bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct therapeutic effect of sulfadoxine-pyrimethamine on nutritional deficiency-induced enteric dysfunction in a human intestine chip
Authors: Kim Seongmin , Naziripour Arash , Prabhala Pranav , Horváth Viktor , Junaid Abidemi , Breault David T. , Goyal Girija , Ingber Donald E.
Published: July 2023

Sulfadoxine-pyrimethamine (SP) antimalarial therapy has been suggested to improve the birth weight of infants in pregnant women in sub-Saharan Africa independently of malarial infection. Here, we investigated whether SP could have a direct impact on improving intestinal function, thereby enhancing the absorption of essential fats and nutrients crucial for fetal growth.

Using a human organ-on-a-chip model, we replicated the adult female intestine with patient organoid-derived duodenal epithelial cells interfaced with human intestinal endothelial cells. Nutrient-deficient (ND) medium was perfused to simulate malnutrition, resulting in the appearance of enteric dysfunction indicators such as villus blunting, reduced mucus production, impaired nutrient absorption, and increased inflammatory cytokine secretion. SP was administered to these chips in the presence or absence of human peripheral blood mononuclear cells (PBMCs).

Treatment with SP successfully reversed many abnormalities observed in malnourished chips, as confirmed by transcriptomic and proteomic analysis. Notably, SP significantly enhanced intestinal absorptive functions. Furthermore, SP suppressed the recruitment of PBMCs in the nutrient deficient chips. SP may improve the birth weight of children born to malnourished mothers by countering the effects of enteric dysfunction and suppressing inflammation. These findings highlight the possibility of using SP as a direct intervention to improve maternal absorption and subsequently contribute to healthier fetal growth.
Domain mapping of disease mutations supports genetic testing of specificSORL1variants in familial Alzheimer’s Disease
Authors: Holstege Henne , de Waal Matthijs W. J. , Tesi Niccolo’ , van der Lee Sven J. , de Geus Christa , van Spaendonk Rosalina , Vogel Maartje , Ahmad Shahzad , Amin Najaf , Amouyel Philippe , Beecham Gary W. , Bellenguez Céline , Berr Claudine , Bis Joshua C. , Boland Anne , Bossù Paola , Bouwman Femke , Bras Jose , Charbonnier Camille , Clarimon Jordi , Cruchaga Carlos , Daniele Antonio , Dartigues Jean-François , Debette Stéphanie , Deleuze Jean-François , Denning Nicola , DeStefano Anita L. , Dols-Icardo Oriol , van Duijn Cornelia M. , Farrer Lindsay A. , Fernández Maria Victoria , van der Flier Wiesje M. , Fox Nick C. , Galimberti Daniela , Genin Emmanuelle , Gille Johan J.P. , Grenier-Boley Benjamin , Grozeva Detelina , Le Guen Yann , Guerreiro Rita , Haines Jonathan L. , Holmes Clive , Hummerich Holger , Ikram M. Arfan , Ikram M. Kamran , Kawalia Amit , Kraaij Robert , Lambert Jean-Charles , Lathrop Marc , Lemstra Afina W. , Lleó Alberto , Myers Richard M. , Mannens Marcel M. A. M. , Marshall Rachel , Martin Eden R. , Masullo Carlo , Mayeux Richard , Mead Simon , Mecocci Patrizia , Meggy Alun , Mol Merel O. , Nacmias Benedetta , Naj Adam C. , Napolioni Valerio , Cochran J. Nicholas , Nicolas Gaël , Pasquier Florence , Pastor Pau , Pericak-Vance Margaret A. , Pijnenburg Yolande A. L. , Piras Fabrizio , Quenez Olivier , Ramirez Alfredo , Raybould Rachel , Redon Richard , Reinders Marcel J.T. , Richard Anne-Claire , Riedel-Heller Steffi G , Rivadeneira Fernando , van Rooij Jeroen G. J. , Rousseau Stéphane , Ryan Natalie S. , Sanchez-Juan Pascual , Schellenberg Gerard D. , Scheltens Philip , Schott Jonathan M. , Seshadri Sudha , Sie Daoud , Sims Rebecca , Sistermans Erik A. , Sorbi Sandro , van Swieten John C. , Tijms Betty , Uitterlinden André G. , Visser Pieter Jelle , Wagner Michael , Wallon David , Wang Li-San , Williams Julie , Yokoyama Jennifer S. , Zarea Aline , Hulsman Marc , Andersen Olav M.
Published: July 2023

Background

Protein truncating variants (PTVs) inSORL1are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rareSORL1missense variants is unclear.

Methods

To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ on the 637 unique codingSORL1variants detected in 18,959 AD-cases and 21,893 non-demented controls.

Results

In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, andAPOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ∼8-10 years earlier than wild-typeSORL1carriers, matched forAPOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects.

Conclusion

Our results justify a debate on whether HPV carriers should be considered for clinical counseling.
Exploring Perceptions and Experiences of ChatGPT in Medical Education: A Qualitative Study Among Medical College Faculty and Students in Saudi Arabia
Authors: Abouammoh Noura , Alhasan Khalid , Raina Rupesh , Malki Khalid A. , Aljamaan Fadi , Tamimi Ibraheem , Muaygil Ruaim , Wahabi Hayfaa , Jamal Amr , Al-Tawfiq Jaffar A. , Al-Eyadhy Ayman , Soliman Mona , Temsah Mohamad-Hani
Published: July 2023

Background

With the rapid development of artificial intelligence (AI) technologies, there is a growing interest in the potential use of AI-based tools like ChatGPT in medical education. However, there is limited research on the perceptions and experiences of faculty and students with ChatGPT, particularly in Saudi Arabia.

Objective

This study aimed to explore the knowledge, perceived benefits, concerns, and limitations of using ChatGPT in medical education, among faculty and students at a leading Saudi Arabian university.

Methods

A qualitative study was conducted, involving focused meetings with medical faculty and students with varying levels of ChatGPT experience. A thematic analysis was used to identify key themes and subthemes emerging from the discussions.

Results

Participants demonstrated good knowledge of ChatGPT and its functions. The main themes were: (1) knowledge and perception of ChatGPT, and (2) roles of ChatGPT in research and medical education. The perceived benefits included collecting and summarizing information and saving time and effort. However, concerns and limitations centered around the potential lack of critical thinking in the information provided, the ambiguity of references, limitations of access, trust in the output of ChatGPT, and ethical concerns.

Conclusions

This study provides valuable insights into the perceptions and experiences of medical faculty and students regarding the use of ChatGPT in medical education. While the benefits of ChatGPT were recognized, participants also expressed concerns and limitations requiring further studies for effective integration into medical education, exploring the impact of ChatGPT on learning outcomes, student and faculty satisfaction, and the development of critical thinking skills.
Decrease in multiple complement protein levels is associated with the development of islet autoimmunity and type 1 diabetes
Authors: Webb-Robertson Bobbie-Jo M , Nakayasu Ernesto S , Dong Fran , Waugh Kathy C , Flores Javier , Bramer Lisa M , Schepmoes Athena , Gao Yuqian , Fillmore Thomas , Onengut-Gumuscu Suna , Frazer-Abel Ashley , Rich Stephen S , Holers V. Michael , Metz Thomas O , Rewers Marian J
Published: July 2023

Type 1 diabetes (T1D) is a chronic condition caused by autoimmune destruction of the insulin-producing pancreatic β-cells. While it is known that gene-environment interactions play a key role in triggering the autoimmune process leading to T1D, the pathogenic mechanism leading to the appearance of islet autoantibodies - biomarkers of autoimmunity – is poorly understood. Here we show that disruption of the complement system precedes the detection of islet autoantibodies and persists through disease onset. Our results suggest that children who exhibit islet autoimmunity and progress to clinical T1D have lower complement protein levels relative to those who do not progress within a similar timeframe. Thus, the complement pathway, an understudied mechanistic and therapeutic target in T1D, merits increased attention for use as protein biomarkers of prediction and potentially prevention of T1D.
High-Dimensional Single-Cell Multimodal Landscape of Human Carotid Atherosclerosis
Authors: Bashore Alexander C. , Yan Hanying , Xue Chenyi , Zhu Lucie Y. , Kim Eunyoung , Mawson Thomas , Coronel Johana , Chung Allen , Ho Sebastian , Ross Leila S. , Kissner Michael , Passegué Emmanuelle , Bauer Robert C. , Maegdefessel Lars , Li Mingyao , Reilly Muredach P.
Published: July 2023

Background

Atherosclerotic plaques are complex tissues composed of a heterogeneous mixture of cells. However, we have limited understanding of the comprehensive transcriptional and phenotypical landscape of the cells within these lesions.

Methods

To characterize the landscape of human carotid atherosclerosis in greater detail, we combined cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing (scRNA-seq) to classify all cell types within lesions (n=21; 13 symptomatic) to achieve a comprehensive multimodal understanding of the cellular identities of atherosclerosis and their association with clinical pathophysiology.

Results

We identified 25 distinct cell populations each having a unique multi-omic signature, including macrophages, T cells, NK cells, mast cells, B cells, plasma cells, neutrophils, dendritic cells, endothelial cells, fibroblasts, and smooth muscle cells (SMCs). Within the macrophage populations, we identified 2 proinflammatory subsets that were enriched in IL1B or C1Q expression, 2 distinct TREM2 positive foam cell subsets, one of which also expressed inflammatory genes, as well as subpopulations displaying a proliferative gene expression signature and one expressing SMC-specific genes and upregulation of fibrotic pathways. An in-depth characterization uncovered several subsets of SMCs and fibroblasts, including a SMC-derived foam cell. We localized this foamy SMC to the deep intima of coronary atherosclerotic lesions. Using CITE-seq data, we also developed the first flow cytometry panel, using cell surface proteins CD29, CD142, and CD90, to isolate SMC-derived cells from lesions. Last, we found that the proportion of efferocytotic macrophages, classically activated endothelial cells, contractile and modulated SMC-derived cell types were reduced, and inflammatory SMCs were enriched in plaques of clinically symptomatic vs. asymptomatic patients.

Conclusions

Our multimodal atlas of cell populations within atherosclerosis provides novel insights into the diversity, phenotype, location, isolation, and clinical relevance of the unique cellular composition of human carotid atherosclerosis. This facilitates both the mapping of cardiovascular disease susceptibility loci to specific cell types as well as the identification of novel molecular and cellular therapeutic targets for treatment of the disease.
CORRELATION OF BODY COMPOSITION (BODY MASS INDEX, WAIST-TO-HIP RATIO, WAIST-TO-HEIGHT RATIO, NECK CIRCUMFERENCE) WITH FITNESS INDEX USING HARVARD STEP TEST
Authors: Baruah Hazra Chinmoyee
Published: July 2023

BACKGROUND

Despite many clear benefits of active lifestyle lack of physical activity are common mostly among students, which further lead to alteration in body compositions. This alteration in body composition is the leading cause of various diseases as well as decrease in Fitness Index level.

OBJECTIVE

To correlate the body compositions i.e. Body Mass Index, Waist-to-Hip Ratio, Waist-to-Height Ratio, Neck Circumference with Fitness Index using Harvard Step Test among students of PEWS Group of Institutions and also to find which body composition is the strongest predictor of Fitness Index.

METHODOLOGY

100 subjects were selected randomly in the study and were divided into two groups i.e Group A (Male) and Group B (Female), each having 50 subjects. For each subject BMI, WHR, WHtR, NC was measured. Harvard Step Test was performed and FI was calculated using it.

RESULT

Based on the statistical analysis i.e Karl Pearson’s Coefficient of Correlation, BMI, WHR, WHtR, NC all are negatively correlated with FI for both males and females. BMI, WHtR, NC of females and WHR of males have greater negative correlation with FI.

CONCLUSION

There is correlation between body compositions i.e. BMI, WHR, WHtR, NC and FI. BMI is the best predictor of FI in both males and females; also it has been observed that the males are fitter than the females.
The Impact of Post-Acute Care on Depression and Anxiety in Stroke Patients: A Prospective Study to Explore the Mediating Effect of Cognitive Function
Authors: Lou Shi-Jer , Lin Hsiu-Fen , Shiu Yu-Tsz , Shi Hon-Yi
Published: July 2023

BACKGROUND

Cognitive function was significantly associated with post-stroke depression and anxiety in stroke patients. However, no studies have examined whether there is an interaction. this study purposed to investigate whether cognitive function mediates the effect of enrollment in post-acute care (PAC) programs on depression or anxiety in stroke patients and whether the indicators are moderated in the pathway.

METHODS

This is a prospective observational cohort study. A group of patients who had received PAC for stroke at one of two medical centers (PAC group, n = 2,087) was compared with a group who had received standard care for stroke at one of four hospitals (three regional hospitals and one district hospital; non-PAC group, n = 1,591) in Taiwan from March, 2015, to March, 2022. The effects of PAC on cognitive function and depression and anxiety at baseline, 12thweek, and 1styear after rehabilitation were investigated using structural equation modeling (SEM). The effect of each variable on the moderation of different pathways in the model was analyzed using AMOS 23.0, and The SPSS PROCESS macro also was used to perform mediation analysis.

RESULTS

The PAC program had a mediating effect on cognition and depression at week 12 (a*b= -0.098, P<0.05) on cognition and anxiety at week 12 (a*b= -0.107, P<0.05), and the PAC program had a direct effect on depression and anxiety in the first year. It was found that acute lengths of stay had a significant moderation effect in the model (X*W→M=0.204, P=0.002), but the model lost its mediating effect when the moderation variable was added.

CONCLUSIONS

Patients with stroke should receive post-acute care as soon as possible to improve their cognitive function after rehabilitation, to maximize the effectiveness of treatment for mental disorders, and to reduce the burden of the disease.

WHAT IS KNOWN

Research suggests that cognitive function, including depression and anxiety, significantly improved for patients using post-acute care (PAC).

Cognitive function was significantly associated with post-stroke depression and anxiety in patients with stroke.

WHAT THE STUDY ADDS

PAC had a mediating effect on cognition and depression at week 12 on cognition and anxiety at week 12, and it also had a direct effect on depression and anxiety in the first year.

Acute lengths of stay had a significant moderation effect in the model, but the model lost its mediating effect when the moderation variable was added.

Patients with stroke should receive post-acute care as soon as possible to improve their cognitive function after rehabilitation, to maximize the effectiveness of treatment for mental disorders, and to reduce the burden of the disease.
A Novel Easy-To-Access Model That Predicts Stroke-Associated Pneumonia
Authors: Chung Cheng-Yu , Wang Wen-Hwa , Yin Chun-Hao , Chen Jin-Shuen , Chen Yao-Shen , Yen Cheng-Chang , Lin Ching-Huang
Published: July 2023

BACKGROUND

Stroke-associated pneumonia (SAP) is a common poststroke complication but the influence of early neurological deterioration (END) on SAP risk remains unclear. We aimed to develop an easy-to-access model to predict SAP and evaluate the SAP–END relationship using the Glasgow Coma Scale (GCS).

METHODS

This retrospective study enrolled consecutive patients aged ≥20 years with first-ever acute ischemic stroke at Kaohsiung Veterans General Hospital between January 1, 2010, and November 30, 2020. SAP was defined according to modified Centers for Disease Control and Prevention criteria. Patients’ baseline characteristics, laboratory data within 24 h, neurological findings, and serial GCS scores within 48 h were collected. Regression analysis was used to identify independent risk factors for SAP.

RESULTS

Among 1009 enrolled patients, SAP occurred in 85 (8.4%) patients. Using multivariate analysis, END after admission (adjusted odds ratio [aOR] 2.94, 95% confidence interval [CI] 1.74–4.95, P<0.001) remained significant after adjusting for confounders. Initial GCS score <10 (aOR 2.30, 95% CI 1.30–4.06, P=0.004), National Institutes of Health Stroke Scale (NIHSS) score 5–15 (aOR 2.02, 95% CI 1.09–3.73, P=0.026) or ≥16 (aOR 3.45, 95% CI 1.72–6.89, P<0.001), cardioembolism (aOR 4.76, 95% CI 1.90–11.91, P=0.014), undetermined etiology (aOR 3.41, 95% CI 1.29–9.03, P=0.001), and neutrophil-to- lymphocyte ratio (NLR) >2.5 (aOR 2.10, 95% CI 1.28–3.46, P=0.004) were also significant. The area under the curve (AUC) of combined GCS score, END, NIHSS score, cardioembolism, stroke with undetermined type, and NLR was 0.83 (95% CI 0.78–0.87, P<0.001), which was superior to that of PANTHERIS scores (0.62, 95% CI 0.55–0.68, P<0.001).

CONCLUSIONS

This study developed a simple predictive model for SAP using easily accessible and generally available parameters. GCS-based END was an independent risk factor for SAP. Early identification of SAP risk factors and reversible END causes may lower SAP incidence.
Deconstructing Complexity: A Computational Topology Approach to Trajectory Inference in the Human Thymus withtviblindi
Authors: Stuchly Jan , Novak David , Brdickova Nadezda , Hadlova Petra , Sadilek Vojen , Iksi Ahmad , Kuzilkova Daniela , Svaton Michael , Saad George Alehandro , Engel Pablo , Luche Herve , Sousa Ana E. , Almeida Afonso R.M. , Kalina Tomas
Published: July 2023

Understanding complex, organ-level single-cell datasets represents a formidable interdisciplinary challenge. This study aims to describe developmental trajectories of thymocytes and mature T cells. We developedtviblindi, a trajectory inference algorithm that integrates several autonomous modules - pseudotime inference, random walk simulations, real-time topological classification using persistent homology, and autoencoder-based 2D visualization using the vaevictis algorithm. This integration facilitates interactive exploration of developmental trajectories, revealing not only the canonical CD4 and CD8 development but also offering insights into checkpoints such as TCRβ selection and positive/negative selection. Furthermore,tviblindiallowed us to thoroughly characterize thymic regulatory T cells, tracing their development passed the negative selection stage to mature thymic regulatory T cells. At the very end of the developmental trajectory we discovered a previously undescribed subpopulation of thymic regulatory T cells. Experimentally, we confirmed its extensive proliferation history and an immunophenotype characteristic of activated and recirculating cells.tviblindirepresents a new class of methods that is complementary to fully automated trajectory inference tools. It offers a semi-automated tool that leverages features derived from data in an unbiased and mathematically rigorous manner. These features include pseudotime, homology classes, and appropriate low-dimensional representations. These features can be integrated with expert knowledge to formulate hypotheses regarding the underlying dynamics, tailored to the specific trajectory or biological process under investigation.
Wobbly hedgehog syndrome- a progressive neurodegenerative disease
Authors: Doss Grayson A. , Radecki Daniel Z. , Kethireddy Arya , Reilly Madelyn J. , Pohly Andrea E. , August Benjamin K. , Duncan Ian D. , Samanta Jayshree
Published: July 2023

Wobbly hedgehog syndrome (WHS) has been long considered to be a myelin disease primarily affecting the four-toed hedgehog. In this study, we have shown for the first time that demyelination is accompanied by extensive remyelination in WHS. However, remyelination is not enough to compensate for the axonal degeneration and neuronal loss, resulting in a progressive neurodegenerative disease reminiscent of progressive forms of multiple sclerosis (MS) in humans. Thus, understanding the pathological features of WHS may shed light on the disease progression in progressive MS and ultimately help to develop therapeutic strategies for both diseases.

Highlights

Wobbly hedgehog syndrome (WHS) is a progressive neurodegenerative disease.

Spongy degeneration of the brain and spinal cord is the diagnostic feature of WHS.

WHS affected brain and spinal cord show extensive demyelination and remyelination.

Axonal degeneration is accompanied by loss of neurons in WHS.

Graphical Abstract
Snowmobile noise alters bird vocalization patterns during winter and pre-breeding season
Authors: Cretois Benjamin , Avery Bick Ian , Balantic Cathleen , Gelderblom Femke B. , Pávon-Jordán Diego , Wiel Julia , Sethi Sarab S. , Betchkal Davyd H. , Banet Ben , Arne Reinen Tor
Published: July 2023

Noise pollution poses a significant threat to ecosystems worldwide, disrupting animal communication and causing cascading effects on biodiversity. In this study, we focus on the impact of snowmobile noise on avian vocalizations during the non-breeding winter season, a less-studied area in soundscape ecology. We developed a pipeline relying on deep learning methods to detect snowmobile noise and applied it to a large acoustic monitoring dataset collected in Yellowstone National Park. Our results demonstrate the effectiveness of the snowmobile detection model in identifying snowmobile noise and reveal an association between snowmobile passage and changes in avian vocalization patterns. Snowmobile noise led to a decrease in the frequency of bird vocalizations during mornings and evenings, potentially affecting winter and pre-breeding behaviors such as foraging, predator avoidance and successfully finding a mate. However, we observed a recovery in avian vocalizations after detection of snowmobiles during mornings and afternoons, indicating some resilience to sporadic noise events. These findings emphasize the need to consider noise impacts in the non-breeding season and provide valuable insights for natural resource managers to minimize disturbance and protect critical avian habitats. The deep learning approach presented in this study offers an efficient and accurate means of analyzing large-scale acoustic monitoring data and contributes to a comprehensive understanding of the cumulative impacts of multiple stressors on avian communities.

Graphical Abstract
ChatGPT-Enhanced ROC Analysis (CERA): A Shiny Web Tool for Finding Optimal Cutoff in Biomarker Analysis
Authors: Agraz Melih , Karniadakis George Em
Published: July 2023

Diagnostic tests play a crucial role in establishing the presence of a specific disease in an individual. Receiver Operating Characteristic (ROC) curve analyses are essential tools that provide performance metrics for diagnostic tests. Accurate determination of the cutoff point in ROC curve analyses is the most critical aspect of the process. A variety of methods have been developed to find the optimal cutoffs. Although the R programming language provides a variety of package programs for conducting ROC curve analysis and determining the appropriate cutoffs, it typically needs coding skills and a substantial investment of time. Specifically, the necessity for data preprocessing and analysis can present a significant challenge, especially for individuals without coding experience. We have developed the CERA (ChatGPT-Enhanced ROC Analysis) tool, a user-friendly ROC curve analysis web tool using the shiny interface for faster and more effective analyses to solve this problem. CERA is not only user-friendly, but it also interacts with ChatGPT, which interprets the outputs. This allows for an interpreted report generated by R-Markdown to be presented to the user, enhancing the accessibility and understanding of the analysis results.

Authors summary

Melih Agraz, after graduating from Dokuz Eylül University in Izmir, Turkiye, with a major in Mathematics from the Department of Education, he pursued his Master’s degree at the same university in the field of Statistics. He furthered his education by obtaining a Ph.D. in Statistics from the Middle East Technical University, Ankara in Turkiye. As part of his academic journey, he also served as a Fulbright postdoctoral researcher at UC Berkeley in the United States. Following this, he worked as a postdoctoral researcher at Brown University and Beth Israel Hospital of Harvard Medical School. Currently, he holds the position of Assistant Professor in the Department of Statistics at Giresun University in Turkey.

George Em Karniadakisis Professor of Applied Mathematics and Engineering at Brown University. He is a member of the National Academy of Engineering of USA. His interests include stochastic multiscale modeling of physical and biological systems, physics-informed machine learning, and deep neural operators. He has co-authored over 500 papers and five books, and he has the highest h-index in Applied Mathematics according to Google Scholar.
What are wereallydecoding? Unveiling biases in EEG-based decoding of the spatial focus of auditory attention
Authors: Rotaru Iustina , Geirnaert Simon , Heintz Nicolas , Van de Ryck Iris , Bertrand Alexander , Francart Tom
Published: July 2023

Objective

Spatial auditory attention decoding (Sp-AAD) refers to the task of identifying the direction of the speaker to which a person is attending in a multi-talker setting, based on the listener’s neural recordings, e.g., electroencephalography (EEG). The goal of this study is to thoroughly investigate potential biases when training such Sp-AAD decoders on EEG data, particularly eye-gaze biases and latent trial-dependent confounds, which may result in Sp-AAD models that decode eye-gaze or trial-specific fingerprints rather than spatial auditory attention.

Approach

We designed a two-speaker audiovisual Sp-AAD protocol in which the spatial auditory and visual attention were enforced to be either congruent or incongruent, and we recorded EEG data from sixteen participants undergoing several trials recorded at distinct timepoints. We trained a simple linear model for Sp-AAD based on common spatial patterns (CSP) filters in combination with either linear discriminant analysis (LDA) or k-means clustering, and evaluated them both across- and within-trial.

Main results

We found that even a simple linear Sp-AAD model is susceptible to overfitting to confounding signal patterns such as eye-gaze and trial fingerprints (e.g., due to feature shifts across trials), resulting in artificially high decoding accuracies. Furthermore, we found that changes in the EEG signal statistics across trials deteriorate the trial generalization of the classifier, even when the latter is retrained on the test trial with an unsupervised algorithm.

Significance

Collectively, our findings confirm that there exist subtle biases and confounds that can strongly interfere with the decoding of spatial auditory attention from EEG. It is expected that more complicated non-linear models based on deep neural networks, which are often used for Sp-AAD, are even more vulnerable to such biases. Future work should perform experiments and model evaluations that avoid and/or control for such biases in Sp-AAD tasks.
A jump-driven self-exciting stochastic fish migration model and its fisheries applications
Authors: Yoshioka Hidekazu , Yamazaki Kazutoshi
Published: July 2023

We introduce a stochastic continuous-time model via a self-exciting process with jumps to describe a seasonal migration event of diadromous fish. The dynamics of the stored population at a point in a river, waiting for their upward migration, increases by the inflow from the downstream/ocean and decreases by the outflow due to their upstream migration. The inflow is assumed to occur at a constant rate until an Erlang-distributed termination time. The outflow is modeled by a self-exciting jump process to incorporate the flocking and social interactions in fish migration. Harvested cases are also studied for fisheries applications. We derive the backward Kolmogorov equations and the associated finite-difference method to compute various performance indices including the mean migration period and harvested populations. Detailed numerical and sensitivity analysis are conducted to study the spring upstream migration of the diadromous AyuPlecoglossus altivelis altivelis.
Solid tumor-on-chip model for efficacy and safety assessment of CAR-T cell therapy
Authors: Maulana Tengku Ibrahim , Teufel Claudia , Cipriano Madalena , Lazarevski Lisa , van den Hil Francijna E. , Orlova Valeria , Koch André , Alb Miriam , Hudecek Michael , Loskill Peter
Published: July 2023

The non-clinical assessment of CAR-T cells demands innovative models that are capable of predicting safety and efficacy in the clinical setting. Here, we present a novel solid tumor-on-chip model that allows CAR-T cell perfusion and integrates the vasculature and tumor lesions to recapitulate key events of CAR-T cell performance including extravasation, tumor infiltration and cytokine release. We assessed CAR-T cells targeting the ROR1 antigen against tumor aggregates that were derived from a breast cancer cell line and primary breast cancer organoids. The data show the temporal kinetic of ROR1 CAR-T cell migration and expansion, lytic activity and cytokine production over the course of 8 days, and reveal a correlation between anti-tumor efficacy and ROR1 antigen density on tumor cells. CAR-modified T cells extravasated faster, infiltrated tumor lesions stronger, persisted longer and in higher numbers than non-CAR modified T cells. Intriguingly, we detected cytokine release levels and kinetics typically observed in patients who developed cytokine release syndrome, and administered dasatinib as a pharmacologic OFF switch to control this inflammatory response. The data illustrate the ability of this tumor-on-chip platform to assess parameters associated withherapeutic outcome and the potential to aid in patient stratification and monitoring of CAR-T cell therapy.
Accurately identifying nucleic-acid-binding sites through geometric graph learning on language model predicted structures
Authors: Song Yidong , Yuan Qianmu , Zhao Huiying , Yang Yuedong
Published: July 2023

The interactions between nucleic acids and proteins are important in diverse biological processes. The high-quality prediction of nucleic-acid-binding sites continues to pose a significant challenge. Presently, the predictive efficacy of sequence-based methods is constrained by their exclusive consideration of sequence context information, whereas structure-based methods are unsuitable for proteins lacKing Known tertiary structures. Though protein structures predicted by AlphaFold2 could be used, the extensive computing requirement of AlphaFold2 hinders its use for genome-wide applications. Based on the recent breaKthrough of ESMFold for fast prediction of protein structures, we have developed GLMSite, which accurately identifies DNA and RNA-binding sites using geometric graph learning on ESMFold predicted structures. Here, the predicted protein structures are employed to construct protein structural graph with residues as nodes and spatially neighboring residue pairs for edges. The node representations are further enhanced through the pre-trained language model ProtTrans. The networK was trained using a geometric vector perceptron, and the geometric embeddings were subsequently fed into a common networK to acquire common binding characteristics. Then two fully connected layers were employed to learn specific binding patterns for DNA and RNA, respectively. Through comprehensive tests on DNA/RNA benchmarK datasets, GLMSite was shown to surpass the latest sequence-based methods and be comparable with structure-based methods. Moreover, the prediction was shown useful for the inference of nucleic-acid-binding proteins, demonstrating its potential for protein function discovery. The datasets, codes, together with trained models are available athttps://github.com/biomed-AI/nucleic-acid-binding.
Predicting Disease-gene Associations through Self-supervised Mutual Infomax Graph Convolution Network
Authors: Xie Jiancong , Rao Jiahua , Xie Junjie , Yang Yuedong
Published: July 2023

Illuminating associations between diseases and genes can help reveal the pathogenesis of syndromes and contributes to treatments, but a large number of associations still remained unexplored. To identify novel disease-gene association, many computational methods have been developed using disease and gene related prior knowledge. However, these methods remain of relatively inferior performance due to the limited external data sources and the inevitable noise among the prior knowledge. In this study, we have developed a new method, Self-Supervised Mutual Infomax Graph Convolution Network (MiGCN), to predict disease-gene associations under the guidance of external disease-disease and gene-gene collaborative graphs. The noises within the collaborative graphs were eliminated by maximizing the mutual information between nodes and neighbors through a graphical mutual infomax layer. In parallel, the node interactions were strengthened by a novel informative message passing layer to improve the learning ability of graph neural network. The extensive experiments showed that our model achieves performance improvement over the state-of-art method by more than 8% on AUC. The datasets, source codes and trained models of MiGCN are available athttps://github.com/biomed-AI/MiGCN.
N-acetylcysteine and acetyl-L-carnitine did not prevent acute PTZ-induced seizure in adult and larvae zebrafish
Authors: Chitolina Rafael , Reis Carlos G. , Stahlhofer-Buss Thailana , Linazzi Amanda , Benvenutti Radharani , Marcon Matheus , Herrmann Ana P. , Piato Angelo
Published: July 2023

Epilepsy is a prevalent neurological disorder, affecting approximately 1 to 2% of the global population. The hallmark of epilepsy is the occurrence of epileptic seizures, which are characterized by predictable behavioral changes reflecting the underlying neural mechanisms of the disease. Unfortunately, around 30% of patients do not respond to the current available pharmacological treatments. Consequently, it is crucial to explore alternative therapeutic options for managing these seizures. Two potential candidates for attenuating seizures are N-acetylcysteine (NAC) and Acetyl-L-carnitine (ALC), as they have shown promising neuroprotective effects through the modulation of the neurotransmitter glutamate. Therefore, this study aims to assess the effects of varying concentrations (0.1, 1.0, and 10 mg/L) of NAC and ALC on acute PTZ-induced seizures in zebrafish, in both adult and larval stages. The evaluation of behavioral parameters such as seizure intensity and latency to the crisis can provide insights into the efficacy of these substances. However, our results indicate that both drugs at any of the tested concentrations were not able to reduce PTZ-induced epileptic seizures. On the other hand, the administration of diazepam demonstrated a notable reduction in seizure intensity and an increase in latencies to higher scores of epileptic seizures. Consequently, we conclude that, under the conditions employed in this study, NAC and ALC do not exhibit any significant effects on acute seizures in zebrafish.
Day and night posture of the bluegill sunfish (Lepomis macrochirus)
Authors: Fath Michael , Tytell Eric D.
Published: July 2023

Many animals assume characteristic postures when resting or sleeping. These postures are often stable and can be maintained passively, thus reducing the energy cost for maintaining an unstable posture. For example, many tetrapods lay prone on the ground and some negatively buoyant fishes are also able to rest on the substrate. Other fishes rest suspended in the water column. Counterintuitively, hovering this way can be of similar energetic cost to swimming. Even if the fish is perfectly neutrally buoyant, any displacement between its center of mass and center of buoyancy will produce destabilizing pitching torques that the fish must constantly work to counteract if they wish to maintain that posture. We hypothesized that a neutrally buoyant fish could rest at an equilibrium – a posture at which no destabilizing torques are produced by the body --to minimize the metabolic costs associated with hovering. Specifically, we studied the bluegill sunfish (Lepomis macrochirus), which is unstable in a horizontal posture. However, by pitching their bodies up or down they may be able to attain a less costly equilibrium posture, one which vertically aligns their center of mass and center of buoyancy. To test this hypothesis, we measured pitch angle of bluegill over the course of 24 hours. We also measured the pitch angles of the body that correspond to stable and unstable equilibria. We found that the stable equilibrium was a belly-up posture, and the unstable equilibrium is a dorsal side up posture pitched 53±26° head-down. The fish rested at a head-down pitch of -10.7±0.4° degrees, which is significantly steeper than the average pitch during the day of -3.4±0.8° degrees head down. These results show that bluegill do not rest at unstable or stable equilibrium. However, they do rest closer to unstable equilibrium at night than during the day. This may allow them to decrease destabilizing torques generated from the relative locations of the COM and COB while maintaining maneuverability.
Chemo-Mechanical Regulation of Tau Phosphorylation Following Traumatic Brain Injuries
Authors: Kant Aayush , Medhekar Nikhil V. , Bhandakkar Tanmay K.
Published: July 2023

Traumatic brain injuries are characterized by damage to axonal cytoskeletal proteins. Here, we present a mathematical model predicting the chemo-mechanical disruption of intra-axonal micro-tubule assembly in terms of hyperphosphorylation-led dysfunction of tubulin-binding tau proteins. Intracellular calcium accumulation following a trauma leads to calpain activation, disturbing the downstream kinase-phosphatase activity balance which causes tau hyperphosphorylation. We develop a computational framework, using finite element methods, predicting the spatiotemporal evolution of mechanical stress and ensuing tau hyperphosphorylation in the human brain after traumatic brain injury-inducing loads. We compare our predictions with previously reported experimental and clinical observations to validate the model. Our model provides important insights into the secondary effects of traumatic brain injuries and can be essential in their clinical management.
Origin and diversity ofCapsella bursa-pastorisfrom the genomic point view
Authors: Penin Aleksey A. , Kasianov Artem S. , Klepikova Anna V. , Omelchenko Denis O. , Makarenko Maksim S. , Logacheva Maria D.
Published: July 2023

Background

Capsella bursa-pastoris, a cosmopolitan weed of hybrid origin, is an emerging model object for the study of early consequences of polyploidy, being a fast growing annual and a close relative ofArabidopsis thaliana. The development of this model is hampered by the absence of a reference genome sequence.

Results

we present here a subgenome-resolved chromosome-scale assembly and a genetic map of the genome ofCapsella bursa-pastoris. It shows that the subgenomes are mostly colinear, with no massive deletions, insertions or rearrangements in any of them. A subgenome-aware annotation reveals the lack of genome dominance – both subgenomes carry similar number of genes. While most chromosomes can be unambiguously recognized as derived from either paternal or maternal parent, we also found homeologous exchange between two chromosomes. It led to an emergence of two hybrid chromosomes; this event is shared between distant populations ofC. bursa-pastoris. The whole-genome analysis of 119 samples belonging toC. bursa-pastorisand its parental speciesC. grandiflora/rubellaandC. orientalisreveals introgression fromC. orientalisbut not fromC. grandiflora/rubella.

Conclusions

C. bursa-pastorisdo not show genome dominance. In the earliest stages of evolution of this species a homeologous exchange occurred; its presence in all present-day populations ofC. bursa-pastorisindicates on a single origin of this species. The evidence coming from whole-genome analysis challenges the current view thatC. grandiflora/rubellawas a direct progenitor ofC. bursa-pastoris; we hypothesize that it was an extinct (or undiscovered) species sister toC. grandiflora/rubella.
BERLIN: Basic Explorer for single-cell RNAseq analysis and cell Lineage Determination
Authors: Nobles Gabrielle , Obermayer Alyssa , Yang Ching Yao , Zelenka Tomas , Nugyen Thanh N , Chen Zhihua , Conejo-Garcia Jose , Avram Dorina , Yu Xiaoqing , Chen Y Ann , Shaw Timothy
Published: July 2023

Single-cell RNA sequencing has revolutionized the study of immuno-oncology, cancer biology, and developmental biology by enabling the joint characterization of gene expression and cellular heterogeneity in a single platform. As of July 2023, the Gene Expression Omnibus now contains over 4000 published single-cell data sets, providing an invaluable opportunity for reanalysis to identify new cell types or cellular states as well as their defining transcriptional programs. To facilitate the reprocessing of these public datasets, we have devised a single-cell RNA sequencing analysis framework for data retrieval, quality control, expression normalization, dimension reduction, cell clustering, and data integration. Additionally, we have developed a Shiny App visualization platform that enables the exploration of gene expression, cell type annotations, and cell lineages through a user interface. We performed a re-analysis of single-cell RNAseq data generated from acute myeloid leukemia and tumor-reactive lymphocytes and found our pipeline to faithfully recapitulated the cell type assignment as well as expected lineage trajectories. Altogether, we present BERLIN, a single-cell RNAseq analysis pipeline that facilitates the integration and public dissemination of results from the reanalysis.
Thermospermine is an evolutionarily ancestral phytohormone required for organ development and stress responses in the basal land plantMarchantia polymorpha
Authors: Furumoto Takuya , Yamaoka Shohei , Kohchi Takayuki , Motose Hiroyasu , Takahashi Taku
Published: July 2023

Thermospermine, a structural isomer of spermine, suppresses auxin-inducible xylem differentiation, whereas spermine is implicated in stress responses in angiosperms. Thermospermine synthase ACAULIS5 (ACL5) is well conserved from algae to land plants, but its physiological function remains elusive in non-vascular plants. Here we focused on MpACL5, a gene in the liverwortMarchantia polymorpha, which rescued the dwarf phenotype of theacl5mutant ofArabidopsis. In the Mpacl5mutants generated by genome editing, growth of the vegetative organ, thallus, and the sexual reproductive organ, gametangiophore, was severely retarded. The mutant gametangiophore exhibited remarkable morphological defects such as short stalks, fasciation, and indeterminate growth; it was formed as a fusion of two gametangiophores and a new gametangiophore was often initiated from the old one. Furthermore, Mpacl5was shown to be hypersensitive to heat and salt stresses. Given the absence of spermine in liverworts includingM. polymorpha, these results reveal that thermospermine has a dual primordial function in organ development and stress responses in the basal land plant lineage, the latter of which may have eventually been assigned to spermine during the land plant evolution.
Patterns of change in nucleotide diversity over gene length
Authors: Ali Farhan
Published: July 2023

Nucleotide diversity at a site is influenced by the relative strengths of neutral and selective population genetic processes. Therefore, attempts to identify sites under positive selection require an understanding of the expected diversity in its absence. The nucleotide diversity of a gene was previously found to correlate with its length. In this work, I measure nucleotide diversity at synonymous sites and uncover a pattern of low diversity towards the translation initiation site (TIS) of a gene. The degree of reduction in diversity at the TIS and the length of this region of reduced diversity can be quantified as “Effect Size” and “Effect Length” respectively, using parameters of an asymptotic regression model. Estimates of Effect Length across bacteria covaried with recombination rates as well as with a multitude of fast-growth adaptations such as the avoidance of mRNA secondary structure around TIS, the number of rRNAs, and relative codon usage of ribosomal genes. Thus, the dependence of nucleotide diversity on gene length is governed by a combination of selective and non-selective processes. These results have implications for the estimation of effective population size and relative mutation rates based on “silent-site” diversity, and for pN/pS-based prediction of genes under selection.
Targeting the glucose-insulin link in head and neck squamous cell carcinoma induces cytotoxic oxidative stress and inhibits cancer growth
Authors: Mazambani Simbarashe , Choe Joshua H. , Oh Tae-Gyu , Singh Pankaj K. , Kim Jung-whan , Kim Tae Hoon
Published: July 2023

Reactive oxygen species (ROS) are a double-edge sword in cancers and can both promote pro-tumorigenic signaling and also trigger oxidative stress dependent cell death. Thus, maintaining redox homeostasis to control levels of ROS within a tumor-promoting range elicits critical tumorigenic potential in cancer. Here, we show that head and neck squamous cell carcinoma (HNSCC) is uniquely characterized by its critical dependence on heightened antioxidant capacity facilitated by elevated glucose uptake to maintain survival and proliferation. Using a basal-epithelial-layer-specific GLUT1 knockout mouse model, we establish that targeting GLUT1-mediated glucose utilization in HNSCC cells of origin robustly inhibits HNSCC progression, providing strong genetic evidence that GLUT1 is indeed a targetable metabolic vulnerability. We further demonstrate that disrupting redox homeostasis with prooxidants such as high dose vitamin C and Auranofin induces potent cytotoxicity in HNSCCs by exerting profound oxidative stress when combined with GLUT1 inhibitors. Given the central role of insulin signaling in glucose homeostasis, we additionally show that circulating insulin levels modulate metabolic and oncogenic pathways of HNSCCs, providing a new perspective on events driving and sustaining HNSCC malignancy. These results establish GLUT1 as a viable therapeutic target for HNSCC in combination with prooxidant chemotherapies and define critical dependencies in HNSCC that can be utilized with existing clinical stage drugs for the treatment of HNSCC and potentially other squamous cancers.
Clockor2: Inferring global and local strict molecular clocks using root-to-tip regression
Authors: Featherstone Leo A. , Rambaut Andrew , Duchene Sebastian , Wirth Wytamma
Published: July 2023

Molecular sequence data from rapidly evolving organisms are often sampled at different points in time. Sampling times can then be used for molecular clock calibration. The root-to-tip (RTT) regression is an essential tool to assess the degree to which the data behave in a clock-like fashion. Here, we introduce Clockor2, a client-side web application for conducting RTT regression. Clockor2 uniquely allows users to quickly fit local and global molecular clocks, thus handling the increasing complexity of genomic datasets that sample beyond the assumption homogeneous host populations. Clockor2 is efficient, handling trees of up to the order of 104tips, with significant speed increases compared to other RTT regression applications. Although clockor2 is written as a web application, all data processing happens on the client-side, meaning that data never leaves the user’s computer. Clockor2 is freely available athttps://clockor2.github.io/.