bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma galectin-9 relates to cognitive performance and inflammation among adolescents with vertically acquired HIV
Authors: Moar Preeti , Linn Kyaw , Premeaux Thomas A. , Bowler Scott , Sardarni Urvinder Kaur , Gopalan Bindu Parachalil , Shwe Ei E. , San Thidar , Han Haymar , Clements Danielle , Hlaing Chaw S. , Kyu Ei H. , Thair Cho , Mar Yi Y. , Nway Nway , Mannarino Julie , Bolzenius Jacob , Mar Soe , Aye Aye Mya M. , Tandon Ravi , Paul Robert , Ndhlovu Lishomwa C. 
Published: April 2024

Objective:
Adolescents with perinatally acquired HIV (AWH) are at an increased risk of poor cognitive development yet the underlying mechanisms remain unclear. Circulating galectin-9 (Gal-9) has been associated with increased inflammation and multimorbidity in adults with HIV despite antiretroviral therapy (ART); however, the relationship between Gal-9 in AWH and cognition remain unexplored.

Design:
A cross-sectional study of two independent age-matched cohorts from India [AWH on ART (n = 15), ART-naive (n = 15), and adolescents without HIV (AWOH; n = 10)] and Myanmar [AWH on ART (n = 54) and AWOH (n = 22)] were studied. Adolescents from Myanmar underwent standardized cognitive tests.

Methods:
Plasma Gal-9 and soluble mediators were measured by immunoassays and cellular immune markers by flow cytometry. We used Mann–Whitney U tests to determine group-wise differences, Spearman's correlation for associations and machine learning to identify a classifier of cognitive status (impaired vs. unimpaired) built from clinical (age, sex, HIV status) and immunological markers.

Results:
Gal-9 levels were elevated in ART-treated AWH compared with AWOH in both cohorts (all P < 0.05). Higher Gal-9 in AWH correlated with increased levels of inflammatory mediators (sCD14, TNFα, MCP-1, IP-10, IL-10) and activated CD8+ T cells (all P < 0.05). Irrespective of HIV status, higher Gal-9 levels correlated with lower cognitive test scores in multiple domains [verbal learning, visuospatial learning, memory, motor skills (all P < 0.05)]. ML classification identified Gal-9, CTLA-4, HVEM, and TIM-3 as significant predictors of cognitive deficits in adolescents [mean area under the curve (AUC) = 0.837].

Conclusion:
Our results highlight a potential role of Gal-9 as a biomarker of inflammation and cognitive health among adolescents with perinatally acquired HIV.
Direct red blood cell effect on thrombosis is dependent on the interaction of tissue factor and calcium with membrane phosphatidylserine
Authors: Price Adam D. , Chae Ryan C. , Wallen Taylor E. , Becker Ellen R. , Baucom Matthew R. , Schuster Rebecca M. , England Lisa , Pritts Timothy A. , Goodman Michael D. 
Published: April 2024

BACKGROUND
Prior literature has implicated red blood cells (RBCs) in the initiation of thrombosis and suggests that posttransfusion hypercoagulability may occur secondary to the effects of RBCs. Elevated serum tissue factor is a known sequelae of acute trauma. Phosphatidylserine (PS) is a prothrombotic phospholipid present within the RBC cell membrane. We hypothesized that RBC aggregation is dependent on the interaction between RBC membrane bound (exposed) PS, extracellular calcium, and tissue factor.

METHODS
Human whole blood (WB) was separated into components, including RBCs and platelet-rich plasma (PRP). Whole blood, PRP, and RBCs underwent impedance aggregometry utilizing arachidonic acid (AA), ADP, collagen, calcium, and tissue factor (TF)-based agonists. Red blood cells then underwent impedance aggregometry utilizing combined calcium and TF agonists. Red blood cells were pretreated with Annexin V, a known PS blocking agent, and underwent impedance aggregometry with combined calcium and TF agonists to determine if the mechanism of calcium/TF-induced RBC aggregability is dependent on PS. Red blood cells treated with calcium, TF, calcium+TF, and pre-treated with Annexin V followed by calcium+TF were perfused through an in vitro model of pulmonary microcirculatory flow.

RESULTS
Red blood cell aggregation was significantly higher than that of WB and PRP when utilizing a TF agonist, an effect unique to TF. The combination of calcium and TF demonstrated significantly higher RBC aggregation than either agonist alone. Pretreatment with Annexin V resulted in a significantly reduced aggregability of RBC following treatment with TF + calcium. Red blood cells aged to 42 days did not exhibit significant change in aggregation. Exposure to calcium and TF significantly reduced time to thrombosis of RBCs perfused through a pulmonary microcirculatory model.

CONCLUSION
Treatment with both TF and calcium synergistically induces RBC aggregation. Phosphatidylserine appears to play an integral role in the TF/calcium-based, age-independent RBC aggregation response. Red blood cells treated with TF + calcium exhibit more rapid thrombus formation in an in vitro model of pulmonary microcirculatory perfusion.
Integrated multiomic analysis identifiesTRIP13as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis
Authors: St. Pierre Laurence , Berhan Asres , Sung Eun K. , Alvarez Juan R. , Wang Hongjun , Ji Yanbin , Liu Yixin , Yu Haoze , Meier Angela , Afshar Kamyar , Golts Eugene M. , Lin Grace Y. , Castaldi Alessandra , Calvert Ben A. , Ryan Amy , Zhou Beiyun , Offringa Ite A. , Marconett Crystal N. , Borok Zea 
Published: April 2024

SUMMARYIdiopathic pulmonary fibrosis (IPF) is a lethal progressive lung disease urgently needing new therapies. Current treatments only delay disease progression, leaving lung transplant as the sole remaining option. Recent studies support a model whereby IPF arises because alveolar epithelial type II (AT2) cells, which normally mediate distal lung regeneration, acquire airway and/or mesenchymal characteristics, preventing proper repair. Mechanisms driving this abnormal differentiation remain unclear. We performed integrated transcriptomic and epigenomic analysis of purified AT2 cells which revealed genome-wide alterations in IPF lungs. The most prominent epigenetic alteration was activation of an enhancer in thyroid receptor interactor 13 (TRIP13), coinciding withTRIP13upregulation.TRIP13is broadly implicated in epithelial-mesenchymal plasticity and transforming growth factor-β signaling. In cultured human AT2 cells and lung slices, small molecule TRIP inhibitor DCZ0415 prevented acquisition of the mesenchymal gene signature characteristic of IPF, suggesting TRIP13 inhibition as a potential therapeutic approach to fibrotic disease.
Alternating Access of a Neurotransmitter:Sodium Symporter Bacterial Homolog Determined from AlphaFold2 Ensembles and DEER Spectroscopy
Authors: Schwartz Alexandra C. , Stein Richard A. , Gil-Iturbe Eva , Quick Matthias , Mchaourab Hassane S. 
Published: April 2024

AbstractNeurotransmitter:sodium symporters (NSSs) play critical roles in neural signaling by regulating neurotransmitter uptake into cells powered by sodium electrochemical gradients. Bacterial NSSs orthologs, including MhsT fromBacillus halodurans, have emerged as model systems to understands the structural motifs of alternating access in NSSs and the extent of conservation of these motifs across the family. Here, we apply a novel computational/experimental methodology to illuminate the energy landscape of MhsT alternating access. Capitalizing on our recently developed method, Sampling Protein Ensembles and Conformational Heterogeneity with AlphaFold2 (SPEACH_AF), we derived clusters of MhsT models spanning the transition from inward-facing to outward-facing conformations. Systematic application of double electron-electron resonance (DEER) spectroscopy revealed ligand-dependent movement of multiple structural motifs that underpins MhsT’s conformational cycle. Remarkably, comparative DEER analysis in detergent micelles and lipid nanodiscs highlight the profound effect of the environment on the energetics of conformational changes. Through experimentally-derived selection of collective variables, we present a model of ion and substrate powered transport by MhsT consistent with the conformational cycle derived from DEER. Our findings not only advance the understanding of MhsT’s function but also uncover motifs of conformational dynamics conserved within the broader context of the NSS family and within the LeuT-fold class of transporters. Importantly, our methodological blueprint introduces a novel approach that can be applied across a diverse spectrum of transporters to describe their energy landscapes.Significance StatementThe neurotransmitter:sodium symporter (NSS) family plays a crucial role in neurotransmitter reuptake, a sodium-dependent process that transports neurotransmitters from the synapse back into the neuron. This study investigates the bacterial tryptophan transporter MhsT, a homolog of human NSSs, using the deep learning method AlphaFold2 in conjunction with double electron-electron resonance spectroscopy. This combined approach enables us to map the energy landscape that dictates the conformational shifts crucial for MhsT’s function. Furthermore, we reveal how the environment modulates the transporter’s dynamics. From our research, we develop a model of MhsT transport that highlights the extent of mechanistic conservation across the NSS family. Additionally, we introduce a comprehensive framework for exploring the energetic landscapes of transporters, effectively integrating computational and experimental methods.
Metabolomics and13C Labelled Glucose Tracing to Identify Carbon Incorporation into Aberrant Cell Membrane Glycans in Cancer
Authors: Reyes-Oliveras Alfredo , Ellis Abigail E. , Sheldon Ryan D. , Haab Brian 
Published: April 2024

AbstractCell membrane glycans contribute to immune recognition, signaling, and cellular adhesion and migration, and altered membrane glycosylation is a feature of cancer cells that contributes to cancer progression. The uptake and metabolism of glucose and other nutrients essential for glycan synthesis could underlie altered membrane glycosylation, but the relationship between shifts in nutrient metabolism and the effects on glycans have not been directly examined. To address this possibility, we created a novel method that combines stable isotope tracing with metabolomics to enable direct observations of glucose allocation to nucleotide sugars and cell-membrane glycans. We compared the glucose allocation to membrane glycans of two pancreatic cancer cell lines that are genetically identical but have differing energy requirements. The 8988-S cells had higher glucose allocation to membrane glycans and intracellular pathways relating to glycan synthesis, but the 8988-T cells had higher glucose uptake and commitment of glucose to non-glycosylation pathways. The cells lines differed in requirements of glucose for energy production, resulting in differences in glucose bioavailability for glycan synthesis. The workflow demonstrated here enables studies on the effects of metabolic shifts on the commitment of media nutrients to cell-membrane glycans. The results support a flux-based regulation of glucose commitment glycosylation and a mode of metabolic control of cell functions such signaling, immune recognition, and adhesion and migration.
A microbial derived bile acid acts as GPBAR1 agonist and RORγt inverse agonist and reverses inflammation in inflammatory bowel disease
Authors: Biagioli Michele , Di Giorgio Cristina , Massa Carmen , Marchianò Silvia , Bellini Rachele , Bordoni Martina , Urbani Ginevra , Roselli Rosalinda , Lachi Ginevra , Morretta Elva , Dal Piaz Fabrizio , Charlier Bruno , Fiorillo Bianca , Catalanotti Bruno , Cari Luigi , Nocentini Giuseppe , Ricci Patrizia , Distrutti Eleonora , Sepe Valentina , Zampella Angela , Monti Maria Chiara , Fiorucci Stefano 
Published: April 2024

AbstractThe interplay between the dysbiotic microbiota and bile acids is a critical determinant for development of a dysregulated immune system in inflammatory bowel disease (IBD). Here we have investigated the fecal bile acid metabolome, gut microbiota composition, and immune responses in IBD patients and murine models of colitis and found that IBD associates with an elevated excretion of primary bile acids while secondary, allo- and oxo- bile acids were reduced in both human and mice models of IBD. These changes correlated with the disease severity, mucosal expression of pro-inflammatory cytokines and chemokines, and reduced inflow of anti-inflammatory macrophages and Treg in the gut. Analysis of bile acids metabolome in the feces allowed the identification of five bile acids: 3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA and 3-oxo-UDCA, whose excretion was selectively decreased in IBD patients and diseased mice. By transactivation assay and docking calculations all five bile acids were shown to act as GPBAR1 agonists and RORγt inverse agonists, skewing Th17/Treg ratio and macrophage polarization toward an M2 phenotype. In a murine model of colitis, administration of 3-oxo-DCA suffices to reverse colitis development and intestinal dysbiosis in a GPBAR1-dependent manner.In vivoadministration of 3-oxo-DCA to colitic mice also reserves disease severity and RORγt activation induced by a RORγt agonist and IL-23, a Th17 inducing cytokine. These results demonstrated intestinal excretion of 3-oxoDCA, a dual GPBAR1 agonist and RORγt inverse agonist, is reduced in IBD and models of colitis and its restitution protects against colitis development, highlighting a potential role for this agent in IBD management.
Changes in wing morphology rather than wingbeat kinematics enabled evolutionary miniaturization of hoverflies
Authors: Le Roy Camille , Tervelde Nina , Engels Thomas , Muijres Florian T. 
Published: April 2024

AbstractDue to physical scaling laws, size greatly affects animal locomotor ability and performance. Whether morphological and kinematic traits always jointly respond to size variation is however poorly known. Here, we examine the relative importance of morphological and kinematic changes in mitigating the consequence of size on aerodynamic force production for weight support in flying insects, focusing on hovering flight of hoverflies (Syrphidae). We compared the flight biomechanics, aerodynamics, and morphology of eight hoverfly species varying from 5 to 100 mg. Our study reveals no effect of body size on wingbeat kinematics among species, suggesting that morphological rather than kinematic changes may compensate for the reduction in weight support associated with an isometric reduction in size. Computational fluid dynamics simulations confirmed that variations in wing morphology, and not kinematics, allow species of different sizes to generate weight support. We specifically show that relatively larger wings and aerodynamically more effective wing shape have evolved in smaller hoverflies, mitigating the reduction in aerodynamic weight support with decreasing size. Altogether, these results suggest that hovering flight of hoverflies underpins highly specialised wingbeat kinematics, which have been conserved throughout evolution; instead, wing morphological adaptations have enabled the evolutionary miniaturisation of hoverflies.
Molecular dynamics study of stiffness and rupture of axonal membranes
Authors: Majdolhosseini Maryam , Kleiven Svein , Villa Alessandra 
Published: April 2024

AbstractDiffuse axonal injury (DAI), characterized by widespread damage to axons throughout the brain, represents one of the most devastating and difficult-to-treat forms of traumatic brain injury. Different theories exist about the mechanism of DAI, among which one hypothesis states that membrane poration of the axons initiates DAI. To investigate the hypothesis, molecular models of axonal membranes, incorporating 25 different lipids distributed asymmetrically in the leaflets, were developed using a coarse-grain description and simulated using molecular dynamics techniques. Different protein concentrations were embedded inside the lipid bilayer to describe the different sub-cellular parts in myelinated and unmyelinated axons. The models were investigated in equilibration and under deformation to characterize the structural and mechanical properties of the membranes, and comparisons were made with other subcellular parts, particularly myelin. Employing a bottom-top approach, the results were coupled with a finite element model representing the axon at the cell level. The results indicate that pore formation in the node-of-Ranvier occurs at a lower rupture strain compared to other axolemma parts, whereas myelin poration exhibits the highest rupture strains among the investigated models. The observed rupture strain for the node-of-Ranvier aligns with experimental studies, indicating a threshold for injury at axonal strains exceeding 10 − 13%epending on the strain rate. The results indicate that the hypothesis suggesting mechanoporation triggers axonal injury cannot be dismissed, as this phenomenon occurs within the threshold of axonal injury.HighlightsDeveloping a realistic molecular model of axolemma based on experimental data about its lipid compositionInvestigating how lipid composition and protein concentration affect the membrane’s structural and mechanical propertiesIdentifying the most vulnerable regions of the axonal membrane
Multi-Niche Human Bone Marrow On-A-Chip for Studying the Interactions of Adoptive CAR-T Cell Therapies with Multiple Myeloma
Authors: Ghoshal Delta , Petersen Ingrid , Ringquist Rachel , Kramer Liana , Bhatia Eshant , Hu Thomas , Richard Ariane , Park Reda , Corbin Jenna , Agarwal Savi , Thomas Abel , Ramirez Sebastian , Tharayil Jacob , Downey Emma , Ketchum Frank , Ochal Abigail , Sonthi Neha , Lonial Sagar , Kochenderfer James N. , Tran Reginald , Zhu Mandy , Lam Wilbur A. , Coskun Ahmet F. , Roy Krishnendu 
Published: April 2024

ABSTRACTMultiple myeloma (MM), a cancer of bone marrow plasma cells, is the second-most common hematological malignancy. However, despite immunotherapies like chimeric antigen receptor (CAR)-T cells, relapse is nearly universal. The bone marrow (BM) microenvironment influences how MM cells survive, proliferate, and resist treatment. Yet, it is unclear which BM niches give rise to MM pathophysiology. Here, we present a 3D microvascularized culture system, which models the endosteal and perivascular bone marrow niches, allowing us to study MM-stroma interactions in the BM niche and model responses to therapeutic CAR-T cells. We demonstrated the prolonged survival of cell line-based and patient-derived multiple myeloma cells within ourin vitrosystem and successfully flowed in donor-matched CAR-T cells. We then measured T cell survival, differentiation, and cytotoxicity against MM cells using a variety of analysis techniques. Our MM-on-a-chip system could elucidate the role of the BM microenvironment in MM survival and therapeutic evasion and inform the rational design of next-generation therapeutics.TEASERA multiple myeloma model can study why the disease is still challenging to treat despite options that work well in other cancers.
A deep learning-based approach for unbiased kinematic analysis in CNS injury
Authors: Ascona Maureen , Tieu Ethan Kim , Gonzalez-Vega Erick , Liebl Daniel J , Brambilla Roberta 
Published: April 2024

AbstractTraumatic spinal cord injury (SCI) is a devastating condition that impacts over 300,000 individuals in the US alone. Depending on the severity of the injury, SCI can lead to varying degrees of sensorimotor deficits and paralysis. Despite advances in our understanding of the underlying pathological mechanisms of SCI and the identification of promising molecular targets for repair and functional restoration, few therapies have made it into clinical use. To improve the success rate of clinical translation, more robust, sensitive, and reproducible means of functional assessment are required. The gold standards for the evaluation of locomotion in rodents with SCI are the Basso Beattie Bresnahan (BBB) and Basso Mouse Scale (BMS) tests.To overcome the shortcomings of current methods, we developed two separate marker-less kinematic analysis paradigms in mice, MotorBox and MotoRater, based on deep-learning algorithms generated with the DeepLabCut open-source toolbox. The MotorBox system uses an originally designed, custom-made chamber, and the MotoRater system was implemented on a commercially available MotoRater device. We validated the MotorBox and MotoRater systems by comparing them with the traditional BMS test and extracted metrics of movement and gait that can provide an accurate and sensitive representation of mouse locomotor function post-injury, while eliminating investigator bias and variability. The integration of MotorBox and/or MotoRater assessments with BMS scoring will provide a much wider range of information on specific aspects of locomotion, ensuring the accuracy, rigor, and reproducibility of behavioral outcomes after SCI.HighlightsMotorBox and MotoRater systems are two novel marker-less kinematic analysis paradigms in mice, based on deep-learning algorithms generated with DeepLabCut.MotorBox and MotoRater systems are highly sensitive, accurate and unbiased in analyzing locomotor behavior in mice.MotorBox and MotoRater systems allow for sensitive detection of SCI-induced changes in movement metrics, including range of motion, gait, coordination, and speed.MotorBox and MotoRater systems allow for detection of movement metrics not measurable with the BMS.
Replicating a High-Impact Scientific Publication Using Systems of Large Language Models
Authors: Bersenev Dennis , Yachie-Kinoshita Ayako , Palaniappan Sucheendra K. 
Published: April 2024

AbstractPublications focused on scientific discoveries derived from analyzing large biological datasets typically follow the cycle of hypothesis generation, experimentation, and data interpretation. The reproduction of findings from such papers is crucial for confirming the validity of the scientific, statistical, and computational methods employed in the study, and it also facilitates the foundation for new research. By employing a multi-agent system composed of Large Language Models (LLMs), including both text and code generation agents built on OpenAI’s platform, our study attempts to reproduce the methodology and findings of a high-impact publication that investigated the expression of viral-entry-associated genes using single-cell RNA sequencing (scRNA-seq). The LLM system was critically evaluated against the analysis results from the original study, highlighting the system’s ability to perform simple statistical analysis tasks and literature reviews to establish the purpose of the analyses. However, we also identified significant challenges in the system, such as nondeterminism in code generation, difficulties in data procurement, and the limitations presented by context length and bias from the model’s inherent training data. By addressing these challenges and expanding on the system’s capabilities, we intend to contribute to the goal of automating scientific research for efficiency, reproducibility, and transparency, and to drive the discussion on the role of AI in scientific discovery.