bluuebunny/crossref_metadata_2025_split huggingface dataset:
A zebrafish model for studying mechanisms of newborn hyperbilirubinemia and bilirubin induced neurological damage
Authors: Guzelkaya Metehan , Onal Ebru , Gelinci Emine , Kumral Abdullah , Cakan-Akdogan Gulcin 
Published: July 2023

AbstractUnresolved neonatal hyperbilirubinemia may lead to accumulation of excess bilirubin in the body, and bilirubin in the neural tissues may induce toxicity. Bilirubin induced neurological damage (BIND) can result in acute or chronic bilirubin encephalopathy, causing temporary or lasting neurological dysfunction or severe damage resulting in infant death. Although serum bilirubin levels are used as an indication of severity, known and unknown individual differences affect the severity of the symptoms. The mechanisms of BIND have not been fully understood yet. Here, a zebrafish newborn hyperbilirubinemia model is developed and characterized. Direct exposure to excess bilirubin induced dose and time dependent toxicity linked to the accumulation of bilirubin in the body and brain. Introduced bilirubin was processed by liver which increased the tolerance of larvae. BIND in larvae was demonstrated by morphometric measurements, histopathological analyses and functional tests. The larvae that survived hyperbilirubinemia displayed mild or severe morphologies associated with defects in eye movements, body posture and swimming problems. Interestingly, the plethora of mild to severe clinical symptoms were reproduced in the zebrafish model.Summary statementThis alternative newborn hyperbilirubinemia model in zebrafish, reports detailed analyses of bilirubin toxicity, recovery, and bilirubin induced neurological damage in varying degrees. Various clinical symptoms of BIND is successfully reproduced.
LipidSIM: inferring mechanistic lipid biosynthesis perturbations from lipidomics with a flexible, low-parameter, systematic Markov Modeling framework
Authors: Liang Chenguang , Murray Sue , Li Yang , Lee Richard , Low Audrey , Sasaki Shruti , Chiang Austin W.T. , Lin Wen-Jen , Mathews Joel , Barnes Will , Lewis Nathan E. 
Published: July 2023

AbstractLipid metabolism is a complex and dynamic system involving numerous enzymes at the junction of multiple metabolic pathways. Disruption of these pathways leads to systematic dyslipidemia, a hallmark of many pathological developments, such as nonalcoholic steatohepatitis and diabetes. Recent advances in computational tools can provide insights into the dysregulation of lipid biosynthesis, but limitations remain due to the complexity of lipidomic data, limited knowledge of interactions among involved enzymes, and technical challenges in standardizing across different lipid types. In this study, we present a low-parameter, biologically interpretable framework named Lipid Synthesis Investigative Markov model (LipidSIM), which models and predicts the source of perturbations in lipid biosynthesis from lipidomic data. LipidSIM achieves this by accounting for the interdependency between the lipid species via the lipid biosynthesis network and generates testable hypotheses regarding changes in lipid biosynthetic reactions. This feature allows the integration of lipidomics with other omics types, such as transcriptomics, to elucidate the direct driving mechanisms of altered lipidomes due to treatments or disease progression. To demonstrate the value of LipidSIM, we first applied it to hepatic lipidomics followingKeap1knockdown and found changes in mRNA expression of the lipid pathways were consistent with the LipidSIM-predicted fluxes. Second, we used it to study lipidomic changes following intraperitoneal injection of CCl4to induce fast NAFLD/NASH development and the progression of fibrosis and hepatic cancer. Finally, to show the power of LipidSIM for classifying samples with dyslipidemia, we used aDgat2-knockdown study dataset. Thus, we show that as it demands noa prioriknowledge of enzyme kinetics, LipidSIM is a valuable and intuitive framework for extracting biological insights from complex lipidomic data.
TRPV1 controls innate immunity duringCitrobacter rodentiumenteric infection
Authors: Cremin Michael , Tay Emmy , Ramirez Valerie T. , Murray Kaitlin , Nichols Rene K. , Brust-Mascher Ingrid , Reardon Colin 
Published: July 2023

AbstractMucosal immunity is critical to host protection from enteric pathogens and must be carefully controlled to prevent immunopathology. Regulation of immune responses can occur through a diverse range of mechanisms including bi-directional communication with the neurons. Among which include specialized sensory neurons that detect noxious stimuli due to the expression of transient receptor potential vanilloid receptor 1 (TRPV1) ion channel and have a significant role in the coordination of host-protective responses to enteric bacterial pathogens. Here we have used the mouse-adapted attaching and effacing pathogenCitrobacter rodentiumto assess the specific role of the TRPV1 channel in coordinating the host response. TRPV1 knockout (TRPV1-/-) mice had a significantly higherC. rodentiumburden in the distal colon and fecal pellets compared to wild-type (WT) mice. Increased bacterial burden was correlated with significantly increased colonic crypt hyperplasia and proliferating intestinal epithelial cells in TRPV1-/-mice compared to WT. Despite the increasedC. rodentiumburden and histopathology, the recruitment of colonic T cells producing IFNγ, IL-17, or IL-22 was similar between TRPV1-/-and WT mice. In evaluating the innate immune response, we identified that colonic neutrophil recruitment inC. rodentiuminfected TRPV1-/-mice was significantly reduced compared to WT mice; however, this was independent of neutrophil development and maturation within the bone marrow compartment. TRPV1-/-mice were found to have significantly decreased expression of the neutrophil-specific chemokineCxcl6and the adhesion moleculesIcam1in the distal colon compared to WT mice. Corroborating these findings, a significant reduction in ICAM-1 and VCAM-1, but not MAdCAM-1 protein on the surface of colonic blood endothelial cells fromC. rodentiuminfected TRPV1-/-mice compared to WT was observed. These findings demonstrate the critical role of TRPV1 in regulating the host protective responses to enteric bacterial pathogens, and mucosal immune responses.Author SummaryNeuroimmune communications are vital in regulating the immune response to invading pathogens. Here, we show that during a gastrointestinal infection, pain-sensing neuronal fibers can modulate the immune response to recruit phagocytic neutrophils via upregulation of cell adhesion molecules on local blood endothelial cells. This research elucidates a novel impact of the pain-sensing ion channel, TRPV1, on host-pathogen interactions in the gastrointestinal tract as well as a potential methodology for modulating the immune response during enteric infections.
Phosphate starvation decouples cell differentiation from DNA replication control in the dimorphic bacteriumCaulobacter crescentus
Authors: Hallgren Joel , Koonce Kira , Felletti Michele , Mortier Julien , Turco Eloisa , Jonas Kristina 
Published: July 2023

AbstractUpon nutrient depletion, bacteria stop proliferating and undergo physiological and morphological changes to ensure their survival. Yet, how these processes are coordinated in response to distinct starvation conditions is poorly understood. Here we compare the cellular responses ofCaulobacter crescentusto carbon (C), nitrogen (N) and phosphorus (P) starvation conditions. We find that DNA replication initiation and abundance of the replication initiator DnaA are, under all three starvation conditions, regulated by a common mechanism involving the inhibition of DnaA translation. By contrast, cell differentiation from a motile swarmer cell to a sessile stalked cell is regulated differently under the three starvation conditions. During C and N starvation, production of the signaling molecules (p)ppGpp is required to arrest cell development in the motile swarmer stage. By contrast, our data suggest that low (p)ppGpp levels under P starvation allow P-starved swarmer cells to differentiate into sessile stalked cells. Further, we show that limited DnaA abundance, and consequently absence of DNA replication initiation, is the main reason that prevents P-starved stalked cells from completing the cell cycle. Together, our findings demonstrate thatC. crescentusdecouples cell differentiation from DNA replication initiation under certain starvation conditions, two otherwise intimately coupled processes. We hypothesize that arresting the developmental program either as motile swarmer cells or as sessile stalked cells improves the chances of survival ofC. crescentusduring the different starvation conditions.Author SummaryBacteria frequently encounter periods of nutrient limitation. To ensure their survival, they dynamically modulate their own proliferation and cellular behaviors in response to nutrient availability. In manyAlphaproteobacteria, progression through the cell cycle is tightly coupled to morphological transitions generating distinct cell types. Here, we show how starvation for either of the major nutrients carbon, nitrogen, or phosphorus affects this coupling between key cell cycle events and cell differentiation in the model bacteriumCaulobacter crescentus. All three starvation conditions prevent cell proliferation by blocking DNA replication initiation. However, while carbon and nitrogen exhaustion cause cells to arrest the cell cycle as non-replicating motile cells, phosphorus starvation leads to accumulation of non-replicating sessile stalked cells. Our data demonstrate that starvation-dependent differences in (p)ppGpp signaling account for these different starvation responses. Together, our work provides insights into the mechanisms that allow bacteria to modulate their developmental program in response to changing environmental conditions.
Integrating Mental Health and Psycho-Social Support (MHPSS) into infectious disease outbreak and epidemic response: an umbrella review and operational framework
Authors: Alkasaby Muhammad , Philip Sharad , Douba Zain , Tu Hanna , Eaton Julian , Mohammed Muftau , Essar Mohammad Yasir , Kamal Manar Ahmed , Adeel Riaz Mehr Muhammad , Moussallem Marianne , Bosu William K , Walker Ian 
Published: July 2023

AbstractIntroductionInfectious disease outbreaks have a substantial impact on people’s psychosocial well-being. Yet, mental health and psychosocial support (MHPSS) interventions are not systemically integrated into outbreak and epidemic response. Our review aims to synthesise evidence on the effectiveness of MHPSS interventions in outbreaks and propose a framework for systematically integrating MHPSS into outbreak response.MethodsWe conducted an umbrella review in accordance with the Joanna Briggs Institute (JBI) methodology for umbrella reviews.ResultsWe identified 23 systematic literature reviews, 6 of which involved meta-analysis, and only 30% (n=7) were of high quality. Most of the available literature was produced during COVID-19 and focused on clinical case management and medical staff well- being, with scarce evidence on the well-being of other outbreak responders and MHPSS in other outbreak response pillars.ConclusionDespite the low quality of the majority of the existing evidence, MHPSS interventions have the potential to improve the psychological well- being of those affected by and those responding to outbreaks. They also can improve the outcomes of the outbreak response activities such as contact tracing, infection prevention and control, and clinical case management. Our proposed framework would facilitate integrating MHPSS into outbreak response and hence mitigate the mental health impact of outbreaks.Review registrationPROSPERO CRD42022297138.
Macrophages heterogeneity and significance during human fetal pancreatic development
Authors: Migliorini Adriana , Ge Sabrina , Atkins Michael H. , Sambathkumar Rangarajan , Sing Angel , Chua Conan , Gehring Adam J. , Keller Gordon M. , Notta Faiyaz , Nostro Maria Cristina 
Published: July 2023

SUMMARYOrganogenesis is a complex process that relies on a dynamic interplay between extrinsic factors originating from the microenvironment and intrinsic factors specific to the tissue. For the endocrine cells of the islet of Langerhans, the local microenvironment consists of various cell types including pancreatic acinar and ductal cells as well as neuronal, immune, endothelial, and stromal cells. Interestingly, hematopoietic cells have been detected in human pancreas as early as 6 post-conception weeks (PCW)1,2, but whether they play a role during islet formation in humans remains largely unknown. To shed light on this question, we performed single nuclei RNA sequencing of the human fetal pancreas during the early weeks of the second trimester, specifically focusing on the molecular interaction between the hematopoietic niche and the pancreatic epithelium. Our analysis identified a wide range of hematopoietic cells as well as two distinct subsets of macrophages that are unique to the fetal pancreas and absent in neonatal or adult pancreatic tissues. Leveraging this discovery, we developed a co-culture system of hESC-derived endocrine-macrophage organoids to model their interactionin vitro. Remarkably, we found that macrophages promoted the differentiation and viability of developing endocrine cellsin vitroand enhanced tissue engraftment in immunocompromised mice, supporting a role for these cells in future tissue engineering strategies for diabetes.
Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease
Authors: Urbauer Elisabeth , Aguanno Doriane , Mindermann Nora , Omer Hélène , Metwaly Amira , Krammel Tina , Faro Tim , Remke Marianne , Reitmeier Sandra , Bärthel Stefanie , Kersting Johannes , Huang Zihua , Xian Feng , Schmidt Manuela , Saur Dieter , Huber Samuel , Stecher Bärbel , List Markus , Gómez-Varela David , Steiger Katja , Allez Matthieu , Rath Eva , Haller Dirk 
Published: July 2023

SummaryMitochondrial dysfunction is associated with inflammatory bowel diseases (IBD). To understand how microbial-metabolic circuits contribute to intestinal tissue injury, we disrupt mitochondrial function in the epithelium by deleting heat shock protein 60 (Hsp60Δ/ΔIEC). While metabolic perturbation causes self-resolving tissue injury, regeneration is disrupted in the absence of aryl hydrocarbon receptor (Hsp60Δ/ΔIEC;AhR-/-) or IL-10 (Hsp60Δ/ΔIEC;Il10-/-) leading to IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60Δ/ΔIECmice, highlighting bacterial control of metabolic injury. Selective colonization of GF Hsp60Δ/ΔIECmice with the synthetic community OMM12confirms consistent expansion of metabolically-flexibleBacteroidesspp. across all models and mono-colonization withB. caecimurisrecapitulates injury. Transcriptional profiling of metabolically-impaired epithelium identifies gene signatures, includingIdo1,Nos2, andDuox2, distinguishing active from inactive tissue inflammation in 343 resected samples from Crohn’s disease patients. In conclusion, mitochondrial perturbation of the epithelium causes microbiota-dependent tissue injury and discriminative inflammatory gene profiles relevant for IBD.Abstract FigureGraphical Abstract:Control of metabolic injury by microbial signals.Mitochondrial perturbation of the intestinal epithelium induces tissue injuryLoss of IL-10 and AhR-related host mechanisms accelerate injury and inflammationMitochondrial dysfunction induces dysbiosis and expansion ofBacteroidesspp.Metabolic injury gene signature discriminates inflamedvs.non-inflamed IBD samples
Deep learning insights into the architecture of the mammalian egg-sperm fusion synapse
Authors: Elofsson Arne , Han Ling , Bianchi Enrica , Wright Gavin J. , Jovine Luca 
Published: July 2023

AbstractA crucial event in sexual reproduction is when haploid sperm and egg fuse to form a new diploid organism at fertilization. In mammals, direct interaction between egg JUNO and sperm IZUMO1 mediates gamete membrane adhesion, yet their role in fusion remains enigmatic. We used AlphaFold to predict the structure of other extracellular proteins essential for fertilization to determine if they could form a complex that may mediate fusion. We first identified TMEM81, whose gene is expressed by mouse and human spermatids, as a protein having structural homologies with both IZUMO1 and another sperm molecule essential for gamete fusion, SPACA6. Using a set of proteins known to be important for fertilization and TMEM81, we then systematically searched for predicted binary interactions using an unguided approach and identified a pentameric complex involving sperm IZUMO1, SPACA6, TMEM81 and egg JUNO, CD9. This complex is structurally consistent with both the expected topology on opposing gamete membranes and the location of predicted N-glycans not modeled by AlphaFold-Multimer, suggesting that its components could organize into a synapse-like assembly at the point of fusion. Finally, the structural modeling approach described here could be more generally useful to gain insights into transient protein complexes difficult to detect experimentally.Impact statementStructural modeling with AlphaFold-Multimer was used to investigate extracellular protein interactions involved in mammalian egg-sperm recognition, suggesting a putative pentameric complex that includes TMEM81, a sperm protein not previously involved in gamete recognition.
USP20 deubiquitinates and stabilizes the ER-phagy receptor FAM134B to drive ER-phagy
Authors: Man Zhang , Wang Zhangshun , Zhao Qing , Yang Qian , Yang Cuiwei , Liu Yanfen 
Published: July 2023

AbstractThe endoplasmic reticulum (ER) serves as a hub for various essential cellular processes, and maintaining ER homeostasis is essential for cell function. ER-phagy is a selective process that removes impaired ER subdomains through autophagosomes and lysosomal degradation. While the involvement of ubiquitination in autophagy regulation is well-established, its role in ER-phagy remains unclear. In our study, we screened deubiquitinating enzymes involved in ER-phagy and identified USP20 (ubiquitin specific peptidase 20) as a key regulator of ER-phagy under stress conditions. USP20 specifically cleaves K63– and K48-linked ubiquitin chains on the ER-phagy receptor FAM134B/RETREG1 (reticulophagy regulator 1), thereby stabilizing the substrate and promoting ER-phagy. Remarkably, despite lacking a transmembrane domain, USP20 is recruited to the ER through its interaction with VAPs (vesicle-associated membrane proteins). VAPs facilitate the recruitment of early autophagy proteins, including WIPI2, to specific ER subdomains, where USP20 and FAM134B are enriched. This recruitment of WIPI2 and other proteins plays a crucial role in facilitating FAM134B-mediated ER-phagy in response to cellular stress. Our findings highlight the critical role of USP20 in maintaining ER homeostasis by deubiquitinating and stabilizing FAM134B at distinct ER subdomains, where USP20 further recruits VAPs and promotes efficient ER-phagy.
Systematic exploration of bacterial form I rubisco maximal carboxylation rates
Authors: de Pins Benoit , Greenspoon Lior , Bar-On Yinon M. , Shamshoum Melina , Ben-Nissan Roee , Milshtein Eliya , Davidi Dan , Sharon Itai , Mueller-Cajar Oliver , Noor Elad , Milo Ron 
Published: July 2023

AbstractAutotrophy is the basis for complex life on Earth. Central to this process is rubisco - the enzyme that catalyzes almost all carbon fixation on the planet. Yet, with only a small fraction of rubisco diversity kinetically characterized so far, the underlying biological factors driving the evolution of fast rubiscos in nature remain unclear. We conducted a high-throughput kinetic characterization of over 100 bacterial form I rubiscos, the most ubiquitous group of rubisco sequences in nature, to uncover the determinants of rubisco’s carboxylation velocity. We show that the presence of a carboxysome CO2concentrating mechanism correlates with faster rubiscos with a median 5-fold higher rate. In contrast to prior studies, we find that rubiscos originating from α-cyanobacteria exhibit the highest carboxylation rates among form I enzymes (≈10 s-1median versus <7 s-1in other groups). Our study systematically reveals biological and environmental properties associated with kinetic variation across rubiscos from nature.
Evolution end classification oftfdgene clusters mediating bacterial degradation of 2,4-dichlorophenoxyacetic acid (2,4-D)
Authors: Iasakov Timur 
Published: July 2023

ABSTRACTThetfd(tfdIandtfdII) are gene clusters originally discovered in plasmid pJP4 which is involved in the bacterial degradation of 2,4-dichlorophenoxyacetic acid (2,4-D) via the ortho-cleavage pathway of chlorinated catechols. They share this activity, with respect to substituted catechols, with clusterstcbandclc. Although great efforts have been devoted over nearly forty years to exploring the structural diversity of these clusters, their evolution has been poorly resolved to date, and their classification is clearly obsolete. Employing comparative genomic and phylogenetic approaches revealed that alltfdclusters can be classified as one of four different types. The following four-type classification and new nomenclature are proposed:tfdI,tfdII,tfdIIIandtfdIV(A,B,C). Horizontal gene transfer betweenBurkholderialesandSphingomonadalesprovided phenomenal linkage betweentfdI,tfdII,tfdIIIandtfdIVtype clusters and their mosaic nature. It is hypothesized that the evolution oftfdgene clusters proceeded within first (tcb,clcandtfdI), second (tfdIIandtfdIII) and third (tfdIV(A,B,C)) evolutionary lineages in each of which the genes were clustered in specific combinations. Their clusterization has been discussed through the prism of hot spots and driving forces of various models, theories, and hypotheses of cluster and operon formation. Two hypotheses about series of gene deletions and displacements have also been proposed to explain the structural variations across members of clusterstfdIIandtfdIII, respectively. Taking everything into account, these findings reconstructing the phylogeny oftfdclusters, have delineated their evolutionary trajectories, and allowed the contribution of various evolutionary processes to be assessed.
The nuclei of human adult stem cells can move within the cell and generate cellular protrusions to contact other cells
Authors: Bueno Carlos , García-Bernal David , Martínez Salvador , Blanquer Miguel , Moraleda José M. 
Published: July 2023

AbstractDespite a considerable interest in understanding the mechanisms regulating nucleus structure, chromatin organization and nuclear positioning over decades, the exact significance of the variety of morphologies and positioning that cell nuclei can adopt and their relationship in cellular function is still far from being clearly understood. In this study, we examined the functional significance of the variety of morphologies and positioning that cell nuclei of human bone marrow-derived mesenchymal stem cells can adopt during neural-like differentiation. Here, we show that after neural induction, human bone marrow-derived mesenchymal stem cells enter an intermediate cellular state in which the nuclei are observed to be able to move within the cells, switching shapes and positioning and even generating cellular protrusions as they attempt to contact the cells around them. These findings suggest that changes in nuclear positioning are due to the fact that human cell nuclei somehow sensing their environment.