bluuebunny/crossref_metadata_2025_split huggingface dataset:
A bispecific antibody overcomes limitations of prior strategies to achieve effective and tumor-selective Death Receptor 5 (DR5) clustering
Authors: Goldmacher Victor S. , Gershteyn Iosif M. , Chari Ravi , Kovtun Yelena 
Published: January 2025

AbstractThe bispecific antibody IMV-M was designed to bind and cluster Death Receptor 5 (DR5) specifically upon engaging the tumor antigen MUC16. This dual-binding mechanism induces apoptosis in MUC16-positive tumor cells through a novel enhancement process. IMV-M exhibited potent, MUC16-selective anti-tumor activityin vitroand in xenograft models, achieving efficacy at safe therapeutic doses without requiring secondary crosslinking. In contrast, earlier DR5-targeting tumor-selective bispecific antibodies either demonstrated limited anti-tumor activity or relied on secondary crosslinking, highlighting that binding of a bispecific antibody to a tumor antigen and DR5 alone is insufficient for effective DR5 clustering. Our findings reveal that an additional crowding mechanism for efficient DR5 clustering by bispecific antibodies is required. In contrast to the targeted delivery approach with antibody-drug conjugates (ADCs), our approach offers a pathway for developing more effective and safer cancer therapies. Importantly, the MUC16 antigen is overexpressed in substantial subsets of ovarian, pancreatic, and lung cancers while being almost completely absent in normal tissues, with highly limited expression in certain epithelial cells, indicating broad applicability of this bispecific antibody.
Influence of solvent, sex, and age on pharmacokinetic and acute behavioral effects of vaporized cannabis extract in mice
Authors: Westbrook S.R. , Jensen A.L. , Copeland-Solorzano V. , Buursma J. , Freeby G. , von Melville T. , Edwards T. , Hayashi K. , McLaughlin R.J. , Delevich K.M. 
Published: January 2025

AbstractThe legalization of cannabis in several states across the US has increased the need to better understand its effects on the body, brain, and behavior, particularly in different populations. Rodent models are particularly valuable in this respect because they provide precise control over external variables. Previous rodent studies have found age and sex differences in response to injected Δ9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis. However, this route of administration does not mimic the most common way humans consume cannabis, i.e. through inhalation. Here, we sought to address this gap by investigating age and sex differences in pharmacokinetics and the acute behavioral effects of vaporized cannabis extract in mice. Adolescent (postnatal day [P] 35-50) and adult (≥ P70) mice of both sexes received noncontingent exposure to 0 mg/ml, 150 mg/ml, or 300 mg/ml vaporized cannabis extract diluted in either 80% propylene glycol/20% vegetable glycerol (PG/VG) or 100% polyethylene glycol 400 (PEG). Immediately after exposure, body temperature, hot plate withdrawal latency, and locomotion were assessed. Blood was collected at 0, 30, and 60 min after vapor exposure, and plasma THC and its metabolites were analyzed. Measured THC levels were higher in both the plasma of vapor-exposed mice and the cannabis extract solutions themselves when PEG was the solvent compared to PG/VG. Vaporized cannabis (dissolved in PEG) at the highest dose tested induced hypothermic, antinociceptive, and locomotor-suppressing effects in all groups of mice. We found a dose-dependent age difference in locomotion, indicating that adolescents were less sensitive to the locomotor-suppressing effects of vaporized cannabis, which may be related to the plasma THC levels achieved. Although we found no significant sex differences in the acute behavioral effects of vaporized cannabis, there were significant sex differences in plasma THC metabolites indicating that female mice may metabolize vaporized cannabis more slowly than male mice. Taken together, the current findings add to a growing number of studies implementing vaporized cannabinoid delivery approaches by revealing PEG as the superior solvent for studies involving cannabis extract.
Giant KASH proteins and ribosomes synergistically establish cytoplasmic biophysical propertiesin vivo
Authors: Ding Xiangyi , Hao Hongyan , Elnatan Daniel , Alinaya Patrick Neo , Kalra Shilpi , Kaur Abby , Kumari Sweta , Holt Liam J. , Luxton G. W. Gant , Starr Daniel A. 
Published: January 2025

AbstractUnderstanding how cells control their biophysical properties during development remains a fundamental challenge. While cytoplasmic macromolecular crowding affects multiple cellular processes in single cells, its regulation in living animals remains poorly understood. Using genetically encoded multimeric nanoparticles forin vivorheology, we discovered thatC. eleganstissues maintain distinct cytoplasmic biophysical properties that differ from those observed across diverse systems, including bacteria, yeast species, and cultured mammalian cells. We identified two conserved mechanisms controlling cytoplasmic macromolecular diffusion: ribosome concentration, a known regulator of cytoplasmic crowding, works in concert with a previously unknown function for the giant KASH protein ANC-1 scaffolding the endoplasmic reticulum. These findings reveal mechanisms by which tissues establish and maintain distinct cytoplasmic biophysical properties, with implications for understanding cellular organization across species.One-Sentence SummaryLiving tissues maintain unique intracellular biophysical properties under the control of cytoplasmic constraints and crowding.
The bile acid-sensitive ion channel is gated by Ca2+-dependent conformational changes in the transmembrane domain
Authors: Freitas Makayla M. , Gouaux Eric 
Published: January 2025

SummaryThe bile acid-sensitive ion channel (BASIC) is the least understood member of the mammalian epithelial Na+channel/degenerin (ENaC/DEG) superfamily of ion channels, which are involved in a variety of physiological processes. While some members of this superfamily, including BASIC, are inhibited by extracellular Ca2+(Ca2+), the molecular mechanism underlying Ca2+modulation remains unclear. Here, by determining the structure of human BASIC in the presence and absence of Ca2+using single particle cryo-electron microscopy (cryo-EM), we reveal Ca2+-dependent conformational changes in the transmembrane domain and β-linkers. Electrophysiological experiments further show that a glutamate residue in the extracellular vestibule of the pore underpins the Ca2+-binding site, whose occupancy determines the conformation of the pore and therefore ion flow through the channel. These results reveal the molecular principles governing gating of BASIC and its regulation by Ca2+ions, demonstrating that Ca2+ions modulate BASIC function via changes in protein conformation rather than solely from pore-block, as proposed for other members of this superfamily.
Enhancer Dynamics and Spatial Organization Drive Anatomically Restricted Cellular States in the Human Spinal Cord
Authors: Kandror Elena K. , Wang Anqi , Carriere Mathieu , Peterson Alexis , Liao Will , Tjärnberg Andreas , Fung Jun Hou , Mahbubani Krishnaa T. , Loper Jackson , Pangburn William , Xu Yuchen , Saeb-Parsy Kourosh , Rabadan Raul , Maniatis Tom , Rizvi Abbas H. 
Published: January 2025

SUMMARYHere, we report the spatial organization of RNA transcription and associated enhancer dynamics in the human spinal cord at single-cell and single-molecule resolution. We expand traditional multiomic measurements to reveal epigenetically poised and bivalent active transcriptional enhancer states that define cell type specification. Simultaneous detection of chromatin accessibility and histone modifications in spinal cord nuclei reveals previously unobserved cell-type specific cryptic enhancer activity, in which transcriptional activation is uncoupled from chromatin accessibility. Such cryptic enhancers define both stable cell type identity and transitions between cells undergoing differentiation. We also define glial cell gene regulatory networks that reorganize along the rostrocaudal axis, revealing anatomical differences in gene regulation. Finally, we identify the spatial organization of cells into distinct cellular organizations and address the functional significance of this observation in the context of paracrine signaling. We conclude that cellular diversity is best captured through the lens of enhancer state and intercellular interactions that drive transitions in cellular state. This study provides fundamental insights into the cellular organization of the healthy human spinal cord.
pH adjustment increases biofuel production from inhibitory switchgrass hydrolysates
Authors: Barten Lillian M. , Crandall Johnathan G. , Xie Dan , Serate Jose , Handowski Evan , Jen Annie , Overmyer Katherine A. , Coon Joshua J. , Hittinger Chris Todd , Landick Robert , Zhang Yaoping , Sato Trey K. 
Published: January 2025

AbstractBiofuels derived from renewable and sustainable lignocellulosic biomass, such as switchgrass, offer a promising means to limit greenhouse gas emissions. However, switchgrass grown under drought conditions contains high levels of chemical compounds that inhibit microbial conversion to biofuels. Fermentation of drought switchgrass hydrolysates by engineeredSaccharomyces cerevisiaeandZymomonas mobilisgenerates less ethanol than fermentation of hydrolyzed switchgrass from an average rainfall year. Here, we demonstrate that this inhibitory effect can be alleviated by altering the pH of drought-switchgrass hydrolysates made from two different pretreatment methods: Ammonia Fiber Expansion (AFEX) and Soaking in Aqueous Ammonia (SAA). Fermentation rates and biofuel production from AFEX- and SAA-pretreated switchgrass hydrolysates from normal and drought years were higher at pH 5.8 than at pH 5.0 for both Saccharomyces cerevisiaeandZymomonas mobilis. Additionally, SAA pretreatment of drought switchgrass enabled increased fermentation rates and titers compared to AFEX pretreatment. Using a synthetic mimic of switchgrass hydrolysate, we identified relief from pH-dependent inhibition by lignocellulose-derived inhibitors as the cause of increased biofuel production above a pH of 5.0. These results demonstrate that SAA pretreatment and pH adjustment can significantly improve fermentation and biofuel production from switchgrass hydrolysates and especially from drought-switchgrass hydrolysates by industrial microorganisms.
CHOLINERGIC MODULATION OF CELLULAR RESONANCE IN NON-HUMAN PRIMATE HIPPOCAMPUS
Authors: Gambrill Abigail , Rueckemann Jon W. , Barria Andres 
Published: January 2025

Acetylcholine modulates the network physiology of the hippocampus, a crucial brain structure that supports cognition and memory formation in mammals1–3. In this and adjacent regions, synchronized neuronal activity within theta-band oscillations (4-10Hz) is correlated with attentive processing that leads to successful memory encoding4–10. Acetylcholine facilitates the hippocampus entering a theta oscillatory regime and modulates the temporal organization of activity within theta oscillations11,12.Unlike rodents that exhibit constant theta oscillations during movement and exploration, primates only manifest theta oscillations in transient bouts during periods of acute attention—despite conserved hippocampal anatomy13–16. The phasic nature of primate theta oscillations and their susceptibility to muscarinic antagonists17, suggest that acetylcholine afferents acutely modulate local circuitry, resulting in a temporary shift in hippocampal rhythmic dynamics. However, we lack a mechanistic understanding that links cellular physiology to emergent theta-rhythmic network dynamics.We explored the hypothesis that acetylcholine induces a distinct modulation of cellular properties to facilitate synchronization within the theta band in non-human primate neurons.Here we show that non-human primate neurons from the CA1 region of monkey hippocampus are not homogeneous in their voltage response to inputs of varying frequencies, a phenomenon known as cellular resonance18,19. We classified these neurons as ‘resonant’ or ‘non-resonant’. Under the influence of carbachol, these two classes of neurons become indistinguishable in their resonance, suggesting that acetylcholine transiently creates a homogeneous susceptibility to inputs within the theta range. This change is mediated by metabotropic acetylcholine receptors that enhance sag potentials, indicating that acetylcholine acts on principal neurons to modulate Hyperpolarization-activated Cyclic Nucleotide-gated channels.Our results reveal a mechanism through which acetylcholine can rapidly modulate intrinsic properties of primate hippocampal neurons to facilitate synchronization within theta-rhythmic circuits, providing insight into the unique features of primate hippocampal physiology.
Attention Modulates Stimulus Representations in Neural Feature Dimension Maps
Authors: Thayer Daniel D. , Sprague Thomas C. 
Published: January 2025

ABSTRACTComputational theories posit that attention is guided by a combination of spatial maps for individual features that can be dynamically weighted according to task goals. Consistent with this framework, when a stimulus contains several features, attending to one or another feature results in stronger fMRI responses in regions preferring the attended feature. We hypothesized that multivariate activation patterns across feature-responsive cortical regions form spatial ‘feature dimension maps’, which combine to guide attentional priority. We tested this prediction by reconstructing neural feature dimension maps from fMRI activation patterns across retinotopic regions of visual cortex using a spatial inverted encoding model. Participants viewed a peripheral visual stimulus at a random location which always contained moving colored dots. On each trial, participants were precued to report the predominant direction of motion or color of the stimulus, or to attend fixation. Stimulus representations in reconstructed priority maps were selectively enhanced in color-selective regions when color was attended, and in motion-selective regions when motion was attended, and this effect was primarily observed at the stimulus location. While enhancement was localized to the stimulus in color-selective regions, motion-selective regions were globally enhanced when motion was task relevant. These results suggest different cortical regions support spatial maps of different visual features, and that each map is uniquely reweighted based on task demands to guide visual behavior towards the most relevant locations based on important features.
Baseline ferritin predicts myocardial iron uptake following intravenous iron therapy- a hypothesis generating study
Authors: Nunez Julio , Mollar Anna , Vera-Aviles Mayra , Kabir Syeeda , Shah Akshay , Polzella Paolo , Desborough Michael , Cardells Ingrid , Miñana Gema , del Canto Irene , Ferreira Vanessa , Piechnik Stefan , Maceira Alicia , Lakhal-Littleton Samira 
Published: January 2025

ABSTRACTAimsIron deficiency (ID) is a common co-morbidity in heart failure (HF). Intravenous iron therapy improves outcomes. Several mechanisms have been proposed, including myocardial iron repletion. However, it is unknown if clinical iron markers predict the extent of this repletion. The aim of this study is to address this question by harnessing data from two clinical studies that evaluated changes in myocardial iron using cardiac magnetic resonance (CMR).Methods and ResultsWe performed a post-hoc analysis of two previously published trials. The Myocardial-IRON trial measured change in myocardial iron, denoted by a decrease in CMR T1-mapping, at 7 and 30 days after FCM in patients with ID and HF. The STUDY trial measured myocardial and spleen iron at multiple timepoints after FCM in patients with ID without HF. In this post-hoc analysis, we examined the association between baseline iron markers (Tsat and ferritin) and change in myocardial iron in the weeks after FCM therapy. Changes in spleen iron were also examined, due its role as an intermediary in the redistribution of iron from iron-carbohydrate complexes such as FCM. In patients with or without HF, higher plasma ferritin at baseline predicted lower rise in myocardial iron in the weeks after therapy with FCM. In contrast, higher plasma ferritin at baseline predicted a greater rise in spleen iron.ConclusionsThese data point towards the hypothesis that functional ID, which is characterized by elevated ferritin, could limit myocardial iron repletion after IV iron therapy, by favoring iron trapping in the spleen.
Predicting Hypertension Among HIV Patients on Antiretroviral Therapy in Rural Eastern Cape, South Africa Using Machine Learning
Authors: Tsuro Urgent , Ncube Trymore , Oladimeji Kelechi E. , Apalata Teke R. 
Published: January 2025

AbstractBackgroundHypertension continues to be a major challenge in developing countries like South Africa, as it significantly contributes to the cardiovascular disease burden in these countries. This study aimed to utilize the machine learning (ML) models to anticipate the incidence of hypertension in HIV patients under antiretroviral therapy (ART) in rural Eastern Cape, South Africa.MethodsThis research carried out a retrospective cohort study and created and tested six machine learning algorithms: Neural Networks, Random Forest, Logistic Regression, Naive Bayes, K-Nearest Neighbours and XGBoost. The goal was to predict the likelihood of developing hypertension. Feature selection was done using the Boruta method and the model was assessed using several metrics including aiming, precision, recall, F1 score, and area under the receiver operating characteristic curve (AUC).ResultsXGBoost outperformed all other models with an AUC of 0.96, which further suggests it can effectively distinguish between hypertensives and normotensives. In the case of Boruta analysis, some aggravated risk factors were age category, time on ART, BMI category, waist to hip ratio, waist size, family history of HBP and relationship status, physical activity, LDL cholesterol level, awareness of high blood pressure, education level, use of ART and diabetes mellitus.ConclusionsThis study has highlighted the utility of XGBoost, as one of the advanced machine learning algorithms, in reliably forecasting the occurrence of hypertension in HIV ART patients in a rural setting. The established risk factors elucidate the complexity behind the hypertension emergence and hence the need for triad approaches which include lifestyle changes, clinical treatments, and demographic solutions to tackle the public health problem.
Effectiveness of Smoking Cessation Interventions in People With Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: Aduse-Poku Livingstone , Cheng Hui G. , Palesh Oxana , Hong Susan 
Published: January 2025

AbstractIntroductionSmoking at or following a cancer diagnosis increases both all-cause and cancer-specific mortality, adverse treatment outcomes, as well as the risk for disease progression and tobacco-related second primary cancers. This protocol outlines a systematic review and meta-analysis evaluating the effectiveness of smoking cessation interventions in cancer patients based on randomized controlled trials (RCTs), delivering the highest quality of evidence for causal inference.MethodsA systematic search of the literature will be conducted across PsychInfo, EMBASE (through OVID), PubMed (also through OVID), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). RCTs published in English, designed to assist adult cancer survivors who smoke to quit, regardless of their cancer type, stage, or treatment, will be included. Title and abstract screening will be carried out independently by two authors. All potentially eligible full-text articles will be independently reviewed. Any disagreements will be resolved through discussion. Extracted data will encompass study characteristics, intervention details, participant numbers and attributes, outcomes, quit attempts, and follow-up duration. We will evaluate the risk of bias using the Cochrane Risk of Bias Tool 2 (ROB-2). To evaluate the outcomes of the combined studies, a meta-analysis and/or network meta-analysis will be performed with both fixed-effect models and random-effects models using R.ConclusionThis systematic review will address a critical research gap and provide tailored insights for smoking cessation among cancer survivors.
SAPID: a Strategy to Analyze Plant Extracts Taste In Depth. Application to the complex taste ofSwertia chirayita(Roxb.) H.Karst.
Authors: Rutz Adriano , Deneulin Pascale , Tonutti Ivano , Bach Benoît , Wolfender Jean-Luc 
Published: January 2025

ABSTRACTBitterness is challenging to analyze due to the diversity of bitter compounds, variability in sensory perception, and its interplay with other tastes. To address this, we developed an untargeted approach to deconvolute the taste and molecular composition of complex plant extracts. We applied our methodology to an ethanolic extract ofSwertia chirayita(Roxb.) H.Karst., a plant known for its unique bitterness. Chemical characterization was performed through nuclear magnetic resonance spectroscopy experiments together with untargeted liquid chromatography-high resolution tandem mass spectrometry analysis coupled to a charged aerosol detector. After clustering the fractions based on chemical similarity, we performed free sensory analysis and classical descriptive analysis on each cluster. Our results confirmed the attribution of bitterness to iridoids and highlighted the role of other important compounds in the overall taste. This method offers a systematic approach to analyzing and enhancing the taste profiles of plant-based beverages.HighlightsAn untargeted method to analyze in depth plant extracts’ taste and chemical composition has been developed.The attribution of the bitterness of an ethanolic extract ofSwertia chirayita(Roxb.) H.Karst. to well-known bitter major and minor iridoids was confirmed using untargeted methods.Chemically informed tastingallowed to highlight other less pronounced tastes within the extract, contributing to its overall complexity.Chemically informed tastingled to interesting insights into the sub-threshold impact on taste and taste modulating properties.Graphical Abstract
Cholesterol deficiency directs autophagy-dependent secretion of extracellular vesicles
Authors: Yaeger Jazmine D. W. , Sengupta Sonali , Walz Austin L. , Morita Mayu , Morgan Terry K. , Vermeer Paola D. , Francis Kevin R. 
Published: January 2025

SUMMARYExtracellular vesicle (EV) secretion is an important, though not fully understood, intercellular communication process. Lipid metabolism has been shown to regulate EV activity, though the impact of specific lipid classes is unclear. Through analysis of small EVs (sEVs), we observe aberrant increases in sEV release within genetic models of cholesterol biosynthesis disorders, where cellular cholesterol is diminished. Inhibition of cholesterol synthesis at multiple synthetic steps mimics genetic models in terms of cholesterol reduction and sEVs secreted. Further analyses of sEVs from cholesterol-depleted cells revealed structural deficits and altered surface marker expression, though these sEVs were also more easily internalized by recipient cells. Transmission electron microscopy of cells with impaired cholesterol biosynthesis demonstrated multivesicular and multilamellar structures potentially associated with autophagic defects. We further found autophagic vesicles being redirected toward late endosomes at the expense of autophagolysosomes. Through CRISPR-mediated inhibition of autophagosome formation, we mechanistically determined that release of sEVs after cholesterol depletion is autophagy dependent. We conclude that cholesterol imbalance initiates autophagosome-dependent secretion of sEVs, which may have pathological relevance in diseases of cholesterol disequilibrium.