bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elucidating Resistance Mechanisms inStaphylococcus epidermidis: A High-Performing MALDI-TOF MS-Based Proteomic Approach for Predictive Modeling
Authors: Ren Michael , Chen Qiang , Zhang Jing 
Published: January 2024

AbstractThe emergence ofStaphylococcus epidermidisas a significant nosocomial pathogen necessitates advancements in more efficient antimicrobial resistance (AMR) profiling. However, existing culture-based antimicrobial susceptibility testing (AST) methods can take up to 96 hours, while holistic PCR assays can cost thousands of dollars. This study combines machine learning with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to develop predictive models for various antibiotics using a comprehensive dataset containing thousands ofS. epidermidisisolates. Optimized machine learning models utilized feature selection and achieved high AUROC scores ranging from 0.80 to 0.95 while maintaining AUPRC scores up to 0.96 for balanced datasets. Shapley Additive exPlanations (SHAP) were employed to analyze relevant features and assess the significance of corresponding protein biomarkers while also verifying that predictive power was derived from the detection of proteins rather than noise. AMR prediction models were validated externally to evaluate model performance outside the original data collection site. The findings in this study demonstrate that combining machine learning with AMR profiling yields significant and relevant results, indicating that such an approach is a promising solution for rapid and cost-effective treatments for nosocomial infections. Models created to predict AMR can also aid in biomarker discovery. The workflow used in the present study is potentially applicable to other microbial pathogens in the future.
Structure, motion, and multiscale search of traveling networks
Authors: Cira Nate J. , Paull Morgan L. , Sinha Shayandev , Zanini Fabio , Ma Eric Yue , Riedel-Kruse Ingmar H. 
Published: January 2024

AbstractNetwork models are widely applied to describe connectivity and flow in diverse systems. In contrast, the fact that many connected systems move through space as the result of dynamic restructuring has received little attention. Therefore, we introduce the concept of ‘traveling networks’, and we analyze a tree-based model where the leaves are stochastically manipulated to grow, branch, and retract. We derive how these restructuring rates determine key attributes of network structure and motion, enabling a compact understanding of higher-level network behaviors such as multiscale search. These networks self-organize to the critical point between exponential growth and decay, allowing them to detect and respond to environmental signals with high sensitivity. Finally, we demonstrate how the traveling network concept applies to real-world systems, such as slime molds, the actin cytoskeleton, and human organizations, exemplifying how restructuring rules and rates in general can select for versatile search strategies in real or abstract spaces.
The Calcitron: A Simple Neuron Model That Implements Many Learning Rules via the Calcium Control Hypothesis
Authors: Moldwin Toviah , Azran Li Shay , Segev Idan 
Published: January 2024

AbstractTheoretical neuroscientists and machine learning researchers have proposed a variety of learning rules for linear neuron models to enable artificial neural networks to accomplish supervised and unsupervised learning tasks. It has not been clear, however, how these theoretically-derived rules relate to biological mechanisms of plasticity that exist in the brain, or how the brain might mechanistically implement different learning rules in different contexts and brain regions. Here, we show that the calcium control hypothesis, which relates plastic synaptic changes in the brain to calcium concentration [Ca2+] in dendritic spines, can reproduce a wide variety of learning rules, including some novel rules. We propose a simple, perceptron-like neuron model that has four sources of [Ca2+]: local (following the activation of an excitatory synapse and confined to that synapse), heterosynaptic (due to activity of adjacent synapses), postsynaptic spike-dependent, and supervisor-dependent. By specifying the plasticity thresholds and amount of calcium derived from each source, it is possible to implement Hebbian and anti-Hebbian rules, one-shot learning, perceptron learning, as well as a variety of novel learning rules.
MAIT Cells Modulate Innate Immune Cells and Inhibit Colon Cancer Growth
Authors: Cheng Olivia J. , Lebish Eric J. , Jensen Owen , Jacenik Damian , Trivedi Shubhanshi , Cacioppo Jackson , Aubé Jeffrey , Beswick Ellen J. , Leung Daniel T. 
Published: January 2024

AbstractMucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we show that peritumoral injection ofin vivo-expanded MAIT cells into RAG1-/-mice with MC38-derived tumors inhibits tumor growth compared to control. Multiplex cytokine analyses show that tumors from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting an association between eosinophil recruitment and tumor inhibition. In a human peripheral leukocyte co-culture model, we show that leukocytes stimulated with MAIT ligand show an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we show that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms. Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy.Brief summaryIn models of colon cancer, MAIT cells have anti-tumor activity, associated with increased production of proinflammatory and eosinophil-modulating cytokines.
It’s all in the timing: Delayed feedback in autism may weaken predictive mechanisms during contour integration
Authors: Knight Emily J. , Altschuler Ted S. , Molholm Sophie , Murphy Jeremy W. , Freedman Edward G. , Foxe John J. 
Published: January 2024

ABSTRACTHumans rely on predictive mechanisms during visual processing to efficiently resolve incomplete or ambiguous sensory signals. While initial low-level sensory data are conveyed by feedforward connections, feedback connections are believed to shape sensory processing through conveyance of statistical predictions based on prior exposure to stimulus configurations. Individuals with autism spectrum disorder (ASD) show biases in stimulus processing toward parts rather than wholes, suggesting their sensory processing may be less shaped by statistical predictions acquired through prior exposure to global stimulus properties. Investigations of illusory contour (IC) processing in neurotypical (NT) adults have established a well-tested marker of contour integration characterized by a robust modulation of the visually evoked potential (VEP) – theIC-effect– that occurs over lateral occipital scalp during the timeframe of the N1 component. Converging evidence strongly supports the notion that thisIC-effectindexes a signal with significant feedback contributions. Using high-density VEPs, we compared theIC-effectin 6–17-year-old children with ASD (n=32) or NT development (n=53). Both groups of children generated anIC-effectthat was equivalent in amplitude. However, theIC-effectnotably onset 21ms later in ASD, even though timing of initial VEP afference was identical across groups. This suggests that feedforward information predominated during perceptual processing for 15% longer in ASD compared to NT children. This delay in the feedback dependentIC-effect, in the context of known developmental differences between feedforward and feedback fibers, suggests a potential pathophysiological mechanism of visual processing in ASD, whereby ongoing stimulus processing is less shaped by statistical prediction mechanisms.SIGNIFICANCE STATEMENTChildren with autism often present with an atypical visual perceptual style that emphasizes parts or details over the whole. Using electroencephalography (EEG), this study identifies delays in the visual feedback from higher order sensory brain areas to primary sensory regions. Because this type of visual feedback is thought to carry information about prior sensory experiences, individuals with autism may have difficulty efficiently using prior experience and predictions to help make sense of incoming new visual information. This provides empirical neural evidence to support theories of disrupted sensory perception mechanisms in autism.
FateNet: an integration of dynamical systems and deep learning for cell fate prediction
Authors: Sadria Mehrshad , Bury Thomas M. 
Published: January 2024

AbstractUnderstanding cellular decision-making, particularly its timing and impact on the biological system such as tissue health and function, is a fundamental challenge in biology and medicine. Existing methods for inferring fate decisions and cellular state dynamics from single-cell RNA sequencing data lack precision regarding decision points and broader tissue implications. Addressing this gap, we present FateNet, a computational approach integrating dynamical systems theory and deep learning to probe the cell decision-making process using scRNA-seq data. By leveraging information about normal forms and scaling behavior near tipping pointscommon to many dynamical systems, FateNet accurately predicts cell decision occurrence and offers qualitative insights into the new state of the biological system. Also, through in-silico perturbation experiments, FateNet identifies key genes and pathways governing the differentiation process in hematopoiesis. Validated using different scRNA-seq data, FateNet emerges as a user-friendly and valuable tool for predicting critical points in biological processes, providing insights into complex trajectories.
Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics
Authors: Liu Youxi , Yin Meimei , Mao Xiaoting , Wu Shuai , Wei Shuangping , Heng Shujun , Yang Yichun , Huang Jinwen , Guo Zhuolin , Li Chuan , Ji Chao , Hu Liu , Liu Wenjie , Zhang Ling-juan 
Published: January 2024

AbstractAllergic contact dermatitis (ACD), a prevalent inflammatory skin disease, is elicited upon repeated skin contact with protein-reactive chemicals through a complex and poorly characterized cellular network between immune cells and skin resident cells. Here, single-cell transcriptomic analysis of the murine hapten-elicited model of ACD reveals that upon elicitation of ACD, infiltrated CD4+or CD8+lymphocytes were primarily the IFNγ-producing type 1 central memory phenotype. In contrast, type 2 cytokines (IL4 and IL13) were dominantly expressed by basophils, IL17A was primarily expressed by δγ T cells, and IL1β was identified as the primary cytokine expressed by activated neutrophils/monocytes and macrophages. Furthermore, analysis of skin resident cells identified a sub-cluster of dermal fibroblasts with preadipocyte signature as a prominent target for IFNγ+lymphocytes and dermal source for key T cell chemokines CXCL9/10. IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. Furthermore, targeted deletion ofIfngr1in dermal fibroblasts in mice reducedCxcl9/10expression, dermal infiltration of CD8+T cell, and alleviated ACD inflammation in mice. Finally, we showed that IFNγ+CD8+T cells and CXCL10-producing dermal fibroblasts co-enriched in the dermis of human ACD skin. Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis.
Beyond the Sin3/HDAC Complex: FAM60A emerges as a regulator of RNA Splicing
Authors: Huda Md Nazmul , Zimmermann Rosalyn , Nagar Preeti , Alam Jahangir , Islam Md Rafikul , Gerald Dayebgadoh , Miah Mojnu , Kempf Cassandra G , Thornton Janet L. , Zhang Ying , Wen Zhihui , Hatem Gaye , Gies Allen , Byrum Stephanie , Rahman Mohammad Alinoor , Florens Laurence , Washburn Michael P. , Miah Sayem 
Published: January 2024

AbstractFAM60A, traditionally linked to chromatin remodeling within the Sin3/HDAC complex, has emerged as a critical regulator in RNA splicing. Employing an integrative approach that combines immunological assays, CRISPR/Cas9 technology, comprehensive genomics, proteomics, and advanced cross-linking mass spectrometry, complemented by sophisticated 3D molecular modeling, our study challenges and extends the existing understanding of FAM60A’s functional dynamics. Contravening previous perceptions, our findings elucidate that FAM60A does not interact directly with SIN3A, rather establishes direct interactions with SAP30 and HDAC1, redefining its relationship with the Sin3/HDAC complex. These interactions, deciphered through detailed 3D structural analysis supported by cross-linking constraints, signify a complex architectural role of FAM60A within chromatin remodeling processes. Moreover, our research unveils FAM60A’s pivotal role in RNA processing, particularly in splicing regulation. Through extensive molecular interactions with a diverse array of mRNA-binding proteins and principal spliceosome components, FAM60A emerges as a key regulator of RNA splicing. This expanded role delineates its influence on gene expression regulation, spotlighting its capacity to modulate critical cellular processes. In sum, this study unveils FAM60A’s key role in gene regulation and RNA splicing, and suggests new paths for cellular and therapeutic research.
SHP2-triggered endothelium activation fuels estradiol-independent endometrial sterile inflammation
Authors: Pan Jie , Zhao Lixin , Fang Wen , Qu Jiao , Zhai Linhui , Tan Minjia , Xu Qiang , Du Qianming , Lv Wen , Sun Yang 
Published: January 2024

AbstractEndometrial hyperplasia (EH) is a common gynecological disease primarily driven by excess estrogen. How endometrial sterile inflammation regulates EH remains unclear. First, we found the upregulation of SHP2 in endometrial endothelial cells from patients with EH by scRNA-Seq. SHP2 promoted inflammatory activation of endothelial cells, which promoted macrophage transendothelial migration. Subsequently, IL1β and TNFα from macrophages gave a feedforward loop to enhance endothelial cell activation and result in more IGF1 secretion, thereby sustaining sterile endometrial inflammation and facilitating endometrial epithelial cell proliferation even after estradiol withdrawal. Mechanistically, results of bulk RNA-Seq and phosphoproteomic analyses showed that endothelial SHP2 dephosphorylated RIPK1Y380after estradiol stimulation. This event promoted activator protein 1 (AP-1) activation, instigating inflammation and increased CXCL10, CXCL13, COX2 and IGF1 secretion. Furthermore, targeting SHP2 by SHP099 or endothelial-specific SHP2 deletion alleviated EH progression in mice. Collectively, our findings demonstrate that SHP2 mediates the transition of endothelial activation, from estradiol-driven short inflammation to macrophage-amplified continuous sterile inflammation. Targeting chronic sterile inflammation mediated by endothelial cell activation is a promising strategy for non-hormonal intervention in EH.
Discovery of Highly Active Kynureninases for Cancer Immunotherapy through Protein Language Model
Authors: Eom Hyunuk , Cho Kye Soo , Lee Jihyeon , Kim Stephanie , Park Sukhwan , Kim Hyunbin , Yang Jinsol , Han Young-Hyun , Lee Juyong , Seok Chaok , Lee Myeong Sup , Song Woon Ju , Steinegger Martin 
Published: January 2024

ABSTRACTOvercoming the immunosuppressive tumor microenvironment is a promising strategy in anticancer therapy. L-kynurenine, a strong immunosuppressive metabolite can be degraded through kynureninases. Through homology searches and protein language models, we identified and then experimentally determined the efficacy of four top-ranked kynureninases. The catalytically most active one nearly doubles turnover number over the prior best, reducing tumor weight by 3.42 times in mouse model comparisons, and thus, presenting substantial therapeutic potential.
Context-sensitive processing in a model neocortical pyramidal cell with two sites of input integration
Authors: Graham Bruce P. , Kay Jim W. , Phillips William A. 
Published: January 2024

AbstractNeocortical layer 5 thick-tufted pyramidal cells are prone to exhibiting burst firing on receipt of coincident basal and apical dendritic inputs. These inputs carry different information, with basal inputs coming from feedforward sensory pathways and apical inputs coming from diverse sources that provide context in the cortical hierarchy. We explore the information processing possibilities of this burst firing using computer simulations of a noisy compartmental cell model. Simulated data on stochastic burst firing due to brief, simultaneously injected basal and apical currents allows estimation of burst firing probability for different stimulus current amplitudes. Information-theory-based partial information decomposition (PID) is used to quantify the contributions of the apical and basal input streams to the information in the cell output bursting probability. Four different operating regimes are apparent, depending on the relative strengths of the input streams, with output burst probability carrying more or less information that is uniquely contributed by either the basal or apical input, or shared and synergistic information due to the combined streams. We derive and fit transfer functions for these different regimes that describe burst probability over the different ranges of basal and apical input amplitudes. The operating regimes can be classified into distinct modes of information processing, depending on the contribution of apical input to out-put bursting:apical cooperation, in which both basal and apical inputs are required to generate a burst;apical amplification, in which basal input alone can generate a burst but the burst probability is modulated by apical input;apical drive, in which apical input alone can produce a burst; andapical integration, in which strong apical or basal inputs alone, as well as their combination, can generate bursting. In particular, PID and the transfer function clarify that the apical amplification mode has the features required for contextually-modulated information processing.
Endogenous retroelement activation is implicated in IFN-α production and anti-CCP autoantibody generation in early RA
Authors: Cooles Faye AH , Pedrola Gemma V , Naamane Najib , Pratt Arthur G , Barron-Millar Ben , Anderson Amy E , Hilkens Catharien MU , Casement John , Bondet Vincent , Duffy Darragh , Zhang Fan , Shukla Ruchi , Isaacs John D 
Published: January 2024

AbstractObjectivesEndogenous retroelements (EREs) stimulate type 1 interferon (IFN-I) production but have not been explored as potential interferonogenic triggers in Rheumatoid Arthritis (RA). We investigated ERE expression in early RA (eRA), a period where IFN-I is increased.MethodsERE expression in DMARD naïve eRA whole blood (LINE1; RT-PCR) and bulk synovial tissue (LTR5, LINE1, SINE; Nanostring) was examined alongside IFN-α activity. Circulating lymphocyte subsets, including B cell subsets, from eRA patients and early psoriatic arthritis (PsA), were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single-cell sequencing data was re-interrogated to identify repeat elements, and associations explored.ResultsThere was significant co-expression of all ERE classes andIFNAin eRA synovial tissue (n=22, p<0.0001) and significant positive associations between whole blood LINE1 expression (n=56) and circulating IFN-α protein (p=0.018) and anti-CCP titres (p<0.0001). ERE expression was highest in circulating eRA B cells, particularly naïve B cells compared with PsA, with ERE regulation by SAMDH1 implicated and associations withIFNAagain observed. Finally, in established RA synovium, LTRs, particularly ERVK, were most increased in RA compared with OA where, for all synovial subsets (monocytes, B cells, T cells and fibroblasts), ERE expression associated with increased IFN-I signalling (p<0.001).ConclusionsPeripheral blood and synovial ERE expression is examined for the first time in eRA highlighting both a potential causal relationship between ERE and IFN-I production and an intriguing association with anti-CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.
Protective Effects of Lipoxin A4and B4Signaling on the Inner Retina in a Mouse Model of Experimental Glaucoma
Authors: Liu Hsin-Hua , Cullen Paul F. , Sivak Jeremy M. , Gronert Karsten , Flanagan John G. 
Published: January 2024

AbstractGlaucoma is a common neurodegenerative disease characterized by progressive degeneration of retinal ganglion cells (RGCs) and the retinal nerve fiber layer (RNFL), resulting in a gradual decline of vision. A recent study by our groups indicated that the levels of lipoxins A4(LXA4) and B4(LXB4) in the retina and optic nerve decrease following acute injury, and that restoring their function is neuroprotective. Lipoxins are members of the specialized pro-resolving mediator (SPM) family and play key roles to mitigate and resolve chronic inflammation and tissue damage. Yet, knowledge about lipoxin neuroprotective activity remains limited. Here we investigate thein vivoefficacy of exogenous LXA4and LXB4administration on the inner retina in a mouse model of chronic experimental glaucoma. To investigate the contribution of LXA4signaling we used transgenic knockout (KO) mice lacking the two mouse LXA4receptors (Fpr2/Fpr3-/-). Functional and structural changes of inner retinal neurons were assessed longitudinally using electroretinogram (ERG) and optical coherence tomography (OCT). At the end of the experiment, retinal samples were harvested for immunohistological assessment. While both lipoxins generated protective trends, only LXB4treatment was significant, and consistently more efficacious than LXA4in all endpoints. Both lipoxins also appeared to dramatically reduce Müller glial reactivity following injury. In comparison, Fpr2/Fpr3 deletion significantly worsened inner retinal injury and function, consistent with an essential protective role for endogenous LXA4. Together, these results support further exploration of lipoxin signaling as a treatment for glaucomatous neurodegeneration.