bluuebunny/crossref_metadata_2025 huggingface dataset:
ConvexGating infers gating strategies from clusters in single cell cytometry data
Authors: Friedrich Vincent D. , Mai Karola , Hofer Thomas P. , Nößner Elfriede , Bonaguro Lorenzo , Hartmann Celia L. , Frolov Aleksej , Carraro Caterina , Hamada Doaa , Hadaddzadeh-Shakiba Mehrnoush , Scholz Markus , Theis Fabian J. , Beyer Marc D. , Schultze Joachim L. , Büttner Maren
Published: November 2024

Manual expert gating remains common practice for the definition of specific cell populations in the analysis of flow cytometry data. The increasing number of measured parameters per individual cell and high inter-rater variability makes manual gating inconsistent in many scenarios such as multi-center studies. Here, we propose ConvexGating, an AI tool that automatically learns gating strategies in an unbiased, fully data-driven, yet interpretable manner. ConvexGating scales efficiently with increasing parameter space, creating proficient strategies with low-contamination in the extracted population for previously known and so far unknown or ill-defined cell populations. The inferred strategies are independent of parent populations, for instance, plasmacytoid dendritic cells (pDCs) can be fully identified as CD45RA- CD123+. In addition to flow cytometry data, ConvexGating derives gating strategies for cyTOF (Cytometry by Time of Flight) and CITEseq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) data and supports optimal design of marker panels for cell sorting.
Prefrontal cortex encodes behavior states decoupled from movement
Authors: Rautio Ida Välikangas , Nevjen Fredrik , Hem Ingeborg , Dunn Benjamin A. , Whitlock Jonathan R.
Published: November 2024

Prefrontal cortex is often viewed as an extension of the motor system, but little is understood of how it relates to natural motor behavior. We therefore tracked the kinematics of freely moving rats performing minimally structured tasks and measured which aspects of behavior were read out in prefrontal neural populations. Naturalistic behaviors such as rearing or chasing a bait were each encoded by unique neural ensembles, but the behavioral representations were not anchored to posture or movement. Rather, the coding of kinematic features depended on their relevance to the animals’ current behavior or which task the animal performed. Behavior-specific ensembles often preceded and outlasted physical actions and, accordingly, prefrontal population activity evolved at slower timescales than in motor cortex. These findings argue that prefrontal coding of behavior is not locked to motor output, and may instead reflect motivations to perform certain actions rather than the actions themselves.

Highlights

Prefrontal neural ensembles uniquely encode different naturalistic actions

Behavioral tuning is not explained by movement kinematics

Population activity in prefrontal cortex evolves slower than in M1

Single-cell coding of behavior varies across tasks yet ensemble coding is stable
Spotiphy enables single-cell spatial whole transcriptomics across the entire section
Authors: Yang Jiyuan , Zheng Ziqian , Jiao Yun , Yu Kaiwen , Bhatara Sheetal , Yang Xu , Natarajan Sivaraman , Zhang Jiahui , Easton John , Yan Koon-Kiu , Peng Junmin , Liu Kaibo , Yu Jiyang
Published: November 2024

Spatial transcriptomics (ST) has advanced our understanding of tissue regionalization by enabling the visualization of gene expression within whole tissue sections, but the approach remains dogged by the challenge of achieving single-cell resolution without sacrificing whole genome coverage. Here we present Spotiphy (Spot imager with pseudo single-cell resolution histology), a novel computational toolkit that transforms sequencing-based ST data into single-cell-resolved whole-transcriptome images. In evaluations with Alzheimer's disease (AD) and normal mouse brains, Spotiphy delivers the most precise cellular compositions. For the first time, Spotiphy reveals novel astrocyte regional specification in mouse brains. It distinguishes sub-populations of DAM (Disease-Associated Microglia) located in different AD mouse brain regions. Spotiphy also identifies multiple spatial domains as well as changes in the patterns of tumor-tumor microenvironment interactions using human breast ST data. Spotiphy enables visualization of cell localization and gene expression in tissue sections, offering key insights into the function of complex biological systems.
CETP expression in females increases body metabolism under both cold exposure and thermoneutrality contributing to a leaner phenotype
Authors: Castelli Júlia Z. , Raposo Helena F. , Navarro Claudia D. C. , Lazaro Carolina M. , Sartori Marina R. , Costa Ana Paula Dalla , Nogueira Pedro A. S. , Velloso Lício A. , Vercesi Anibal E. , Oliveira Helena C. F.
Published: November 2024

Susceptibility to obesity differs depending on the genetic background and housing temperatures. We have recently reported that CETP expressing female mice are leaner due to increased lipolysis, brown adipose tissue (BAT) activity and body energy expenditure compared to non-transgenic (NTg) littermates under standard housing temperature (22°C). The aim of this study is to evaluate how CETP expression affect body temperature, composition and metabolism during cold exposure (4°C) and thermoneutrality (30°C). When submitted to cold, CETP mice maintained rectal temperature, body weight and food intake similarly to NTg mice along acute or chronic exposure to 4ºC. The body oxygen consumption in response to an isoproterenol challenge was 21% higher at 22ºC, and 41% higher after 7 days of cold exposure in CETP than in NTg mice. In addition, BAT biopsies from CETP mice showed reduced lipid content and increased basal oxygen consumption rates. Under thermoneutrality (30ºC), when BAT activity is inhibited, CETP mice showed higher rectal and tail temperatures, increased food intake and increased energy expenditure. Lean mass was elevated and fat mass reduced in CETP mice kept at 30ºC. In this thermoneutrality condition, soleus muscle, but not gastrocnemius or liver of CETP mice showed increased mitochondrial respiration rates. These data indicate that CETP expression confers a greater capacity of elevating body metabolic rates at both cold exposure, through BAT activity, and at thermoneutrality, through increased muscle metabolism. Thus, the CETP expression levels in females should be considered as a new influence in the contexts of obesity and metabolic disorders propensity.

NEW & NOTEWORTHY

We demonstrate here that CETP expression in females increases body metabolism under cold (4ºC) and thermoneutrality (30ºC). Since this has also been shown at 22ºC, it seems a constitutive feature of CETP expression. Brown adipose tissue and red fiber muscle contribute to the overall high metabolism and leaner phenotype of CETP mice. Elevated mitochondrial respiration rates were demonstrated in these tissues. Thus, CETP is a new relevant variable in the context of obesity and metabolic disorders.

GRAPHICAL ABSTRACT
Multimodal state-dependent connectivity analysis of arousal and autonomic centers in the brainstem and basal forebrain
Authors: Pourmotabbed Haatef , Martin Caroline G , Goodale Sarah E , Doss Derek J , Wang Shiyu , Bayrak Roza G , Kang Hakmook , Morgan Victoria L , Englot Dario J , Chang Catie
Published: November 2024

Vigilance is a continuously altering state of cortical activation that influences cognition and behavior and is disrupted in multiple brain pathologies. Neuromodulatory nuclei in the brainstem and basal forebrain are implicated in arousal regulation and are key drivers of widespread neuronal activity and communication. However, it is unclear how their large-scale brain network architecture changes across dynamic variations in vigilance state (i.e., alertness and drowsiness). In this study, we leverage simultaneous EEG and 3T multi-echo functional magnetic resonance imaging (fMRI) to elucidate the vigilance-dependent connectivity of arousal regulation centers in the brainstem and basal forebrain. During states of low vigilance, most of the neuromodulatory nuclei investigated here exhibit a stronger global correlation pattern and greater connectivity to the thalamus, precuneus, and sensory and motor cortices. In a more alert state, the nuclei exhibit the strongest connectivity to the salience, default mode, and auditory networks. These vigilance-dependent correlation patterns persist even after applying multiple preprocessing strategies to reduce systemic vascular effects. To validate our findings, we analyze two large 3T and 7T fMRI datasets from the Human Connectome Project and demonstrate that the static and vigilance-dependent connectivity profiles of the arousal nuclei are reproducible across 3T multi-echo, 3T single-echo, and 7T single-echo fMRI modalities. Overall, this work provides novel insights into the role of neuromodulatory systems in vigilance-related brain activity.
Serum metabolome profiling in patients with mild cognitive impairment reveals sex differences in lipid metabolism
Authors: Diaz Escarcega Rocio , M. J. Vijay Kumar , Kyriakopoulos Vasilia E. , Ortiz Guadalupe J. , Gusdon Aaron M. , Fan Huihui , Peesh Pedram , Blasco Conesa Maria P. , Colpo Gabriela Delevati , Ahnstedt Hilda W. , Couture Lucy , Kim Stella H. , Hinojosa Miriam , Farrell Christine M. , Marrelli Sean P. , Urayama Akihiko , Ganesh Bhanu P. , Schulz Paul E. , McCullough Louise D. , Tsvetkov Andrey S.
Published: November 2024

Alzheimer’s disease (AD) affects more women than men. Although women live longer than men, it is not longevity alone, but other factors, including metabolic changes, that contribute to the higher risk of AD in women. Metabolic pathways have been implicated in AD progression, but studies to date examined targeted pathways, leaving many metabolites unmeasured. Sex is often a neglected biological variable, and most metabolomic studies were not designed to investigate sex differences in metabolomic profiles. Here, we performed untargeted metabolomic profiling of sera from male and female patients with mild cognitive impairment (MCI), a common precursor to AD, and matched controls. We discovered significant metabolic changes in individuals with MCI, and found several pathways that were strongly associated with sex. Peptide energy metabolism demonstrated sexual dimorphism. Lipid pathways exhibited the strongest differences between female and male MCI patients, including specific phosphatidylcholine lipids, lysophospholipids, long-chain fatty acids, and monoacylglycerols. 1-palmitoleoyl glycerol and 1-arachidonoyl glycerol were higher in female MCI subjects than in male MCI subjects with no differences between control males and females. Conversely, specific dicarboxylic fatty acids were lower in female MCI subjects than male MCI subjects. In cultured astrocytes, 1-arachidonoyl glycerol promoted phosphorylation of the transcriptional regulator sphingosine kinase 2, which was inhibited by the transient receptor potential vanilloid 1 receptor antagonists, as well as chromatin remodelling. Overall, we identified novel sex-specific metabolites in MCI patients that could serve as biomarkers of MCI in both sexes, help further define AD etiology, and reveal new potential prevention strategies for AD.

Highlights

▪

Individuals with MCI experience significant metabolic changes.

▪

Lipid pathways demonstrated the strongest sexual dimorphism in MCI.

▪

1-monoacylglycerols showed a robust sex association, being higher in MCI females.

▪

Sex-specific metabolites may be MCI biomarkers in each sex.
Proof-of-Concept Validation of Noninvasive Detection of Cortical Spreading Depolarization with High Resolution Direct Current-Electroencephalography
Authors: Brown Benjamin R. , Hund Samuel J. , Easley Kirk A. , Singer Eric L. , Shuttleworth C. William , Carlson Andrew P. , Jones Stephen C.
Published: November 2024

Background/Objective

Cortical spreading depolarization (SD) is increasingly recognized as a major contributor to secondary brain injury. Noninvasive SD monitoring would enable the institution of SD-based therapeutics. Our primary objective is to establish proof-of-concept validation that scalp DC-potentials can provide noninvasive SD detection by comparing scalp direct-current (DC)-shifts from a high-density electrode array to SDs detected by gold-standard electrocorticography (ECoG). Our secondary objective is to assess usability and artifact tolerance.

Methods

An 83×58 mm thermoplastic elastomer array with 29 6-mm diameter Ag/AgCl 1-cm spaced electrodes, the CerebroPatch™ Proof-of-Concept Prototype, was adhesively placed on the forehead with an intervening electrode gel interface to record DC-electroencephalography in normal volunteers and severe acute brain injury patients in the neuro-intensive care unit some with and some without invasive ECoG electrodes. The scalp and ECoG voltages were collected by a Moberg® Advanced ICU Amplifier. Artifacts were visually identified and usability issues were recorded. SD was scored on ECoG based on DC-shifts with associated high-frequency suppression and propagation. A six-parameter Gaussian plus quadratic baseline model was used to estimate ECoG and scalp electrode time-courses and scalp-voltage heat-map movies. The similarity of the noninvasive scalp and invasive ECoG DC-shift time-courses was compared via the Gaussian fit parameters and confirmed if the Coefficient-of-Determination was >0.80.

Results

Usability and artifact issues obscured most scalp Prototype device data of the 140 ECoG-coded SDs during 11 days in one sub-arachnoid hemorrhage patient. Twenty-six of these DC-shifts were in readable, artifact-free portions of scalp recordings and 24 of these had a >0.80 Coefficient-of-Determination (0.98[0.02], median[IQR]) between invasive ECoG and noninvasive Prototype device DC-shifts. Reconstructed heat-map movies of the scalp DC-potentials showed a 5-cm extent, -460 µV peak region that persisted for ∼70 sec. These data suggest that these scalp DC-shifts (peak -457±69 µV [mean±StD], full-width-half maximum 70.9±5.92 sec, area 18.7±2.76 cm2) depicted in the heat-map movies represent noninvasively detected SDs.

Conclusions

These results using 26 SDs as the observational units suggest that noninvasive SD detection is possible using scalp DC-potential signals with a high spatial resolution EEG array. Although the high artifact burden data and low usability records were limiting, negative results, they serve as an important entrepreneurial recipe for a future, re-designed device that would reduce artifacts and improve usability for DC-EEG SD detection needed to enable multi-modal monitoring for secondary brain injury.
The impact of research results feedback on the lived experiences of elderly participants in the DIMAMO health demographic site: a case of AWI-Gen Participants
Authors: Mashaba Reneilwe G. , Ntimana Cairo B. , Makoti Precious , Mothapo Katlego , Tlouyamma Joseph , Seakamela Kagiso P.
Published: November 2024

Backgrounds

The concept of engaging the community on the results if research or returning individual result to the respective participants seems more of an afterthought than an integral part of research processes. Therefore, the current study aims to assess the impact of research results feedback among study participants from a rural black community of low socio-economic status.

Methods

The study was qualitative. The consolidated criteria for reporting qualitative research (COREQ) guiding principle was used to present study findings. Data was collected through qualitative face-to-face in-depth interviews using an interview guide, between September and October 2024 in the Dikgale area, Limpopo province, South Africa. The transcripts were anonymized before entering them into QSR NVivo 10 (QSR International, Warrington, UK) to aid in analysis. The interview data was analyzed using a deductive content analysis method to develop themes.

Results

The present study included about 31 individuals of which 79% were women and 29% were men. Most participants in the present study had high school qualification as their highest level of education (74.20%) followed by those with no formal education and primary school level education at 16.15% and 12.90% respectively. Themes, identified through deductive analysis include health and lifestyle awareness, perceived benefits of research participation, community perception of health research, economic and social motivations, and challenges and concerns.

Conclusion

The present study shed light on the importance of retaining individual results for participants in health research. The themes that were generated showed that participants altered their lives and health-seeking behavior because of the information they got from participating in research a situation that would not have happened if they did not have the results back.
Descriptive epidemiology of COVID-19 outcomes in England, from September 2023 to April 2024
Authors: Abdul Aziz Nurin , Allen Hester , Assaraf Kiara , Dabrera Gavin , Ramsay Mary , Allen Alex
Published: November 2024

Introduction

COVID-19 disease has been associated with severe illness, hospitalisation and death, however, widespread vaccination coverage in England has resulted in reduced disease severity. From 2022, the national vaccination programme has been run twice per year, prioritising older age groups or those classified as clinically vulnerable. Here we assess the trends in COVID-19 outcomes between September 2023 and April 2024, using national-level data held by the UK Health Security Agency (UKHSA).

Methods

Data linkage of national-level COVID-19 episode data, NHS emergency and hospital attendance data, and death registrations were used to analyse COVID-19 outcomes. Outcomes were defined as COVID-19 associated A&E attendances, hospital admissions, severe hospitalisations, and deaths.

The number and rate of each COVID-19 outcome category between September 2023 and April 2024 was calculated, stratified by clinical risk status and age and sex.

Results

The most common COVID-19 outcomes during this time-period were A&E attendance and hospital admission, with the rates highest among those aged 75 and over. Among this age group, all outcomes disproportionately affect those who have been identified as at clinical risk and those who were immunosuppressed.

High rates of A&E attendance and hospital admission were also observed among infants (under 6 months old) but were lower for more severe outcomes.

Discussion

Groups that were most affected by COVID-19 outcomes were currently prioritised for COVID-19 vaccination in England, which will help protect against more severe outcomes including admission to intensive care and death.

Routine national levels surveillance of COVID-19 outcomes is essential to monitor populations most of severe disease and informing vaccination policy.
Perioperative oxygen concentration and postoperative organ damage in pediatric neurosurgery: a retrospective cohort study
Authors: Hu Zhengfang , Wang Chenwei , Wang Huiwen , Zhang Kangda
Published: November 2024

Purpose

To investigate the correlation between perioperative oxygen concentration and postoperative organ damage and other adverse reactions in children undergoing neurosurgery.

Materials and methods

This study was a single-center retrospective cohort study that included 512 children undergoing neurosurgery, aged ≤14 years old, and with an operative duration ≥2 hours who were transferred to the Postanesthesia Care Unit (PACU) of the Department of Anesthesiology, Beijing Tiantan Hospital, postop eratively during the period of October 2018 to September 2023. The medical records of the included children during hospitalization were meticulously reviewed and systematically collected through the Hospital Information System (His).The area under oxygen concentration-time curve AUCFIO2= the product of intraoperative oxygen concentration (percentage) and duration of anesthesia (minutes) was calculated, and then 512 children were divided into 3 groups according to the trichotomies of the AUCFIO2(Group1:AUCFIO2<8720%min, Group2: 8720% min ≤ AUCFIO2≤ 13800% min, Group 3: AUCFIO2> 13800% min) for inclusion in the data analysis.

Results

The incidence of Emergency delirium was 24%, 26.9% and 19.4%, and the incidence of acute kidney injury was 0.6%, 2.3% and 0.6% in the three groups, respectively. There was no significant difference between the three groups (P> 0.05). The incidence of postoperative pulmonary complications in the three groups was 20.6%, 20.8% and 31.5%, respectively, and there was a statistically significant difference between the three comparisons (P<0.05). There were no significant differences in nausea, vomiting, hypoxemia, VAS score and PACU residence time among the three groups during PACU (P>0.05), and there was a statistically significant differences between infections and hospital stay during hospitalization (P<0.05).

Conclusions

Although the oxygen concentration AUCFIO2was not correlated with the occurrence of both postoperative AKI and ED, the longer the exposure time of conventional oxygen administration strategy, the higher the incidence of postoperative pulmonary complications and postoperative infections, and the longer the hospitalization time of children.
Comparison of Early and Intermediate-Term Outcomes Between Hybrid Arch Debranching and Total Arch Replacement: A Systematic Review and Meta-analysis of Propensity-Matched Studies
Authors: Kaewboonlert Naritsaret , Slisatkorn Worawong , Tantraworasin Apichat , Pleehachinda Punthiti , Prapassaro Tossapol , Pongsuwan Natthipong , Chatkaewpaisal Chanut , Ruangpratyakul Tummarat
Published: November 2024

OBJECTIVES

To systematically review and pool the clinical outcomes of hybrid arch repair (HAR) and total arch replacement (TAR) with or without a frozen elephant trunk for treating aortic arch aneurysms, dissections, or other pathology in propensity score-matched studies.

METHODS

We conducted electronic database searches in PubMed, Embase, the Cochrane Library, and Google Scholar to identify studies reporting outcomes of HAR versus TAR. Risk of bias was assessed using non-randomized studies of interventions (ROBINS-I) tool. The primary outcome was in-hospital mortality analyzed using a random-effects model to compute the odds ratio (OR). Survival probability was expressed as hazard ratios (HR) calculated through the inverse variance method. The results were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

RESULTS

This meta-analysis included 13 studies with 3,392 patients. There was no significant difference in in-hospital mortality between HAR and TAR groups (OR 1.08; 95% CI 0.78-1.49; p = 0.630). However, HAR group showed a higher incidence of permanent neurological dysfunction (PND) (OR 1.71; 95% CI 1.22-2.41; p < 0.001). In subgroup meta-analysis with isolated type A aortic dissection (ITAAD), HAR showed significantly lower in-hospital mortality (p = 0.040) but no difference in PND. Other post-operative complications were significantly lower in the HAR group for renal failure (OR 0.65; 95% CI 0.49-0.87; p < 0.001), sternal re-entry due to bleeding (OR 0.55; 95% CI 0.34-0.89; p = 0.010), and tracheostomy (OR 0.61; 95% CI 0.38-0.96; p = 0.030). There is no statistical difference in 3-year survival probability (HR 0.97; 95% CI 0.70-1.35; p = 0.870).

CONCLUSIONS

TAR has more favorable than HAR in MDAD patients, offering lower rates of neurological dysfunction and better 3-year freedom from re-intervention. For ITAAD patients, HAR potentially provides better in-hospital mortality and 3-year survival rates, with fewer complications such as renal failure, re-sternotomy, and tracheostomy.
Music education reduces emotional symptoms in children: A quasi-experimental study in the Guri Program in Brazil
Authors: Bortz Graziela , Ilari Beatriz , Di Giuseppe Germano Nayana , Jackowski Andrea Parolin , Cogo-Moreira Hugo , Lúcio Patrícia Silva
Published: November 2024

The transferability of music education to cognitive and social skills has been explored recently, but its causal effects remain debatable. This quasi-experimental study aimed to examine the impact of a music education program (Guri) on aspects attention, working memory and socioemotional skills in children from underserved communities of São Paulo, Brazil. The music group (n = 38, 5-9 years) was recruited from 10 centers (polos) distributed across the metropolitan area of São Paulo and the control group (n = 67) consisted of aged-matched children who attended public schools surrounding the polos. The ABEP SES questionnaire and the Raven test were used as control variables, the SDQ questionnaire, the Digit-span subtest from WISC-IV, the PARB-Q questionnaire, and the BPA test were used as subject variables. A significant effect of the intervention in emotional symptoms in the music group as opposed to controls was found (F(1,89) = 4.562, p = 0.035, η2= 0.049), indicating benefits for the music group. Children whose mothers had low levels of education benefited with gains between 0.70 and 0.95 standard deviations in both groups for divided attention, indicating a significant interaction with maternal education.
Parental Knowledge, Attitudes, and Practices Regarding Antibiotic Use in Pediatric Respiratory Infections: A Qualitative Study
Authors: Khan Muhammad Uneeb , Khan Zakir , Khan Areej
Published: November 2024

Antibiotic misuse for respiratory tract infections (RTIs) is on the rise particularly among developing nations like Pakistan. This study evaluates parental knowledge, attitudes, and practices regarding RTI antibiotic use, which significantly impact antibiotic resistance trends. Targeted interventions to promote antibiotic use and reduce community resistance require understanding these dynamics.

Parents were recruited and interviewed in a tertiary care hospital and community pharmacies, representing both urban and rural areas, regardless of ethnicity or occupation. Face-to-face interviews with 21 parents were audio-recorded and transcribed verbatim. Conducted by one male and one female interviewer, these qualitative interviews provided an in-depth understanding of parental knowledge, attitudes, and practices (KAP) regarding antibiotic use for respiratory tract infections (RTIs) in children. Deductive thematic analysis was used, with predefined codes and themes refined throughout the process to capture evolving insights.

In total, 21 parents were interviewed, with 76% mothers and 24% fathers, and a median age of 24 for younger parents and 38 for older. Key barriers to accessing medical care for children with RTIs included financial constraints (38%) and transportation issues (34%). While 57% of parents preferred herbal remedies, 71% stated they would consult a doctor rather than reuse previously prescribed antibiotics. Additionally, 52% of parents believed doctors should take responsibility for educating families about proper antibiotic use and resistance.

This study highlights gaps in parental knowledge and practices regarding antibiotic use for RTIs in children, with financial and transportation barriers influencing access to medical care. While a significant portion of parents prefer herbal remedies, most would consult a doctor rather than reuse antibiotics. Targeted interventions, particularly through healthcare provider education, are crucial to promoting appropriate antibiotic use and combating resistance in developing nations like Pakistan.
Evaluating Multicultural Autism Screening for Toddlers Using Machine Learning on the QCHAT-10
Authors: Sollis Lydia J. , Wall Dennis P. , Washington Peter Y.
Published: November 2024

Early identification and intervention often leads to improved life outcomes for individuals with Autism Spectrum Disorder (ASD). However, traditional diagnostic methods are time-consuming, frequently delaying treatment. This study examines the application of machine learning (ML) techniques to 10-question Quantitative Checklist for Autism in Toddlers (QCHAT-10) datasets, aiming to evaluate the predictive value of questionnaire features and overall accuracy metrics across different cultures. We trained models using three distinct datasets from three different countries: Poland, New Zealand, and Saudi Arabia. The New Zealand and Saudi Arabian-trained models were both tested on the Polish dataset, which consisted of diagnostic class labels derived from clinical diagnostic processes. The Decision Tree, Random Forest, and XGBoost models were evaluated, with XGBoost consistently performing best. Feature importance rankings revealed little consistency across models; however, Recursive Feature Elimination (RFE) to select the models with the four most predictive features retained three common features. Both models performed similarly on the Polish test dataset with clinical diagnostic labels, with the New Zealand models with all 13 features achieving an AUROC of 0.94 ± 0.06, and the Saudi Model having an AUROC of 93% ± 6. This compared favorably to the cross-validation analysis of a Polish-trained model, which had an AUROC of 94% ± 5, suggesting that answers to the QCHAT-10 can be predictive of an official autism diagnosis, even across cultures. The New Zealand model with four features had an AUROC of 85% ± 13, and the Saudi model had a similar result of 87% ± 11. These results were somewhat lower than the Polish cross-validation AUROC of 91% ± 5. Adjusting probability thresholds improved sensitivity in some models, which is crucial for screening tools. However, this threshold adjustment often resulted in low levels of specificity during the final testing phase. Our findings suggest that these screening tools may generalize well across cultures; however, more research is needed regarding differences in feature importance for different populations.
Transcriptome Signatures for Cognitive Resilience Among Individuals with Pathologically Confirmed Alzheimer Disease
Authors: Li Donghe , Han Xudong , Farrer Lindsay A. , Stein Thor D. , Jun Gyungah R.
Published: November 2024

INTRODUCTION

Limited success to date in development of drugs that target hallmark Alzheimer disease (AD) proteins as a means to slow AD-related cognitive decline has sparked interest in approaches focused on cognitive resilience. We sought to identify transcriptome signatures among brain donors with neuropathologically confirmed AD that distinguish those with cognitive impairment from those that were cognitively intact.

METHODS

We compared gene expression patterns in brain tissue from donors in four cohorts who were cognitively and pathologically normal (controls), met clinical and pathological criteria for AD (SymAD), or were cognitively normal prior to death despite pathological evidence of AD (cognitively resilient or AsymAD). Differentially expressed genes (DEGs) at the transcriptome-wide significance (TWS) level (P<10-6) in the total sample and nominally significant (P<0.05) in at least two datasets were further evaluated in analyses testing association of gene expression with co-calibrated and harmonized cognitive domain scores and AD-related neuropathological traits.

RESULTS

We identified 52 TWS DEGs, including 14 that surpassed a significance threshold of P<5×10−8. The three most significant DEGs,ADAMTS2(Log2 fold change [Log2FC]=0.46, P=2.94×10−14),S100A4(Log2FC=0.61, P=3.98×10−11) andNRIP2(Log2FC=0.32, P=9.52×10−11) were up-regulated in SymAD compared to AsymAD brains.ADAMTS2andSLC6A9were also significantly and nominally differentially expressed between AsymAD cases and controls (FDR P=0.45 and FDR P=0.57, respectively). Significant associations (P<0.0038) were identified for executive function with expression ofADAMTS2(P=4.15×10−8) andARSG(P=1.09×10−3), and for memory withPRELP(P=3.92×10−5) andEMP3(P=7.75×10−4), and for language withSLC38A2(P=6.76×10−5) andSLC6A9(P=2.13 ×10−3). Expression ofARSGandFHIP1Bwere associated with measures of Tau pathology (AT8: P=1.5×10−3, and pTau181: P=3.64×10−3, respectively), andSLC6A9expression was associated with multiple pTau isoforms including pTau181 (P=1.5×10−3) and pTau396 (P=2.05×10−3).PRELPexpression was associated with synaptic density(PSD.95: P=6.18×10−6). DEGs were significantly enriched in pathways involving E2F targets, cholesterol homeostasis, and oxidative phosphorylation.

CONCLUSION

We identified multiple DEGs that differentiate neuropathologically confirmed AD cases with and without cognitive impairment prior to death. Expression of several of these genes was also associated with measures of cognitive performance and AD-related neuropathological traits, thus providing important insights into cognitive resilience mechanisms and strategies for delaying clinical symptoms of AD.
Wireless recordings from dragonfly target detecting neurons during prey interception flight
Authors: Lin Huai-Ti , Siwanowicz Igor , Leonardo Anthony
Published: November 2024

Target interception is a complex sensorimotor behavior which requires fine tuning of the sensory system and its strategic coordination with the motor system. Despite various theories about how interception is achieved, its neural implementation remains unknown. We have previously shown that hunting dragonflies employ a balance of reactive and predictive control to intercept prey, using sophisticated model driven predictions to account for expected prey and self-motion. Here we explore the neural substrate of this interception system by investigating a well-known class of target-selective descending neurons (TSDNs). These cells have long been speculated to underlie interception steering but have never been studied in a behaving dragonfly. We combined detailed neuroanatomy, high-precision kinematics data and state-of-the-art neural telemetry to measure TSDN activity during flight. We found that TSDNs are exquisitely tuned to prey angular size and speed at ethological distances, and that they synapse directly onto neck and wing motoneurons in an unusual manner. However, we found that TSDNs were only weakly active during flight and are thus unlikely to provide the primary steering signal. Instead, they appear to drive the foveating head movements that stabilize prey on the eye before and likely throughout the interception flight. We suggest the TSDN population implements the reactive portion of the interception steering control system, coordinating head and wing movements to compensate for unexpected prey motion.
Unravelling the Molecular Footprints of Diabetic Foot Ulcers: In Silico Discovery of Key Protein and MicroRNA Signatures
Authors: Chudasama Jay Mukesh , Parmar Ghanshyam
Published: November 2024

Diabetic foot ulcers (DFUs) present a significant clinical challenge, characterized by chronic inflammation and impaired wound healing. This study employs Gene Ontology (GO) analysis to identify critical biological processes, molecular functions, cellular components, and pathways associated with DFUs, aiming to uncover novel therapeutic targets. The analysis reveals significant enrichment in biological processes such as Positive Regulation of miRNA Transcription and Regulation of miRNA Transcription, highlighting the crucial role of microRNAs, including hsa-miR-34a-5p, hsa-miR-155-5p, hsa-miR-17-5p, hsa-miR-29b-3p, hsa-miR-7-5p, hsa-miR-1-3p, and hsa-miR-23b-3p, in regulating wound healing and inflammation. Enriched molecular functions, such as DNA-binding Transcription Activator Activity and Protein Phosphatase Binding, suggest that targeting genes like TP53, GAPDH, AKT1, MYC, TNF, EGFR, STAT3, FN1, VEGFA, and JUN could modulate critical cellular processes and improve DFU management. The analysis also identifies key cellular components, including Vesicle and Platelet Alpha Granule Lumen, as crucial for cellular transport and signaling, suggesting that interventions targeting these components could enhance wound repair. Furthermore, enriched pathways such as Proteoglycans in Cancer and Human Cytomegalovirus Infection indicate potential mechanisms and viral influences relevant to DFUs. These findings provide a comprehensive framework for developing targeted therapies that address the multifaceted pathology of DFUs, offering promising avenues for improving patient outcomes and advancing wound healing strategies.
Spatial confinement induces reciprocating migration of epidermal keratinocytes and forms triphasic epithelia
Authors: Nohara Takuma , Kumamoto Junichi , Mai Yosuke , Shimano Mayuna , Kato Sora , Kitahata Hiroyuki , Nakamura Hideki , Takashima Shota , Watanabe Mika , Nagayama Masaharu , Oikawa Tsukasa , Ujiie Hideyuki , Natsuga Ken
Published: November 2024

Epithelial cells undergo epithelial–mesenchymal transition (EMT) during migration and regain their epithelial phenotype in the post-migration phase (mesenchymal– epithelial transition; MET). We established an experimental system that reproduced three-dimensional triphasic epithelia, i.e., the original epithelium, its EMT, and MET. Keratinocytes (KCs), skin epithelial cells, placed on a microporous membrane migrated through 3.0-µm or larger micropores. The 3.0-µm-pored membrane induced an epithelial structure with three states: stratified KCs above the membrane, KCs showing EMT within the micropores, and a new stratified epithelium under the membrane. The membrane with larger micropores failed to maintain the triphasic epithelia. Live imaging revealed that KCs moved in a reciprocating manner, with actin-rich filopodia-like KC structures extending into and out of the 3.0-µm micropores, while the cells migrated unidirectionally into larger micropores. Piezo1 and keratin 6 were identified as negative modulators of KC entry to and exit from the 3.0-µm micropores. These results demonstrate that non-cancerous epithelial cells migrate through confined spaces in a reciprocating manner, which might help form triphasic epithelia, recapitulating wound healing processes.
Binding of CEP152 to PLK4 stimulates kinase activity to promote centriole assembly
Authors: Gürkaşlar Hazal Kübra , Hoffmann Ingrid
Published: November 2024

Centriole duplication is regulated by polo-like kinase 4 (PLK4) and several conserved initiator proteins. The precise timing and regulation of PLK4 activation are critical for ensuring that centriole duplication occurs only once per cell cycle. While significant progress has been made in understanding how PLK4 is activated, many aspects remain unclear. Here, we show how CEP152 contributes to the activation of PLK4. We utilize human cell lines that have been genetically engineered to rapidly degrade CEP152. Upon degradation of CEP152, localization of PLK4 at the proximal end of the centriole is disrupted. We show that binding of CEP152 N-terminal part to PLK4 increases phosphorylation and kinase activation. CEP152 controls the localization and levels of phosphorylated PLK4 at the proximal end of the centriole. CEP152 can phosphorylate and activate PLK4 bothin vitroandin vivowhich might stabilize PLK4 dimer formation, thus allowing autophosphorylation. We propose that CEP152 activates PLK4 to ensure proper centriole duplication at the onset of S-phase.
AKCNC1Variant Linked to Rett Syndrome Disrupts ER to Golgi Trafficking of Kv3.1 Channel
Authors: Maureira Diego , Rubilar Carla , López Joaquín , Santander Paola , Moldenhauer Hans , Silva Ian , Cruz Pablo , Riquelme Denise , Baeza Javiera , González Wendy , Orio Patricio , Servili Evrim , Troncoso Mónica , Leiva-Salcedo Elías , Cerda Oscar
Published: November 2024

Intrinsic neuronal excitability, defined by the balance between input and output signals, is crucial to neural function, and its disruption underlies various neurological diseases. Kv3.1 channels, encoded byKCNC1, are essential for high-frequency action potential firing. Variants in these channels are associated with several subtypes of epilepsy. We report a patient with developmental regression and epilepsy, meeting Rett syndrome criteria, who carries aKCNC1variant encoding the S474C substitution in Kv3.1 (Kv3.1S474C). Electrophysiological and biochemical assays reveal that Kv3.1S474Creduces channel presence in the plasma membrane and is retained in the endoplasmic reticulum (ER). In murine primary cultures expressing Kv3.1S474C, we observed reduced neuronal firing frequency and exclusion of the channel from the axon initial segment (AIS). Consistently, we found a decreased firing frequency using a conductance-based computational neuronal model. In summary, this study identifies a novel link between aKCNC1variant and Rett syndrome, highlighting the importance of S474 residue in Kv3.1 channel trafficking and function in neurons.

This study identifies and characterizes a novelKCNC1variant associated with classical Rett syndrome. This variant disrupts endoplasmic reticulum (ER) to Golgi trafficking of the Kv3.1 channels, highlighting the variant’s potential role in altered neuronal excitability and neurodevelopmental disorders.
Investigating the genetic relationship ofTrichosporon asahiiisolates using a newly developed microsatellite typing assay
Authors: Francisco Elaine C. , Fernández Norma B. , Carbia Mauricio , Dieleman Chendo , Bostanaru-Iliescu Andra-Cristina , Houbraken Jos , Colombo Arnaldo L. , Hagen Ferry
Published: November 2024

The basidiomycetous yeast-like fungusTrichosporon asahiiis increasingly encountered in the clinic and has been known to cause nosocomial infections. Here, we aim to develop a microsatellite typing tool to investigate the genetic relatedness ofTrichosporon asahiiisolates. Six microsatellite markers were selected from a nanopore long-read sequencing de novo assembled genome of theT. asahiitype-strain CBS 2479. PCR reactions amplified three di-, tri-, or tetranucleotide repeats, respectively. All six microsatellite markers were used to analyze 111T. asahiiisolates, including single and related-patient isolates from clinical and environmental sources. Each marker exhibited between 11 and 37 alleles in this population, resulting in 71 different microsatellite genotypes. The Simpson’s diversity index ranged from 0.6452 to 0.8280 for the individual markers, and for the combined set of microsatellites 0.9793, indicating the high discriminatory power of the reported panel. In summary, this panel combines high reproducibility and specificity, making it suitable for use in epidemiological studies ofT. asahiiand in investigations of potential outbreaks caused by this pathogen.
A conservedin vivoburn wound infection model for diverse pathogenic fungi
Authors: Mercado Soto Nayanna M. , Horn Adam , Keller Nancy P. , Huttenlocher Anna , Wagner Andrew S.
Published: November 2024

Secondary fungal infections represent a major complication following thermal injuries. However, the mechanisms of fungal colonization of burn tissue and how the host subsequently responds to fungi within this niche remain unclear. We have previously reported a zebrafish model of thermal injury that recapitulates many of the features of human burn wounds. Here, we characterize host-fungal interaction dynamics within the burn wound niche using two of the most common fungal pathogens isolated from burn injuries,Aspergillus fumigatusandCandida albicans. BothA. fumigatusandC. albicanscolonize burned tissue in zebrafish larvae and induce a largely conserved innate immune response following colonization. Using drug-induced cell depletion strategies and transgenic zebrafish lines with impaired innate immune function, we found that macrophages control fungal burden while neutrophils primarily control invasive hyphal growth at the early stages of infection. However, we also found that loss of either immune cell can be compensated by the other at the later stages of infection, and that fish with both macrophage and neutrophil deficiencies show more invasive hyphal growth that is sustained throughout the infection process, suggesting redundancy in their antifungal activities. Finally, we demonstrate thatC. albicansstrains with increased β(1,3)-glucan exposure are cleared faster from the burn wound, demonstrating a need for shielding this immunogenic cell wall epitope for successful fungal colonization of burn tissue. Together, our findings support the use of zebrafish larvae as a model to study host-fungal interaction dynamics within burn wounds.

Importance

Secondary fungal infections within burn wound injuries are a significant problem that delay wound healing and increase the risk of patient mortality. Currently, little is known about how fungi colonize and infect burn tissue or how the host responds to pathogen presence. In this report, we expand upon an existing thermal injury model using zebrafish larvae to begin to elucidate both the host immune response to fungal burn colonization and fungal mechanisms for persistence within burn tissue. We found that bothAspergillus fumigatusandCandida albicans, common fungal burn wound isolates, successfully colonize burn tissue and are effectively cleared in immunocompetent zebrafish by both macrophages and neutrophils. We also find thatC. albicansmutants harboring mutations that impact their ability to evade host immune system recognition are cleared more readily from burn tissue. Collectively, our work highlights the efficacy of using zebrafish to study host-fungal interaction dynamics within burn wounds.
Loss of TMEM55B modulates lipid metabolism through dysregulated lipophagy and mitochondrial function
Authors: Qin Yuanyuan , Teker Sheila , Cunza Nilsa La , Theusch Elizabeth , Yang Neil , Venkatesan Leela , Su Julia , Krauss Ronald M. , Lakkaraju Aparna , Mattis Aras N. , Medina Marisa W.
Published: November 2024

Lipophagy is a form of selective autophagy that targets the lipid droplets for lysosomal decay and has been implicated in the onset and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Factors that augment lipophagy have been identified as targets for MASLD therapeutic development. TMEM55B is a key regulator of lysosomal positioning which is critical for the lysosome fusion with the autophagosome, but less studied. Here, we demonstrate that inhibition of TMEM55B in murine models accelerates MASLD onset and progression. In cellular models, TMEM55B deficiency enhances lipophagy, leading to increased fatty acid release from lysosomes to mitochondria but simultaneously impairs mitophagy, causing an accumulation of dysfunctional mitochondria. This imbalance leads to increased lipid accumulation and oxidative stress, worsening MASLD. These findings underscore the importance of lysosomal positioning in lipid metabolism and suggest that augmenting lipophagy may exacerbate disease in the context of mitochondrial dysfunction.
Diagnostic-avoidingChlamydia trachomatisvariants detected in cervical and endometrial specimens from women during 16S microbiome profiling
Authors: Jeong Sangmi , Tollison Tammy , Brochu Hayden , Chou Hsuan , Yu Tammy , Baghaie Priyanka , Yount Kacy S. , Darville Toni , Wiesenfeld Harold C , Hillier Sharon L , Peng Xinxia , O’Connell Catherine M.
Published: November 2024

Background

Performance of a 16S rRNA analysis of the cervicovaginal microbiome of 220 participants recruited into the T Cell Response against Chlamydia (TRAC) cohort between February 2011 and August 2014 in Allegheny County, Pennsylvania USA detected DNA encoding chlamydial 16S rRNA in samples from seven participants whose tests were negative forChlamydia trachomatis(CT) and DNA encoding gonococcal 16S rRNA from five participants whose tests were negative forNeisseria gonorrhoeae(NG) infection with the Aptima Combo2 assay (Hologic).

Methods

We used targeted PCR amplification followed by sequencing to characterize the chlamydial 23S rRNA locus and qPCR to detect gonococcal DNA in residual diagnostic swab eluates or DNA used to generate 16S rRNA libraries.

Results

Discrepant specimens that contained chlamydial DNA carried a diagnostic-avoidant, G1526A variant in the 23S rRNA locus identical to variants previously detected in Finland, Denmark, and the UK. PCR validation of gonococcal DNA was confirmed for all participants whose tests were negative, with stochastic effects consistent with infection levels close to the limit of detection by the diagnostic assay.

Conclusions

These data indicate that this probe-avoidant CT mutant, and possibly others, were circulating in the northeastern US prior to their detection and characterization in 2019. Although infrequent, documentation of false negative results for CT indicates a need for clinicians to consider performance of a second test that uses alternate PCR targets if patients have persistent symptoms or have known contact to an infected sex partner and their initial NAAT is negative.