bluuebunny/crossref_metadata_2025 huggingface dataset:
Universal Exome Sequencing in Critically Ill Adults: A Diagnostic Yield of 25% and Race-Based Disparities in Access to Genetic Testing
Authors: Gold Jessica , Kripke Colleen M. ,   Regeneron Genetics Center,   Penn Medicine BioBank, Drivas Theodore G.
Published: March 2024

Numerous studies have underscored the diagnostic and therapeutic potential of exome or genome sequencing in critically ill pediatric populations. However, an equivalent investigation in critically ill adults remains conspicuously absent. We retrospectively analyzed whole exome sequencing (WES) data available through the PennMedicine Biobank (PMBB) from all 365 young adult patients, aged 18-40 years, with intensive care unit (ICU) admissions at the University of Pennsylvania Health System who met inclusion criteria for our study. For each participant, two Medical Genetics and Internal Medicine-trained clinicians reviewed WES reports and patient charts for variant classification, result interpretation, and identification of genetic diagnoses related to their critical illness.

Of the 365 individuals in our study, 90 (24.7%) were found to have clearly diagnostic results on WES; an additional 40 (11.0%) had a suspicious variant of uncertain significance (VUS) identified; and an additional 16 (4.4%) had a medically actionable incidental finding. The diagnostic rate of exome sequencing did not decrease with increasing patient age. Affected genes were primarily involved in cardiac function (18.8%), vascular health (16.7%), cancer (16.7%), and pulmonary disease (11.5%). Only half of all diagnostic findings were known and documented in the patient chart at the time of ICU admission. Significant disparities emerged in subgroup analysis by EHR-reported race, with genetic diagnoses known/documented for 63.5% of White patients at the time of ICU admission but only for 28.6% of Black or Hispanic patients. There was a trend towards patients with undocumented genetic diagnoses having a 66% increased mortality rate, making these race-based disparities in genetic diagnosis even more concerning. Altogether, universal exome sequencing in ICU-admitted adult patients was found to yield a new definitive diagnosis in 11.2% of patients. Of these diagnoses, 76.6% conferred specific care-altering medical management recommendations.

Our study suggests that the diagnostic utility of exome sequencing in critically ill young adults is similar to that observed in neonatal and pediatric populations and is age-independent. The high diagnostic rate and striking race-based disparities we find in genetic diagnoses argue for broad and universal approaches to genetic testing for critically ill adults. The widespread implementation of comprehensive genetic sequencing in the adult population promises to enhance medical care for all individuals and holds the potential to rectify disparities in genetic testing referrals, ultimately promoting more equitable healthcare delivery.
White Matter Integrity Differences in 2-year-old Children Treated with ECMO: A Diffusion-Weighted Imaging Study
Authors: Ruttorf Michaela , Filip Julia , Schaible Thomas , Weis Meike , Zöllner Frank G.
Published: March 2024

School-aged and adolescent survivors of neonatal extracorporeal membrane oxygenation (ECMO) treatment still suffer from neurodevelopmental delays such as verbal, visuo-spatial and working memory problems, motor dysfunction and sensorineural hearing loss, respectively, later in life. These neurodevelopmental delays are normally assessed by neuropsychological testing within follow-up programs. The purpose of this study is to demonstrate that diffusion-weighted imaging (DWI) in 2-year-old survivors of neonatal ECMO treatment might be a predictor of neurodevelopmental outcome. Therefore, 56 children underwent DWI at 3 T. Fractional anisotropy (FA), first fibre partial volume fraction estimate (F1) and radial diffusivity (RD) are compared using tract-based spatial statistics adapted to a paediatric brain atlas and whole-brain voxelwise statistics with age and gender as covariates of no interest. A significant difference in FA, F1 and RD between no-ECMO and ECMO group is seen in major white matter tracts and subcortical white matter in gyri leading to the conclusion that these differences are driven by alterations in axon coherence. Additionally, we examine individual diffusion measures by looking at masks from 50 brain regions taken from a paediatric brain atlas. We find left anterior corona radiata, left and right corpus callosum (genu, body and splenium), left and right crus of fornix, left anterior limb of internal capsule, left anterior commissure, left tapetum and right uncinate fasciculus to have significantly different means in no-ECMO compared to ECMO group which matches the reports of neuropsychological delays found in behavioural tests. To conclude, analysing diffusion measures at an early stage of life serves as a good tool to detect structural white matter changes in survivors of neonatal ECMO treatment like lacking axon coherence in fibre bundles which develop early in life. The advantage of DWI lies in looking only at the neurobiology, e.g. white matter integrity. Compared to neuropsychological testing, DWI in this age range is a very time-efficient method which does not depend on the child’s active participation. Additional targeted training could help to mitigate the neurodevelopmental deficits ECMO survivors face later in life.
Radiotherapy combined with EGFR-TKIs for stage III EGFR-Mutated lung cancer: A retrospective cohort study
Authors: Gang Liu , Yuan Wei , Langge Gan , Mei Gan , Qingping Zheng , Jing Huang
Published: March 2024

The present study aimed to evaluate the efficacy and safety of combining thoracic RT with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors(TKIs) in managing stage III lung cancer with EGFR mutation. Cases of patients with stage III EGFR-mutant lung cancer who received thoracic RT between December 2014 and December 2022 from multiple hospitals including The People’s Hospital of Laibin, The First People’s Hospital of Yulin and Guangxi Medical University Kaiyuan Langdong Hospital, were collected. The patients were divided into two groups based on the initial treatment approach: RT + TKIs(RT+TKI) group and RT + chemotherapy (RT+CT) group. The primary measure of interest was progression-free survival (PFS), and additional measures evaluated included objective response rate (ORR), overall survival (OS), patterns of treatment failure and adverse events. Survival analysis was performed using the Kaplan-Meier method, and the log-rank test was used to compare survival rates among different subgroups. A total of 54 patients were ultimately included, with 36 in the RT+TKI group and 18 in the RT+CT group. Regarding short-term efficacy, the ORR for the RT+TKI and RT+CT groups were 86.1 and 66.7%, respectively, with no statistically significant difference (P=0.189). Regarding long-term efficacy, the median PFS for the RT+TKI and RT+CT groups was 26.0 and 11.0 months, respectively, showing a significant difference (P<0.01). The 3 and 5-year OS rates between the RT+TKI and RT+CT groups did not exhibit statistical significance (P=0.825). Subgroup analysis revealed a statistically significant difference in PFS between the combination of RT with third-generation TKIs and first-generation TKIs (P=0.046). The Del19 subgroup exhibited a prolonged median PFS compared with the L858R subgroup, although the difference was not statistically significant (P=0.854). In terms of adverse reactions, the incidence rates of grade ≥3 hematological toxicity and gastrointestinal reactions in the RT+TKI group were significantly lower than those in the RT+CT group (P<0.05). However, the incidence rate of grade ≥3 radiation-related pneumonitis was similar between the RT+TKI and RT+CT groups, with no statistically significant difference. The results suggest that combination of RT and TKIs has superior efficacy and is a safer therapeutic approach for stage III EGFR-mutated lung cancer compared with concurrent radio-chemotherapy.

The present study was registered on theClinicalTrials.govwebsite on 2nd June 2023, with the trial registration numberNCT05934461.
Cross-validation coordinate analysis (CVCA): performing coordinate based meta-analysis using cross-validation
Authors: Tench C.R.
Published: March 2024

Coordinate based meta-analysis (CBMA) can be used to estimate where a future neuroimaging study testing a particular hypothesis might report summary results (activation foci, for example). However, current methods cannot be validated for all possible analyses, and use empirical features that might not always be ideal. Indeed, the various algorithms that perform CBMA tend to produce somewhat different results even on the same data. Furthermore, the use of null hypothesis significance testing (NHST) in the algorithms is not strictly in keeping with meta-analysis, where the aim is usually effect estimation rather than statistical significance.

Given the limitations of current CBMA algorithms, a new algorithm has been developed that will perform its analysis using cross validation: cross-validation coordinate analysis (CVCA). Although a full validation cannot be performed, CVCA optimises its parameters in such a way as to make the analysis results most similar to the held-out data. The algorithm can be used as a stand-alone meta-analysis method, or to provide confidence in results from other algorithms where no validation is performed.

Software to perform CVCA is freely available.
Integrating Social Determinants of Health with SOFA Scoring to Enhance Mortality Prediction in Septic Patients: A Multidimensional Prognostic Model
Authors: Sarraf Elie , Sadr Alireza Vafaei , Abedi Vida , Bonavia Anthony S
Published: March 2024

Background

The Sequential Organ Failure Assessment (SOFA) score is an established tool for monitoring organ failure and defining sepsis. However, its predictive power for sepsis mortality may not account for the full spectrum of influential factors. Recent literature highlights the potential impact of socioeconomic and demographic factors on sepsis outcomes.

Objective

This study assessed the prognostic value of SOFA scores relative to demographic and social health determinants in predicting sepsis mortality, and evaluated whether a combined model enhances predictive accuracy.

Methods

We utilized the Medical Information Mart for Intensive Care (MIMIC)-IV database for retrospective data and the Penn State Health (PSH) cohort for prospective external validation. SOFA scores, social/demographic data, and the Charlson Comorbidity Index were used to train a Random Forest model using the MIMIC-IV dataset, and then to externally validate it using the PSH dataset.

Findings

Of 32,970 sepsis patients in the MIMIC-IV dataset, 6,824 (20.7%) died within 30 days. The model incorporating demographic, socioeconomic, and comorbidity data with SOFA scores showed improved predictive accuracy over SOFA parameters alone. Day 2 SOFA components were highly predictive, with additional factors like age, weight, and comorbidity enhancing prognostic precision. External validation demonstrated consistency in the model’s performance, with delta SOFA between days 1 and 3 emerging as a strong mortality predictor.

Conclusion

Integrating patient-specific information with clinical measures significantly enhances the predictive accuracy for sepsis mortality. Our findings suggest the need for a multidimensional prognostic framework, considering both clinical and non-clinical patient information for a more accurate sepsis outcome prediction.
Aeron vs. Gaming Chair - Performance, Perception and Muscle Stiffness in Video Game Players: A Comparative Investigation
Authors: DiFrancisco-Donoghue Joanne , Zwibel Hallie , Werner William G
Published: March 2024

This study compared an Aeron office chair and a commercial gaming chair (GC) on muscle stiffness (MS), performance, and perceptions during a 2-hour gaming session.

Thirty-three esports players (23 ± 4.9) signed consent to participate in this mixed-methods randomized study. Subjects played League of Legends (LoL) in a controlled environment for two 2-hour sessions. MS was measured using oscillation frequency. Investigators recorded evaluations, game statistics, and player perceptions.

Descriptive statistics showed lower MS in the thoracic and lumbar region (left -4.4% vs. 0.32%; -2.7% vs. -2.1%; right 0.2% vs. 8.3%; 7% vs. 10.8%). The upper shoulder was higher in the GC only on the right (9.2% vs. -6.4; left 4.7 vs. 7.5). Most participants preferred the GC (58%), and players won 25% more and achieved 15% more kills in the GC.

The GC exhibited lower levels of muscle stiffness in the thoracic and lumbar regions. This data suggests that the GC is the preferred choice among this group of LoL gamers and is associated with enhanced performance.
The impact of measures set by national regulatory authority to enhance affordability of medicines in Sudan: when good intention leads to worse outcomes
Authors: Ali Gamal Khalafalla Mohamed , Abuelrish Yasir Abubaker Mohamed , Alfadl Abubakr Abdelraouf , Shigidi Mohamed Abdelrahman Mohamed
Published: March 2024

Introduction

The aim of this paper is to assess the impact of the measures and procedures imposed by the National Medicines and Poisons Board (NMPB) on the availability of safe, effective and quality medicines of affordable price on the Sudanese market.

Methods

This is a descriptive study in which pharmacists, who were responsible for the regulatory affairs within their importing and locally manufacturing medicine companies, were asked to complete a 45-question online survey using the Google application, covering relevance and challenges of medicines quality and pricing system. A link to the data collection tool website was sent to all members of the Sudanese Society of Regulatory Affairs Pharmacists through WhatsApp. The survey was available on 6th May 2020 through 6th June 2020. Descriptive statistics were used to report results.

Results

Survey respondents were 70 regulatory affairs’ pharmacists. 38% of participants believe that the technical procedures adopted by the NMPB do not achieve the goal of establishing Medicine Regulatory Authorities as described by World Health Organization. Almost all respondents believe that Sudan current economic situation, including the scarcity of foreign currency, has greatly impacted the availability of quality-assured medicines in pharmacies. Participants said that the situation is exacerbated by the intervention of NMPB in determining the exchange rate and controlling the medicine prices.

Conclusion

The NMPB should consider options for balancing patient access to quality medicines, and reasonable pricing policies that encourage the local pharmaceutical manufacturing to flourish and a steady flow of quality-assured medicines from abroad to the Sudan market.
Navigating the global egg shortage: a comprehensive study of interconnected challenges
Authors: Gunjan K , Pandey Ramendra Pati , Himanshu  , Mukherjee Riya , Chang Chung-Ming
Published: March 2024

Poultry eggs are a critical source of protein, vitamins, and minerals for people worldwide; facing the current global egg shortage is a significant concern. The shortage results from various factors, including avian flu outbreaks, changes in consumer demand, and supply chain disruptions caused by the COVID-19 pandemic. The economic crisis caused by the pandemic has also impacted the availability and affordability of eggs, particularly in low-income countries. The global egg shortage has implications for public health, particularly for vulnerable populations who rely on eggs for essential nutrients. One Health, an approach that recognizes the interconnectedness of human, animal, and environmental health, provides a useful framework for understanding and addressing the egg shortage. One Health approach to the egg shortage involves collaboration between agriculture and environmental sectors to address the root causes of the lack and ensure the sustainable production and distribution of eggs. Addressing the global egg shortage requires a multifaceted approach considering the complex social, economic, and environmental factors. One Health perspective offers a way to understand and address the interconnected factors contributing to the shortage to ensure access to affordable, nutritious eggs for all in a healthy way.
Molecular Insights into the Rescue Mechanism of an hERG Activator Against Severe LQT2 Mutations.
Authors: Kumawat Amit , Tavazzani Elisa , Lentini Giovanni , Trancuccio Alessandro , Kukavica Deni , Denegri Marco , Priori Silvia G , Camilloni Carlo
Published: March 2024

Mutations in the hERG potassium channel are a major cause of long QT syndrome type 2 (LQT2), which can lead to sudden cardiac death. The hERG channel plays a critical role in the repolarization of the myocardial action potential, and loss-of-function mutations prolong cardiac repolarization. In this study, we investigated the efficacy and mechanism of ICA-105574, an hERG activator, in shortening the duration of cardiac repolarization in severe LQT2 variants. We characterized the in vivo efficacy of ICA-105574 in shortening the QT duration in an animal model and in vitro in enhancing IKr current in cellular models mimicking severe hERG channel mutations (A561V, G628S, and L779P). We then used molecular dynamics simulations to investigate the molecular mechanism of ICA-105574 action. In vivo, ICA-105574 significantly shortened the QT interval. LQT2 mutations drastically reduced IKr amplitude and suppressed tail currents in cellular models. ICA-105574 restored IKr in A561V and G628S. Finally, in silico data showed that ICA-105574 stabilizes a pattern of interactions similar to gain-of-function SQT1 mutations and can reverse the G628S modifications, through an allosteric network linking the binding site to the selectivity filter and the S5P turret helix, thereby restoring its K+ ion permeability. Our results support the development of hERG activators as pharmacological molecules against some severe LQT2 mutations and suggest that molecular dynamics simulations can be used to test the ability of molecules to modulate hERG function in silico, paving the way for the rational design of new hERG activators.
Modeling the impact of optimized airflow and sick pen management on the spread of infectious diseases in swine barns
Authors: Safari Maryam , Fleming Christian , Galvis Jason A. , Deka Aniruddha , Sanchez Felipe , Machado Gustavo , Yeh Chi-An
Published: March 2024

The airborne spread of infectious livestock diseases plays a crucial role in the propagation of epidemics, particularly in populations confined to densely populated facilities, such as commercial swine barns. Therefore, quantitative assessments for the performance of barn ventilation systems may serve as an alternative biocontainment control strategy to reduce the spread of infectious pathogens. In this study, we present a framework to simulate airborne disease dissemination within swine barns and facilitate the strategic design of control actions, including optimization of ventilation and placement of sick animals (sick pen). This framework is based on a susceptible-infected-recovered (SIR) model that accounts for the between-pen disease spread within swine barns. A pen-to-pen contact network is used to construct a transmission matrix according to the transport of airborne respiratory pathogens across pens in the barns, via our Reynolds-averaged Navier-Stokes computational fluid dynamics (CFD) solver. By employing this CFD-augmented SIR model, we demonstrated that the location of the sick pen and the barn ventilation configuration played crucial roles in modifying disease dissemination dynamics at the barn level. In addition, we examined the effect of natural ventilation through different curtain adjustments. We observed that curtain adjustments either suppress the disease spread by an average of 56.5% or exacerbate the outbreak potential by an average of 5.7%, compared to the scenario where side curtains are not raised. Furthermore, we optimize the ventilation configuration via the selection and placement of ventilation fans through the integration of the CFD-augmented framework with the genetic algorithm to minimize the dissemination of swine disease within barns. Compared to regular barn ventilation settings, our optimized ventilation system significantly reduced disease spread by an average of 43.2%. Our study emphasizes the role of airborne transmission and a strategy for sick pen management in controlling the spread of within-barn disease.
Time series-free rhythm profiling using COFE reveals multi-omic circadian rhythms in in-vivo human cancers
Authors: Ananthasubramaniam Bharath , Venkataramanan Ramji
Published: March 2024

The study of the ubiquitous circadian rhythms in human physiology typically requires regular measurements across time. Repeated sampling of the different internal tissues that house circadian clocks is both practically and ethically infeasible. Here, we present a novel unsupervised machine learning approach (COFE) that can use single high-throughput (omics) samples from individuals to reconstruct circadian rhythms across cohorts. COFE can both assign time-labels to samples, and identify rhythmic data features used for temporal reconstruction. With COFE, we discovered widespread de novo circadian gene expression rhythms in eleven different human adenocarcinomas using data from the TCGA database. The arrangement of peak times of core clock gene expression was conserved across the cancers and resembled a healthy functional clock except for the mistiming of few key genes. The commonly rhythmic genes were involved in metabolism and the cell cycle. Although these rhythms were synchronized with the cell cycle in many cancers, they were uncoupled with clocks in healthy matched tissue. Moreover, rhythms in the transcriptome were strongly associated with the cancer-relevant proteome. The targets of most of FDA-approved and potential anti-cancer drugs were rhythmic in tumor tissue with different amplitudes and peak times, emphasizing the utility of considering "time" in cancer therapy. Our approach thus creates new opportunities to repurpose data without time-labels to study circadian rhythms.
Simultaneous and Dynamic Super-Resolution Imaging of Two Proteins inArabidopsis thalianausing dual-color sptPALM
Authors: Rohr Leander , Ehinger Alexandra , Burmeister Nina Glöckner , Meixner Alfred J. , Kemmerling Birgit , Harter Klaus , Oven-Krockhaus Sven zur
Published: March 2024

Super-resolution microscopy techniques have revolutionized cell biology by providing insights into the dynamics of single molecules and nanoscale organization within living cells. However, the application of dynamic live-cell methods in plants has been limited by the lack of suitable fluorophores for simultaneous visualization of multiple proteins. To address this challenge, we implemented a two-color sptPALM approach using codon-optimized photoactivatable fluorescent proteins PA-GFP and PATagRFP. Recently, we showed their individual usability in single-color experiments inNicotiana benthamianaandArabidopsis thalianacells. Here, we now demonstrate the suitability of these fluorophores and their combined use for dual-color sptPALM for the simultaneous observation of two different protein fusions in the same plant cell.
A sensorimotor enhanced neuromusculoskeletal model for simulating postural control of upright standing
Authors: Shanbhag Julian , Fleischmann Sophie , Wechsler Iris , Gassner Heiko , Winkler Jürgen , Eskofier Bjoern M. , Koelewijn Anne D. , Wartzack Sandro , Miehling Jörg
Published: March 2024

The human’s upright standing is a complex control process that is not yet fully understood. Postural control models can provide insights into the body’s internal control processes of balance behaviour. Using physiologically plausible models can also help explaining pathophysiological motion behaviour. In this paper, we introduce a neuromusculoskeletal postural control model using sensor feedback consisting of somatosensory, vestibular and visual information. The sagittal plane model was restricted to effectively six degrees of freedom and consisted of nine muscles per leg. Physiological plausible neural delays were considered for balance control. We applied forward dynamic simulations and a single shooting approach to generate healthy reactive balance behaviour during quiet and perturbed upright standing. Control parameters were optimized to minimize muscle effort. We showed that our model is capable of fulfilling the applied tasks successfully. We observed joint angles and ranges of motion in physiological plausible ranges and comparable to experimental data. This model represents the starting point for subsequent simulation of pathophysiological postural control behaviour.
Intra-Lymph Node Crosslinking of Antigen-Bearing Polymers Enhances Humoral Immunity and Dendritic Cell Activation
Authors: Euliano Erin M. , Agrawal Anushka , Yu Marina H. , Graf Tyler P. , Henrich Emily M. , Kunkel Alyssa A. , McHugh Kevin J.
Published: March 2024

Lymph node (LN)-resident dendritic cells (DCs) are a promising target for vaccination given their professional antigen-presenting capabilities and proximity to a high concentration of immune cells. Direct intra-LN injection has been shown to greatly enhance the immune response to vaccine antigens compared to traditional intramuscular injection but is infeasible to implement clinically. Employing the passive lymphatic flow of antigens to target LNs has been shown to increase total antigen uptake by DCs more than inflammatory adjuvants, which recruit peripheral DCs. Herein, we describe a novel vaccination platform in which two complementary multi-arm poly(ethylene glycol) (PEG) polymers—one covalently bound to the model antigen ovalbumin (OVA)—are injected subcutaneously into two distinct sites that drain to the same LN through different lymphatic vessels and, upon meeting in the LN, rapidly crosslink. This system improves OVA delivery to, and residence time within, the draining LN compared to all control groups, with the crosslinking of the two PEG components improving humoral immunity without the need for any pathogen-mimicking adjuvants. Further, we observed a significant increase in non-B/T lymphocytes in LNs cross-presenting the OVA peptide SIINFEKL on MHC I over a dose-matched control containing alum, the most common clinical adjuvant, as well as an increase in DC activation in the LN. These data suggest that this platform can be used to deliver antigens to LN-resident immune cells to produce a stronger humoral and cellular immune response over materials-matched controls without the use of traditional adjuvants.

Translational Impact Statement

Vaccines save millions of lives each year; however, they often require more than one injection to confer protection and do not always provide long-term immunity. Transitioning from intramuscular injections to intra-lymph node injections has been shown to greatly increase immunity conferred by vaccination but is infeasible to implement clinically. Herein, we present a biomaterial-based vaccination strategy that delivers antigen to the lymph nodes after a pair of remote injections, which increases the duration of immune cell exposure to the vaccine and, consequently, enhances humoral immunity.
Defining Network Topologies that Can Achieve Molecular Memory
Authors: Sevlever F.
Published: March 2024

In the context of cellular signaling and gene regulatory networks, the concept of molecular memory emerges as a crucial determinant of molecular mechanisms. This study introduces a novel memory quantifier designed to comprehensively capture and quantify the memory of a system in response to transient stimuli. We proposed and validate this quantifier through toy models, showcasing its effectiveness in systems with positive feedback loops and bistability. In addition, we develop an algorithm to assess long-term memory in circuits, leading to the identification of minimal motifs that play pivotal roles in conferring memory.

The research explores the comparative impact of positive and negative feedback loops on memory, revealing that positive feedback enhances memory while certain negative feedbacks may diminish it. An intriguing finding emerges as oscillating circuits, even in the absence of positive feedback, exhibit memory, with the phase of oscillations storing information about stimulus duration.

Finally, we experimentally validate the quantifier using mouse Embryonic Stem Cells (mESCs) subjected to transient differentiation stimuli. The proposed memory quantifier is applied to gene expression dynamics, revealing varying degrees of memory retention among different genes. The vectorial nature of the quantifier proves advantageous in capturing the holistic memory dynamics of the system.
Lipophilic compounds restore wt function of neurodevelopmental-associated KCNQ3 mutations
Authors: Edmond Michaela A. , Hinojo-Perez Andy , Efrem Mekedlawit , Lin Yi-Chun , Shams Iqra , Hayoz Sebastien , Cruz Alicia de la , Rodriguez Marta E. Perez , Diaz-Solares Maykelis , Dykxhoorn Derek M. , Luo Yun Lyna , Barro-Soria Rene
Published: March 2024

A major driver of neuronal hyperexcitability is dysfunction of K+channels, including voltage-gated KCNQ2/3 channels. Their slow activation and deactivation kinetics produces a current that regulates membrane potential and impedes repetitive firing. Mutations in KCNQ2 and KCNQ3 lead to a wide spectrum of neurodevelopmental disorders (NDDs), ranging from benign familial neonatal seizures to severe epileptic encephalopathies and autism spectrum disorders. However, the impact of these mutations on KCNQ channel function remains poorly understood and existing treatments have unpleasant side effects. Here we use voltage clamp fluorometry and molecular dynamic simulations to investigate how R227Q and R236C, two novel NDD-causing mutations in the voltage sensor of KCNQ3, impair channel function. We show that the two mutations perturb channel gating by two distinct mechanisms: R227Q altering voltage sensor movement and R236C altering voltage sensor-to-gate coupling. Our study further shows that polyunsaturated fatty acids (PUFAs), a novel class of ion channel modulators, primarily target the voltage sensor domain in its activated conformation and yield partial and complete restoration of wt function in R227Q– and R236C-containing channels, respectively. Our results reveal the potential of PUFAs to be developed into therapies for diverse KCNQ3-based channelopathies.
First insights of the Danube sturgeon (Acipenser gueldenstaedtii) skin adherent microbiota
Authors: Matache Răzvan , Deák György , Jawdhari Abdulhusein , Sadîca Isabela , Pop Cristian-Emilian , Fendrihan Sergiu , Crăciun Nicolae
Published: March 2024

This study assesses the microbial composition associated with the skin of Acipenser gueldenstaedtii, emphasizing species that are adherent. Various growth media were employed to cultivate samples collected from a group of 12 sturgeons from the same batch, revealing a diverse and atypical bacterial population. Notably, Ralstonia pickettii is documented here for the first time, as there have been no prior associations reported between this species and either wild or aquaculture sturgeon populations, to the best of our knowledge. The identification of presented adherent and non-adherent species raises questions and concerns regarding the existing microbial communities in sturgeons.
A physically inspired approach to coarse-graining transcriptomes reveals the dynamics of aging
Authors: Li Tao , Mani Madhav
Published: March 2024

Single-cell RNA sequencing has enabled the study of aging at a molecular scale. While substantial progress has been made in measuring age-related gene expression, the underlying patterns and mechanisms of aging transcriptomes remain poorly understood. To address this gap, we propose a physics-inspired, data-analysis approach to extract additional insights from single-cell RNA sequencing data. By considering the genome as a many-body interacting system, we leverage central idea of the Renormalization Group to construct an approach to hierarchically describe aging across a spectrum of scales for the gene expresion. This framework provides a quantitative language to study the multiscale patterns of aging transcriptomes. Overall, our study demonstrates the value of leveraging theoretical physics concepts like the Renormalization Group to gain new biological insights from complex high-dimensional single-cell data.
HaploSight: An alternative approach for Y chromosomal haplogroup identification
Authors: Laoprapaipan Lukkaet , Phusawang Kittichai , Laorchairangsi Peerapan , Kitnitchee Arnond , Wachirawanitchkit Hataitip , Suwanparsert Bun , Promnun Pattarapon
Published: March 2024

Identification of Y chromosomal haplogroups holds significance in the study of human evolution. In this context, an alternative approach named HaploSight was introduced for identifying Y chromosomal haplogroups. This approach relied on the algorithm of matched and unmatched informative SNPs extracted from the reference phylogenetic tree, implemented in Python. HaploSight demonstrated high accuracy in identifying haplogroups and offered adequate depth in haplogroup analysis. Furthermore, it was compatible with various genotyping arrays, enabling users to work with both sequencing and SNPs dataset.
A maternal high-fat diet predisposes to infant lung disease via increased neutrophil-mediated IL-6 trans-signaling
Authors: Curren Bodie , Ahmed Tufael , Rashid Ridwan B. , Sebina Ismail , Sikder Md. Al Amin , Howard Daniel R. , Alorro Mariah , Ullah Md. Ashik , Bissell Alec , Rahman Muhammed Mahfuzur , Pearen Michael A. , Ramm Grant A. , Varelias Antiopi , Rose-John Stefan , Hoelzle Robert , Cuív Páraic Ó , Spann Kirsten M. , Dennis Paul G. , Phipps Simon
Published: March 2024

Poor maternal diet during pregnancy predisposes to severe lower respiratory tract infections (sLRI) in infancy, which in turn, increases childhood asthma risk, however the underlying mechanisms remain poorly understood. Here, we show that the offspring of high fat diet (HFD)-fed mothers (‘HFD-reared pups’) developed a sLRI following pneumovirus inoculation in early-life and subsequent asthma in later-life upon allergen exposure. Prior to infection, HFD-reared pups developed microbial dysbiosis and low-grade systemic inflammation (LGSI), characterized by hyper-granulopoiesis in the liver and elevated inflammatory cytokine expression, most notably IL-17A, IL-6 and sIL-6R (indicative of IL-6 trans-signaling) in the circulation and multiple organs, but most prominently the liver. Inhibition of IL-6 trans-signaling, using sgp130Fc transgenic mice or via specific genetic deletion of IL-6Ra on neutrophils, conferred protection against both diseases. Taken together, our findings suggest that a maternal HFD induces neonatal LGSI that predisposes to sLRI and subsequent asthma via neutrophil-mediated IL-6 trans-signaling.
Frequency of Depressive Symptoms and Suicidal Ideation Among University Students Before and After the COVID-19 Pandemic
Authors: Macalli Mélissa , Castel Laura , Jacqmin-Gadda Hélène , Tournier Marie , Galéra Cédric , Pereira Edwige , Tzourio Christophe
Published: March 2024

Background

The COVID-19 pandemic and lockdown have had negative effects on students’ mental health. However, little information is available regarding the frequencies of depressive symptoms and suicidal ideation during the post-pandemic period. We aimed to compare prevalence rates of depressive symptoms and suicidal ideation among university students, before versus after the COVID-19 pandemic.

Methods

In this comparative study, 4464 students were recruited during the pre-COVID-19 pandemic period (2013-2020) and 1768 students, during the post-COVID-19 pandemic period (2022-2023). Standardized frequencies of depressive symptoms and suicidal ideation were compared between the two time periods. Adjusted logistic regression models were used to assess the association between the pandemic period (with the pre-COVID-19 period as reference) and depressive symptoms and suicidal ideation.

Results

Compared to participants from the pre-pandemic sample, participants from the post-pandemic sample had higher standardized rates of depressive symptoms (40.6% vs 25.6%) and suicidal ideation (29.3% vs 21.1%). With adjustment for age, gender, university campus, scholarship, and past history of depression and suicide attempt, students in the post-pandemic period experienced more depressive symptoms (aOR, 1.89; 95% CI, 1.67-2.13) and suicidal ideation (aOR, 1.46; 95% CI, 1.28-1.67) compared to students in the pre-COVID-19 era.

Limitations

The main limitations were self-selection bias and information bias due to potential over-reporting linked to media coverage, as well as measures of past history of depression and suicide attempt across the lifespan.

Conclusions

These findings reveal an alarming deterioration of students’ mental health in the post-pandemic period compared to the pre-pandemic era. Pending replications in others countries, these results suggest that it is crucial to continue monitoring students’ mental health, strengthening communication on this topic, and reinforcing university mental healthcare systems.
Early warning signals observed in motor activity preceding mood state change in bipolar disorder
Authors: Jakobsen Petter , Côté-Allard Ulysse , Riegler Michael Alexander , Stabell Lena Antonsen , Stautland Andrea , Nordgreen Tine , Torresen Jim , Fasmer Ole Bernt , Oedegaard Ketil Joachim
Published: March 2024

Background

Alterations in motor activity are well-established symptoms of bipolar disorder, and time series of motor activity can be considered complex dynamical systems. In such systems, early warning signals (EWS) occur in a critical transition period preceding a sudden shift (tipping point) in the system. EWS are statistical observations occurring due to a system’s declining ability to maintain homeostasis when approaching a tipping point. The aim was to identify critical transition periods preceding bipolar mood state changes.

Methods

Participants with a validated bipolar diagnosis were included to a one-year follow-up study, with repeated assessments of the participants’ mood. Motor activity was recorded continuously by a wrist-worn actigraph. Participants assessed to have relapsed during follow-up were analyzed. Recognized EWS features were extracted from the motor activity data and analyzed by an unsupervised change point detection algorithm, capable of processing multi-dimensional data and developed to identify when the statistical property of a time series changes.

Results

Of 49 participants, four depressive and four hypomanic/manic relapses among six individuals occurred, recording actigraphy for 23.8 ± 0.2 hours/day, for 39.8 ± 4.6 days. The algorithm detected change points in the time series and identified critical transition periods spanning 13.5 ± 7.2 days. For depressions 11.4 ± 1.8, and hypomania/mania 15.6 ± 10.2 days.

Conclusion

The change point detection algorithm seems capable of recognizing impending mood episodes in continuous flowing data streams. Hence, we present an innovative method for forecasting approaching relapses to improve the clinical management of bipolar disorder.
Childhood traumatic experiences and sleepwalking events in the lower GDP counties in Hungary
Authors: Correa Vivian M.
Published: March 2024

Purpose

The aim of the study was to identify injurious behavior during sleepwalking events and childhood traumatic experiences.

Study design

Eight questions from a sleepwalking study (02/2023) in different counties in Hungary were analyzed to find a relationship between traumatic experiences in the life of the participants, such as physical, emotional, or sexual abuse in childhood, and injurious behaviors during sleepwalking.

Methods

We estimated an association between the Hungarian counties by GDP per capita and individuals that reported injurious sleepwalking events and childhood trauma by logistic regression.

Results

A total of 749 participants agreed to answer all questions, of which 357 were over 50 years old and 363 males. The results have shown that sleepwalking events were reported in patients with childhood trauma significantly more frequently in the lower GDP counties in Hungary (OR:5.8, 1.21-27.99, P:0.02) even without family predisposition.

Conclusion

The results suggest that a childhood traumatic experience could be a ssociated with sleepwalking activities. Thus, family history and traumatic experiences can increase the probability of injurious behavior during sleepwalking in Hungary.
A distinctive tumor compartment in pancreatic lobules defined by nascent stroma and classical tumor cell phenotype
Authors: Söderqvist Sara , Viljamaa Annika , Geyer Natalie , Strell Carina , Hekmati Neda , Engstrand Jennie , Sparrelid Ernesto , Salmén Caroline , Heuchel Rainer L. , Zacharouli Argyro , Ghorbani Poya , Harrizi Sara , Hamidi Yousra , Khorosjutina Olga , Milanova Stefina , Schmierer Bernhard , Bozóky Béla , Moro Carlos Fernández , Gerling Marco
Published: March 2024

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type characterized by a particularly extensive stroma. While different types of cancer-associated fibroblasts (CAFs) in this desmoplastic stroma have been described, areas of early invasion and nascent stroma are understudied. Here, we identify a distinctive PDAC niche within the pancreatic lobules, a compartment dominated by pancreatic exocrine cells and slender stroma. Cellular interaction profiling using machine learning on whole slide images of human PDAC reveals that the tumor invasion front in the lobules is dominated by specific interactions of tumor cells and exocrine cells that have undergone acinar-to-ductal metaplasia (ADM). Multiplex protein and mRNA stains confirm that tumor growth in the lobules is closely linked to ADM in the lobules, and reveal stromal protein gradients from the gracile lobular stroma to the characteristic desmoplastic stroma. We identify nascent CAFs (nCAFs), co-expressing expressing nerve growth factor receptor (NGFR) and platelet-derived growth factor receptor alpha (PDGFRa) that are absent in the mature, desmoplastic stroma. Lobular invasion and nCAFs are intertwined with phenotypic changes of the cancer cells, such that tumor cells in lobules express classical subtype markers, while those embedded in the desmoplastic are on the basal end of the phenotypic continuum. In mice, the PDAC subtype – basal or classical – similarly depends on tissue location, suggesting microenvironmental factors rather than clonal selection as important drivers of tumor phenotype identity. Clinically, our results mandate factoring in tumor tissue location when calling PDAC subtypes. Biologically, they identify pancreatic lobules as a distinctive tissue niche associated with nascent stroma, and they suggest that lobular colonization by tumor cells is a significant route of PDAC progression.
A hemagglutinin and neuraminidase biased immunological memory shapes the dynamics of antibody responses to Influenza A virus
Authors: Lin Xia , Wang Jiaqi , Ling Shiman , Xiao Cheng , Liang Zaolan , Chow Cheuk Long , Yang Bingyi , Xiao Biying , Cowling Benjamin , Webby Richard , Zanin Mark , Wong Sook-San
Published: March 2024

Influenza A virus (IAV) infection establishes a more diverse immunological memory to different viral proteins compared to vaccination. We hypothesized that the relative abundance of pre-existing immune memory to different viral antigens could skew post-infection antibody responses. To explore this, we generated mouse models with either an IAV hemagglutinin (HA)- or neuraminidase (NA)-biased immunological memory. We inoculated groups of mice with cocktails of isogenic viruses bearing antigenically-distinct HA (H3v) or NA (N2v) chosen to span the IAV H3N2 human circulation history. We challenged the mice with two H3N2 strains of opposing virulence and antigenic distance (AD) and examined the post-infection antibody landscapes. In both challenges, immune-naïve mice seroconverted to both HA and NA whereas in primed mice, antibody response was detected to the antigen for which there is no pre-existing memory. In cases where the homologous antibody response was blunted, there was diversification on the breadth of response to antigenically-related strains with low baseline titers. Our findings clarifies the concept of “original antigenic sin” and demonstrate a mechanism by which the dynamics of antibody responses to HA and NA after infection can be altered by pre-existing immunity.
Olfaction in Tephritidae: a balance between detection and discrimination
Authors: Ramiaranjatovo Gaëlle , Charlery de la Masselière Maud , Dekker Teun , Duyck Pierre-François , Larsson Herrera Sebastian , Reynaud Bernard , Jacob Vincent
Published: March 2024

Phytophagous insects are capable of detecting and locating suitable hosts, which emit volatile compounds. Polyphagous species appear to have a complex olfactory strategy given that their numerous hosts have diverse emission profiles. In particular, their hosts’ volatile emissions share some of the same compounds, providing chemical bridges between them. However, the behavioural plasticity observed in insect host selection suggests that other volatiles have a complementary role. Here we explore how the specialization of polyphagous Tephritidae fruit fly in detecting and discriminating between host fruits has driven their chemical selectivity. The volatile emissions from intact or mechanically damaged fruit of 28 different species were analysed using gas chromatography-mass spectrometry and fed into a neuronal model of an olfactory system. We predictedin silicoa functional trade-off between the two tasks, with optimal performance depending on detecting a higher proportion of shared fruit compounds, but with lower sensitivity compared to unshared compounds, or vice-versa. Using triple point electroantennography and a behavioural assay, we studied the olfactory response of Tephritidae fruit fly species that oviposit on fruit. Amplitude of the olfactory responses of eight species were negatively correlated with the compound’s degree of sharedness among fruit emissions, while response probability was previously shown to correlate positively with a similar metric. A dose-dependent switch in the fly’s preference confirmed the ecological importance of both shared and unshared fruit compounds. Thus, we propose that insect olfactory systems are chemically tuned to detect suitable hosts and accurately discriminate between them.
How motility drives the glassy dynamics in confluent epithelial monolayers?
Authors: Sadhukhan Souvik , Nandi Manoj Kumar , Pandey Satyam , Paoluzzi Matteo , Dasgupta Chandan , Gov Nir , Nandi Saroj Kumar
Published: March 2024

As wounds heal, embryos develop, cancer spreads, or asthma progresses, the cellular monolayer undergoes glass transition between solid-like jammed and fluid-like flowing states. During some of these processes, the cells undergo an epithelial-to-mesenchymal transition (EMT): they acquire in-plane polarity and become motile. Thus, how motility drives the glassy dynamics in epithelial systems is critical for the EMT process. However, no analytical framework that is indispensable for deeper insights exists. Here, we develop such a theory inspired by a well-known glass theory. One crucial result of this work is that the confluency affects the effective persistence time-scale of active force, described by its rotational diffusivity,.differs from the bare rotational diffusivity,Dr, of the motile force due to cell shape dynamics, which acts to rectify the force dynamics:is equal toDrwhenDris small and saturates whenDris large. We test the theoretical prediction ofand how it affects the relaxation dynamics in our simulations of active Vertex model. This novel effect ofis crucial to understanding the new and previously published simulation data of active glassy dynamics in epithelial monolayers.