bluuebunny/crossref_metadata_2025_split huggingface dataset:
RealtimeDecoder: A fast software module for online clusterless decoding
Authors: Chu Joshua P. , Coulter Michael E. , Denovellis Eric L. , Nguyen Trevor T. K. , Liu Daniel F. , Deng Xinyi , Eden Uri T. , Kemere Caleb T. , Frank Loren M. 
Published: May 2024

AbstractDecoding algorithms provide a powerful tool for understanding the firing patterns that underlie cognitive processes such as motor control, learning, and recall. When implemented in the context of a real-time system, decoders also make it possible to deliver feedback based on the representational content of ongoing neural activity. That in turn allows experimenters to test hypotheses about the role of that content in driving downstream activity patterns and behaviors. While multiple real-time systems have been developed, they are typically implemented in C++ and are locked to a specific data acquisition system, making them difficult to adapt to new experiments.Here we present a Python software system that implements online clusterless decoding using state space models in a manner independent of data acquisition systems. The parallelized system processes neural data with temporal resolution of 6 ms and median computational latency <50 ms for medium- to large-scale (32+ tetrodes) rodent hippocampus recordings without the need for spike sorting. It also executes auxiliary functions such as detecting sharp wave ripples from local field potential (LFP) data. Performance is similar to state-of-the-art solutions which use compiled programming languages. We demonstrate this system use in a rat behavior experiment in which the decoder allowed closed loop neurofeedback based on decoded hippocampal spatial representations . This system provides a powerful and easy-to-modify tool for real-time feedback experiments.
Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host
Authors: Gonzalez-Aponte Maria F. , Damato Anna R. , Simon Tatiana , Aripova Nigina , Darby Fabrizio , Rubin Joshua B. , Herzog Erik D. 
Published: May 2024

SummaryGlioblastoma (GBM) is the most common primary brain tumor in adults with a poor prognosis despite aggressive therapy. A recent, retrospective clinical study found that administering Temozolomide in the morning increased patient overall survival by 6 months compared to evening. Here, we tested the hypothesis that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We found daily Dexamethasone promoted or suppressed GBM growth depending on time of day of administration and on the clock gene,Bmal1. Blocking circadian signals, like VIP or glucocorticoids, dramatically slowed GBM growth and disease progression. Finally, mouse and human GBM models have intrinsic circadian rhythms in clock gene expressionin vitroandin vivothat entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We conclude that GBM entrains to the circadian circuit of the brain, which modulates its growth through clock-controlled cues, like glucocorticoids.
Quantification ofTrypanosoma Bruceisocial motility indicates different colony growth phases
Authors: Kuhn Andreas , Krueger Timothy , Schüttler Magdalena , Engstler Markus , Fischer Sabine C. 
Published: May 2024

AbstractIn vitrocolonies of the flagellated parasiteTrypanosoma bruceigrow in characteristic fingering instability patterns. The underlying cause of this this type of collective migration and the associated behavior called social motility remains a topic of intense debate in the scientific community. In order to study these mechanisms in detail, it is crucial to develop quantitative methods to assess and measure social motility patterns at the level of the whole colony beyond qualitative image comparisons. Here, we show a quantification of the growth process based on two scale free metrics designed to quantify the shape of two-dimensional colonies. While initially developed for yeast colonies, we adapted, modified and extended the analysis pipeline for theTrypanosomasystem. Combining the quantitative measurements with colony growth simulations based on the Eden model, we discovered two distinct growth phases in social motility showing colonies: In the first phase, the colonies shown mainly circular expansion and later switch to an almost exclusive finger growing phase. These phases are robust when increasing the number of cells as well as upon partial inhibition of the finger formation. A newly developed anisotropy index shows that upon partial inhibition the anisotropy in the colony increases over time. Our results provide objective measurements that help advance the understanding of social motility of trypanosomes. Furthermore, our approach is suitable as a blueprint for investigations of other colony forming cells such as yeast or bacteria.
Effect of Sulfate Availability on Phytoplankton Stoichiometry
Authors: Whitney Larisa , Segura-Noguera Mariona , Ruan Zuoxi , Giordano Mario 
Published: May 2024

SummarySulfur is a key element in multiple metabolic pathways of phytoplankton cells. The effect of environmental S availability on phytoplankton elemental quotas and stoichiometry has been addressed in few studies, using a limited number of species and with contradictory results.Using high-temperature combustion oxidation and X-ray fluorescence methods, we measured the concentrations of micro- and trace elements in monocultures of 20 phytoplankton species, grown with different sulfate concentrations representing those of early and modern oceans.The red lineage species, with higher S requirement and metabolic S fluxes, have higher S content than those of the green lineage, resulting in lower C:S (93) and higher S:P (1.06) than the green lineage species (226 and 0.76, respectively). Zn was the only trace element affected by the environmental concentration of sulfate.Phytoplankton cells respond to different sulfate availability by either increasing Zn or decreasing P quotas, where the P response is more characteristic in the red lineage, and the Zn response is independent of genotypic constraints or plastid type. This study sheds light on a metabolic basis for the expansion of the red lineage algae and their current dominance in ocean waters.Plain language summaryMicroalgae assimilate dissolved sulfate as a source of sulfur, an element that takes part in multiple biochemical pathways and cellular functions. Changes in the concentration of dissolved sulfate in the environment have an effect on the cellular dynamics of several essential biological elements, essencially phosphorus and zinc. The results of this study help to understand the biogeochemical cycling of these elements in the ocean and the dominance of certain phytoplankton lineages.
Oxidative Stress is a shared characteristic of ME/CFS and Long COVID
Authors: Shankar Vishnu , Wilhelmy Julie , Curtis Ellis J. , Michael Basil , Cervantes Layla , Mallajosyula Vamsee A. , Davis Ronald W. , Snyder Michael , Younis Shady , Robinson William H. , Shankar Sadasivan , Mischel Paul S. , Bonilla Hector , Davis Mark M. 
Published: May 2024

AbstractMore than 65 million individuals worldwide are estimated to have Long COVID (LC), a complex multisystemic condition, wherein patients of all ages report fatigue, post-exertional malaise, and other symptoms resembling myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). With no current treatments or reliable diagnostic markers, there is an urgent need to define the molecular underpinnings of these conditions. By studying bioenergetic characteristics of peripheral blood lymphocytes in over 16 healthy controls, 15 ME/CFS, and 15 LC, we find both ME/CFS and LC donors exhibit signs of elevated oxidative stress, relative to healthy controls, especially in the memory subset. Using a combination of flow cytometry, bulk RNA-seq analysis, mass spectrometry, and systems chemistry analysis, we also observed aberrations in ROS clearance pathways including elevated glutathione levels, decreases in mitochondrial superoxide dismutase levels, and glutathione peroxidase 4 mediated lipid oxidative damage. Critically, these changes in redox pathways show striking sex-specific trends. While females diagnosed with ME/CFS exhibit higher total ROS and mitochondrial calcium levels, males with an ME/CFS diagnosis have normal ROS levels, but larger changes in lipid oxidative damage. Further analyses show that higher ROS levels correlates with hyperproliferation of T cells in females, consistent with the known role of elevated ROS levels in the initiation of proliferation. This hyperproliferation of T cells can be attenuated by metformin, suggesting this FDA-approved drug as a possible treatment, as also suggested by a recent clinical study of LC patients. Thus, we report that both ME/CFS and LC are mechanistically related and could be diagnosed with quantitative blood cell measurements. We also suggest that effective, patient tailored drugs might be discovered using standard lymphocyte stimulation assays.
CASTpFold: Computed Atlas of Surface Topography of the universe of protein Folds
Authors: Ye Bowei , Tian Wei , Wang Boshen , Liang Jie 
Published: May 2024

AbstractGeometric and topological properties of protein structures, including surface pockets, interior cavities, and cross channels, are of fundamental importance for proteins to carry out their functions. Computed Atlas of Surface Topography of proteins (CASTp) is a widely used web server for locating, delineating, and measuring these geometric and topological properties of protein structures. Recent developments in AI-based protein structure prediction such as AlphaFold2 (AF2) have significantly expanded our knowledge on protein structures. Here we present CASTpFold, a continuation of CASTp that provides accurate and comprehensive identifications and quantifications of protein topography. It now provides (i) results on an expanded database of proteins, including the Protein Data Bank (PDB) and non-singleton representative structures of AlphaFold2 structures, covering 183 million AF2 structures; (ii) functional pockets prediction with corresponding Gene Ontology (GO) terms or Enzyme Commission (EC) numbers for AF2-predicted structures; and (iii) pocket similarity search function for surface and protein-protein interface pockets. The CASTpFold web server is freely accessible athttps://cfold.bme.uic.edu/castpfold/.
Cloning and functional characterization of novel human neutralizing anti-interferon-alpha and anti-interferon-beta antibodies
Authors: Papasavvas Emmanouil , Lu Lily , Fair Matthew , Oliva Isabela , Cassel Joel , Majumdar Sonali , Mounzer Karam , Kostman Jay R. , Tebas Pablo , Bar-Or Amit , Muthumani Kar , Montaner Luis J. 
Published: May 2024

SUMMARYType I interferons (IFNs) play a pivotal role in immune response modulation, yet dysregulation is implicated in various disorders. Therefore, it is crucial to develop tools that facilitate the understanding of their mechanism of action and enable the development of more effective anti-IFN therapeutic strategies. In this study, we isolated, cloned, and characterized anti-IFN-α and anti-IFN-β antibodies (Abs) from peripheral blood mononuclear cells of individuals treated with IFN-α or IFN-β, harboring confirmed neutralizing Abs. Clones AH07856 and AH07857 were identified as neutralizing anti-IFN-α-specific with inhibition against IFN-α2a, -α2b, and -αK subtypes. Clones AH07859 and AH07866 were identified as neutralizing anti-IFN-β1a-specific signaling, and able to block Lipopolysaccharide or S100 calcium binding protein A14-induced IFN-β signaling effects. Cloned Abs bind rhesus but not murine IFNs. The specificity of inhibition between IFN-α and IFN-β suggests potential for diverse research and clinical applications.
Functional coexistence theory: a mechanistic framework linking biodiversity to ecosystem function
Authors: Wan Joe , Ke Po-Ju , Hordijk Iris , Bialic-Murphy Lalasia , Crowther Thomas W. 
Published: May 2024

AbstractTheory and experiments show that diverse ecosystems often have higher levels of function (for instance, biomass production), yet it remains challenging to identify the biological mechanisms responsible. We synthesize developments in coexistence theory into a general theoretical framework linking community coexistence to ecosystem function. Our framework, which we term functional coexistence theory, identifies three components determining the total function of a community of coexisting species. The first component directly corresponds to the niche differences that enable pairwise species coexistence, and to the complementarity component from the additive partition of biodiversity effects. The second component measures whether higher functioning species also have higher competitive fitness, providing a missing link between the additive partition’s selection effect and modern coexistence theory’s concept of equalization. The third component is least well-studied: reducing functional imbalances between species increases niche difference’s positive effect on function. Using a mechanistic model of resource competition, we show that our framework can identify how traits drive the effect of competition on productivity, and confirm our theoretical expectations by fitting this model to data from a classic plant competition experiment. Furthermore, we apply our framework to simulations of communities with multiple ecosystem functions or more than two species, demonstrating that relationships between niche, fitness, and function also predict total function beyond the case studied by classical theory. Taken together, our results highlight fundamental links between species coexistence and its consequences for ecosystem function, providing an avenue towards a predictive theory of community–ecosystem feedbacks.
Unravelling Immune Cell Signatures: CIBERSORTx-assisted Construction of Signature Matrix from Single-Cell Data
Authors: Verma Madhulika 
Published: May 2024

AbstractThe immune system’s intricate orchestration is pivotal in combating infections and diseases, often leaving discernible signatures within circulating blood cells. Peripheral blood mononuclear cells (PBMCs), comprising diverse immune cell populations, serve as crucial indicators of immune system status and its responses to various conditions, including cancer. While traditional bulk metrics pose challenges in dissecting specific immune cell functionalities, advancements in single-cell technologies offer unprecedented insights into the dynamic activities of immune cell populations.In this study, we analyzed single-cell data from droplet sequencing to delineate immune cell types and subtypes within PBMCs. Employing the CIBERSORTx tool, we constructed a signature matrix to comprehensively represent significant cell populations within tissue. Through iterative optimization and minimization of the condition number based on marker genes, we aimed to enhance the robustness and stability of the gene signature matrices, enabling scalable investigation of novel or poorly understood phenotypic states in bulk tissue gene expression profiles. The resultant matrix consisted of 14 immune cell types represented by 275 gene having significant highest expression for their respective cell types and the least in other cells.This approach facilitates precise characterization of immune cell populations and their responses to diverse diseases, contributing to a deeper understanding of immunological processes and paving the way for targeted therapeutic interventions.
Haem toxicity in the aged spleen impairs T-cell immunity through iron deprivation
Authors: Ezuz David , Ombashe Heba , watted Lana , Atar Orna , Ron-Harel Noga 
Published: May 2024

SummaryAgeing profoundly impacts T cell immunity, compromising vaccine responses, susceptibility to infections, and immunosurveillance. Mechanisms of T cell ageing involve cell-intrinsic alterations and interactions with other immune and stromal cells1. This study investigates how a tissue’s microenvironment influences T cell ageing trajectories, following our discovery of varying rates of T cell ageing within a single host. Spleen-derived lymphocytes exhibited functional decline compared to those from lymph nodes, with proteomic analysis revealing increased expression of haem detoxification and iron storage proteins in aged spleen-derived lymphocytes. Exposure to the aged spleen microenvironment or to haem induced multiple ageing phenotypes in young lymphocytes, characterized by reduced proliferation and upregulation of the ectonucleotidases CD39 and CD73. Mechanistically, we show that T cells survive the hostile microenvironment of the aged spleen by maintaining low labile iron pools to resist ferroptosis. Finally, vaccination responses in aged mice were enhanced by timed iron infusions. Our findings underscore a trade-off between T cell survival and function in the aged host. Recent studies show how Dysfunctional T cells induce premature ageing phenotypes in multiple solid organs of a young host2,3. Our findings highlight the bidirectional relationship between T cells and their ageing microenvironment. Understanding these mechanisms will inform strategies to enhance immune responses in the elderly.
Mitochondrial Oxidative Phosphorylation Capacity in Skeletal Muscle Measured by Ultrafast Z-Spectroscopy (UFZ) MRI at 3T
Authors: Ju Licheng , Schär Michael , Wang Kexin , Li Anna , Wu Yihan , Samuel T. Jake , Ganji Sandeep , van Zijl Peter C. M. , Yadav Nirbhay N. , Weiss Robert G. , Xu Jiadi 
Published: May 2024

AbstractBackgroundTo investigate the feasibility of rapid CEST MRI acquisition for evaluating oxidative phosphorylation (OXPHOS) in human skeletal muscle at 3 Tesla, utilizing ultrafast Z-spectroscopy (UFZ) MRI combined with the Polynomial and Lorentzian line-shape Fitting (PLOF) technique.MethodsUFZ MRI on muscle was evaluated with turbo spin echo (TSE) and segmented 3D EPI readouts. Five healthy subjects performed in-magnet plantar flexion exercise (PFE) and subsequent changes of amide, phosphocreatine (PCr) and partial PCr mixed creatine (Cr+) CEST dynamic signals post-exercise were enabled by PLOF fitting. PCr/Cr CEST signal was further refined through pH correction by using the ratios between PCr/Cr and amide signals, named PCAR/CAR, respectively.ResultsUFZ MRI with TSE readout significantly reduces acquisition time, achieving a temporal resolution of <50 seconds for collecting high-resolution Z-spectra. Following PFE, the recovery/decay times (τ) for both PCr and Cr in the gastrocnemius muscle of the calf were notably longer when determined using PCr/Cr CEST compared to those after pH correction with amideCEST, namelys andτPCr= 98.1 ± 20.4 s versusτCAR=36.4 ± 18.6 s andτPCAR= 43.0 ± 13.0 s, respectively. Literature values ofτPCrobtained via31P MRS closely resemble those obtained from pH-corrected PCr/Cr CEST signals.ConclusionThe outcomes suggest potential of UFZ MRI as a robust tool for non-invasive assessment of mitochondrial function in skeletal muscles. pH correction is critical for the reliable OXPHOS measurement by CEST.
Recombinant manufacturing of multispecies biolubricants
Authors: Colville Marshall J. , Huang Ling-Ting , Schmidt Samuel , Chen Kevin , Vishwanath Karan , Su Jin , Williams Rebecca M. , Bonassar Lawrence J. , Reesink Heidi L. , Paszek Matthew J. 
Published: May 2024

ABSTRACTLubricin, a lubricating glycoprotein abundant in synovial fluid, forms a low-friction brush polymer interface in tissues exposed to sliding motion including joints, tendon sheaths, and the surface of the eye. Despite its therapeutic potential in diseases such as osteoarthritis and dry eye disease, there are few sources available. Through rational design, we developed a series of recombinant lubricin analogs that utilize the species-specific tissue-binding domains at the N- and C-termini to increase biocompatibility while replacing the central mucin domain with an engineered variant that retains the lubricating properties of native lubricin. In this study, we demonstrate the tissue binding capacity of our engineered lubricin product and its retention in the joint space of rats. Next, we present a new bioprocess chain that utilizes a human-derived cell line to produceO-glycosylation consistent with that of native lubricin and a purification strategy that capitalizes on the positively charged, hydrophobic N- and C-terminal domains. The bioprocess chain is demonstrated at 10 L scale in industry-standard equipment utilizing commonly available ion exchange, hydrophobic interaction and size exclusion chromatography resins. Finally, we confirmed the purity and lubricating properties of the recombinant biolubricant. The biomolecular engineering and bioprocessing strategies presented here are an effective means of lubricin production and could have broad applications to the study of mucins in general.
kinact/KIValue Determination for Penicillin-Binding Proteins in Live Cells
Authors: Shirley Joshua D. , Nauta Kelsie M. , Gillingham Jacob R. , Diwakar Shivani , Carlson Erin E. 
Published: May 2024

AbstractPenicillin-binding proteins (PBPs) are an essential family of bacterial enzymes that are inhibited by the β-lactam class of antibiotics. PBP inhibition disrupts cell wall biosynthesis, which results in deficient growth and proliferation, and ultimately leads to lysis. IC50values are often employed as descriptors of enzyme inhibition and inhibitor selectivity but can be misleading in the study of time-dependent, irreversible inhibitors. Due to this disconnect, the second order rate constantkinact/KIis a more appropriate metric of covalent inhibitor potency. Despite being the gold standard measurement of potency,kinact/KIvalues are typically obtained fromin vitroassays, which limits assay throughput if investigating an enzyme family with multiple homologs (such as the PBPs). Therefore, we developed a whole-cellkinact/KIassay to define inhibitor potency for the PBPs inStreptococcus pneumoniaeusing the fluorescent activity-based probe Bocillin-FL. Our results align within vitro kinact/KIdata and show a comparable relationship to previously established IC50values. These results support the validity of ourin vivo kinact/KImethod as a means of obtaining a full picture of β-lactam potency for a suite of PBPs.Abstract Figure
PROTAC-induced Protein Structural Dynamics in Targeted Protein Degradation
Authors: Wu Kingsley Y. , Hung Ta I , Chang Chia-en A. 
Published: May 2024

AbstractPROteolysis TArgeting Chimeras (PROTACs) are small molecules that induce target protein degradation via the ubiquitin-proteasome system. PROTACs recruit the target protein and E3 ligase; a critical first step is forming a ternary complex. However, while the formation a ternary complex is crucial, it may not always guarantee successful protein degradation. The dynamics of the PROTAC-induced degradation complex play a key role in ubiquitination and subsequent degradation. In this study, we computationally modelled protein complex structures and dynamics associated with a series of PROTACs featuring different linkers to investigate why these PROTACs, all of which formed ternary complexes with Cereblon (CRBN) E3 ligase and the target protein bromodomain-containing protein 4 (BRD4BD1), exhibited varying degrees of degradation potency. We constructed the degradation machinery complexes with Culling-Ring Ligase 4A (CRL4A) E3 ligase scaffolds. Through atomistic molecular dynamics simulations, we illustrated how PROTAC-dependent protein dynamics facilitating the arrangement of surface lysine residues of BRD4BD1into the catalytic pocket of E2/ubiquitin cascade for ubiquitination. Despite featuring identical warheads in this PROTAC series, the linkers were found to affect the residue-interaction networks, and thus governing the essential motions of the entire degradation machine for ubiquitination. These findings offer a structural dynamic perspective on ligand-induced protein degradation, providing insights to guide future PROTAC design endeavors.