bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative spatiotemporal modeling of biomolecular processes: application to the assembly of the Nuclear Pore Complex
Authors: Latham Andrew P. , Tempkin Jeremy O. B. , Otsuka Shotaro , Zhang Wanlu , Ellenberg Jan , Sali Andrej 
Published: August 2024

AbstractDynamic processes involving biomolecules are essential for the function of the cell. Here, we introduce an integrative method for computing models of these processes based on multiple heterogeneous sources of information, including time-resolved experimental data and physical models of dynamic processes. We first compute integrative structure models at fixed time points and then optimally select and connect these snapshots into a series of trajectories that optimize the likelihood of both the snapshots and transitions between them. The method is demonstrated by application to the assembly process of the human Nuclear Pore Complex in the context of the reforming nuclear envelope during mitotic cell division, based on live-cell correlated electron tomography, bulk fluorescence correlation spectroscopy-calibrated quantitative live imaging, and a structural model of the fully-assembled Nuclear Pore Complex. Modeling of the assembly process improves the model precision over static integrative structure modeling alone. The method is applicable to a wide range of time-dependent systems in cell biology, and is available to the broader scientific community through an implementation in the open sourceIntegrative Modeling Platformsoftware.
Alternative Conformations of lncRNAs Identified Through Structural Deconvolution of SHAPE- and DMS-MaP Datasets
Authors: Fallon Lucy , Jones Alisha N 
Published: August 2024

AbstractThe biological function of many classes of RNAs depend on their structures, which can exist as structural ensembles, rather than a single minimum free energy fold. In the past decade, long noncoding RNAs (lncRNAs) have emerged as functional transcripts in gene regulation that behave through their primary sequences and the structures they adopt. Chemical probing experiments, like selective 2’-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP), and dimethyl sulfate-MaP (DMS-MaP), facilitate the characterization of RNA secondary structure both inside and outside the cell. But chemical probing experiments yield anaveragereactivity profile, representative of all the structures a particular RNA transcript adopts at the time of chemical probing, weighted by their relative populations. Chemical probing experiments often struggle to identify coexisting conformations a lncRNA might sample. Computational methods (DRACO, DREEM, DANCE-MaP) have been developed to identify alternate conformations of RNAs by deconvoluting chemical probing data. In this work, we investigate the propensity for lncRNAs to sample multiple structured states, and find each of the studied lncRNAs possess coexisting folds. We discuss the implications of lncRNAs harboring multiple structures and how it may contribute to their multifunctionality in regulating biological processes.
The heme-scavenger, hemopexin, protects against fungal lung injury by mitigating NETosis: an experimental and computational study
Authors: Qu Ganlin , Ribeiro Henrique A. L. , Solomon Angelica L. , Vieira Luis Sordo , Goddard Yana , Diodati Nickolas G. , Lazarte Arantxa V , Wheeler Matthew , Laubenbacher Reinhard , Mehrad Borna 
Published: August 2024

AbstractInvasive aspergillosis is characterized by lung hemorrhage and release of extracellular heme, which promotes fungal growth. Heme can also mediate tissue injury directly, and both fungal growth and lung injury may induce hemorrhage. To assimilate these interdependent processes, we hypothesized that, during aspergillosis, heme mediates direct lung injury independent of fungal growth, leading to worse infection outcomes, and the scavenger protein, hemopexin, mitigates these effects. Mice with neutropenic aspergillosis were found to have a time-dependent increase in lung extracellular heme and a corresponding hemopexin induction. Hemopexin deficiency resulted in markedly increased lung injury, fungal growth, and lung hemorrhage. Using a computational model of the interactions ofAspergillus, heme, and the host, we predicted a critical role for heme-mediated generation of neutrophil-extracellular traps in this infection. We tested this prediction using a fungal strain unable to grow at body temperature, and found that extracellular heme and fungal exposure synergize to induce lung injury by promoting NET release, and disruption of NETs was sufficient to attenuate lung injury and fungal burden. These data implicate heme-mediated NETosis in both lung injury and fungal growth during aspergillosis, resulting in a detrimental positive feedback cycle that can be interrupted by scavenging heme or disrupting NETs.
A cytochromebdrepressed by a MarR family regulator confers resistance to metals, nitric oxide, sulfide, and cyanide inChromobacterium violaceum
Authors: Batista Bianca B. , Will W. Ryan , de Lima Vinicius M. , Fang Ferric C. , da Silva Neto José F. 
Published: August 2024

ABSTRACTChromobacterium violaceumis a ubiquitous environmental pathogen. Despite its remarkable adaptability, little is known about the mechanisms of stress resistance in this bacterium. Here, in a screen for iron-susceptible transposon mutants, we identified a cytochromebdthat protectsC. violaceumagainst multiple stresses. The two subunits of this cytochromebd(CioAB) are encoded by thecioRABoperon, which also encodes a GbsR-type MarR family transcription factor (CioR). A ΔcioABmutant strain was sensitive to iron and the iron-requiring antibiotic streptonigrin and showed a decrease in siderophore production. Growth curves and survival assays revealed that the ΔcioABstrain was also sensitive to zinc, hydrogen peroxide, nitric oxide, sulfide, and cyanide. Expression analysis showed that the promoter activity of thecioRABoperon and the transcript levels of thecioABgenes were increased in a ΔcioRmutant. CioR bound the promoter region of theciooperonin vitro, indicating that CioR is a direct repressor of its own operon. Expression of theciooperon increased at high cell density and was dependent on the quorum-sensing regulator CviR. As cyanide is also a signal forcioexpression, and production of endogenous cyanide is known to be a quorum sensing-regulated trait inC. violaceum, we suggest that CioAB is a cyanide-insensitive terminal oxidase that allow respiration under cyanogenic growth conditions. Our findings indicate that the cytochromebdCioAB protectsC. violaceumagainst multiple stress agents that are potentially produced endogenously or during interactions with a host.IMPORTANCEThe terminal oxidases of bacterial respiratory chains rely on heme-copper (heme-copper oxidases) or heme (cytochromebd) to catalyze reduction of molecular oxygen to water.Chromobacterium violaceumis a facultative anaerobic bacterium that uses oxygen and other electron acceptors for respiration under conditions of varying oxygen availability. TheC. violaceumgenome encodes multiple respiratory terminal oxidases, but their role and regulation remain unexplored. Here, we demonstrate that CioAB, the single cytochromebdfromC. violaceum, protects this bacterium against multiple stressors that are inhibitors of heme-copper oxidases, including nitric oxide, sulfide, and cyanide. CioAB also confersC. violaceumresistance to iron, zinc, and hydrogen peroxide. This cytochromebdis encoded by thecioRABoperon, which is under direct repression by the MarR-type regulator CioR. In addition, thecioRABoperon responds to quorum sensing and to cyanide, suggesting a protective mechanism of increasing CioAB in the setting of high endogenous cyanide production.
Histone demethylase LSD1 regulates lipid homeostasis duringCryptococcus neoformansinfection
Authors: Lohia Gaurav Kumar , Shah Awantika , Balaji Kithiganahalli Narayanaswamy 
Published: August 2024

AbstractAn opportunistic fungal pathogen,Cryptococcus neoformans (C. neoformans), causes cryptococcal meningitis and is frequently associated with high mortality in immunocompromised individuals, particularly in HIV patients. Formation of metabolically altered lipid-rich foamy macrophages has been reported as a successful strategy employed by various intracellular pathogens to secure a nutrient source and niche within the host. Herein, we elucidate the involvement of macroautophagy, specifically lipophagy, in lipid dysregulation duringC. neoformansinfection. Our study highlights a pivotal role of lipophagy during infection, showing thatC. neoformansdriven activation of WNT-signaling leads to an aberrant lipid accumulation in host macrophages under the regulatory role of a histone modifier, Lysine Specific Demethylase 1 (LSD1). In a murine model of pulmonary infection, targeting host LSD1 led to a significant reduction in lung fungal burden, accompanied by amelioration of lung pathology and reduction of lipid content in the lungs. The study highlights the significance of host epigenetic regulation in modulating foamy macrophage formation through the regulation of lipophagy duringC. neoformanspathogenesis.
Prefrontal Cortex subregions provide distinct visual and behavioral feedback modulation to the Primary Visual Cortex
Authors: Ährlund-Richter S. , Osako Y. , Jenks K.R. , Odom E. , Huang H. , Arnold D.B. , Sur M. 
Published: August 2024

AbstractThe mammalian Prefrontal Cortex (PFC) has been suggested to modulate sensory information processing across multiple cortical regions via long-range axonal projections. These axonal projections arise from PFC subregions with unique brain-wide connectivity and functional repertoires, which may provide the architecture for modular feedback intended to shape sensory processing. Here, we used axonal tracing, axonal and somatic 2-photon calcium imaging, and chemogenetic manipulations in mice to delineate how projections from the Anterior Cingulate Cortex (ACA) and ventrolateral Orbitofrontal Cortex (ORB) of the PFC modulate sensory processing in the primary Visual Cortex (VISp) across behavioral states. Structurally, we found that ACA and ORB have distinct patterning of projections across both cortical regions and layers. ACA axons in VISp had a stronger representation of visual stimulus information than ORB axons, but both projections showed non-visual, behavior-dependent activity. ACA input to VISp enhanced the encoding of visual stimuli by VISp neurons, and modulation of visual responses scaled with arousal. On the other hand, ORB input shaped movement and arousal related modulation of VISp visual responses, but specifically reduced the encoding of high-contrast visual stimuli. Thus, ACA and ORB feedback have separable projection patterns and encode distinct visual and behavioral information, putatively providing the substrate for their unique effects on visual representations and behavioral modulation in VISp. Our results offer a refined model of cortical hierarchy and its impact on sensory information processing, whereby distinct as opposed to generalized properties of PFC projections contribute to VISp activity during discrete behavioral states.
SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma
Authors: Elaimy Ameer L. , El-Derany Marwa O. , James Jadyn , Wang Zhuwen , Pearson Ashley N. , Holcomb Erin A. , Huber Amanda K. , Gijón Miguel , Bell Hannah N. , Sanghvi Viraj R. , Frankel Timothy L. , Su Grace L. , Tapper Elliot B. , Tai Andrew W. , Ramnath Nithya , Centonze Christopher P. , Dobrosotskaya Irina , Moeller Julie A. , Bryant Alex K. , Elliott David A. , Choi Enid , Evans Joseph R. , Cuneo Kyle C. , Fitzgerald Thomas J. , Wahl Daniel R. , Morgan Meredith A. , Chang Daniel T. , Wicha Max S. , Lawrence Theodore S. , Shah Yatrik M. , Green Michael D. 
Published: August 2024

AbstractEnd stage liver disease is marked by portal hypertension, systemic elevations in ammonia, and development of hepatocellular carcinoma (HCC). While these clinical consequences of cirrhosis are well described, it remains poorly understood whether hepatic insufficiency and the accompanying elevations in ammonia contribute to HCC carcinogenesis. Using preclinical models, we discovered that ammonia entered the cell through the transporter SLC4A11 and served as a nitrogen source for amino acid and nucleotide biosynthesis. Elevated ammonia promoted cancer stem cell propertiesin vitroand tumor initiationin vivo. Enhancing ammonia clearance reduced HCC stemness and tumor growth. In patients, elevations in serum ammonia were associated with an increased incidence of HCC. Taken together, this study forms the foundation for clinical investigations using ammonia lowering agents as potential therapies to mitigate HCC incidence and aggressiveness.
Phylogenomic prediction of interaction networks in the presence of gene duplication
Authors: Forsythe Evan S , Gatts Tony C , Lane Linnea E , deRoux Chris , Berggren Monica , Rehmann Elizabeth A , Zak Emily N , Bartel Trinity , L’Argent Luna , Sloan Daniel B 
Published: August 2024

AbstractAssigning gene function from genome sequences is a rate-limiting step in molecular biology research. A protein’s position within an interaction network can potentially provide insights into its molecular mechanisms. Phylogenetic analysis of evolutionary rate covariation (ERC) in protein sequence has been shown to be effective for large-scale prediction of functional relationships and interactions. However, gene duplication, gene loss, and other sources of phylogenetic incongruence are barriers for analyzing ERC on a genome-wide basis. Here, we developedERCnet, a bioinformatic program designed to overcome these challenges, facilitating efficient all- vs-all ERC analyses for large protein sequence datasets. We simulated proteome datasets and found thatERCnetachieves combined false positive and negative error rates well below 10% and that our novel ‘branch-by-branch’ length measurements outperforms ‘root-to-tip’ approaches in most cases, offering a valuable new strategy for performing ERC. We also compiled a sample set of 35 angiosperm genomes to test the performance ofERCneton empirical data, including its sensitivity to user-defined analysis parameters such as input dataset size and branch-length measurement strategy. We investigated the overlap betweenERCnetruns with different species samples to understand how species number and composition affect predicted interactions and to identify the protein sets that consistently exhibit ERC across angiosperms. Our systematic exploration of the performance ofERCnetprovides a roadmap for design of future ERC analyses to predict functional interactions in a wide array of genomic datasets.ERCnetcode is freely available athttps://github.com/EvanForsythe/ERCnet.
Trioxane-based MS-cleavable Cross-linking Mass Spectrometry for Profiling Multimeric Interactions of Cellular Networks
Authors: Yu Clinton , Novitsky Eric , Wang Xiaorong , Echeverria Ignacia , Rychnovsky Scott , Huang Lan 
Published: August 2024

ABSTRACTCross-linking mass spectrometry (XL-MS) is a powerful technology for mapping protein-protein interactions (PPIs) at the systems-level. By covalently connecting pairs of proximal residues, cross-linking reagents provide distance restraints to infer protein conformations and interaction interfaces. While binary cross-links have been remarkably informative, multimeric cross-links can offer enhanced spatial resolution to facilitate the characterization of dynamic and heterogeneous protein complexes. However, the identification of multimeric cross-links remains extremely challenging due to fragmentation complexity and the vast expansion of database search space. Here, we present a novel trioxane-based MS-cleavable homotrifunctional cross-linker TSTO, which can target three proximal lysine residues simultaneously. Owing to its unique structure and MS-cleavability, TSTO enables fast and unambiguous identification of cross-linked peptides using LC-MSnanalysis. Importantly, we have demonstrated that the TSTO-based XL-MS platform is effective for mapping PPIs of protein complexes and cellular networks. The trimeric interactions captured by TSTO have uncovered new structural details that cannot be easily revealed by existing reagents, allowing in-depth description of PPIs to facilitate structural modeling. This development not only advances XL-MS technologies for global PPI profiling from living cells, but also offers a new direction for creating multifunctional MS-cleavable cross-linkers to further push structural systems biology forward in the future.
Thermally-induced neuronal plasticity that mediates heat tolerance
Authors: Ambroziak Wojciech , Nencini Sara , Pohle Jörg , Zuza Kristina , Pino Gabriela , Lundh Sofia , Araujo-Sousa Carolina , Goetz Larissa I. L. , Schrenk-Siemens Katrin , Manoj Gokul , Herrera Mildred A. , Acuna Claudio , Siemens Jan 
Published: August 2024

AbstractHeat acclimation is an adaptive process that improves physiological performance and supports survival in the face of increasing environmental temperatures. Understanding the underlying mechanisms holds potential to mitigate health risks and reduces the steadily increasing number of heat-related casualties associated with global warming. Here we report the identification of a discrete group of hypothalamic preoptic neurons that transform to rheostatically increase their activity over the course of heat acclimation, a property required for mice to become heat tolerant. Peripheral thermo-afferent pathways via the parabrachial nucleus activate preoptic neurons and mediate acute heat-defense mechanisms in non-acclimated animals. However, long-term heat exposure promotes the preoptic neurons to gain intrinsically warm-sensitive activity, independent of thermo-afferent parabrachial input. Our data shows that their newly gained cell-autonomous warm-sensitivity is required to recruit peripheral heat tolerance mechanisms in acclimated animals. Mechanistically, we find a combination of increased sodium leak current and enhanced utilization of the Nav1.3 ion channel to drive their pacemaker-like, warm-sensitive activity. We propose a salient neuronal plasticity mechanism, adaptively driving acclimation to promote heat tolerance.HighlightsHeat acclimation induces tonic, warm-sensitive firing in hypothalamic VMPO neuronsTonic activity in VMPO neurons primes peripheral organs to gain heat tolerance capacityWarm-sensitive tonic firing recruits heat tolerance mechanisms in acclimated animalsNaV1.3 persistent sodium currents drive tonic, warm-sensitive firing in VMPO neurons
Improving Clarity and Interpretability of Items in a Bilingual Index of Propensity to Integrate Research Evidence into Clinical Decision-Making in Rehabilitation
Authors: Roberge-Dao Jacqueline , Mayo Nancy , Rochette Annie , Shikako Keiko , Thomas Aliki 
Published: August 2024

AbstractPurposeTo contribute evidence for the clarity and interpretability of a new five-item bilingual multidimensional index of a rehabilitation clinician’s propensity to integrate research evidence into clinical decision-making.MethodsThis study was conducted in three sequential steps: (1) We conducted a focus group with occupational therapists, physical therapists, and researchers to review the items and response options for clarity, consistency, and interval properties and agree on equivalency in English and French. (2) We conducted cognitive interviews whereby clinicians elaborated on their interpretation of the item, comprehensibility of items, and appropriateness of response options. Accepted modifications were integrated and tested with subsequent participants. (3) We conducted an online survey to validate the English and French equivalency of response options on a 0 to 100 scale.ResultsDuring the qualitative revision process (one focus group with 7 participants followed by 27 interviews), the index was revised 12 times with substantial modifications to theuse of research evidenceandattitudesitems.ConclusionThis research increases the clinical relevance and reduces measurement error of this brief index which can inform on individual or organizational factors influencing a clinician’s propensity of integrating research evidence into decision-making and ultimately, improve rehabilitation outcomes.
Predicting Cerebrospinal Fluid Alpha-Synuclein Seed Amplification Assay Status from Demographics and Clinical Data
Authors: Venuto Charles S. , Herbst Konnor , Chahine Lana M. , Kieburtz Karl 
Published: August 2024

ABSTRACTObjectiveTo develop and externally validate models to predict probabilities of alpha-synuclein (a-syn) positive or negative status in vivo in a mixture of people with and without Parkinson’s disease (PD) using easily accessible clinical predictors.MethodsUni- and multi-variable logistic regression models were developed in a cohort of participants from the Parkinson Progression Marker Initiative (PPMI) study to predict cerebrospinal fluid (CSF) a-syn status as measured by seeding amplification assay (SAA). Models were externally validated in a cohort of participants from the Systemic Synuclein Sampling Study (S4) that had also measured CSF a-syn status using SAA.ResultsThe PPMI model training/testing cohort consisted of 1260 participants, of which 76% had manifest PD with a mean (± standard deviation) disease duration of 1.2 (±1.6) years. Overall, 68.7% of the overall PPMI cohort (and 88.0% with PD of those with manifest PD) had positive CSF a-syn SAA status results. Variables from the full multivariable model to predict CSF a-syn SAA status included age-and sex-specific University of Pennsylvania Smell Identification Test (UPSIT) percentile values, sex, self-reported presence of constipation problems, leucine-rich repeat kinase 2 (LRRK2) genetic status and pathogenic variant, andGBAstatus. Internal performance of the model on PPMI data to predict CSF a-syn SAA status had an area under the receiver operating characteristic curve (AUROC) of 0.920, and sensitivity/specificity of 0.881/0.845. When this model was applied to the external S4 cohort, which included 71 participants (70.4% with manifest PD for a mean 5.1 (±4.8) years), it performed well, achieving an AUROC of 0.976, and sensitivity/specificity of 0.958/0.870. Models using only UPSIT percentile performed similarly well upon internal and external testing.ConclusionData-driven models using non-invasive clinical features can accurately predict CSF a-syn SAA positive and negative status in cohorts enriched for people living with PD. Scores from the UPSIT were highly significant in predicting a-syn SAA status.