bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell transcriptomics of X-ray irradiatedDrosophilawing discs reveals heterogeneity related to cell-cycle status and cell location
Authors: Cruz Joyner , Sun Willam Y. , Verbeke Alexandra , Hariharan Iswar K. 
Published: December 2024

AbstractEven seemingly homogeneous populations of cells can express phenotypic diversity in response to environmental changes. Thus, X-ray irradiation of tissues composed of diverse cell types can have complex outcomes. We have used single-cell RNA-sequencing to study the effects of X-ray radiation on theDrosophilawing imaginal disc, a relatively simple tissue composed mostly of epithelial cells. Transcriptomic clustering of cells collected from the wing disc generates clusters that are mainly grouped based on proximodistal cell location. To quantify heterogeneity of gene expression among clusters, we adapted a metric used to study market concentration, the Herfindahl-Hirschman Index. Genes involved in DNA damage repair, defense against reactive oxygen species, cell cycle progression, and apoptosis are expressed relatively uniformly. In contrast, genes encoding a subset of ligands, notably cytokines that activate the JAK/STAT pathway, some transcription factors includingEts21C, previously implicated in regeneration, and several signaling proteins are expressed more regionally. Though the radiation-responsive transcription factor p53 is expressed relatively uniformly in the wing disc, several regionally-induced genes still require p53 function, indicating that regional and radiation-induced factors combine to regulate their expression. We also examined heterogeneity within regions using a clustering approach based on cell cycle gene expression. A subpopulation of cells, characterized by high levels oftribblesexpression, is amplified in irradiated discs. Remarkably, this subpopulation accounts for a considerable fraction of radiation-induced gene expression, indicating that cellular responses are non-uniform even within regions. Thus, both inter-regional and intra-regional heterogeneity are important features of tissue responses to X-ray radiation.
Regional disparity in surgical residency training and work environment between urban and regional hospitals: an additional perspective from a nationwide survey for surgical residents
Authors: Watanabe Genki , Watanabe Jun , Hayashi Saki , Konishi Takaaki , Poudel Saseem , Kiyasu Yoshiyuki , Fukumoto Masayuki , Korai Takahiro , Nomura Shinsuke , Yamamoto Naohiro , Nakajima Masao , Hosoya Keiko , Saito Mitsue 
Published: December 2024

Structured AbstractPurposeTo investigate the current status of regional disparity of surgical residency training between urban and regional hospitals.MethodsBased on a nationwide online questionnaire survey for newly certified surgical trainees, the responding residents were divided into two groups according to the size of the city where they had trained: an urban city (>1 million, UC group) versus a regional city (<1 million, RC group). These groups were compared regarding surgical education and work environment.ResultsThe UC group (n = 317, 42%) included surgeons with more post-graduate years, older age, females, and full-time working partners compared to the RC group (n = 439, 58%). More residents in the UC group were from urban areas, while the RC group had more residents from regional areas. No differences were observed in the number of experienced surgeries, published papers, opportunities for off-the-job training, or satisfaction with the surgical residency training program. Except for a higher income in the RC group, no differences were observed for other factors regarding the work environment.ConclusionsThere was little regional disparity regarding the impressions of surgical residency training between urban and regional cities including surgical education and work environment.
Beyond Accuracy: A Cost-Aware Approach to Skin Lesion Detection Across Skin Tone Imbalances
Authors: Hasan Md Mohit , Suchi Mahbuba Tasnime , Habib Md Hasibul , Akter Sumya , Rothy Zarin Tasnim , Islam A.M.Tayeful , Pias Tanmoy Sarkar , Eisenberg David , Bin Akter Simon 
Published: December 2024

AbstractSkin lesion prediction using artificial intelligence (AI) models is highly dependent on skin tone, yet current approaches largely overlook this critical factor. The Fitzpatrick 17k dataset, which contains six skin tone categories: lighter to darker, is severely imbalanced, with most models biased toward lighter skin tones. Previous efforts to improve overall accuracy fall short: overall accuracy fails to reflect true performance across imbalances. This creates a significant gap, as effective skin lesion detection must work across all skin tones, not just a few. To address this, we introduce the Cost-Aware EfficientNet (CAEN) model, combining cost-sensitive learning (CSL) and attention mechanisms to tackle imbalanced data and ensure the model generalizes well across all skin tones with detailed interpretability. Rather than simply improving accuracy, our model enhances class-specific performance, achieving 79% recall for non-neoplastic, 88% for benign, and 80% for malignant lesions. This indicates an overall improvement in darker tones of approximately 44.86% compared to state-of-the-art results from prior studies. Furthermore, it remains robust across augmented test conditions, such as changes in brightness, contrast, blur, and zoom, providing balanced outcomes for diverse skin tones. This novel approach offers a significant leap toward fair and reliable skin lesion prediction for all skin tones with interpretability.
Renal arterial dysfunction, impaired pressure natriuresis and salt-sensitivity in a mouse model of Cushing syndrome
Authors: Costello Hannah M , Grenier Céline , Ivy Jessica R , Jones Natalie K. , Stewart Kevin , Holmes Megan C , Livingstone Dawn E.W. , Dhaun Neeraj , Bailey Matthew A 
Published: December 2024

ABSTRACTBackgroundCushing Syndrome arises from endogenous overproduction of ACTH by a tumour or is acquired through chronic exposure to glucocorticoid medication. Hypertension is a major complication, increasing cardiovascular risk, but underlying mechanisms are not clearly defined.MethodsWe infused male C57BL/6J mice with ACTH or vehicle for 14-21 days, inducing cardinal features of Cushing Syndrome. The renal pressure natriuresis response was measured under anesthesia and ex vivo artery function assessed by myography.ResultsACTH infusion blunted the natriuretic and diuretic responses to incremental increases in blood pressure. Renal hemodynamics did not change with blood pressure in controls, but renal autoregulation was impaired in ACTH mice. Theex vivocontractile response of the renal artery to phenylephrine was diminished in Cushing Syndrome mice, as was endothelium-dependent and endothelium-independent relaxation. On 0.3% sodium diet, there was no evidence of sodium retention in ACTH-treated mice but the diurnal rhythm of sodium excretion was abnormal and mice had non-dipping BP. The Cushing Syndrome model also displayed enhanced salt preference and amplified salt-sensitive blood pressure.ConclusionCushing Syndrome induces a cluster of phenotypes impacting sodium homeostasis and blood pressure regulation. Hypertension, salt-sensitivity and non-dipping blood pressure are important cardiovascular risk factors, and, beyond Cushing Syndrome, our findings are relevant to obesity and the metabolic syndrome, in which tissue glucocorticoid homeostasis is abnormal.
New insights into the cultivability of human milk microbiota from ingestion to digestion and implications for its immunomodulatory properties
Authors: Bras Charles Le , Mouchard Alizé , Rault Lucie , Cochet Marie-Françoise , Ménard Olivia , Jacquet Nolwenn , Chuat Victoria , Valence Florence , Loir Yves Le , Bellanger Amandine , Deglaire Amélie , Huërou-Luron Isabelle Le , Even Sergine 
Published: December 2024

AbstractHuman milk (HM) microbiota is increasingly studied for its potential health benefits. However, the physiological state of HM bacteria and consequently their effects on gut homeostasis remain a question. This study investigated the physiological state of the HM microbiota by characterizing its cultivable fraction, as it might be at the point of ingestion and assessing the effects of digestion on the cultivability and immunomodulatory properties of six prevalent HM strains. The microbiota of 28 HM samples was analysed by 16S metabarcoding either directly on raw milk (raw milk microbiota, RM) or on the complete cultivable fraction obtained from seven non-selective media (cultivable milk microbiota, CM). Diversity was lower in CM than in RM, with 32 versus 435 genera and a median of 7 versus 69 genera per sample in CM and RM, respectively. CM also showed under-representation of strictly anaerobic genera. Factors like parity and iron or vitamin supplementation affected RM and/or CM.In vitrogastrointestinal digestion moderately impacted strain cultivability. However, most strains partially or completely lost their immunomodulatory properties on the monocyte THP1 cell line after digestion, excepta Staphylococcus epidermidisstrain that gained immunomodulatory potential.
Msp1 and Pex19-Pex3 cooperate to achieve correct localization of Pex15 to peroxisomes
Authors: Matsumoto Shunsuke , Kogure Yoshiki , Ono Suzuka , Numata Tomoyuki , Endo Toshiya 
Published: December 2024

AbstractYeast Msp1 is a dual-localized AAA-ATPase on the mitochondrial outer membrane (OM) and peroxisomal membrane. We previously showed that Msp1 transfers mistargeted tail-anchored (TA) proteins from mitochondria to the endoplasmic reticulum (ER) for degradation or delivery to their original destinations. However, the mechanism by which Msp1 in mitochondria and peroxisomes handles authentic peroxisomal TA proteins remains unclear. We show that newly synthesized Pex15 is targeted to peroxisomes primarilyviathe Pex19- and Pex3-dependent pathway. Mistargeted Pex15 on the mitochondrial OM is extracted by mitochondrial Msp1, and transferred to the ERviathe guided-entry of TA proteins pathway for degradation or to peroxisomesviathe Pex19-Pex3 pathway. Intriguingly, endogenous Pex15 localized in peroxisomes is also extracted from the membranes by peroxisomal Msp1, but returns to peroxisomesviathe Pex19-Pex3 pathway. These results suggest that correct Pex15 localization to peroxisomes relies on not only the initial targeting by Pex19-Pex3 but also the constant re-routing by Msp1 and Pex19-Pex3.
Serotonin system development and adult function are regulated by GDNF
Authors: Garton Daniel R. , Runneberger Isabel , Casserly Laoise , Schorling Tabea , Montaño-Rodríguez Ana R. , Iivananen Vilma , Kopra Jaakko J. , Mätlik Kärt , Fagerström-Billai Fredrik , Damdimopoulos Anastasios , Petteri Piepponen T. , Andressoo Jaan-Olle 
Published: December 2024

AbstractCognitive functions, neuropsychiatric disorders and behaviors from feeding to mood relate to the serotonin (5-hydroxytryptamine; 5-HT) system. We report that expression of glial cell line-derived neurotrophic factor (GDNF), a known potent stimulator of the brain dopamine system, correlates with serotonergic markers in humans, and increased GDNF defines a subset of psychiatric patients with a characteristic 5-HT-related gene expression pattern. A similar ∼1.5- to 2-fold upregulation of endogenous GDNF expression in mice increases brain 5-HT levels and function, both developmentally and during adulthood, and modulates response to fluoxetine. Notably, increasing GDNF more than approximately 2-fold does not increase 5-HT further and instead produces an inverted U-shaped curve of 5-HT levels, suggesting why the GDNF/5-HT correlation has remained controversial. Collectively, our data indicate that GDNF levels fine-tune 5-HT system development and adult function while excess GDNF exclusively associates with neuropsychiatric illness, making it an important target for future research.
Lipid specificity of action of SARS-CoV-2 fusion peptide fragments on model membranes
Authors: Shekunov Egor V. , Volynsky Pavel E. , Efimova Svetlana S. , Aliper Elena T. , Efremov Roman G. , Ostroumova Olga S. 
Published: December 2024

AbstractThe study focuses on investigating the interaction of SARS-CoV-2 fusion peptide fragment with model membranes of various lipid composition to elucidate the molecular mechanisms of peptide-derived membrane fusion. The work utilized the short fragment of SARS-CoV-2 fusion peptide which is homologous to 816-827 region of the native SARS-CoV-2 FP (FP816-827) and contains the highly conserved LLF motif responsible for membrane fusion, and its ineffective analogue (mFP816-827), where LLF motif was replaced for AAA. Using fluorescence fusion assay, it was demonstrated that the LLF motif plays a key role in inducing liposome fusion, whereas its replacement completely abolishes this capability. The fusogenic activity of the peptide strictly depended on the vesicle lipid composition. It was potentiated by phosphatidylethanolamine and inhibited by phosphatidylserine. Molecular dynamics revealed that both peptides predominantly adopt an α-helical conformation; however, the native peptide interacts more strongly with the hydrophobic core of the membrane by increasing peptide-lipid hydrophobic contacts, while the mutant version exhibits a more superficial localization. Differential scanning microcalorimetry data indicated that the ability of FP816-827to disturb lipid packing increased with decreasing membrane lipid tail length. The molecular mechanisms underlying the fusogenic activity of the SARS-CoV-2 fusion peptide were identified, specifically its ability to cluster phospholipid head groups in its own vicinity. As a result, local regions with positive spontaneous curvature are formed in the outer monolayer, facilitating membrane fusion. The findings highlight the role of membrane composition and lipid architecture in the mechanism of viral fusion with host cells.
Lifespan Normative Models of White Matter Fractional Anisotropy: Applications to Early Psychosis
Authors: Cirstian Ramona , Forde Natalie J. , Zhang Gary , Hellemann Gerhard S. , Beckmann Christian F. , Kraguljac Nina V. , Marquand Andre F. 
Published: December 2024

AbstractThis study presents large-scale normative models of white matter (WM) organization across the lifespan, using diffusion MRI data from over 25,000 healthy individuals aged 0-100 years. These models capture lifespan trajectories and inter-individual variation in fractional anisotropy (FA), a marker of white matter integrity. By addressing non-Gaussian data distributions, race, and site effects, the models offer reference baselines across diverse ages, ethnicities, and scanning conditions. We applied these FA models to the HCP Early Psychosis cohort and performed a multivariate analysis to map symptoms onto deviations from multimodal normative models using multi-view sparse canonical correlation analysis (msCCA). Our results reveal extensive white matter heterogeneity in psychosis, which is not captured by group-level analyses, with key regions identified, including the right uncinate fasciculus and thalami. These normative models offer valuable tools for individualized WM deviation identification, improving precision in psychiatric assessments. All models are publicly available for community use.TeaserLifespan models of white matter offer insights into brain health, providing tools for tracking individual deviations across ages.
RegVelo: gene-regulatory-informed dynamics of single cells
Authors: Wang Weixu , Hu Zhiyuan , Weiler Philipp , Mayes Sarah , Lange Marius , Wang Jingye , Xue Zhengyuan , Sauka-Spengler Tatjana , Theis Fabian J. 
Published: December 2024

AbstractRNA velocity has emerged as a popular approach for modeling cellular change along the phenotypic landscape but routinely omits regulatory interactions between genes. Conversely, methods that infer gene regulatory networks (GRNs) do not consider the dynamically changing nature of biological systems. To integrate these two currently disconnected fields, we present RegVelo, an end-to-end dynamic, interpretable, and actionable deep learning model that learns a joint model of splicing kinetics and gene regulatory relationships and allows us to perform in silico perturbation predictions. When applied to datasets of the cell cycle, human hematopoiesis, and murine pancreatic endocrinogenesis, RegVelo demonstrates superior predictive power for interactions and perturbation simulations, for example, compared to methods that focus solely on dynamics or GRN inference. To leverage RegVelo’s full potential, we studied the dynamics of zebrafish neural crest development and underlying regulatory mechanisms using our Smart-seq3 dataset and shared gene expression and chromatin accessibility measurements. Using RegVelo’s in silico perturbation predictions, validated by CRISPR/Cas9-mediated knockout and single-cell Perturb-seq, we establish transcription factortfecas an early driver andelf1as a novel regulator of pigment cell fate and propose a gene-regulatory circuit involvingtfecandelf1interactions via the toggle-switch model.
Food-Derived Compounds Extend the Shelf-Life of Frozen Human Milk
Authors: Silpe Justin E. , Damian-Medina Karla , Bassler Bonnie L. 
Published: December 2024

SummaryBreastmilk is known to provide optimal nutrition for infant growth and development. A cross-sectional analysis of nationally representative US data from 2016 to 2021 revealed that >90% of lactating mothers reported using breast pumps to express milk.1We conducted a survey ofn= 1,049 lactating or recently lactating individuals from a US nationally representative population to explore breastmilk storage practices among this group. The data revealed that 83% of respondents store breastmilk in their homes, with 68% using freezers to do so for >1 month. The lowest available temperature in most household freezers is -20 °C, a temperature that is inadequate to maintain human milk’s emulsified structure, leading to separation, degradation of fats, loss of key vitamins, and changes in palatability. We developed a first-of-its-kind high-throughput screening platform to identify food-derived compounds and combinations of compounds that, when added to human breastmilk, preserve fat content, retain antioxidant capacity, and reduce production of rancid-associated free fatty acids during extended freezer storage. These formulations represent leads for the development of safe and affordable frozen breastmilk shelf-life extenders for easy at-home use to increase the longevity of stored breastmilk.
Sorbate Induces Lysine Sorbylation Through Non-Canonical Activities of Class I HDACs to Regulate the Expression of Inflammation Genes
Authors: Sin Yi-Cheng , Abernathy Breann , Mashek Douglas G. , Chen Yue 
Published: December 2024

AbstractMetabolic and environmental factors may impact gene expression through the production of active metabolites and epigenetic modifications of histones and transcription factors. In this study, we discovered that cellular uptake of sorbate, an FDA-approved and widely used food preservative, can induce lysine sorbylation (Ksor), a new posttranslational modification and epigenetic mark. We identified over 40 Ksor sites on core histones from mammalian cells and tissue upon sorbate uptake and further showed that the dynamics of histone Ksor could be regulated by the non-canonical activities of Class I histone deacetylases (HDAC1-3). We demonstrated that Class I HDACs catalyzed sorbylation upon sorbate uptake and desorbylation in the absence of sorbate both in vitro and in vivo. Sorbate uptake in mice livers led to a significant increase in histone Ksor without affecting overall histone acetylation, which correlated with the decreased expression of genes in inflammation signaling pathways. Accordingly, sorbate treatment in macrophage RAW264.7 cells upon LPS stimulation dose-dependently downregulated the expression of proinflammatory genes and production of nitric oxide. Global proteomic profiling revealed widespread lysine sorbylation substrates in diverse metabolic and signaling pathways and identified RelA (p65), a component of the NF-ĸB complex, and its interacting proteins as bona fide Ksor targets. Sorbate treatment significantly decreased NF-ĸB transcriptional activities in response to LPS stimulation in RAW264.7 cells. Taken together, our study demonstrated a non-canonical mechanism of sorbate uptake in regulating epigenetic histone modifications and inflammatory gene expression.
Effects of transmembrane phenylalanine residues on γ-secretase-mediated Notch-1 proteolysis
Authors: Malvankar Shweta R. , Wolfe Michael S. 
Published: December 2024

ABSTRACTγ-Secretase is a presenilin-containing intramembrane aspartyl protease complex that cleaves within the transmembrane domain (TMD) of nearly 150 substrates, with the amyloid precursor protein (APP) being the most well studied. APP cleavage by γ-secretase generates amyloid β-peptides (Aβ) that pathologically deposit in Alzheimer’s disease. APP TMD substrate undergoes initial endoproteolysis (ε-cleavage) followed by processive carboxypeptidase trimming of long Aβ intermediates in ∼tripeptide intervals. Although γ-secretase cleavage of Notch1 is essential in developmental biology and altered in many cancers, the processing of this cell-surface receptor is relatively understudied. Only one sequence specificity rule is known for γ-secretase substrate processing: Aromatic residues such as phenylalanine are not tolerated in the P2’ position with respect to any processing event on the APP TMD. Here we show using biochemical and mass spectrometry (MS) techniques that this specificity rule holds for Notch1 as well. Analysis of products from the reactions of purified enzyme complex and Notch1 TMD substrate variants revealed that P2’ Phe relative to ε-site cleavage reduced proteolysis and shifted initial cleavage N-terminally by one residue. Double Phe mutation near the ε site resulted in reduced proteolysis with shifting to two major initial cleavage sites, one N-terminally and one C-terminally, both of which avoid Phe in the P2’ position. Additionally, three natural Phe residues were mutated to corresponding residues in the APP TMD, which led to increased ε proteolysis. Thus, Phe residues can affect the enzyme reaction rate as well as cleavage site specificity in the Notch1 TMD.