bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Stochastic Dynamic Operator framework that improves the precision of analysis and prediction relative to the classical spike-triggered average method, extending the toolkit
Authors: Smith Trevor S. , Abolfath-Beygi Maryam , Sanger Terence D. , Giszter Simon F. 
Published: May 2024

ABSTRACTHere we test the Stochastic Dynamic Operator (SDO) as a new framework for describing physiological signal dynamics relative to spiking or stimulus events. The SDO is a natural extension of existing spike-triggered averaging (STA), or stimulus-triggered averaging, methods currently used in neural analysis. It extends the classic STA to cover state-dependent and probabilistic responses where STA may fail. SDO methods are more sensitive and specific than the STA for identifying state-dependent relationships in simulated data. We have tested SDO analysis for interactions between electrophysiological recordings of spinal interneurons, single motor units, and aggregate muscle electromyograms (EMG) of major muscles in the spinal frog hindlimb. When predicting target signal behavior relative to spiking events, the SDO framework outperformed or matched classical spike-triggered averaging methods. SDO analysis permits more complicated spike-signal relationships to be captured, analyzed, and interpreted visually and intuitively. SDO methods can be applied at different scales of interest where spike-triggered averaging methods are currently employed, and beyond, from single neurons to gross motor behaviors. SDOs may be readily generated and analyzed using the providedSDO Analysis Toolkit. We anticipate this method will be broadly useful for describing dynamical signal behavior and uncovering state-dependent relationships of stochastic signals relative to discrete event times.SIGNIFICANCEHere the authors introduce new tools and demonstrate data analysis using a new probabilistic and state-dependent technique, which is an expansion and extension of the classical spike-triggered average, the Stochastic Dynamic Operator. Stochastic Dynamic Operator methods extend application into domains where classical spike triggered averages fail, capture more information on spike correlations, and match or outperform the spike-triggered average when generating predictions of signal amplitude based on spiking events. A data and code package toolkit for utilizing and interpreting Stochastic Dynamic Operator methods is provided together with example analyses. Both the method and the associated toolkit are thus expected to be broadly useful in research domains where the spike triggered average is currently used for analysis, and beyond.
Enterococcal quorum-controlled protease alters phage infection
Authors: Sheriff Emma K. , Salvato Fernanda , Andersen Shelby E. , Chatterjee Anushila , Kleiner Manuel , Duerkop Breck A. 
Published: May 2024

ABSTRACTIncreased prevalence of multidrug resistant bacterial infections has sparked interest in alternative antimicrobials, including bacteriophages (phages). Limited understanding of the phage infection process hampers our ability to utilize phages to their full therapeutic potential. To understand phage infection dynamics we performed proteomics onEnterococcus faecalisinfected with the phage VPE25. We discovered numerous uncharacterized phage proteins are produced during phage infection ofEnterococcus faecalis. Additionally, we identified hundreds of changes in bacterial protein abundances during infection. One such protein, enterococcal gelatinase (GelE), anfsrquorum sensing regulated protease involved in biofilm formation and virulence, was reduced during VPE25 infection. Plaque assays showed that mutation of either thefsrAorgelEresulted in plaques with a “halo” morphology and significantly larger diameters, suggesting decreased protection from phage infection. GelE-associated protection during phage infection is dependent on the murein hydrolase regulator LrgA and antiholin-like protein LrgB, whose expression have been shown to be regulated by GelE. Our work may be leveraged in the development of phage therapies that can modulate the production of GelE thereby altering biofilm formation and decreasingE. faecalisvirulence.
Paired vagus nerve stimulation drives precise remyelination and motor recovery after myelin loss
Authors: Huang Rongchen , Carter Elise R. , Hughes Ethan G. , Welle Cristin G. 
Published: May 2024

SummaryMyelin loss in the central nervous system can cause permanent motor or cognitive deficits in patients with multiple sclerosis (MS). While current immunotherapy treatments decrease the frequency of demyelinating episodes, they do not promote myelin repair or functional recovery. Vagus nerve stimulation (VNS) is a neuromodulation therapy which enhances neuroplasticity and the recovery of motor function after stroke, but its effects on myelin repair are not known. To determine if VNS influences myelin repair, we applied VNS following a demyelinating injury and measured longitudinal myelin dynamics and functional recovery. We found that VNS promotes remyelination by increasing the generation of myelinating oligodendrocytes. Pairing VNS with a skilled reach task leads to the regeneration of myelin sheaths on previously myelinated axon segments, enhancing the restoration of the original pattern of myelination. Moreover, the magnitude of sheath pattern restoration correlates with long-term motor functional improvement. Together, these results suggest that recovery of the myelin sheath pattern is a key factor in the restoration of motor function following myelin loss and identify paired VNS as a potential remyelination therapy to treat demyelinating diseases.
Homodimerization of CB2cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling
Authors: Navarro Gemma , Gómez-Autet Marc , Morales Paula , Rebassa Joan Biel , Llinas del Torrent Claudia , Jagerovic Nadine , Pardo Leonardo , Franco Rafael 
Published: May 2024

ABSTRACTG protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we have shown that a homobivalent ligand formed by equal chromenopyrazole moieties as pharmacophores, connected by 14 methylene units, can modulate the dynamics of the cannabinoid CB2receptor (CB2R) homodimerization by simultaneously binding both protomers of the CB2R-CB2R homodimer. Computational and pharmacological experimentals showed that one of the ligand pharmacophores binds to the orthosteric site of one protomer, and the other pharmacophore to a membrane-oriented pocket between transmembranes 1 and 7 of the partner protomer. This provides unique pharmacological properties, such as increased potency in Gibinding and increased recruitment of β-arrestin. Thus, by modulating dimerization dynamics, it may be possible to fine-tune CB2R activity with potentially improved therapeutic outcomes.HIGHLIGHTSA homobivalent ligand of CB2R (PM369) modulates the dynamics of receptor homodimerizationPM369 binds to the orthosteric site of one protomer and to a complementary, membrane-facing, site of the other protomerPM369 triggers CB2R homodimerization via the TM 1/7 interface that provides unique pharmacological propertiesPM369 potentiates signaling, increased potency in Gibinding and increased recruitment of β-arrestinThese results highlight new approaches to control GPCR signalingGRAPHICAL ABSTRACT
Bacterial Modulation of Intestinal Motility through Macrophage Redistribution
Authors: Ngo Julia S. , Amitabh Piyush , Sokoloff Jonah G. , Trinh Calvin , Wiles Travis J. , Guillemin Karen , Parthasarathy Raghuveer 
Published: May 2024

AbstractIntestinal microbes, whether resident or transient, influence the physiology of their hosts, altering both the chemical and the physical characteristics of the gut. An example of the latter is the human pathogenVibrio cholerae’sability to induce strong mechanical contractions, discovered in zebrafish. The underlying mechanism has remained unknown, but the phenomenon requires the actin crosslinking domain (ACD) ofVibrio’sType VI Secretion System (T6SS), a multicomponent protein syringe that pierces adjacent cells and delivers toxins. By using a zebrafish-nativeVibrioand imaging-based assays of host intestinal mechanics and immune responses, we find that macrophages mediate the connection between the T6SS ACD and intestinal activity: ACD-dependent tissue damage activates macrophages and recruits them from their unperturbed positions near enteric neurons lining the midgut, spurring strong gut contractions resembling those resulting from genetic depletion of macrophages. In addition to illuminating host-directed actions of the widespread T6SS protein apparatus, our findings highlight how localized bacteria-induced injury can reshape neuro-immune cellular dynamics to impact whole-organ physiology.
SNP assays for DVI: cost, time, and performance information for decision-makers
Authors: Gettings Katherine Butler , Tillmar Andreas , Sturk-Andreaggi Kimberly , Marshall Charla 
Published: May 2024

AbstractIn mass disaster events, forensic DNA laboratories may be called upon to quickly pivot their operations toward identifying bodies and reuniting remains with family members. Ideally, laboratories have considered this possibility in advance and have a plan in place. Compared with traditional short tandem repeat (STR) typing, single nucleotide polymorphisms (SNPs) may be better suited to these disaster victim identification (DVI) scenarios due to their small genomic target size, resulting in an improved success rate in degraded DNA samples. As the landscape of technology has shifted toward DNA sequencing, many forensic laboratories now have benchtop instruments available for massively parallel sequencing (MPS), facilitating this operational pivot from routine forensic STR casework to DVI SNP typing. Herein, we review the commercially available SNP sequencing assays amenable to DVI, we use data simulations to explore the potential for kinship prediction from SNP panels of varying size, and we give an example DVI scenario as context for presenting the matrix of considerations: kinship predictive potential, cost, and throughput of current SNP assay options. This information is intended to assist laboratories in choosing a SNP system for disaster preparedness.Highlights3 to 5 bullet points (maximum 100 characters per bullet point, including spaces). Each bullet point should be a full sentence and should outline the key contributions of your manuscript and how it impacts forensic science.Single nucleotide polymorphisms (SNPs) are useful in disaster victim identification (DVI).SNP panels amenable to human identification and extended kinship are described.Simulations demonstrate the potential for kinship prediction from SNP panels of varying size.Kinship predictive potential, cost, and throughput are presented for an example DVI scenario.Information is intended to assist laboratories in choosing a SNP system for disaster preparedness.
Conformational switching of Arp5 subunit differentially regulates INO80 chromatin remodeling
Authors: Garcia Jeison , Paul Somnath , Shukla Shagun , Zhong Yuan , Beauchemin Karissa , Bartholomew Blaine 
Published: May 2024

AbstractThe INO80 chromatin remodeler is a versatile enzyme capable of several functions, including spacing nucleosomes equal distances apart, precise positioning of nucleosomes based on DNA shape/sequence and exchanging histone dimers. Within INO80, the Arp5 subunit plays a central role in INO80 remodeling, evidenced by its interactions with the histone octamer, nucleosomal and extranucleosomal DNA, and its necessity in linking INO80’s ATPase activity to nucleosome movement. Our investigation reveals that the grappler domain of Arp5 interacts with the acidic pocket of nucleosomes through two distinct mechanisms: an arginine anchor or a hydrophobic/acidic patch. These two modes of binding serve distinct functions within INO80 as shown in vivo by mutations in these regions resulting in varying phenotypes and in vitro by diverse effects on nucleosome mobilization. Our findings suggest that the hydrophobic/acidic patch of Arp5 is likely important for dimer exchange by INO80, while the arginine anchor is crucial for mobilizing nucleosomes.
Complete list of canonical post-transcriptional modifications in theBacillus subtilisribosome and their link to RbgA driven large subunit assembly
Authors: Popova Anna M. , Jain Nikhil , Dong Xiyu , Abdollah-Nia Farshad , Britton Robert A. , Williamson James R. 
Published: May 2024

ABSTRACTRibosomal RNA modifications in prokaryotes have been sporadically studied, but there is a lack of a comprehensive picture of modification sites across bacterial phylogeny.B. subtilisis a preeminent model organism for gram-positive bacteria, with a well-annotated and editable genome, convenient for fundamental studies and industrial use. Yet remarkably, there has been no complete characterization of its rRNA modification inventory. By expanding modern MS tools for the discovery of RNA modifications, we found a total of 25 modification sites in 16S and 23S rRNA ofB. subtilis,including the chemical identity of the modified nucleosides and their precise sequence location. Furthermore, by perturbing large subunit biogenesis using depletion of an essential factor RbgA and measuring the completion of 23S modifications in the accumulated intermediate, we provide a first look at the order of modification steps during the late stages of assembly inB. subtilis. While our work expands the knowledge of bacterial rRNA modification patterns, addingB. subtilisto the list of fully annotated species afterE. coliandT. thermophilus,in a broader context, it provides the experimental framework for discovery and functional profiling of rRNA modifications to ultimately elucidate their role in ribosome biogenesis and translation.
Decoding Early Psychoses: Unraveling Stable Microstructural Features Associated with Psychopathology Across Independent Cohorts
Authors: Wang Haley R. , Liu Zhen-Qi , Nakua Hajer , Hegarty Catherine E. , Thies Melanie Blair , Patel Pooja K. , Schleifer Charles H. , Boeck Thomas P. , McKinney Rachel A. , Currin Danielle , Leathem Logan , DeRosse Pamela , Bearden Carrie E. , Misic Bratislav , Karlsgodt Katherine H. 
Published: May 2024

AbstractBackgroundEarly Psychosis patients (EP, within 3 years after psychosis onset) show significant variability, making outcome predictions challenging. Currently, little evidence exists for stable relationships between neural microstructural properties and symptom profiles across EP diagnoses, limiting the development of early interventions.MethodsA data-driven approach, Partial Least Squares (PLS) correlation, was used across two independent datasets to examine multivariate relationships between white matter (WM) properties and symptomatology, to identify stable and generalizable signatures in EP. The primary cohort included EP patients from the Human Connectome Project-Early Psychosis (n=124). The replication cohort included EP patients from the Feinstein Institute for Medical Research (n=78). Both samples included individuals with schizophrenia, schizoaffective disorder, and psychotic mood disorders.ResultsIn both cohorts, a significant latent component (LC) corresponded to a symptom profile combining negative symptoms, primarily diminished expression, with specific somatic symptoms. Both LCs captured comprehensive features of WM disruption, primarily a combination of subcortical and frontal association fibers. Strikingly, the PLS model trained on the primary cohort accurately predicted microstructural features and symptoms in the replication cohort. Findings were not driven by diagnosis, medication, or substance use.ConclusionsThis data-driven transdiagnostic approach revealed a stable and replicable neurobiological signature of microstructural WM alterations in EP, across diagnoses and datasets, showing a strong covariance of these alterations with a unique profile of negative and somatic symptoms. This finding suggests the clinical utility of applying data-driven approaches to reveal symptom domains that share neurobiological underpinnings.
Alternative splicing ofclocktranscript mediates the response of circadian clocks to temperature changes
Authors: Cai Yao D. , Chow Gary K. , Hidalgo Sergio , Liu Xianhui , Jackson Kiya C. , Vasquez Cameron D. , Gao Zita Y. , Lam Vu H. , Tabuloc Christine A. , Zheng Haiyan , Zhao Caifeng , Chiu Joanna C. 
Published: May 2024

AbstractCircadian clocks respond to temperature changes over the calendar year, allowing organisms to adjust their daily biological rhythms to optimize health and fitness. InDrosophila, seasonal adaptations and temperature compensation are regulated by temperature-sensitive alternative splicing (AS) ofperiod(per) andtimeless(tim) genes that encode key transcriptional repressors of clock gene expression. Althoughclock(clk) gene encodes the critical activator of clock gene expression, AS of its transcripts and its potential role in temperature regulation of clock function have not been explored. We therefore sought to investigate whetherclkexhibits AS in response to temperature and the functional changes of the differentially spliced transcripts. We observed thatclktranscripts indeed undergo temperature-sensitive AS. Specifically, cold temperature leads to the production of an alternativeclktranscript, hereinafter termedclk-cold, which encodes a CLK isoform with an in-frame deletion of four amino acids proximal to the DNA binding domain. Notably, serine 13 (S13), which we found to be a CK1α-dependent phosphorylation site, is among the four amino acids deleted in CLK-cold protein. Using a combination of transgenic fly, tissue culture, andin vitroexperiments, we demonstrated that upon phosphorylation at CLK(S13), CLK-DNA interaction is reduced, thus decreasing CLK occupancy at clock gene promoters. This is in agreement with our findings that CLK occupancy at clock genes and transcriptional output are elevated at cold temperature, which can be explained by the higher amounts of CLK-cold isoforms that lack S13 residue. This study provides new insights into the complex collaboration between AS and phospho-regulation in shaping temperature responses of the circadian clock.
A 96-Well Polyacrylamide Gel for Electrophoresis and Western Blotting
Authors: Birtwistle Marc R. , Huggins Jonah R. , Zadeh Cameron O. , Sarmah Deepraj , Srikanth Sujata , Jones B. Kelly , Cascio Lauren N. , Dean Delphine 
Published: May 2024

AbstractWestern blotting is a stalwart technique for analyzing specific proteins and/or their post-translational modifications. However, it remains challenging to accommodate more than ~10 samples per experiment without substantial departure from trusted, established protocols involving accessible instrumentation. Here, we describe a 96-sample western blot that conforms to standard 96-well plate dimensional constraints and has little operational deviation from standard western blotting. The main differences are that (i) submerged polyacrylamide gel electrophoresis is operated horizontally (similar to agarose gels) as opposed to vertically, and (ii) a 6 mm thick gel is used, with 2 mm most relevant for membrane transfer (vs ~1 mm typical). Results demonstrate both wet and semi-dry transfer are compatible with this gel thickness. The major tradeoff is reduced molecular weight resolution, due primarily to less available migration distance per sample. We demonstrate proof-of-principle using gels loaded with molecular weight ladder, recombinant protein, and cell lysates. We expect the 96-well western blot will increase reproducibility, efficiency (cost and time ~8-fold), and capacity for biological characterization relative to established western blots.
Learning to handle flowers increases pollen collection benefits for bees but does not affect pollination success for plants
Authors: Mayberry Maggie M. , Naumer Katherine C. , Novinger Annaliese N. , McCart Dalton M. , Wilkins Rachel V. , Muse Haley , Ashman Tia-Lynn , Russell Avery L. 
Published: May 2024

ABSTRACTBehavior frequently affects cooperation as well as conflict in plant-pollinator interactions. Pollinators such as bees often modify how they handle flowers with experience and such learning is generally assumed to increase collection of floral food rewards. The complexity of flower morphology also affects how quickly pollinators learn and recall how to access floral rewards from a given flower type. Because learning to handle a flower can increase extraction of food rewards (such as pollen) and often involves the pollinator altering how it interacts with the flower’s reproductive organs, pollinator learning could affect pollination success. Yet how pollinator cognition and flower morphology interact to affect pollination success is unknown. We therefore asked how learning and memory of flower handling by pollen-foraging generalist bumble bees (Bombus impatiens) varied among four morphologically distinct flower types(Phacelia campanularia, Exacum affine,Solanum elaeagnifolium, andErythranthe guttata) and affected pollen collection and pollen deposition on these flowers. We found that bees learned and remembered how to handle some flower types more quickly than others. Learning typically involved development of motor routines unique to each flower type. While bees invariably learned to improve pollen collection, how quickly bees learned and remembered each flower type did not affect pollen collection. Surprisingly, pollen deposition on flowers was not affected by bee foraging experience. Thus, even though learning benefits the bee, it does not alter female (and potentially male) fitness benefits for the plant. We discuss potential reasons for these patterns and consequences for bee behavior and flower evolution.
Visualization of intracellular ATP dynamics in the whole kidney under pathophysiological conditions using the kidney slice culture system
Authors: Yamamoto Shigenori , Yamamoto Shinya , Takahashi Masahiro , Mii Akiko , Okubo Akihiro , Toriu Naoya , Nakagawa Shunsaku , Abe Takaaki , Fukuma Shingo , Imamura Hiromi , Yamamoto Masamichi , Yanagita Motoko 
Published: May 2024

AbstractATP depletion plays a central role in the pathogenesis of kidney diseases. Recently, we reported spatiotemporal intracellular ATP dynamics during ischemia reperfusion (IR) using GO-ATeam2 mice systemically expressing an ATP biosensor. However, observation from the kidney surface did not allow visualization of deeper nephrons or accurate evaluation of ATP synthesis pathways. Here we established a novel ATP imaging system using slice culture of GO-ATeam2 mouse kidneys, evaluated ATP synthesis pathway, and analyzed intracellular ATP dynamics usingex vivoIR and cisplatin nephropathy models. We demonstrated that proximal tubules (PTs) were strongly dependent on oxidative phosphorylation (OXPHOS), whereas podocytes relied on both OXPHOS and glycolysis using ATP synthesis inhibitors. We also confirmed that theex vivoIR model could recapitulate ATP dynamicsin vivo; ATP recovery in PTs after reperfusion varied depending on ischemia length, whereas ATP in distal tubules (DTs) recovered well even after long ischemia. After cisplatin administration, ATP levels in PTs decreased first, followed by a decrease in DTs. An organic cation transporter 2 inhibitor suppressed cisplatin uptake in kidney slices, leading to better ATP recovery in PTs, but not in DTs. Finally, we confirmed that a mitochondria protection reagent delayed cisplatin-induced ATP decrease in PTs. This novel system may provide new insights into the energy dynamics and pathogenesis of kidney disease.