bluuebunny/crossref_metadata_2025 huggingface dataset:
A flexoelectric actuator model with shear-lag and peel stress effects
Authors: Rout Suraj Kumar , Kapuria Santosh
Published: May 2023

Flexoelectric materials are being extensively studied in recent years for potential sensing, actuation, energy harvesting and structural health monitoring applications. However, no analytical model exists in the literature to predict the stress transfer between a flexoelectric transducer and the host structure, considering bonding compliance. In this article, we present an analytical model for the interfacial stresses and deformations of flexoelectric patch actuator(s) bonded to an isotropic host plate considering both shear-lag and peel stress effects at the interface(s). The model is valid for both piezoelectric and flexoelectric effects. The system’s one-dimensional governing equations are derived consistently from the three-dimensional equations for linear dielectric solids obtained using the bulk electric Gibbs energy density function and extended Hamilton’s principle. The transducer and substrate, modelled as classical Kirchhoff plates, undergo both extension and bending deformations. The formulation produces a seventh-order differential equation for the interfacial shear stress, which is solved analytically, satisfying all boundary conditions. The solution is validated by comparing with the available results for piezoelectric actuators with a non-rigid interface and those of flexoelectric actuators based on the pin-force-moment model assuming a rigid interface. Detailed numerical studies are presented to show the effect of the plate, actuator and adhesive parameters on the interfacial stresses and deformations. Finally, the size effect of the actuators at the micro-scale is illustrated.
The turnover of plant–frugivore interactions along plant range expansion: consequences for natural colonization processes
Authors: Isla Jorge , Jácome-Flores Miguel , Arroyo Juan M. , Jordano Pedro
Published: May 2023

Plant–animal mutualisms such as seed dispersal are key interactions for sustaining plant range shifts. It remains elusive whether the organization of interactions with seed dispersers is reconfigured along the expansion landscape template and, if so, whether its effects accelerate or slow colonization. Here we analyse plant–frugivore interactions in a scenario of rapid population expansion of a Mediterranean juniper. We combined network analyses with field surveys, sampling interactions between individual plants and frugivores by DNA-barcoding and phototrapping over two seasons. We assess the role of intrinsic and extrinsic intraspecific variability in shaping interactions and we estimate the individual plant contributions to the seed rain. The whole interaction network was highly structured, with a distinct set of modules including individual plants and frugivore species arranged concordantly along the expansion gradient. The modular configuration was partially shaped by individual neighbourhood context (density and fecundity) and phenotypic traits (cone size). Interaction reconfiguration resulted in a higher and more uneven propagule contribution, with most effective dispersers having a prominent role at the colonization front stand, where a distinct subset of early arriving plants dominated the seed rain. Our study offers new insights into the key role of mutualistic interactions in colonization scenarios by promoting fast plant expansion processes.
Female reproductive fluids ‘rescue’ sperm from phenotypic ageing in an external fertilizer
Authors: Hadlow Jessica H. , Evans Jonathan P. , Lymbery Rowan A.
Published: May 2023

Female reproductive fluids (FRFs) serve key reproductive functions in sexually reproducing animals, including modifying the way sperm swim and detect eggs, and influencing sperm lifespan. Despite the central role of FRF during fertilization, we know surprisingly little about sperm–FRF interactions under different environmental conditions. Theory suggests that in external fertilizers FRF may ‘rescue’ sperm from ageing effects as they search to fertilize eggs. Here, we test the interaction between these two fundamental properties of the fertilization environment, ejaculate age (i.e. time since ejaculation) and FRF, on a range of functional sperm phenotypes in a broadcast spawning mussel,
Mytilus galloprovincialis
. We found that the effects of ejaculate age on multivariate sperm motility traits and total sperm motility were altered by FRF, and that longer-lived sperm exhibit stronger, likely more advantageous, responses to FRF after periods of ageing. We also detected significant among-male variation in the relationship between sperm motility traits and ejaculate age; notably, these patterns were only revealed when sperm encountered FRF. Collectively these findings underscore the importance of considering female reproductive physiology when interpreting ageing-related declines in sperm motility, as doing so may expose importance sources of variation in sperm phenotypic plasticity among males and environments.
PREDICTION OF MORTALITY USING GET WITH THE GUIDELINE HEART FAILIURE SCORE (GWTG-HF), ITS COMPARISON WITH APACHE 2 SCORE AND ITS CORRELATION WITH NTPRO BNP LEVELS: A STUDY AMONG PATIENTS OF ACUTE DECOMPENSATED HEART FAILURE FROM SOUTH EAST ASIAN REGION
Authors: Kumar Lalit , Mahla Himanshu , Chaturvedi Neeraj , Sharma Shashi Mohan , Bagarhatta Rajeev , Agrawal V.V. , Pathak Vijay , Meena Chandrabhan , Maheshwari Deepak , Meena Pradeep , Pachar Balbir Singh , Sharma Sohan Kumar , Gautam Dinesh , Chaudhary Sarita , Shekhawat Dhananjay , Sidhu Navdeep Singh
Published: May 2023

Objectives

To study Get with the guidelines heart failure Score (GWTG-HF) among patients of acute decompensated heart failure, correlate it with outcome of survival or death till 4 week of illness, compare its performance with APACHE 2 score and to Compare its results with NT PROBNP in predicting mortality amongst patient of south east Asian ethnicity.

Study design

prospective observational study at medical wards and ICUs in the Department of Cardiology, SMS medical college.

Methods

In this study 300 patients of acute decompensated heart failure, as per Framingham criteria were analyzed and each patient underwent a complete clinical evaluation along with calculation of GWTG HF and APACHE 2 score. All the patients had NT pro BNP test within 48 hours of admission. Patient were then followed till 4 weeks of illness for outcome of survival or death, whichever occurred earlier. GWTG HF score of the patient was then compared with APACHE 2 score and it was correlated with the outcome of patients and NT pro BNP levels.

Results

The GWTG-HF score could predict the outcome of survival and death in ADHF patients of south east Asian ethnicity. When compared, APACHE 2 score performed better than GWTG-HF score in predicting outcome. However, GWTG-HF score was easily calculated at the bedside and was easy to use. GWTG-HF score correlated with NT-pro BNP levels with rising score having higher NT pro BNP levels.
Mapping patient interactions in psychiatric presentations to a tertiary emergency department
Authors: McCullough Michael H , Small Michael , Jayawardena Binu , Hood Sean
Published: May 2023

Reliable assessment of suicide and self-harm risk in emergency medicine is critical for effective intervention and treatment of patients affected by mental health disorders. Teams of clinicians are faced with the challenge of rapidly integrating medical history, wide-ranging psychosocial factors, and real-time patient observations to inform diagnosis, treatment and referral decisions. Patient outcomes therefore depend on the reliable flow of information though networks of clinical staff and information systems. We studied information flow at a systems-level in a tertiary hospital emergency department using network models and machine learning. Data were gathered by mapping trajectories and recording clinical interactions for patients at suspected risk of suicide or self-harm. A network model constructed from the data revealed communities closely aligned with underlying clinical team structure. By analysing connectivity patterns in the network model we identified a vulnerability in the system with the potential to adversely impact information flow. We then developed an algorithmic strategy to mitigate this risk by targeted strengthening of links between clinical teams. Finally, we investigated a novel application of machine learning for distinguishing specific interactions along a patient’s trajectory which were most likely to precipitate a psychiatric referral. Together, our results demonstrate a new framework for assessing and reinforcing important information pathways that guide clinical decision processes and provide complimentary insights for improving clinical practice and operational models in emergency medicine for patients at risk of suicide or self-harm.
Comparing the Demographic and Health Survey’s timing-based measure of unintended pregnancy to the London Measure of Unplanned Pregnancy in Bangladesh
Authors: Khan Md Nuruzzaman , Khanam Shimlin Jahan , Harris Melissa L.
Published: May 2023

Background

Demographic and Health Survey’s timing-based measure is commonly used in Low and Middle Income Countries to estimate unintended pregnancy despite its limitations, including ambivalent responses and failure to consider the partner’s intention, while LMUP, which can address these limitations, is not widely used in LMICs and is yet to be administered in Bangladesh. This study compared unintended pregnancy rates measured by the DHS timing-based measure and LMUP, as well as explored the extent of discordance between the measures and their determinants.

Methods

A cross-sectional survey was conducted in four districts of Bangladesh using two-stage stratified random sampling. Data was collected from 1,200 postnatal women. The study focused on discordance in reporting pregnancy intention between DHS timing-based measure and LMUP. Multivariate logistic regression models were used to identify predictors of discordant responses in reporting pregnancy intention.

Results

The prevalence of unintended pregnancy was found to be 24.3% through the DHS timing-based measure and 31.0% through the LMUP. Discordance in responses to pregnancy intention in the two measures was around 28%. Key predictors of discordance included older age, female last child, more than two children, poorer wealth quintile, and rural residence. Conclusions: Prevalence of unintended pregnancy in Bangladesh and other LMICs, measured by DHS timing-based measure, may grossly underestimated. This suggests that the negative effects of unintended pregnancy are even more significant than currently believed, further highlighting the need to strengthen the family planning program in Bangladesh.
Accuracy of digital chest x-ray analysis with artificial intelligence software as a triage and screening tool in hospitalized patients being evaluated for tuberculosis in Lima, Peru
Authors: Biewer Amanda , Tzelios Christine , Tintaya Karen , Roman Betsabe , Hurwitz Shelley , Yuen Courtney M. , Mitnick Carole D. , Nardell Edward , Lecca Leonid , Tierney Dylan B. , Nathavitharana Ruvandhi R.
Published: May 2023

Introduction

Tuberculosis (TB) transmission in healthcare facilities is common in high-incidence countries. Yet, the optimal approach for identifying inpatients who may have TB is unclear. We evaluated the diagnostic accuracy of qXR (Qure.ai, India) computer-aided detection (CAD) software versions 3.0 and 4.0 (v3 and v4) as a triage and screening tool within the FAST (Find cases Actively, Separate safely, and Treat effectively) transmission control strategy.

Methods

We prospectively enrolled two cohorts of patients admitted to a tertiary hospital in Lima, Peru: one group had cough or TB risk factors (triage) and the other did not report cough or TB risk factors (screening). We evaluated the sensitivity and specificity of qXR for the diagnosis of pulmonary TB using culture and Xpert as primary and secondary reference standards, including stratified analyses based on risk factors.

Results

In the triage cohort (n=387), qXR v4 sensitivity was 0.91 (59/65, 95% CI 0.81-0.97) and specificity was 0.32 (103/322, 95% CI 0.27-0.37) using culture as reference standard. There was no difference in the area under the receiver-operating-characteristic curve (AUC) between qXR v3 and qXR v4 with either a culture or Xpert reference standard. In the screening cohort (n=191), only one patient had a positive Xpert result, but specificity in this cohort was high (>90%). A high prevalence of radiographic lung abnormalities, most notably opacities (81%), consolidation (62%), or nodules (58%), was detected by qXR on digital CXR images from the triage cohort.

Conclusions

qXR had high sensitivity but low specificity as a triage in hospitalized patients with cough or TB risk factors. Screening patients without cough or risk factors in this setting had a low diagnostic yield. These findings further support the need for population and setting-specific thresholds for CAD programs.
Identification of SYT10 as a potential prognostic biomarker in esophageal cancer by comprehensive analysis of a mRNA-pseudogene/lncRNA-miRNA ceRNA network
Authors: Daneshmand-Parsa Milad , Mahmoudian-Hamedani Sharareh , Nikpour Parvaneh
Published: May 2023

Background

Esophageal carcinoma (ESCA) is often diagnosed at the advanced stages, has a poor survival rate and overall is one of the deadliest cancers world-wide. Recent studies have elaborated the significance of non-coding RNAs like pseudogenes, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in cancer progression. In this study, we constructed a four-component competing endogenous RNA (ceRNA) network in ECSA and suggested an RNA with prognostic potential.

Materials and methods

Expression profiles of mRNAs, pseudogenes, lncRNAs and miRNAs were collected from The Cancer Genome Atlas (TCGA) database. A ceRNA network was constructed based on differentially-expressed RNAs. KEGG and GO functional analysis and PPI network analysis was carried out on differentially-expressed (DE) RNAs of the ceRNA network. Survival analysis was carried out on a selection of RNAs with the highest degree centrality ranks to discover potential prognostic biomarkers.

Results

A four-component ceRNA network with 529 nodes and 729 edges was constructed. The most significant GO biological process terms included signal transduction, cell adhesion and positive regulation of gene expression. The analysis of KEGG pathways showed that DEmRNAs were significantly enriched in pathways such as cytokine-cytokine receptor interaction and Cell cycle. Amongst the RNAs that were found to be associated with survival,SYT10had the highest hazard ratio and thus, proved to be a potential prognostic biomarker for ESCA.

Conclusion

Our study presented a four-component ceRNA network for ESCA, and identified RNA candidates that were associated with survival of ECSA. Further experimental evaluations and precise validation studies are needed for their clinical significances and roles in the progression of ESCA.
National Increase but Pronounced Regional Disparities in Naloxone Prescribing to United States Medicaid and Medicare Patients
Authors: Manko Christopher D. , Ahmed Mohamed S. , Harrison Lavinia H. , Kodavatiganti Sree , Lugo Noelia , Konadu Jason O. , Khan Farrin , Massari Carrie A. , Sealey Tenisha K. , Addison Maame Efua , Mbah Celine N. , McCall Kenneth L. , Fraiman Joseph B. , Piper Brian J.
Published: May 2023

Background

Opioid overdoses in the US have increased to unprecedented levels. Administration of the opioid antagonist naloxone can prevent overdoses. This study was conducted to reveal the pharmacoepidemiologic patterns in naloxone prescribing to Medicaid patients from 2018-2021 as well as Medicare in 2019.

Methods

The Medicaid State Drug Utilization Data File was utilized to extract information on number of prescriptions and amount prescribed of naloxone at a national and state level. States with naloxone prescription rates differing from the mean by ≥ 1.96 standard deviations were considered statistically significant. The Medicare Provider Utilization and Payment was also utilized to analyze prescription data from 2019.

Results

The number of generic naloxone prescriptions per 100,000 Medicaid enrollees decreased 5.15% whereas brand naloxone prescriptions increased 245.00% from 2018-2021. There was a 33.14-fold difference in prescriptions between the highest (New Mexico = 1809.55) and lowest (South Dakota = 54.61) states in 2019. Medicare saw a 30.32-fold difference in prescriptions between the highest (New Mexico) and lowest states (also South Dakota) after correcting per 100,000 enrollees.

Conclusions

This pronounced increase in the number of naloxone prescriptions to Medicaid patients from 2018-2021 indicates a national response to this widespread public health emergency. Further research into the origins of the pronounced state-level disparities is warranted.
eoPred: Predicting the placental phenotype of early-onset preeclampsia using DNA methylation
Authors: Fernández-Boyano I. , Inkster A.M. , Yuan V. , Robinson W.P.
Published: May 2023

Background

A growing body of literature has reported molecular and histological changes in the human placenta in association with preeclampsia (PE). Placental DNA methylation (DNAme) and transcriptomic patterns have revealed molecular subgroups of PE that are associated with placental histopathology and clinical phenotypes of the disease. However, the heterogeneity of PE both across and within subtypes, whether defined clinically or molecularly, complicates the study of this disease. PE is most strongly associated with placental pathology and adverse fetal and maternal outcomes when it develops early in pregnancy. We focused on placentae from pregnancies affected by preeclampsia that were delivered before 34 weeks of gestation to develop eoPred, a predictor of the DNAme signature associated with the placental phenotype of early-onset preeclampsia (EOPE).

Results

Public data from 83 placental samples (HM450K), consisting of 42 EOPE and 41 normotensive preterm birth (nPTB) cases, was used to develop eoPred - a supervised model that relies on a highly discriminative 45 CpG DNAme signature of EOPE in the placenta. The performance of eoPred was assessed using cross-validation (AUC=0.95) and tested in an independent validation cohort (n=49, AUC=0.725). A subset of fetal growth restriction (FGR) and late-PE cases showed a similar DNAme profile at the 45 predictive CpGs, consistent with the overlap in placental pathology between these conditions. The relationship between the EOPE probability generated by eoPred and various phenotypic variables was also assessed, revealing that it is associated with gestational age, and it is not driven by cell composition differences.

Conclusions

eoPred relies on a 45 CpG DNAme signature to predict EOPE, and it can be used in a discrete or continuous manner. Using this classifier should 1) improve the consistency of future placental DNAme studies of PE and placental insufficiency, 2) facilitate identifying cases of EOPE in public data sets and 3) importantly, standardize the placental diagnosis to allow better cross-cohort comparisons. Lastly, classification of cases with eoPred should be useful for testing associations between placental pathology and genetic or environmental variables.
Trends in age, sex and racial differences in the incidence of infective endocarditis in Florida and New York
Authors: Anuforo Anderson , Aneni Ehimen , Akintoye Emmanuel , Anikpezie Nnabuchi , Patel Smit D. , Soipe Ayorinde , Olojakpoke Eloho , Burke Devin , Latorre Julius Gene , Khandelwal Priyank , Chaturvedi Seemant , Ovbiagele Bruce , Otite Fadar Oliver
Published: May 2023

Background

How the incidence of infective endocarditis (IE) changed in various age, sex and racial/ethnic subgroups of the United States along with the worsening opioid epidemic over the last decade is unknown.

Methods

We utilized data from the 2007-2018 State Inpatient Databases (SID)) of two large demographically diverse states (Florida and New York) to conduct a retrospective cohort study. Cases of incident IE identified using validated International Classification of Diseases codes were combined with census data to compute age, sex- and race-specific incidence. Joinpoint regression was used to quantify the annualized percentage change (APC) in incidence over time.

Results

Of 98,221 incident IE admissions, 70.0% were Non-Hispanic White (NHW) and 60.6% were ≥ 65 years old (yo). The average annual age and sex-standardized incidence of IE in cases/100,000 population was 19.2 (95%CI 18.7-19.6) but this varied by age, sex and race. Incidence was ≈20% higher in men (20.9 [95%CI 20.2-21.7]) compared to women (17.5 [95%CI 16.8-18.2]) and increased with age in both sexes. Incidence was higher in Non-Hispanic Blacks (NHB); 22.5(95%CI 21.0-23.9) compared to NHW: 20.0(95%CI 19.3 to 20.6), Hispanic: 13.2(95%CI 12.3-14.1) and Asian/Pacific Islander patients: 5.9(95%CI 4.7 to 7.1). The age and sex-standardized incidence did not change over time (APC 0.5%,p=0.646). However, incidence increased in women 18-44 (APC 11.0%,p<0.001), men 18-44 (APC 7.3,p<0.001) and 45-64 yo (APC 1.5%,p=0.002) but declined in women ≥ 65 yo (APC −2.8,p=0.049). Most of this increased incidence occurred in NHW women 18-44 (APC 16.6%,p<0.001), NHW men 18-44 (APC 10.6%,p<0.001), NHW men 45-64 (APC 2.8%,p<0.001) and Hispanic Men 18-44 yo (APC 5.6%,p<0.001). Incidence did not change over time in these age/sex groups of NHB and in other age/sex groups. Prevalence of opioid use disorder increased by >2-fold in all age/sex groups over time but the pace of increase was faster in NHW women and men 18-44 yo compared to other races of similar demography (p-for-time interaction <0.001).

Conclusion

Over the last two decades, among residents of Florida and New York, incidence of IE increased in several demographic groups, but the most prominent rise was among young NHWs, particularly young NHW women.
The transcription factor OsbZIP48 governs rice responses to zinc deficiency
Authors: Hu Shubao , Du Binbin , Mu Guangmao , Jiang Zichen , Li Hui , Song Yuxinrui , Zhang Baolei , Xia Jixing , Rouached Hatem , Zheng Luqing
Published: May 2023

Zinc deficiency is the most prevalent micronutrient disorder in rice and leads to delayed development and decreased yield. Nevertheless, despite its primary importance, how rice responds to zinc deficiency remains poorly understood. Herein, we present genetic evidence that OsbZIP48 is essential for regulating rice responses to zinc deficiency. Using the reverse genetics approach, genetic inactivation ofOsbZIP48in rice seedlings caused a hyper sensitivity to zinc deficiency, associated with a significant decrease in the root-to-shoot translocation of zinc. Consistently,OsbZIP48was constitutively expressed in roots, slightly induced by zinc deficiency in shoots, and localized into nuclei induced by Zn deficiency. Comparative transcriptome analysis of the wild-type plants andosbzip48mutant grown under zinc deficiency enabled the identification of OsbZIP48 target genes, including key zinc transporter genes (OsZIP4andOsZIP8). We demonstrated that OsbZIP48 controlled the expressions of these genes by directly binding to their promoters, specifically to the zinc deficiency response element (ZDRE) motif. Collectively, we showed that theOsbZIP48gene encodes for a transcription factor in rice, and demonstrates its critical role in the response to zinc deficiency in this crop. This knowledge is crucial for the design of rice plants that are resilient to the globally prevalent zinc limitation through zinc bio-fortification programs.
HIV co-infection increases the risk of post-tuberculosis mortality among persons who initiated treatment for drug-resistant tuberculosis
Authors: Salindri Argita D. , Kipiani Maia , Lomtadze Nino , Tukvadze Nestani , Avaliani Zaza , Blumberg Henry M. , Masyn Katherine E. , Rothenberg Richard B. , Kempker Russell R. , Magee Matthew J.
Published: May 2023

Little is known regarding the relationship between common comorbidities in persons with tuberculosis (TB) (including human immunodeficiency virus [HIV], diabetes, and hepatitis C virus [HCV]) with post-TB mortality. We conducted a retrospective cohort study among persons who initiated treatment for rifampicin-resistant and multi/extensively drug-resistant (RR and M/XDR) TB reported to the country of Georgia’s TB surveillance during 2009-2017. Exposures included HIV serologic status, diabetes, and HCV status. Our outcome was all-cause post-TB mortality determined by cross-validating vital status with Georgia’s death registry through November 2019. We estimated adjusted hazard rate ratios (aHR) and 95% confidence intervals (CI) of post-TB mortality among participants with and without comorbidities using cause-specific hazard regressions. Among 1032 eligible participants, 34 (3.3%) died during treatment and 87 (8.7%) died post-TB treatment. Among those who died post-TB treatment, the median time to death was 21 months (interquartile range 7–39) post-TB treatment. After adjusting for confounders, the hazard rates of post-TB mortality were higher among participants with HIV co-infection (aHR=3.74, 95%CI 1.77–7.91) compared to those without HIV co-infection. In our cohort, post-TB mortality occurred most commonly in the first three years post-TB treatment. Linkage to care for common TB comorbidities post-treatment may reduce post-TB mortality rates.
Lack of univariate, clinically-relevant biomarkers of autism in resting state EEG: a study of 776 participants
Authors: Dede Adam J. O , Xiao Wenyi , Vaci Nemanja , Cohen Michael X , Milne Elizabeth
Published: May 2023

Mental health conditions are difficult to diagnose, requiring expert clinicians and subjective judgements. There has been interest in finding quantitative biomarkers using resting state electroencephalogram (EEG) data. Here, we focus on resting state EEG biomarkers of autism. Although many previous reports have pointed to differences between autistic and neurotypical participants, results have often failed to replicate and sample sizes have typically been small. Taking a big-data, open-science approach, we combined data from 5 studies to create a large sample of autistic and neurotypical individuals (n=776) and used high-power computing to extract 942 variables from each participant’s data. Using a systematic, preregistered analysis pipeline, we failed to identify even a single EEG-based variable that could serve as a practically useful biomarker of autism clinical diagnosis. Our results highlight that a biomarker for autism drawn from EEG data is an elusive construct that may not exist.
ECG predictors of AF: a systematic review (Predicting AF in Ischaemic Stroke-PrAFIS)
Authors: Berry-Noronha Alexander , Bonavia Luke , Song Edmund , Grose Daniel , Johnson Damian , Maylin Erin , Oqueli Ernesto , Sahathevan Ramesh
Published: May 2023

In 25% of patients presenting with embolic stroke, a cause is not determined. Atrial fibrillation (AF) is a commonly identified mechanism of stroke in this population, particularly in older patients. Conventional investigations are used to detect AF, but can we predict AF in this population and generally? We performed a systematic review to identify potential predictors of AF on 12-lead electrocardiogram (ECG).

Method

We conducted a search of EMBASE and Medline databases for prospective and retrospective cohorts, meta-analyses or case-control studies of ECG abnormalities in sinus rhythm predicting subsequent atrial fibrillation. We assessed quality of studies based on the Newcastle-Ottawa scale and data were extracted according to PRISMA guidelines.

Results

We identified 42 studies based on our criteria. ECG patterns that predicted the risk of developing AF included interatrial block, P-wave terminal force lead V1, P-wave dispersion, abnormal P-wave-axis, abnormal P-wave amplitude, prolonged PR interval, left ventricular hypertrophy, QT prolongation, ST-T segment abnormalities and atrial premature beats. Furthermore, we identified that factors such as increased age, high CHADS-VASC, chronic renal disease further increase the positive-predictive value of some of these parameters. Several of these have been successfully incorporated into clinical scoring systems to predict AF.

Conclusion

There are several ECG abnormalities that can predict AF both independently, and with improved predictive value when combined with clinical risk factors, and if incorporated into clinical risk scores. Improved and validated predictive models could streamline selection of patients for cardiac monitoring and initiation of oral anticoagulants.
Preregistration and Credibility of Clinical Trials*
Authors: Decker Christian , Ottaviani Marco
Published: May 2023

Preregistration at public research registries is considered a promising solution to the credibility crisis in science, but empirical evidence of its actual benefit is limited. Guaranteeing research integrity is especially vital in clinical research, where human lives are at stake and investigators might suffer from financial pressure. This paper analyzes the distribution of p-values from pre-approval drug trials reported toClinicalTrials.gov, the largest registry for research studies in human volunteers, conditional on the preregistration status. The z-score density of non-preregistered trials displays a significant upward discontinuity at the salient 5% threshold for statistical significance, indicative of p-hacking or selective reporting. The density of preregistered trials appears smooth at this threshold. With caliper tests, we establish that these differences between preregistered and non-preregistered trials are robust when conditioning on sponsor fixed effects and other design features commonly indicative of research integrity, such as blinding and data monitoring committees. Our results suggest that preregistration is a credible signal for the integrity of clinical trials, as far as it can be assessed with the currently available methods to detect p-hacking.
Vaccine-mediated protection against merbecovirus and sarbecovirus challenge in mice
Authors: Martinez David R. , Schaefer Alexandra , Gavitt Tyler D. , Mallory Michael L. , Lee Esther , Catanzaro Nicholas J. , Chen Haiyan , Gully Kendra , Scobey Trevor , Korategere Pooja , Brown Alecia , Smith Lena , Parks Rob , Barr Maggie , Newman Amanda , Bowman Cindy , Powers John M. , Mansouri Katayoun , Edwards Robert J. , Baric Ralph S. , Haynes Barton F. , Saunders Kevin O.
Published: May 2023

The emergence of three distinct highly pathogenic human coronaviruses – SARS-CoV in 2003, MERS-CoV in 2012, and SARS-CoV-2 in 2019 – underlines the need to develop broadly active vaccines against theMerbecovirusandSarbecovirusbetacoronavirus subgenera. While SARS-CoV-2 vaccines are highly protective against severe COVID-19 disease, they do not protect against other sarbecoviruses or merbecoviruses. Here, we vaccinate mice with a trivalent sortase-conjugate nanoparticle (scNP) vaccine containing the SARS-CoV-2, RsSHC014, and MERS-CoV receptor binding domains (RBDs), which elicited live-virus neutralizing antibody responses and broad protection. Specifically, a monovalent SARS-CoV-2 RBD scNP vaccine only protected against sarbecovirus challenge, whereas the trivalent RBD scNP vaccine protected against both merbecovirus and sarbecovirus challenge in highly pathogenic and lethal mouse models. Moreover, the trivalent RBD scNP elicited serum neutralizing antibodies against SARS-CoV, MERS-CoV and SARS-CoV-2 BA.1 live viruses. Our findings show that a trivalent RBD nanoparticle vaccine displaying merbecovirus and sarbecovirus immunogens elicits immunity that broadly protects mice against disease. This study demonstrates proof-of-concept for a single pan-betacoronavirus vaccine to protect against three highly pathogenic human coronaviruses spanning two betacoronavirus subgenera.
StructuralDPPIV: A novel deep learning model based on atom-structure for predicting dipeptidyl peptidase-IV inhibitory peptides
Authors: Wang Ding , Jin Junru , Li Zhongshen , Wang Yu , Fan Mushuang , Liang Sirui , Su Ran , Wei Leyi
Published: May 2023

Motivation

Diabetes is a chronic metabolic disorder that has been a major cause of blindness, kidney failure, heart attacks, stroke, and lower limb amputation across the world. To alleviate the impact of diabetes, researchers have developed the next generation of anti-diabetic drugs, known as dipeptidyl peptidase IV inhibitory peptides (DPP-IV-IPs). However, the discovery of these promising drugs has been restricted due to the lack of effective peptide-mining tools.

Results

Here, we presented StructuralDPPI V, a deep learning model designed for DPP-IV-IP identification, which takes advantage of both molecular graph features in amino acid and sequence information. Experimental results on the independent test dataset and two wet experiment datasets show that our model outperforms the other state-of-art methods. Moreover, to better study what StructuralDPPIV learns, we used CAM technology and perturbation experiment to analyze our model, which yielded interpretable insights into the reasoning behind prediction results.

Availability

The project code is available athttps://github.com/WeiLab-BioChem/Structural-DPP-IV.

Contact

weileyi@sdu.edu.cn,ran.su@tju.edu.cn
GASOLINE: detecting germline and somatic structural variants from long-reads data
Authors: Magi Alberto , Mattei Gianluca , Mingrino Alessandra , Caprioli Chiara , Ronchini Chiara , Frigè GianMaria , Semeraro Roberto , Bolognini Davide , Colombo Emanuela , Mazzarella Luca , Pelicci Pier Giuseppe
Published: May 2023

Long-read sequencing allows analyses of single nucleic-acid molecules and produces sequences in the order of tens to hundreds kilobases. Its application to whole-genome analyses allows identification of complex genomic structural-variants (SVs) with unprecedented resolution. SV identification, however, requires complex computational methods, based on either read-depth or intra- and inter-alignment signatures approaches, which are limited by size or type of SVs. Moreover, most currently available tools only detect germline variants, thus requiring separate computation of sample pairs for comparative analyses. To overcome these limits, we developed a novel tool (Germline And SOmatic structuraL varIants detectioN and gEnotyping; GASOLINE) that groups SV signatures using a sophisticated clustering procedure based on a modified reciprocal overlap criterion, and is designed to identify germline SVs, from single samples, and somatic SVs from paired test and control samples. GASOLINE is a collection of Perl, R and Fortran codes, it analyzes aligned data in BAM format and produces VCF files with statistically significant somatic SVs. Germline or somatic analysis of 30x sequencing coverage experiments requires 4-5 hours with 20 threads. GASOLINE outperformed currently available methods in the detection of both germline and somatic SVs in synthetic and real long-reads datasets. Notably, when applied on a pair of metastatic melanoma and matched-normal sample, GASOLINE identified 6 genuine somatic SVs that were missed using five different sequencing technologies and state-of-the art SV calling approaches. Thus, GASOLINE identifies germline and somatic SVs with unprecedented accuracy and resolution, outperforming currently available state-of-the-art WGS long-reads computational methods.
Conditional control of universal CAR T cells by cleavable OFF-switch adaptors
Authors: Kvorjak Michael , Ruffo Elisa , Tivon Yaniv , So Victor , Parikh Avani B. , Deiters Alexander , Lohmueller Jason
Published: May 2023

As living drugs, engineered T cell therapies are revolutionizing disease treatment with their unique functional capabilities. However, they suffer from limitations of potentially unpredictable behavior, toxicities, and non-traditional pharmacokinetics. Engineering conditional control mechanisms responsive to tractable stimuli such as small molecules or light is thus highly desirable. We and others previously developed “universal” chimeric antigen receptors (CARs) that interact with co-administered antibody adaptors to direct target cell killing and T cell activation. Universal CARs are of high therapeutic interest due to their ability to simultaneously target multiple antigens on the same disease or different diseases by combining with adaptors to different antigens. Here, we further enhance the programmability and potential safety of universal CAR T cells by engineering OFF-switch adaptors that can conditionally control CAR activity, including T cell activation, target cell lysis, and transgene expression, in response to a small molecule or light stimulus. Moreover, in adaptor combination assays, OFF-switch adaptors were capable of orthogonal conditional targeting of multiple antigens simultaneously following Boolean logic. OFF-switch adaptors represent a robust new approach for precision targeting of universal CAR T cells with potential for enhanced safety.
A single-cell atlas of the single versus multiple parous Hu Sheep ovary
Authors: Ge Ting , Wen Yifan , Li Bo , Huang Xiaoyu , Jiang Shaohua , Zhang Enping
Published: May 2023

In the modern sheep production system, the reproductive performance of ewes determines the economic profitability of farming. The mechanism of difference in litter size is important for the selection and breeding of high-fecundity ewes. Hu sheep is a high-quality sheep breed with high fecundity in China and is ideal for investigating high reproductive traits. In the current study, the sheep with lambing number ≥3 in three consecutive lambing records were assigned to the HLS group, and lambing number = 1 as the LLS group selected from the same farm with three consecutive lambing. Three randomly picked ewes were slaughtered within 12 h of estrus, and unilateral ovarian tissue was collected and analyzed by single-cell RNA sequencing in each group. A total of five types of somatic cells were identified, and corresponding expression profiles were mapped in the ovaries of the Hu sheep. Additionally, the results of the difference in ovary somatic cell expression profiles between HLS and LLS present that the differences between multiples vs. singleton Hu sheep were mainly clustered in the GCs. In addition, 4 granulosa cell subtypes were identified. GeneSwitches results revealed the opening ofJPH1expression and the closure ofLOC101112291, which leads to different evolutionary directions of the granular cells. The expression levels ofFTH1andFTLin GCs of Hu sheep in the HLS group were significantly higher, which inhibited necroptosis and ferroptosis of mural– GCs from decreasing follicular atresia. This study constructed the cellular atlas of the ovary and revealed related biological characteristics at the cellular molecular level. It provides a theoretical basis for the mechanisms underlying the differences in ovulation numbers, which contributes to breeding high-fertility sheep and molecular genetics-based selection.
ChAdOx1 COVID vaccines express RBD open prefusion SARS-CoV-2 spikes on the cell surface
Authors: Ni Tao , Mendonça Luiza , Zhu Yanan , Howe Andrew , Radecke Julika , Shah Pranav M. , Sheng Yuewen , Krebs Anna-Sophia , Duyvesteyn Helen M. E. , Allen Elizabeth , Lambe Teresa , Bisset Cameron , Spencer Alexandra , Morris Susan , Stuart David I. , Gilbert Sarah , Zhang Peijun
Published: May 2023

Vaccines against SARS-CoV-2 have been proven to be an effective means of decreasing COVID-19 mortality, hospitalization rates, and transmission. One of the vaccines deployed worldwide is ChAdOx1 nCoV-19, which uses an adenovirus vector to drive the expression of the original SARS-CoV-2 spike on the surface of transduced cells. Using cryo-electron tomography and subtomogram averaging, we determined the native structures of the vaccine product expressed on cell surfacesin situ. We show that ChAdOx1-vectored vaccines expressing the Beta SARS-CoV-2 variant produce abundant native prefusion spikes predominantly in one-RBD-up conformation. Furthermore, the ChAdOx1 vectored HexaPro stabilized spike yields higher cell surface expression, enhanced RBD exposure, and reduced shedding of S1 compared to the wild-type. We demonstratein situstructure determination as a powerful means for studying antigen design options in future vaccine development against emerging novel SARS-CoV-2 variants and broadly against other infectious viruses.
Compression strategies for large-scale electrophysiology data
Authors: Buccino Alessio P. , Winter Olivier , Bryant David , Feng David , Svoboda Karel , Siegle Joshua H.
Published: May 2023

Abstract

With the rapid adoption of high-density electrode arrays for recording neural activity, electrophysiology data volumes within labs and across the field are growing at unprecedented rates. For example, a one-hour recording with a 384-channel Neuropixels probe generates over 80 GB of raw data. These large data volumes carry a high cost, especially if researchers plan to store and analyze their data in the cloud. Thus, there is a pressing need for strategies that can reduce the data footprint of each experiment. Here, we establish a set of benchmarks for comparing the performance of various compression algorithms on experimental and simulated recordings from Neuropixels 1.0 (NP1) and 2.0 (NP2) probes. For lossless compression, audio codecs (FLACandWavPack) achieve compression ratios 6% higher for NP1 and 10% higher for NP2 than the best general-purpose codecs, at the expense of a slower decompression speed. For lossy compression, theWavPackalgorithm in “hybrid mode” increases the compression ratio from 3.59 to 7.08 for NP1 and from 2.27 to 7.04 for NP2 (compressed file size of∼14% for both types of probes), without adverse effects on spike sorting accuracy or spike waveforms. Along with the tools we have developed to make compression easier to deploy, these results should encourage all electrophysiologists to apply compression as part of their standard analysis workflows.
Domain-specific cognitive impairment reflects prefrontal dysfunction in aged common marmosets
Authors: Glavis-Bloom Courtney , Vanderlip Casey R , Asch Payton A , Reynolds John H
Published: May 2023

Age-related cognitive impairment is not expressed uniformly across cognitive domains. Cognitive functions that rely on brain areas that undergo substantial neuroanatomical changes with age often show age-related impairment, while those that rely on brain areas with minimal age-related change typically do not. The common marmoset has grown in popularity as a model for neuroscience research, but robust cognitive phenotyping, particularly as a function of age and across multiple cognitive domains, is lacking. This presents a major limitation for the development and evaluation of the marmoset as a model of cognitive aging, and leaves open the question of whether they exhibit age-related cognitive impairment that is restricted to some cognitive domains, as in humans. In this study, we characterized stimulus-reward association learning and cognitive flexibility in young adults to geriatric marmosets using a Simple Discrimination and a Serial Reversal task, respectively. We found that aged marmosets show transient impairment in “learning-to-learn” but have conserved ability to form stimulus-reward associations. Furthermore, aged marmosets have impaired cognitive flexibility driven by susceptibility to proactive interference. Since these impairments are in domains critically dependent on the prefrontal cortex, our findings support prefrontal cortical dysfunction as a prominent feature of neurocognitive aging. This work positions the marmoset as a key model for understanding the neural underpinnings of cognitive aging.

Significance Statement

Aging is the greatest risk factor for neurodegenerative disease development, and understanding why is critical for the development of effective therapeutics. The common marmoset, a short-lived non-human primate with neuroanatomical similarity to humans, has gained traction for neuroscientific investigations. However, the lack of robust cognitive phenotyping, particularly as a function of age and across multiple cognitive domains limits their validity as a model for age-related cognitive impairment. We demonstrate that aging marmosets, like humans, have impairment that is specific to cognitive domains reliant on brain areas that undergo substantial neuroanatomical changes with age. This work validates the marmoset as a key model for understanding region-specific vulnerability to the aging process.
Auditory brainstem responses are resistant to pharmacological modulation in Sprague Dawley wildtype and Neurexin1α knockout rats
Authors: Marashli Samuel , Janz Philipp , Redondo Roger
Published: May 2023

Sensory processing in the auditory brainstem can be studied with auditory brainstem responses (ABRs) across species. Although ABRs have been widely utilized to evaluate abnormalities in auditory brainstem physiology, there is limited understanding if ABRs can be useful tool to assess the effect of pharmacological interventions. Therefore, we set out to understand how pharmacological agents that target key transmitter systems of the auditory brainstem circuitry affect ABR physiology in rats. Given previous studies, demonstrating that Nrxn1α KO Sprague Dawley rats show substantial auditory processing deficits and altered sensitivity to GABAergic modulators, we used both Nrxn1α KO and wildtype littermates in our study. First, we probed how different commonly used anesthetics (isoflurane, ketamine/xylazine, medetomidine) affect ABRs waveforms. In the next step, we assessed the effects of different pharmacological compounds (diazepam, gaboxadol, retigabine, nicotine, baclofen and bitopertin) either under isoflurane or medetomidine anesthesia. We found that under our experimental conditions, ABRs are largely unaffected by diverse pharmacological modulation. Significant modulation was observed with i.) nicotine, affecting the late ABR components at 90 dB stimulus intensity under isoflurane anesthesia in both genotypes, and ii.) retigabine, showing a slight decrease in late ABRs deflections at 80 dB stimulus intensity, mainly in isoflurane-anesthetized Nrxn1α KO rats. Our study suggest that ABRs in anesthetized rats are resistant to a wide range of pharmacological modulators, which has important implications for the applicability of ABRs to study auditory brainstem physiology.
Inertial effect of cell state velocity on the quiescence-proliferation fate decision in breast cancer
Authors: Venkatachalapathy Harish , Brzakala Cole , Batchelor Eric , Azarin Samira M. , Sarkar Casim A.
Published: May 2023

Energy landscapes can provide intuitive depictions of population heterogeneity and dynamics. However, it is unclear whether individual cell behavior, hypothesized to be determined by initial position and noise, is faithfully recapitulated. Using the p21-/Cdk2-dependent quiescence-proliferation decision in breast cancer dormancy as a testbed, we examined single-cell dynamics on the landscape when perturbed by hypoxia, a dormancy-inducing stress. Combining trajectory-based energy landscape generation with single-cell time-lapse microscopy, we found that initial position on a p21/Cdk2 landscape did not fully explain the observed cell-fate heterogeneity under hypoxia. Instead, cells with higher cell state velocities prior to hypoxia, influenced by epigenetic parameters, tended to remain proliferative under hypoxia. Thus, the fate decision on this landscape is significantly influenced by “inertia”, a velocity-dependent ability to resist directional changes despite reshaping of the underlying landscape, superseding positional effects. Such inertial effects may markedly influence cell-fate trajectories in tumors and other dynamically changing microenvironments.