bluuebunny/crossref_metadata_2025_split huggingface dataset:
Citrobacter rodentiuminfection activates colonic lamina propria group 2 innate lymphoid cells
Authors: Berkachy Rita , Mishra Vishwas , Biswas Priyanka , Frankel Gad 
Published: January 2025

AbstractGroup 3 innate lymphoid cells (ILC3s) play a major role in protecting against infection with the enteric mouse pathogenCitrobacter rodentium,used to model infections with enteropathogenic and enterohaemorrhagicEscherichia coli. ILC3s-secreted IL-22, shown to be indispensable for protection againstC. rodentiuminfection, induces secretion of IL-18, antimicrobial peptides and nutritional immunity proteins as well as activation of tissue regeneration processes. While ILC2s have traditionally been associated with immune responses to helminth infection and allergic inflammation via the production of type 2 cytokines (e.g. IL-4, IL-5, IL-9 and IL-13), more recently they have been implicated in protection againstClostridium difficileandHelicobacter pyloriinfections. Here we show that colonic lamina propria ILC2s proliferate in response toC. rodentiuminfection and secrete IL-4, IL-5 and IL-13, which are involved in maintenance of the intestinal barrier function, tissue repair and mucus secretion. When stimulated with IL-18, colonic ILC2s from uninfected naïve mice secreted type 2 cytokines. Injection of IL-18 binding protein (IL18BP), at 2- and 3-days postC. rodentiuminfection, blocked activation of ILC2s. These data show that ILC2s are activated in response to infection with an enteric Gram-negative pathogen, where stimulation with IL-18 plays a role in inducing proliferation and secretion of type 2 cytokines.Author SummaryWhile group 3 innate lymphoid cells (ILC3s) play a key role in protecting from bacterial infections, ILC2s are mainly associated with immune responses to helminth infection. Here we investigated if ILC2s are activated in responses to infection with the enteric mouse pathogenCitrobacter rodentium.We show that in infected mice, gut ILC2s expand and secreted type 2 cytokines. ILC2 isolated from uninfected mice were activated by IL-18. Consistently, administration of IL-18 binding protein intoC. rodentium-infected mice inhibited ILC2 activation. These findings suggest that gut ILC2s are activated by Gram negative enteric pathogens, which is mediated in part by IL-18.
Variational Autoencoder-based Model Improves Polygenic Prediction in Blood Cell Traits
Authors: Li Xiaoqi , Pang Minxing , Wen Jia , Zhou Laura Y. , Raffield Laura M. , Zhou Haibo , Yao Huaxiu , Chen Can , Sun Quan , Li Yun 
Published: January 2025

AbstractGenetic prediction of complex traits, enabled by large-scale genomic studies, has created new measures to understand individual genetic predisposition. Polygenic Risk Scores (PRS) offer a way to aggregate information across the genome, enabling personalized risk prediction for complex traits and diseases. However, conventional PRS calculation methods that rely on linear models are limited in their ability to capture complex patterns and interaction effects in high-dimensional genomic data. In this study, we seek to improve the predictive power of PRS through applying advanced deep learning techniques. We show that the Variational AutoEncoder-based model for PRS construction (VAE-PRS) outperforms currently state-of-the-art methods for biobank-level data in 14 out of 16 blood cell traits, while being computationally efficient. Through comprehensive experiments, we found that the VAE-PRS model offers the ability to capture interaction effects in high-dimensional data and shows robust performance across different pre-screened variant sets. Furthermore, VAE-PRS is easily interpretable via assessing the contribution of each individual marker to the final prediction score through the SHapley Additive exPlanations (SHAP) method, providing potential new insights in identifying trait-associated genetic variants. In summary, VAE-PRS presents a novel measure to genetic risk prediction by harnessing the power of deep learning methods, which could further facilitate the development of personalized medicine and genetic research.
IL-21-STAT3 axis negatively regulates LAIR1 expression in B cells
Authors: Yoshida Kenji , Kurata-Sato Izumi , Atisha-Fregoso Yemil , Aranow Cynthia , Diamond Betty 
Published: January 2025

AbstractLAIR1 is an inhibitory receptor broadly expressed on human immune cells, including B cells. LAIR1 has been shown to modulate BCR signaling, however, it is still unclear whether its suppressive activity can be a negative regulator for autoreactivity. In this study, we demonstrate the LAIR1 expression profile on human B cells and prove its regulatory function and relationships to B cell autoreactivity. We show that both the frequency and level of LAIR1 expression decreases during B cell differentiation. LAIR1 expressing (LAIR1+) switched memory (SWM) B cells have a transcriptional profile less differentiated toward a plasma cell (PC) phenotype, harbor more autoreactive B cells and exhibit less PC differentiationin vitrothan the LAIR1 negative (LAIR1-) counterpart. These data suggests that LAIR1 functions as a B cell tolerance checkpoint. We confirm previous data showing that patients with systemic lupus erythematosus (SLE) express less LAIR1 on B cells, implying a breakdown of the checkpoint, consistent with the enhanced PC differentiation seen in SLE. We further demonstrate that LAIR1 expression is down-regulated through the IL-21/STAT3 pathway which is known to be upregulated in SLE. These data suggest therapeutic targets that might decrease the aberrant PC differentiation observed in SLE.
Harnessing Extracellular Vesicles for Stabilized and Functional IL-10 Delivery in Macrophage Immunomodulation
Authors: Saleh Najla A. , Gagea Matthew A. , Vitija Xheneta , Janovic Tomas , Schmidt Jens C. , Deng Cheri X. , Kanada Masamitsu 
Published: January 2025

ABSTRACTExtracellular vesicles (EVs) are gaining recognition as promising therapeutic carriers for immune modulation. We investigated the potential of EVs derived from HEK293FT cells to stabilize and deliver interleukin-10 (IL-10), a key anti-inflammatory cytokine. Using minicircle (MC) DNA vectors, we achieved IL-10 overexpression and efficient incorporation into EVs, yielding superior stability compared to free, recombinant IL-10 protein. Detailed biophysical and functional analyses revealed that IL-10+EVs contain both monomeric and oligomeric forms of IL-10 on their external surface and encapsulated within vesicles. IL-10+EVs suppressed inflammatory cytokine expression in pro-inflammatory macrophages (from two to 14-fold compared to naïve EVs) without inducing anti-inflammatory polarization, demonstrating a distinct immunosuppressive mechanism. Interestingly, naïve EVs from non-transfected cells also exhibited significant anti-inflammatory effects, suggesting that the intrinsic bioactive cargo of EVs substantially contributes to their function, complicating the interpretation of IL-10-specific effects. Size-based fractionation analyses of IL-10+large EVs (lEVs), small EVs (sEVs), and non-vesicular extracellular particles (NVEPs) revealed IL-10 presence across all fractions, predominantly in monomeric form, with anti-inflammatory activity distributed among subpopulations. Anion exchange chromatography successfully enriched IL-10+exosomes while retaining immunomodulatory effects. However, the shared properties of naïve and IL-10+exosomes underscore the complexity of their immunomodulatory functions. These findings highlight the therapeutic potential of EVs while emphasizing the need to disentangle the contributions of engineered cytokines from endogenous vesicular components.
Airqtl dissects cell state-specific causal gene regulatory networks with efficient single-cell eQTL mapping
Authors: Wang Lingfei 
Published: January 2025

AbstractSingle-cell expression quantitative trait loci (sceQTL) mapping offers a powerful approach for understanding gene regulation and its heterogeneity across cell types and states. It has profound applications in genetics and genomics, particularly causal gene regulatory network (cGRN) inference to unravel the molecular circuits governing cell identity and function. However, computational scalability remains a critical bottleneck for sceQTL mapping, prohibiting thorough evaluation and optimization of statistical accuracy. We present airqtl, a novel method to overcome these challenges through algorithmic advances and efficient implementations of linear mixed models. Airqtl achieves superior time complexity and over eight orders of magnitude of acceleration, enabling objective method evaluation and optimization. Airqtl offersde novoinference of robust, experimentally validated cell state-specific cGRNs that reflect perturbation outcomes. Our results dissect the drivers of cGRN heterogeneity and underscore the value of natural genetic variations in primary human cell types for biologically relevant single-cell cGRN inference.
GlycoAvatars: Bead-Coated Membrane Models for Studying the Cancer-Immune Cells Interactome
Authors: Miranda Andreia , Relvas-Santos Marta , Lourenço Camila , Ferreira Eduardo , Cunha Diogo M. , Palmeira Carlos , Santos Lúcio Lara , Mattila Pieta K , Ferreira José Alexandre 
Published: January 2025

AbstractImmatureO-glycosylation of plasma membrane proteins, characterized by the presence of glycosites with a single GalNAc residue (the Tn antigen) rather than more extended and complex glycans, is a prominent feature of many advanced solid tumors across different origins and aetiologies. This form of glycosylation has been strongly associated with poor prognosis and is known to play a crucial role in the progression of the disease. Notably, it has been directly implicated in the crosstalk with the immune system, inducing tolerogenic phenotypes in both innate and adaptive immune cells. Despite this, the specific receptors involved in these interactions remain largely unidentified. To address this gap, we propose a novel high-throughput proteomics assisted strategy for characterizing the glycan interactome using plasma membrane-derived glycoprotein coated magnetic beads. Glycoproteins were isolated from plasma membranes of glycoengineered cell models with immature glycosylation and were then cloaked on the surface of magnetic beads, creating simplified cell “GlycoAvatars.” These GlycoAvatars were primarily employed to characterize the interactome between gastric and colorectal cancer cell lines and immune cells (dendritic cells and macrophages), providing a tool for identifying potentially relevant molecular nodes in glycan-mediated immune synapses, foreseeing their application in deciphering tumor-immune interactions.
Temporal Microenvironment Mapping (μMap) of Intracellular Trafficking Pathways of Cell-Penetrating Peptides Across the Blood-Brain Barrier
Authors: Morgan Danielle C. , Knutson Steve D. , Pan Chenmengxiao (Roderick) , MacMillan David W. C. 
Published: January 2025

AbstractPeptides play critical roles in cellular functions such as signaling and immune regulation, and peptide-based biotherapeutics show great promise for treating various diseases. Among these, cell-penetrating peptides (CPPs) are particularly valuable for drug delivery due to their ability to cross cell membranes. However, the mechanisms underlying CPP-mediated transport, especially across the blood-brain barrier (BBB), remain poorly understood. Mapping intracellular CPP pathways is essential for advancing drug delivery systems, particularly for neurological disorders, as understanding how CPPs navigate the complex environment of the BBB could enable the development of more effective brain-targeted therapies. Here, we leverage a nanoscale proximity labeling technique, termed µMap, to precisely probe the peptide– receptor interactions and intracellular trafficking mechanisms of photocatalyst-tagged CPPs. The unique advantage of the μMap platform lies in the ability to control the timing of light exposure, which enables the collection of time-gated data, depending on when the blue light is applied to the cells. By harnessing this spatiotemporal precision, we can uncover key peptide–receptor interactions and cellular processes, setting the stage for new innovations in drug design and brain-targeted therapies.Abstract Figure
Protein phosphatase 4 is required for centrosome asymmetry in fly neural stem cells
Authors: Segura Roberto Carlos , Gallaud Emmanuel , von Barnau Sythoff Adam , Aavula Kumar , Taylor Jennifer A. , Vahdat Danielle , Pielage Jan , Cabernard Clemens 
Published: January 2025

ABSTRACTAsymmetric cell division is used by stem cells to create diverse cell types while self-renewing the stem cell population. Biased segregation of molecularly distinct centrosomes could provide a mechanism to maintain stem cell fate, induce cell differentiation or both. However, the molecular mechanisms generating molecular and functional asymmetric centrosomes remain incompletely understood. Here, we show that in asymmetrically dividing fly neural stem cells, Protein phosphatase 4 (Pp4) is necessary for correct centrosome asymmetry establishment during mitosis, and microtubule organizing center (MTOC) maintenance in interphase. Usingin-vivolive cell imaging we show that while wild type neural stem cells always maintain one active MTOC,Pp4mutant neuroblasts contain two inactive centrioles in interphase. Furthermore, centrosomes ofPp4mutant neural stem cells mature in mitosis but fail to correctly transfer the centriolar protein Centrobin (Cnb) from the mother to the daughter centriole. Using superresolution imaging, we find that phosphomimetic Centrobin fails to accurately relocalize in mitosis. We propose that Pp4 regulates the timely relocalization of Cnb in mitosis to establish two molecularly distinct centrosomes. In addition, Pp4 is also necessary to maintain MTOC activity in interphase, ensuring biased centrosome segregation. Mechanistically, Pp4 could regulate centrosome asymmetry by dephosphorylating both Cnb and gamma-Tubulin.SIGNIFICANCE STATEMENTAsymmetric centrosome segregation occurs in stem cells and has been linked with cell fate decisions.Protein phosphatase 4 (Pp4), a conserved Serine/Threonine phosphatase, regulates centrosome asymmetry inDrosophilaneural stem cells by acting upon gamma tubulin and Centrobin.Pp4 regulates centrosome asymmetry establishment in mitosis and interphase, necessary for biased centrosome segregation.
Understanding the roles and experiences of mental health peer support workers in England: a qualitative study
Authors: Cooper Ruth E , Lyons Natasha , Nicholls Vicky , Foye Una , Shah Prisha , Mitchell Lizzie , Machin Karen , Chipp Beverley , Grundy Andrew , Pemovska Tamara , Ahmed Nafiso , Appleton Rebecca , Repper Julie , Lloyd-Evans Brynmor , Simpson Alan , Johnson Sonia 
Published: January 2025

AbstractBackgroundPeer support roles in mental health services are rapidly increasing in the UK and internationally. However, there is wide variation in these roles and limited research exploring the ways in which Peer Support Workers (PSWs) are currently working. We aimed to explore: 1) the distinctive features of PSWs approaches in mental healthcare; 2) the values underpinning the role and 3) the perceived impact of the role.MethodsWe conducted semi-structured qualitative interviews with paid mental health PSWs working across a range of settings. We took a co-produced, participatory approach: interviews were carried out by researchers with lived experience of mental health conditions and data were analysed using collaborative methods, guided by general principles of thematic analysis.ResultsWe interviewed 35 PSWs. Overarching themes identified from iterative analysis included: 1) The centrality of an individualised, flexible, approach, facilitating recovery through sharing lived experiences and building connection. PSWs advocated for service-user needs and most worked in non-clinical ways, offering holistic, recovery-orientated support. Tensions could arise with more clinical approaches. 2) Underpinning values included: i) Recovery is possible: bringing hope, role-modelling and encouraging change, ii) Mutuality: sharing lived experiences to bring empathy and build connection, iii) Person-centred approach: adapting ways of working to the individual, iv) Empowering instead of ‘fixing’ service users. 3) the role had benefits for participants’ own recovery, although its emotional demands could lead to burnout. Participants thought that peer support helped service users feel understood, leading to greater openness and facilitating recovery, although some felt that it may not be right for everyone. Participants felt that PSWs could bring systemic improvements to services and use their lived experience to help teams -meet service user needs.ConclusionPSWs work in a range of ways, but, a unifying feature is a flexible, person-centred approach, facilitating recovery through shared lived experience. A range of potential benefits of peer work were identified for PSWs and for service users, as well as reports of positive systemic change.These could be facilitated by recovery-orientated models in services, space for shared learning with PSWs, and flexibility to incorporate PSWs’ unique ways of working.
Glymphatic Flow after Thrombectomy is Associated with Futile Recanalization in Large Vessel Occlusion Stroke
Authors: Finkelstein Alan J. , Sipple Matthew T. , Akkipeddi Sajal M. , White Racquel , Kohli Gurkirat Singh , Susa Stephen , Singh Rohin , Romiyo Prasanth , Zhong Jianhui , Bhalla Tarun , Mattingly Thomas , Nguyen Vincent , Nedergaard Maiken , Bender Matthew T. , Schartz Derrek 
Published: January 2025

ABSTRACTBackgroundStroke is a leading cause of global death and disability, with mechanical thrombectomy remaining the optimal treatment approach for large vessel occlusion (LVO) ischemic stroke. Despite endovascular recanalization, nearly half of patients experience poor functional outcomes, a phenomenon termed “futile recanalization”. The cerebral glymphatic system has emerged as a potential, yet underexplored therapeutic target. In this retrospective study, we utilized glymphatic diffusion tensor analysis on post-thrombectomy MRIs scans to evaluate the association between glymphatic flow, clinical outcomes, and futile recanalization in LVO ischemic stroke.MethodsIn this retrospective study, 133 patients with anterior LVO ischemic stroke and MRI post-thrombectomy were identified. Futile recanalization was defined as a modified Rankin score >2 at 90 days, despite achieving complete or near-complete angiographic recanalization (mTICI 2b-3). We employed diffusion tensor imaging along the perivascular space (DTI-ALPS) to evaluate glymphatic function in individuals with futile recanalization and those with functional independence at 90 days. Spearman’s rank correlation was used to examine associations between the ALPS index and clinical variables. Effect sizes were calculated and reported using Cohen’s d.ResultsIn total, 55 anterior circulation LVO patients (mean age 73.9, 44% male) were included with adequate post-thrombectomy MRIs for analysis. Overall, glymphatic clearance was lower in the infarct side compared to the contralateral side (p = 0.035). Patients with futile recanalization had lower glymphatic flow compared to those with functional independence (p=0.049). Additionally, glymphatic flow was significantly associated with presenting NIHSS (R=-0.46, p = 0.002).ConclusionsThese findings suggest that patients with futile recanalization have comparatively worse glymphatic clearance. Further research is required to clarify the relationship between futile recanalization and the glymphatic system, which may facilitate the development of therapeutic adjuncts.
Arc: a therapeutic hub for Alzheimer’s disease
Authors: VanDongen Antonius M. 
Published: January 2025

ABSTRACTAlzheimer’s disease (AD) is poised to reach epidemic levels as the world population ages. There is currently no treatment that halts this debilitating disease. Our recent finding that the memory gene Arc regulates the expression of many genes associated with the pathophysiology of AD sets the stage for a new therapeutic approach that is not structurally based on the amyloid hypothesis that has driven most research to date. Neuronal activity-dependent Arc expression is controlled by a chromatin-modification complex containing two enzymes: Tip60 and PHF8. Here, we show that small molecules targeting these proteins inhibit Arc expression. This finding sets the stage for a novel therapeutic approach to combat Alzheimer’s disease. Targeting Arc opens a new frontier of “multi-target” therapy designed to intervene in several aspects of the disease simultaneously. Because of Arc’s role in controlling the expression of multiple genes and pathways implicated in AD, it could serve as a therapeutic hub.
LARP6 regulates the mRNA translation of fibrogenic genes in liver fibrosis
Authors: Kim Hyun Young , Mizrahi Orel , Lee Wonseok , Rosenthal Sara B. , Han Cuijuan , Yee Brian A. , Blue Steven M. , Diaz Jesiel , Jonnalagadda Jyotiprakash , Hokutan Kanani , Jang Haeum , Ma Chen-Ting , Bobkov Andrey , Sergienko Eduard , Jackson Michael R. , Stefanovic Branko , Kisseleva Tatiana , Yeo Gene W. , Brenner David A. 
Published: January 2025

SummaryMetabolic syndrome and excessive alcohol consumption result in liver injury and fibrosis, which is characterized by increased collagen production by activated Hepatic Stellate Cells (HSCs). LARP6, an RNA-binding protein, was shown to facilitate collagen production. However, LARP6 expression and functionality as a regulator of fibrosis development in a disease relevant model remains elusive. By using snRNA-sequencing, we show that LARP6 is upregulated mainly in HSCs of liver fibrosis patients. Moreover, LARP6 knockdown in human HSCs suppresses fibrogenic gene expression. By integrating eCLIP analysis and ribosome profiling in HSCs, we show that LARP6 interacts with mature mRNAs comprising over 300 genes, including RNA structural elements withinCOL1A1,COL1A2, andCOL3A1to regulate mRNA expression and translation. Furthermore, LARP6 knockdown in HSC attenuates fibrosis development in human liver spheroids. Altogether, our results suggest that targeting LARP6 in human HSCs may provide new strategies for anti-fibrotic therapy.HighlightsLARP6 is upregulated in liver fibrosis, mainly in HSCs.LARP6 knockdown in human HSCs reduces liver fibrosis development.Of the hundreds of gene targets, LARP6 interacts most with collagen mRNAs.LARP6 regulates mRNA translation via interaction with 5’UTRs.
Genetically encoded mechano-sensors with versatile readouts and compact size
Authors: Ren Yuan , Yang Jie , Saito Takumi , Glomb Oliver , Mousavi Sayed Iman , Naughton Brigitte , de Fontnouvelle Christina , Fujita Barbara , Schlieker Christian , Yogev Shaul , Zhang Yongli , Berro Julien 
Published: January 2025

AbstractMechanical forces are critical for virtually all fundamental biological processes, yet quantification of mechanical forces at the molecular scalein vivoremains challenging. Here, we present a new strategy using calibrated coiled-coils as genetically encoded, compact, tunable, and modular mechano-sensors to substantially simplify force measurementin vivo, via diverse readouts (luminescence, fluorescence and analytical biochemistry) and instrumentation readily available in biology labs. We demonstrate the broad applicability and ease-of-use of these coiled-coil mechano-sensors by measuring forces during cytokinesis (formin Cdc12) and endocytosis (epsin Ent1) in yeast, force distributions in nematode axons (β-spectrin UNC-70), and forces transmitted to the nucleus (mini-nesprin-2G) and within focal adhesions (vinculin) in mammalian cells. We report discoveries in intracellular force transmission that have been elusive to existing tools.