachel , Ajiboye Oluwatosin , Beck Moriah R.
Published: September 2022

Palladin is an actin binding protein that is specifically upregulated in metastatic cancer cells but also co-localizes with actin stress fibers in normal cells and is critical for embryonic development as well as wound healing. Of nine isoforms present in humans, only the 90 kDa isoform of palladin, comprising three immunoglobulin (Ig) domains and one proline-rich region, is ubiquitously expressed. Previous work has also established that the Ig3 domain of palladin is the minimal binding site for F-actin. In this work, we compare functions of the 90 kDa isoform of palladin to the isolated actin binding domain. To understand the mechanism of action for how palladin can influence actin assembly, we monitored F-actin binding and bundling as well as actin polymerization, depolymerization, and copolymerization. We also provide initial evidence that 90 kDa palladin exists in a closed conformation that prevents binding by the Ig3 domain to G-actin as compared to the isolated domain. Understanding the role of palladin in regulating the actin cytoskeleton may help us develop means to prevent cancer cells from reaching the metastatic stage of cancer progression.
Unsupervised identification of significant lineages of SARS-CoV-2 through scalable machine learning methods
Authors: Cahuantzi Roberto , Lythgoe Katrina A. , Hall Ian , Pellis Lorenzo , House Thomas A.
Published: September 2022

Since its emergence in late 2019, SARS-CoV-2 has diversified into a large number of lineages and globally caused multiple waves of infection. Novel lineages have the potential to spread rapidly and internationally if they have higher intrinsic transmissibility and/or can evade host immune responses, as has been seen with the Alpha, Delta, and Omicron variants of concern (VoC). They can also cause increased mortality and morbidity if they have increased virulence, as was seen for Alpha and Delta, but not Omicron. Phylogenetic methods provide the gold standard for representing the global diversity of SARS-CoV-2 and to identify newly emerging lineages. However, these methods are computationally expensive, struggle when datasets get too large, and require manual curation to designate new lineages. These challenges together with the increasing volumes of genomic data available provide a motivation to develop complementary methods that can incorporate all of the genetic data available, without down-sampling, to extract meaningful information rapidly and with minimal curation. Here, we demonstrate the utility of using algorithmic approaches based on word-statistics to represent whole sequences, bringing speed, scalability, and interpretability to the construction of genetic topologies, and while not serving as a substitute for current phylogenetic analyses the proposed methods can be used as a complementary approach to identify and confirm new emerging variants.
Angiotensin 1-7 in severe COVID-19 patients: a phase 1 clinical trial
Authors: Valle Martins Ana Luiza , Annoni Filippo , da Silva Filipe Alex , Bolais-Ramos Lucas , Capanema de Oliveira Gisele , dos Santos Matos Alana Helen , Jardim Heyden Maria Cecília , Pinheiro Beatriz Dias , Rodrigues Natália Abdo , Alves Pereira Danilo Augusto , Lana Diniz Mirella Monique , Granato Fonseca Silva Thuanny , Cardoso Alexandre Carvalho , Martins Juliana Carvalho , Motta-Santos Daisy , Campagnole-Santos Maria José , Verano-Braga Thiago , Taccone Fabio Silvio , dos Santos Robson Augusto Souza
Published: September 2022

Background

The coronavirus-related disease (COVID-19) is mainly characterized by a respiratory involvement, with few available therapeutics for critically cases. The renin-angiotensin system (RAS) has a relevant role in the pathogenesis of COVID-19, as the virus enter host’s cells via the angiotensin-converting enzyme 2 (ACE2) and RAS disequilibrium promote inflammation and fibrosis. Exogenous angiotensin-(1-7) might modulate RAS in COVID-19 patients; however, no data on its safety are available in this setting.

Methods

This investigator-initiated, open label, phase I clinical trial was conducted to test the safety of intravenous administration of Angiotensin-(1-7) in severe COVID-19 patients admitted in two intensive care units (ICU) in Belo Horizonte, Brazil. In addition to standard of care, intravenous administration of Angiotensin-(1-7) was started at 5 mcg/Kg*day and increased to 10 mcg/Kg*day after 24 hours and continued for a maximum of 7 days or until ICU discharge. The rate of serious adverse events (SAEs) served as the primary outcome of the study.

Results

Between August and December 2020, 28 patients were included (mean age of 55.8±12.0 years). All but one patient underwent dose escalation after 24 hours and 8 (28.5%) received the treatment until day 7. No significant differences in mean blood pressure and heart rate were observed before and after the initiation of the drug. During the period of intervention, 5/28 (17.8%) patients required vasopressors, 4 at low dose norepinephrine (i.e. <0.05 mcg/kg*min), while one patient required higher doses because of septic shock. One patient presented with sinus bradycardia, which was considered possibly related to the study drug and resolved after discontinuation. Six patients (21.4%) died before ICU discharge.

Conclusions

Intravenous infusion of Angiotensin-(1-7) up to 10 mcg/Kg*day was safe in severe COVID-19 patients and could represent a potential therapeutic strategy in this setting.

Trial Registration

Registro Brasileiro de Ensaios Clínicos, UTN code: U1111-1255-7167, registered on 08/05/2020; ClinicalTrials.gov Identifier: NCT04633772; retrospectively registered on November 18 2020
Periodic solutions for a class of perturbed sixth-order autonomous differential equations
Authors: Berrehail Chems Eddine , Makhlouf Amar
Published: September 2022

Purpose

The objective of this work is to study the periodic solutions for a class of sixth-order autonomous ordinary differential equations x(6)+(1+p2+q2)x… .+(p2+q2+p2q2)x¨+p2q2x=εF(x,ẋ,x¨,x…,x… .,x(5)), where p and q are rational numbers different from 1, 0, −1 and p ≠ q, ε is a small enough parameter and F ∈ C2 is a nonlinear autonomous function.

Design/methodology/approach

The authors shall use the averaging theory to study the periodic solutions for a class of perturbed sixth-order autonomous differential equations (DEs). The averaging theory is a classical tool for the study of the dynamics of nonlinear differential systems with periodic forcing. The averaging theory has a long history that begins with the classical work of Lagrange and Laplace. The averaging theory is used to the study of periodic solutions for second and higher order DEs.

Findings

All the main results for the periodic solutions for a class of perturbed sixth-order autonomous DEs are presenting in the Theorem 1. The authors present some applications to illustrate the main results.

Originality/value

The authors studied Equation 1 which depends explicitly on the independent variable t. Here, the authors studied the autonomous case using a different approach.
Minority shareholder activism in light of the Indian companies act, 2013
Authors: Sharma Pooja , Sachdeva Shikha
Published: September 2022

Purpose

The genesis of “shareholder activism” in the USA may be traced back to several decades, but it only evolved in India at the start of the 21st century. This paper aims to explore the concept of “shareholder activism” in the Indian context, in light of the New Companies Act, 2013. The act is envisioned as a precursor to invoking the intention of shareholders to confront managers. Further, it aims to look at the possibilities of using tools of shareholder activism to make companies aware of their concerns.

Design/methodology/approach

Authors explore the concept of shareholder activism with the help of textual analysis, using R. Then, the authors study the mediating effects of “shareholder’s intention towards activism” between the “regulatory mechanisms” and “the usage of various tools of activism”, using the partial least square approach.

Findings

Regulatory mechanisms, such as the Companies Act, 2013, enhance the shareholders’ power to sensitise companies towards various corporate governance issues. It also increases their intention towards shareholder activism, eventually leading to favourable opinion on using various tools of “activism” in their investee companies.

Practical implications

This study is a unique attempt to assess the minority shareholders’ potential to become active in their investee companies induced by changes in the rules and regulations of a country.

Originality/value

Shareholder activism in India has not been thoroughly explored thus far. This paper specifically studies the opinions of retail investors, who possibly could increase companies’ accountability towards their minority shareholders, especially in light of the New Companies Act, 2013.
Gender pay-gap: exploring the school-to-work transition of graduates in Italy
Authors: Ferri Valentina , García-Pereiro Thaís , Pace Roberta
Published: September 2022

Purpose

In this article, the authors study the gender pay-gap (GPG) among graduates in Italy (2011 cohort) who were employed four years after graduation. The authors focus on individuals who are new entering in the labour market or who match a low level of experience with a high level of education.

Design/methodology/approach

Aimed at estimating the amount of the differential between male and female average wages, the authors have applied the Oaxaca–Blinder (O–B) decomposition. The results identify the presence of a GPG at the very beginning of graduates’ careers given that, shortly after graduation, women receive lower salaries than men, even after controlling for several characteristics (individual, academic, job and local labour market). The authors completed the analysis with the reweighted O–B decomposition using the recentered influence function (RIF) and the Juhn, Murphy and Pierce and Machado and Mata decomposition approaches.

Findings

The results show that the GPG is already present at the very beginning of graduates’ careers, and it increases when correcting for women’s lower level of participation in the labour market. The authors also identified sticky floor and the glass ceiling effects due to the existence of a relevant high GPG both at the bottom and the top of the graduates’ wage distribution.

Originality/value

By focussing attention particularly on graduates, this paper adds to the existing literature a deeper understanding not only of individuals who have recently entered the labour market, but also those who are highly skilled but have little on-the-job experience. In fact, the authors are looking at a particular sample (graduates who are all transitioning from university to work during the same period) with small heterogeneity which allows the authors to compare very similar young men and women graduates and gain a deeper understanding of GPGs in early careers while controlling for confounding and hidden sources of variability.
Effect of emotional intelligence and cognitive flexibility on entrepreneurial intention: mediating role of entrepreneurial self-efficacy
Authors: Mishra Ankita , Singh Parwinder
Published: September 2022

Purpose

Entrepreneurship is one of the significant drivers of economic growth, development and job generation in several countries worldwide. Realizing its significant contribution to the nation’s development, policymakers and educators have also drawn attention to fostering entrepreneurship among the youth. Researchers attempted to comprehend the dynamics and investigate the factors influencing entrepreneurial intention (EI). As is true for other abilities and response tendencies, individual differences exist for EI also. This study aims to explore the relationship of emotional intelligence (EIn) and cognitive flexibility (CF) with EI and mediating effect of entrepreneurial self-efficacy (ESE) in the relationship between CF, EIn and EI.

Design/methodology/approach

The cross-sectional survey was conducted to gather responses from 635 individuals aged 17–26 years (M = 19.2, SD = 1.49). The hypotheses were tested using correlation, regression and mediation analysis.

Findings

The findings indicated that EIn and CF were significantly and positively related to EI. Furthermore, ESE was found to be a partial mediator between EIn and EI and a full mediator between CF and EI.

Research limitations/implications

Results reflected the critical significance of ESE and implied that EI might be strengthened by intervening in ESE through various sources.

Originality/value

This study adds to the existing literature by incorporating less studied individual factors (EIn and CF) to better understand EI by explaining the mediation mechanism through ESE.