SEARCH · Search bioRxiv

Results for “Pathology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 793 records · Page 44Linked to original sources

bioRxiv2018

Dynamic Brain Connectivity Alternation Detection via Matrix-variate Differential Network Model

MotivationNowadays brain connectivity analysis has attracted tremendous attention and has been at the foreground of neuroscience research. Brain functional connectivity reveals the synchronization of brain systems through correlations in neurophysiological measures of brain activity. Growing evidence now suggests that the brain connectivity network experiences alternations with the presence of numerous neurological disorders, thus differential brain network analysis may provides new insights into disease pathologies. For the matrix-valued data in brain connectivity analysis, existing graphical model estimation methods assume a vector normal distribution that in essence requires the columns of the matrix data to be independent. It is obviously not true, they have limited applications. Among the few solutions on graphical model estimation under a matrix normal distribution, none of them tackle the estimation of differential graphs across different populations. This motivates us to consider the differential network for matrix-variate data to detect the brain connectivity alternation.\n\nResultsThe primary interest is to detect spatial locations where the connectivity, in terms of the spatial partial correlation, differ across the two groups. To detect the brain connectivity alternation, we innovatively propose a Matrix-Variate Differential Network (MVDN) model. MVDN assumes that the matrix-variate data follows a matrix-normal distribution. We exploit the D-trace loss function and a Lasso-type penalty to directly estimate the spatial differential partial correlation matrix where the temporal information is fully excavated. We propose an ADMM algorithm for the Lasso penalized D-trace loss optimization problem. We investigate theoretical properties of the estimator. We show that under mild and regular conditions, the proposed method can identify all differential edges accurately with probability tending to 1 in high-dimensional setting where dimensions of matrix-valued data p, q and sample size n are all allowed to go to infinity. Simulation studies demonstrate that MVDN provides more accurate differential network estimation than that achieved by other state-of-the-art methods. We apply MVDN to Electroencephalography (EEG) dataset, which consists of 77 alcoholic individuals and 45 controls. The hub genes and differential interaction patterns identified are consistent with existing experimental studies.\n\nContactheyong@sdufe.edu.cn\n\nSupplementary informationSupplementary data are available online.

bioinformatics↗

bioRxiv2018

HiAlc Klebsiella pneumonia, one of potential chief culprits of non-alcoholic fatty liver disease: through generation of endogenous ethanol

Non-alcoholic fatty liver disease (NAFLD), a prelude of cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. NAFLD has been considerated to be associated with the composition of gut microbiota. However, causal relationship between change of gut microbiome and NAFLD remains unclear. Here we show that Klebsiella pneumoniae was significantly associated with NAFLD through inducing generation of endogenous ethanol. A strain of high alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) was initially isolated from fecal samples of patient with non-alcoholic steatohepatitis (NASH) accompanied with auto-brewery syndrome (ABS). Gavage of HiAlc Kpn was capable of inducing murine model of fatty liver disease (FLD) in which had typical pathological changes of hepatic steatosis and similar liver gene expression profiles to those of alcohol intake in mice. Data derived from germ-free mice by gnotobiotic gavage further demonstrated that the HiAlc Kpn is the major cause of the changes in FLD mice. Furthermore, using proteomic and metabolitic analysis, we found that HiAlc Kpn induced generation of endogenous alcohol through the 2,3-butanediol fermentation pathway. More interestingly, the blood alcohol concentration was elevated in FLD mice induced by HiAlc Kpn after glucose intake. Clinical analysis showed that HiAlc Kpn were observed in up to 60% of patients with NAFLD. Our results suggested that HiAlc Kpn make important contribution to NAFLD, possibly through generation of the endogenous alcohol. Thus, targeting these bacteria might provide a novel therapeutic for clinical treatment of NAFLD.\n\nIn BriefFatty liver disease induced by high alcohol-producing Klebsiella pneumoniae\n\nCompeting Financial Interest StatementThe authors declare no conflicts of interest.

microbiology↗

bioRxiv2018

Correlation between the epigenetic modification of histone H3K9 acetylation of NR2B gene promoter in rat hippocampus and ethanol withdrawal syndrome

Our results showed that, in rat hippocampus, the ethanol withdrawal syndrome score was increased at 2 h, peaked at 6 h after withdrawal of ethanol, and reduced to the level parallel to the normal control group at day 3 after ethanol withdrawal. The NR2B mRNA expression and protein levels of rat hippocampus region showed similar patterns. Further correlation analyses indicted that both histone H3K9 acetylation in NR2B gene promoter and the expression levels of NR2B were positively associated with ethanol withdrawal syndrome. Chronic ethanol exposure may result in epigenetic modification of histone H3K9 acetylation in NR2B gene promoter in rat hippocampus, and the expression levels of NR2B were found to be positively correlated with EWS.\n\nAbstractPrevious studies showed that an epigenetic modification of N-methyl-D-aspartate (NMDA) receptor, especially NMDA receptor 2B subunit (NR2B), was involved in the pathological process of ethanol withdrawal syndrome (EWS). However, the relationship between the epigenetic regulation of the NR2B gene in the rat hippocampus region and EWS were inconsistent. A rat model of chronic ethanol exposure was established. EWS score and the behavioral changes were recorded at different points in time. The NR2B expression levels and the histone H3K9 acetylation level in the NR2B gene promoter region were measured using qRT-PCR, Western blot, immunofluorescence and chromatin immunoprecipitation, respectively. Finally, the relationships between the epigenetic modification of histone H3K9 acetylation of NR2B gene promoter and EWS were examined. Our results showed that the EWS score was increased at 2 h, peaked at 6 h after withdrawal of ethanol, and reduced to the level parallel to the normal control group at day 3 after ethanol withdrawal. The NR2B mRNA expression and protein levels showed similar patterns. Further correlation analyses indicted that both histone H3K9 acetylation in NR2B gene promoter and the expression levels of NR2B were positively associated with EWS. Chronic ethanol exposure may result in epigenetic modification of histone H3K9 acetylation in NR2B gene promoter in rat hippocampus, and the expression levels of NR2B were found to be positively correlated with EWS.

neuroscience↗

bioRxiv2018

Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated using in silico simulations as well as in vitro mixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics.

molecular biology↗

bioRxiv2018

Whole blood and hypertonic saline resuscitation improve the outcomes of controlled hemorrhagic shock combined with penetrating brain injury in rat

One of the most frequent injury patterns leading to early death of polytraumatized patients is hemorrhagic shock combined with traumatic brain injury. Currently, there is no agreement on the best treatment protocol of such injury. This study was aimed to compare the outcomes of resuscitation with various volumes of hypertonic saline (HTS), whole blood (WB) and fresh frozen plasma (FFP) in a rat model of penetrating brain injury combined with controlled hemorrhagic shock in order to look for optimal treatment. Anesthetized rats were intubated and ventilated. 30% of circulating blood volume was withdrawn following open brain injury, and intravenous resuscitation with various volumes of HTS, WB and FFP (3, 9, and 18 ml/kg) was administered. Blood samples were collected during the experiment for measurements of lactate and base excess levels, and before sacrifice for neutrophil counts. Twenty four and 48 hours after the injury, rats neurological status was examined. Rats were, then, sacrificed and pathological studies of brain and lung sections were performed. Regardless of fluid type, resuscitation improved the mean arterial pressure and lactate levels in accordance to fluids volume. However, base excess was improved only when rats were treated with WB and FFP. Improvement in behavioral performance of the rats was observed when treated with 3 and 9 ml/kg HTS or with 18 ml/kg WB or FFP. Blood and lung neutrophils were reduced in rats treated with 9 or 18 ml/kg WB. Mortality rates were reduced in rats administered with 9 and 18 ml/kg of HTS or WB. Taken together, resuscitation with WB at 9-18ml/kg or HTS at 9ml/kg is optimal for treatment of combined injury.

physiology↗

bioRxiv2018

A genetically encoded fluorescent sensor for rapid and specific in vivo detection ofnorepinephrine

Norepinephrine (NE) and epinephrine (Epi), two key biogenic monoamine neurotransmitters, are involved in a wide range of physiological processes. However, their precise dynamics and regulation remain poorly characterized, in part due to limitations of available techniques for measuring these molecules in vivo. Here, we developed a family of GPCR Activation-Based NE/Epi (GRABNE) sensors with a 230% peak {Delta}F/F0 response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second rapid kinetics, high specificity to NE vs. dopamine. Viral- or transgenic- mediated expression of GRABNE sensors were able to detect electrical-stimulation evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRABNE sensors are a robust tool for rapid and specific monitoring of in vivo NE/Epi transmission in both physiological and pathological processes.

neuroscience↗

bioRxiv2018

Macrophage migration inhibitory factor (MIF) of Syrian golden hamster (Mesocricetus auratus) has similar structure and function as human MIF and promotes pancreatic tumor growth in vivo

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that increasingly is being studied in cancers and inflammatory diseases. Though murine models have been instrumental in understanding the functional role of MIF in different pathological conditions, the information obtained from these models is biased towards a specific species. In experimental science, results obtained from multiple clinically relevant animal models always provide convincing data that might recapitulate in humans. Syrian golden hamster (Mesocricetus auratus), is a clinically relevant animal model for multiple human diseases. Hence, the major objectives of this study were to characterize structure and function of hamster MIF, and finally evaluate its effect on pancreatic tumor growth in vivo. Initially, the recombinant hamster MIF (rha-MIF) was cloned, expressed and purified in bacterial expression system. The rha-MIF primary sequence, biochemical properties and crystal structure analysis showed a greater similarity with human MIF. The crystal structure of hamster MIF illustrates that it forms a homotrimer as known in human and mouse. However, hamster MIF exhibits some minor structural variations when compared to human and mouse MIF. The in vitro functional studies show that rha-MIF has tautomerase activity and enhances activation and migration of hamster peripheral blood mononuclear cells (PBMCs). Interestingly, injection of rha-MIF into HapT1 pancreatic tumor bearing hamsters significantly enhanced the tumor growth and tumor associated angiogenesis. Together, the current study shows a structural and functional similarity between hamster and human MIF. Moreover, it has demonstrated that a high-level of circulating MIF originating from non-tumor cells might also promote pancreatic tumor growth in vivo.

biochemistry↗

bioRxiv2018

Sonodynamic therapy as an adjunctivw treatment on porphyromonas gingivalis induced periodontitis in rats with diabetes

ObjectivesThe purpose of our research was to examine the effects of Minocycline combined hyaluronic acid (HA)-mediated Ultrasound therapy of infected wound in wister rats.\n\nMethods40 female wister rats were made wound on the two side of the backbone, then infected in Staphylococcus aureus at the comic for three times. then, they are divided into four groups: control group, minocycline combined HA alone, ultasound alone, minocycline combined HA-mediated ultasound group, respective. After 3 times of treatments, the rats were killed and made into specimens. Assessments consisted of visual inspection in the change of the skin, scar formation pathological morphology by hematoxylin and eosin(HE) stain with optical microscopy, IL-1B assaying and TNF-a were performed.\n\nResultCompared with control group, minocycline combined HA alone, ultasound alone, minocycline combined HA-mediated ultasound group all have effect for wound healing, there was a obvious improvement in all parameters over the duration of the experiment(P<0.05). Compared with the control group, minocycline combined HA-mediated ultasound group indicated less inflammation cells (P<0.001) and the reduce of and IL-1B and TNF-a (P<0.001).\n\nConclusionMinocycline combined HA-mediated ultrasound can accelerate tissue regrowth, which exert significant benefits in healing the wounds.

microbiology↗

bioRxiv2018

Reversing compulsive cocaine seeking with low frequency deep brain stimulation of the subthalamic nucleus

Cocaine seeking despite a foot-shock contingency is used to model compulsive drug seeking, a core component of drug addiction, in rodents. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is efficient on other addiction criteria models and we show here that 30-Hz STN stimulation reduces pathological cocaine seeking in compulsive-like rats. This confirms STN DBS as a potential strategy to treat addiction. We also observed that only compulsive-like rats displayed a progressive increase in STN low frequency oscillations, especially in the alpha/theta band (6-13 Hz), during cocaine escalation. Conversely, applying 8-Hz STN DBS to mimic alpha/theta oscillations in non-compulsive animals changed them into compulsive ones. We have thus identified a predictive neuronal biomarker of compulsivity. Since one critical challenge in addiction research is to identify vulnerable individuals before they transition to harmful drug consumption pattern, our results could lead to new diagnostic tools and prevention strategies.

neuroscience↗

bioRxiv2018

Loss of TP73 function contributes to amyotrophic lateral sclerosis pathogenesis

Much remains unknown about the genetics and pathophysiology underlying the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We analyzed exome sequences from a cohort of 87 sporadic ALS (SALS) patients and 324 healthy individuals. TP73, a homolog of the TP53 tumor suppressor gene, had five rare deleterious protein-coding variants; in a separate collection of >2,900 ALS patients we identified an additional 19 rare deleterious variants in TP73. An in vitro C2C12 myoblast growth assay confirmed that these variants impair or alter TP73 function. In vivo mutagenesis of zebrafish tp73 using CRISPR led to impaired motor neuron development and abnormal axonal morphology, concordant with ALS pathology. Together, these results demonstrate that TP73 is a risk factor for ALS, and identifies a novel dysfunctional cellular process in the pathogenesis of ALS.

genetics↗

bioRxiv2018

LEM domain proteins control the efficiency of adaptation through copy number variation

While loss of genome integrity is at the basis of numerous pathologies, including cancer, genome plasticity is necessary to adapt to a changing environment and thus is essential for long-term organismal success. Here we present data supporting a targeted mechanism that promotes adaptation to environmental stress by driving site-specific genome instability tied to transcriptional induction and the formation of RNA-DNA hybrids. Using an in vitro evolution assay we observe that the inner nuclear membrane LEM domain proteins Heh1 and Heh2 play antagonistic roles in inhibiting or promoting adaptation through copy number expansion, respectively, which is also reflected in their genetic interaction networks with genes responsible for transcription-dependent genome instability. Taken together, our data suggest the existence of a LEM domain protein-mediated mechanism by which an immediate transcriptional response to a changing environment drives targeted genome instability to promote increased variation on which selection can act to support long-term adaptation.

genetics↗

bioRxiv2018

Translational control of cardiac fibrosis

Abstract BackgroundFibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global post-transcriptional mechanisms underlying fibroblast-to-myofibroblast conversion in the heart have not been explored.\n\nMethodsGenome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used miRNA-and RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes. To reveal post-transcriptional mechanisms in the human fibrotic heart, we then integrated our findings with cardiac ribosome occupancy levels of 30 dilated cardiomyopathy patients.\n\nResultsWe generated nucleotide-resolution translatome data during the TGF{beta}1-driven cellular transition of human cardiac fibroblasts to myofibroblasts. This identified dynamic changes of RNA transcription and translation at several time points during the fibrotic response, revealing transient and early-responder genes. Remarkably, about one-third of all changes in gene expression in activated fibroblasts are subject to translational regulation and dynamic variation in ribosome occupancy affects protein abundance independent of RNA levels. Targets of RNA-binding proteins were strongly enriched in post-transcriptionally regulated genes, suggesting genes such as MBNL2 can act as translational activators or repressors. Ribosome occupancy in the hearts of patients with dilated cardiomyopathy suggested an extensive post-transcriptional regulatory network underlying cardiac fibrosis. Key network hubs include RNA-binding proteins such as PUM2 and QKI that work in concert to regulate the translation of target transcripts in human diseased hearts.\n\nConclusionsWe reveal widespread translational effects of TGF{beta}1 and define novel post-transcriptional events that control the fibroblast-to-myofibroblast transition. Regulatory networks that affect ribosome occupancy in fibroblasts are paralleled in human heart disease. Our findings show the central importance of translational control in fibrosis and highlight novel pathogenic mechanisms in heart failure.

genomics↗

bioRxiv2018

Loss of SATB1 Induces a p21 Dependent CellularSenescence Phenotype in Dopaminergic Neurons

Cellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson s, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear. SATB1 is a DNA binding protein associated with Parkinsons disease. We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons, both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes which are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor, p21, in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor to the pathology of Parkinsons disease.

neuroscience↗

bioRxiv2018

Hippocampal theta bursting and waveform shape reflect CA1 spiking patterns

Brain rhythms are nearly always analyzed in the spectral domain in terms of their power, phase, and frequency. While this conventional approach has uncovered spike-field coupling, as well as correlations to normal behaviors and pathological states, emerging work has highlighted the physiological and behavioral importance of multiple novel oscillation features. Oscillatory bursts, for example, uniquely index a variety of cognitive states, and the nonsinusoidal shape of oscillations relate to physiological changes, including Parkinsons disease. Open questions remain regarding how bursts and nonsinusoidal features relate to circuit-level processes, and how they interrelate. By analyzing unit and local field recordings in the rodent hippocampus, we uncover a number of significant relationships between oscillatory bursts, nonsinusoidal waveforms, and local inhibitory and excitatory spiking patterns. Bursts of theta oscillations are surprisingly related to a decrease in pyramidal neuron synchrony, and have no detectable effect on firing sequences, despite significant increases in neuronal firing rates during periods of theta bursting. Theta burst duration is predicted by the asymmetries of its first cycle, and cycle asymmetries relate to firing rate, synchrony, and sequences of pyramidal neurons and interneurons. These results provide compelling physiological evidence that time-domain features, of both nonsinusoidal hippocampal theta waveform and the theta bursting state, reflects local circuit properties. These results point to the possibility of inferring circuit states from local field potential features in the hippocampus and perhaps other brain regions with other rhythms.

neuroscience↗

bioRxiv2018

An enriched network motif family regulates multistep cell fate transitions with restricted reversibility

Multistep cell fate transitions with stepwise changes of transcriptional profiles are common to many developmental, regenerative and pathological processes. The multiple intermediate cell lineage states can serve as differentiation checkpoints or branching points for channeling cells to more than one lineages. However, mechanisms underlying these transitions remain elusive. Here, we explored gene regulatory circuits that can generate multiple intermediate cellular states with stepwise modulations of transcription factors. With unbiased searching in the network topology space, we found a motif family containing a large set of networks can give rise to four attractors with the stepwise regulations of transcription factors, which limit the reversibility of three consecutive steps of the lineage transition. We found that there is an enrichment of these motifs in a transcriptional network controlling the early T cell development, and a mathematical model based on this network recapitulates multistep transitions in the early T cell lineage commitment. By calculating the energy landscape and minimum action paths for the T cell model, we quantified the stochastic dynamics of the critical factors in response to the differentiation signal with fluctuations. These results are in good agreement with experimental observations and they suggest the stable characteristics of the intermediate states in the T cell differentiation. These dynamical features may help to direct the cells to correct lineages during development. Our findings provide general design principles for multistep cell linage transitions and new insights into the early T cell development. The network motifs containing a large family of topologies can be useful for analyzing diverse biological systems with multistep transitions.\n\nAuthor summaryThe functions of cells are dynamically controlled in many biological processes including development, regeneration and disease progression. Cell fate transition, or the switch of cellular functions, often involves multiple steps. The intermediate stages of the transition provide the biological systems with the opportunities to regulate the transitions in a precise manner. These transitions are controlled by key regulatory genes of which the expression shows stepwise patterns, but how the interactions of these genes can determine the multistep processes were unclear. Here, we present a comprehensive analysis on the design principles of gene circuits that govern multistep cell fate transition. We found a large network family with common structural features that can generate systems with the ability to control three consecutive steps of the transition. We found that this type of networks is enriched in a gene circuit controlling the development of T lymphocyte, a crucial type of immune cells. We performed mathematical modeling using this gene circuit and we recapitulated the stepwise and irreversible loss of stem cell properties of the developing T lymphocytes. Our findings can be useful to analyze a wide range of gene regulatory networks controlling multistep cell fate transitions.

systems biology↗

bioRxiv2018

NanoMEA: a versatile platform for high-throughput analysis of structure-function relationships in human stem cell-derived excitable cells and tissues

Somatic cells derived from human pluripotent stem cell (hPSC) sources hold significant potential as a means to improve current in vitro screening assays. However, their inconsistent ability to recapitulate the structural and functional characteristics of native cells has raised questions regarding their ability to accurately predict the functional behavior of human tissues when exposed to chemical or pathological insults. In addition, the lack of cytoskeletal organization within conventional culture platforms prevents analysis of how structural changes in human tissues affect functional performance. Using cation-permeable hydrogels, we describe the production of multiwell nanotopographically-patterned microelectrode arrays (nanoMEAs) for studying the effect of structural organization on hPSC-derived cardiomyocyte and neuronal function in vitro. We demonstrate that nanoscale topographic substrate cues promote the development of more ordered cardiac and neuronal monolayers while simultaneously enhancing cytoskeletal organization, protein expression patterns, and electrophysiological function in these cells. We then show that these phenotypic improvements act to alter the sensitivity of hPSC-derived cardiomyocytes to treatment with arrhythmogenic and conduction-blocking compounds that target structural features of the cardiomyocyte. Similarly, we demonstrate that neuron sensitivity to synaptic blockers is increased when cells are maintained on nanotopographically-patterned Nafion surfaces. The improved structural and functional capacity of hPSC-derived cardiomyocyte and neuronal populations maintained on nanoMEAs may have important implications for improving the predictive capabilities of cell-based electrophysiological assays used in preclinical screening applications.

bioengineering↗

bioRxiv2018

Unc 51-like autophagy-activating kinase (ULK1) mediates clearance of free {alpha}-globin in {beta}-thalassemia

Erythroid maturation is coordinated to maximize the production of hemoglobin A heterotetramers (2{beta}2) and minimize the accumulation of potentially toxic free - or {beta}-globin subunits. In {beta}-thalassemia, mutations in the {beta}-globin gene cause a build-up of free -globin, which forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality-control systems mitigate {beta}-thalassemia pathophysiology by degrading toxic free -globin. We show that loss of the Unc 51-like autophagy-activating kinase gene Ulk1 in {beta}-thalassemic mice reduces autophagic clearance of -globin in red cell precursors and exacerbates disease phenotypes, whereas inactivation of the canonical autophagy gene Atg5 has minimal effects. Systemic treatment with rapamycin to inhibit the ULK1 inhibitor mTORC1 reduces -globin precipitates and lessens pathologies in {beta}-thalassemic mice, but not in those lacking Ulk1. Similarly, rapamycin reduces free -globin accumulation in erythroblasts derived from {beta}-thalassemic patient CD34+ hematopoietic progenitors. Our findings identify a new, drug-regulatable pathway for ameliorating {beta}-thalassemia.\n\nOne Sentence SummaryRapamycin alleviates {beta}-thalassemia by stimulating ULK1-dependent autophagy of toxic free -globin.

cell biology↗

bioRxiv2026

Microglia drive demyelination via multiple sclerosis antibodies and BTK signaling

Microglia are the predominant immune cells in multiple sclerosis (MS) demyelinating lesions, where they phagocytose myelin, but whether they destroy myelin or merely scavenge its debris is unknown. Here, we explore whether pathogenic autoantibodies found in MS may induce the phagocytic destruction of myelin by microglia. Applying patient-derived, myelin-targeting antibodies to the mouse cortex, we developed an in vivo model of MS with focal demyelination that depended on epitope specificity and Fc gamma receptor and complement binding. Longitudinal monitoring of microglia-myelin interactions using in vivo two-photon microscopy revealed rapid microglial envelopment of intact myelin driving myelin loss, while single-cell RNA sequencing identified a demyelination-associated microglial signature. Parallel changes were observed in human MS lesions, where microglia enveloped intact myelin and similar genes were upregulated. Inhibition of Brutons tyrosine kinase (BTK) limited microglial transcriptional changes and prevented myelin loss following microglial envelopment. These findings directly implicate microglia in pathological myelin loss and support BTK inhibition as a therapeutic strategy to prevent demyelination by modulating microglia behavior.

neuroscience↗