Biology subjects

Zhang, R.

Publications and source records attributed to Zhang, R..

At least 361 records · Page 20Linked to original sources

bioRxiv2023

asmbPLS: Adaptive Sparse Multi-block Partial Least Square for Survival Prediction using Multi-Omics Data

BackgroundAs high-throughput studies advance, more and more high-dimensional multi-omics data are available and collected from the same patient cohort. Using multi-omics data as predictors to predict survival outcomes is challenging due to the complex structure of such data. ResultsIn this article, we introduce an adaptive sparse multi-block partial least square (asmbPLS) regression method by assigning different penalty factors to different blocks in different PLS components for feature selection and prediction. We compared the proposed method with several competitive algorithms in many aspects including prediction performance, feature selection and computation efficiency. The performance and the efficiency of our method were demonstrated using both the simulated and the real data. ConclusionsIn summary, asmbPLS achieved a competitive performance in prediction, feature selection, and computation efficiency. We anticipate asmbPLS to be a valuable tool for multi-omics research. An R package called asmbPLS implementing this method is made publicly available on GitHub.

bioinformatics↗

bioRxiv2023

Cortical gradient perturbation in attention deficit hyperactivity disorder correlates with neurotransmitter-, cell type-specific and chromosome- transcriptomic signatures

Neurofunctional dysregulations in spatially discrete areas or isolated pathways have been suggested as neural markers for attention deficit hyperactivity disorder (ADHD). However, multiscale perspectives into the neurobiological underpins of ADHD spanning multiple biological systems remain sparse. This points to the need of multi-levels of analysis encompassing brain functional organization and its correlation with molecular and cell-specific transcriptional signatures are stressed. Here, we capitalized on diffusion mapping embedding model to derive the functional connectome gradient, and deployed multivariate partial least square (PLS) method to uncover the enrichment of neurotransmitomic, cellular and chromosomal connectome-transcriptional signatures of ADHD. Compared to typical control, ADHD children presented connectopic cortical perturbations in lateral orbito-frontal and superior temporal regions, which had also been validated in another independent sample. This gradient-derived variants in ADHD further aligned spatially with distributions of GABAA/BZ and 5-HT2A receptors and co-varied with genetic transcriptional expression. Cognitive decoding and gene-expression annotation showed the correlates of these variants in memory, emotional regulation and spatial attention. Moreover, the gradient-derived transcriptional signatures of ADHD exhibited enriched expression of oligodendrocyte precursors and endothelial cells, and were mainly involved as variants of chromosome 18, 19 and X. In conclusion, our findings bridged in-vivo neuroimging assessed functional brain organization patterns to a multi-level molecular pathway in ADHD, possibly shedding light on the interrelation of biological systems that may coalesce to the emergence of this disorder.

neuroscience↗

bioRxiv2023

Single-cell multi-scale footprinting reveals the modular organization of DNA regulatory elements

Cis-regulatory elements control gene expression and are dynamic in their structure, reflecting changes to the composition of diverse effector proteins over time1-3. Here we sought to connect the structural changes at cis-regulatory elements to alterations in cellular fate and function. To do this we developed PRINT, a computational method that uses deep learning to correct sequence bias in chromatin accessibility data and identifies multi-scale footprints of DNA-protein interactions. We find that multi-scale footprints enable more accurate inference of TF and nucleosome binding. Using PRINT with single-cell multi-omics, we discover wide-spread changes to the structure and function of candidate cis-regulatory elements (cCREs) across hematopoiesis, wherein nucleosomes slide, expose DNA for TF binding, and promote gene expression. Activity segmentation using the co-variance across cell states identifies "sub-cCREs" as modular cCRE subunits of regulatory DNA. We apply this single-cell and PRINT approach to characterize the age-associated alterations to cCREs within hematopoietic stem cells (HSCs). Remarkably, we find a spectrum of aging alterations among HSCs corresponding to a global gain of sub-cCRE activity while preserving cCRE accessibility. Collectively, we reveal the functional importance of cCRE structure across cell states, highlighting changes to gene regulation at single-cell and single-base-pair resolution.

genomics↗

bioRxiv2023

HCC-1 accelerates atherosclerosis by inducing endothelial cells and macrophages pyroptosis and serves as an early diagnostic biomarker

BACKGROUNDHCC-1 (Hemofiltrate CC chemokine-1), a CC-type chemokine, exerts function to change intracellular calcium concentration, induce leukocyte and manipulate enzyme release especially in monocytes. It has been reported that HCC-1 could predict the persistent acute kidney injury (AKI) or suppress hepatocellular carcinoma (HCC) by modulating cell cycle and promoting apoptosis, but the effect of HCC-1 on atherosclerosis is poorly understood. Here, we aimed to clarify the function and mechanism of HCC-1 in atherosclerosis and whether it could serve as a novel biomarker for the diagnosis of atherosclerosis. METHODSHCC-1 expression in serum, atherosclerotic plaques and normal arterial tissue from patients with atherosclerosis and control group was assessed by enzyme-linked immunosorbent assay, immunohistochemistry and con-focal microscope. The atherosclerotic model of HCC-1 overexpressing mice and control mice were generated by infection of AAV9-HCC-1 on an ApoE-/- background. Cell adhesion, polarization and pyroptosis were evaluated in vitro. The relationship between HCC-1 concentration in serum and atherosclerosis was analyzed in patients with atherosclerosis. RESULTSHCC-1 expression increased in patients with atherosclerosis both in serum and atherosclerotic plaque. HCC-1 overexpression mice had an enhancement in macrophage accumulation in plaque, higher levels of inflammatory factors, increased pyroptotic rate in ECs and Macrophages in plaque and decreased atherosclerotic plaque stability. In vitro, HCC-1 promoted monocytes to adhere to endothelial cells and M1 polarization, induced inflammation and pyroptosis both in ECs and Macrophages. CONCLUSIONSHCC-1 expression markedly increased in patients with atherosclerosis and HCC-1 overexpression accelerated atherosclerotic burden via an enhancement in monocytes recruitment, M1 polarization and pyroptosis both in ECs and Macrophages. Our findings suggested that HCC-1 may serve as an early biomarker for the diagnosis of atherosclerosis, with the capacity to reflect the degree of stenosis. GRAPHIC ABSTRACTA graphic abstract is available for this article.

cell biology↗

bioRxiv2023

A simple stochastic model for cell population dynamics in colonic crypts

The questions of how healthy colonic crypts maintain their size, and how homeostasis is disrupted by driver mutations, are central to understanding colorectal tumorigenesis. We propose a three-type stochastic branching process, which accounts for stem, transit-amplifying (TA) and fully differentiated (FD) cells, to model the dynamics of cell populations residing in colonic crypts. Our model is simple in its formulation, allowing us to estimate all but one of the model parameters from the literature. Fitting the single remaining parameter, we find that model results agree well with data from healthy human colonic crypts, capturing the considerable variance in population sizes observed experimentally. Importantly, our model predicts a steady state population in healthy colonic crypts for relevant parameter values. We show that APC and KRAS mutations, the most significant early alterations leading to colorectal cancer, result in increased steady-state populations in mutated crypts, in agreement with experimental results. Finally, our model predicts a simple condition for unbounded growth of cells in a crypt, corresponding to colorectal malignancy. This is predicted to occur when the division rate of TA cells exceeds their differentiation rate, with implications for therapeutic cancer prevention strategies.

cancer biology↗

bioRxiv2023

AB-Gen: Antibody Library Design with Generative Pre-trained Transformer and Deep Reinforcement Learning

Antibody leads must fulfill multiple desirable properties to be clinical candidates. Primarily due to the low throughput in the experimental procedure, the need for such multi-property optimization causes the bottleneck in preclinical antibody discovery and development, because addressing one issue usually causes another. We developed a reinforcement learning (RL) method, named AB-Gen, for antibody library design using a generative pre-trained Transformer (GPT) as the policy network of the RL agent. We showed that this model can learn the antibody space of heavy chain complementarity determining region 3 (CDRH3) and generate sequences with similar property distributions. Besides, when using HER2 as the target, the agent model of AB-Gen was able to generate novel CDRH3 sequences that fulfill multi-property constraints. 509 generated sequences were able to pass all property filters and three highly conserved residues were identified. The importance of these residues was further demonstrated by molecular dynamics simulations, which consolidated that the agent model was capable of grasping important information in this complex optimization task. Overall, the AB-Gen method is able to design novel antibody sequences with an improved success rate than the traditional propose-then-filter approach. It has the potential to be used in practical antibody design, thus empowering the antibody discovery and development process.

bioinformatics↗

bioRxiv2023

MultiomicsTracks96: A high throughput PIXUL-Matrix-based toolbox to profile frozen and FFPE tissues multiomes

BackgroundThe multiome is an integrated assembly of distinct classes of molecules and molecular properties, or "omes," measured in the same biospecimen. Freezing and formalin-fixed paraffin-embedding (FFPE) are two common ways to store tissues, and these practices have generated vast biospecimen repositories. However, these biospecimens have been underutilized for multi-omic analysis due to the low throughput of current analytical technologies that impede large-scale studies. MethodsTissue sampling, preparation, and downstream analysis were integrated into a 96-well format multi-omics workflow, MultiomicsTracks96. Frozen mouse organs were sampled using the CryoGrid system, and matched FFPE samples were processed using a microtome. The 96-well format sonicator, PIXUL, was adapted to extract DNA, RNA, chromatin, and protein from tissues. The 96-well format analytical platform, Matrix, was used for chromatin immunoprecipitation (ChIP), methylated DNA immunoprecipitation (MeDIP), methylated RNA immunoprecipitation (MeRIP), and RNA reverse transcription (RT) assays followed by qPCR and sequencing. LC-MS/MS was used for protein analysis. The Segway genome segmentation algorithm was used to identify functional genomic regions, and linear regressors based on the multi-omics data were trained to predict protein expression. ResultsMultiomicsTracks96 was used to generate 8-dimensional datasets including RNA-seq measurements of mRNA expression; MeRIP-seq measurements of m6A and m5C; ChIP-seq measurements of H3K27Ac, H3K4m3, and Pol II; MeDIP-seq measurements of 5mC; and LC-MS/MS measurements of proteins. We observed high correlation between data from matched frozen and FFPE organs. The Segway genome segmentation algorithm applied to epigenomic profiles (ChIP-seq: H3K27Ac, H3K4m3, Pol II; MeDIP-seq: 5mC) was able to recapitulate and predict organ-specific super-enhancers in both FFPE and frozen samples. Linear regression analysis showed that proteomic expression profiles can be more accurately predicted by the full suite of multi-omics data, compared to using epigenomic, transcriptomic, or epitranscriptomic measurements individually. ConclusionsThe MultiomicsTracks96 workflow is well suited for high dimensional multi-omics studies - for instance, multiorgan animal models of disease, drug toxicities, environmental exposure, and aging as well as large-scale clinical investigations involving the use of biospecimens from existing tissue repositories.

systems biology↗

bioRxiv2023

A rapid genome-wide analysis of isolated giant viruses only using MinION sequencing

Following the discovery of Acanthamoeba polyphaga mimivirus, diverse giant viruses have been isolated. However, only a small fraction of these isolates has been completely sequenced, limiting our understanding of the genomic diversity of giant viruses. MinION is a portable and low-cost long-read sequencer that can be readily used in a laboratory. Although MinION provides highly error-prone reads that require correction through additional short-read sequencing, recent studies assembled high-quality microbial genomes only using MinION sequencing. Here, we evaluated the accuracy of MinION-only genome assemblies for giant viruses by re-sequencing a prototype marseillevirus. Assembled genomes presented over 99.98% identity to the reference genome with a few gaps, demonstrating a high accuracy of the MinION-only assembly. As a proof of concept, we de novo assembled five newly isolated viruses. Average nucleotide identities to their closest known relatives suggest that the isolates represent new species of marseillevirus, pithovirus, and mimivirus. Assembly of subsampled reads demonstrated that their taxonomy and genomic composition could be analyzed at the 50x sequencing coverage. We also identified a pithovirus gene whose homologues were detected only in metagenome-derived relatives. Collectively, we propose that MinION-only assembly is an effective approach to rapidly perform a genome-wide analysis of isolated giant viruses.

microbiology↗

bioRxiv2023

Transcription factor GLK2 regulates key steps of anthocyanin biosynthesis to antagonize photo-oxidative stress during greening of Arabidopsis seedlings

The greening of young seedling is light induced but vulnerable to photo-oxidative stress at the same time, due to the immature status of chloroplasts. Accumulation of anthocyanin is a protective response to high light, by absorbing excess energy and serving as antioxidant. In this work with Arabidopsis, we found that GARP family transcription factors GOLDEN2-LIKE 2 (GLK2), as a key regulator to chloroplast development, also plays an intensive role in regulating anthocyanin biosynthesis during seedling de-etiolation, especially under high light stress. We demonstrate that GLK2 positively regulates anthocyanin biosynthesis by directly activating the transcription of anthocyanin late biosynthetic genes (LBGs) as well as TRANSPARENT TESTA GLABRA 1 (TTG1) gene, which encodes a key component of the regulatory MYB-bHLH-WDR (MBW) complex (which also activates LBGs). Our data further show that GLK2 and MBW each could activate the expression of DFR gene (key LBG) independently, via distinct promoter regions. We therefore propose a multifaceted involvement of GLK2 in anthocyanin biosynthesis as an important protective measure for developing chloroplasts, against excessive light exposure during seedling photomorphogenesis.

plant biology↗

bioRxiv2023

Temporal landscape and translational regulation of A-to-I editing in mouse retina development

The significance of A-to-I RNA editing in neurological development is widely recognized, however, its influence on retina development remains to be thoroughly understood. In this study, we aimed to characterize the temporal landscape of A-to-I editing in mouse retina development using total RNA-seq and Ribosome profiling, with a specific emphasis on its effect on gene translation. Our findings revealed that the editing underwent plastic changes and distinct editing contents facilitated stage-specific functions. Further analysis showed a dynamic interplay between A-to-I editing and alternative splicing, with A-to-I editing having a significant impact on splicing efficiency and increasing the quantity of splicing events. A-to-I editing held the potential of enhancing the translatomes diversity, but this came at the expense of reduced translational efficiency. When coupled with splicing, it could produce a coordinated regulatory effect on translatome dynamics. Overall, our study presents a temporally resolved atlas of A-to-I editing, connecting its dynamic changes with the regulatory impact on splicing and translation.

neuroscience↗

bioRxiv2023

Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression

Exposure to an acute stressor triggers a complex cascade of neurochemical events in the brain. However, deciphering their individual impact on stress-induced molecular changes remains a major challenge. Here we combine RNA-sequencing with selective pharmacological, chemogenetic and optogenetic manipulations to isolate the contribution of the locus coeruleus - noradrenaline (LC-NA) system to the acute stress response. We reveal that NA-release during stress exposure regulates a large and reproducible set of genes in the dorsal and ventral hippocampus via {beta}-adrenergic receptors. For a smaller subset of these genes, we show that NA release triggered by LC stimulation is sufficient to mimic the stress-induced transcriptional response. We observe these effects in both sexes, and independent of the pattern and frequency of LC activation. Using a retrograde optogenetic approach, we demonstrate that hippocampus-projecting LC neurons directly regulate hippocampal gene expression. Overall, a highly selective set of astrocyte-enriched genes emerges as key targets of LC-NA activation, most prominently several subunits of protein phosphatase 1 (Ppp1r3c, Ppp1r3d, Ppp1r3g) and type II iodothyronine deiodinase (Dio2). These results highlight the importance of astrocytic energy metabolism and thyroid hormone signaling in LC-mediated hippocampal function and offer new molecular targets for understanding how NA impacts brain function in health and disease.

neuroscience↗

bioRxiv2022

Autophagy inspects Rim4-mRNA interaction to safeguard programmed meiotic translation

Autophagy can degrade RNA, with an intricate preference for specific RNAs. However, the mechanism remains unclear. During yeast meiosis, autophagy is active, while a subset of transcripts needs to survive until their programmed translation during and at the end of meiotic divisions. Thus, the challenge here is how meiotic autophagy temporally spares specific mRNAs. Rim4, a meiosis-specific RNA binding protein (RBP), sequesters a specific set of mid-late meiotic transcripts during early meiosis to suppress premature translation. Recently, we reported that autophagy degrades Rim4, while the underlying mechanism and the fate of transcripts in complex with Rim4 remain uncharacterized. Here, we show that Rim4 utilizes a nuclear localization signal (NLS) to enter the nucleus to load its mRNA substrates before the nuclear export. Once in the cytoplasm, the active autophagy spares Rim4-mRNA. Using combined genetic, biochemical, and cell imaging approaches, we show that autophagy selectively degrades Rim4 during meiotic divisions in an Atg11-dependent manner upon Rim4-bound mRNAs released for translation; meanwhile, released mRNAs also become sensitive to autophagy. In vitro, purified Rim4 and its RRM-motif-containing variants, but not Rim4-mRNA complex, activate Atg1 kinase activity in meiotic cell lysates and in the immunoprecipitated Atg1 complex, suggesting that the conserved RRMs are involved in stimulating Atg1 and hence selective autophagy. These findings indicate that autophagy inspects Rim4-mRNA interaction to ensure meiotic stage-specific translation.

cell biology↗

bioRxiv2022

Cdc14 spatiotemporally regulates Rim4-mRNA complex assembly and stability during meiosis

In budding yeast, Rim4 sequesters a subset of meiotic transcripts and essentially suppresses their translation until being degraded at the end of meiosis I. We found that Rim4 loads mRNAs in the nucleus as a prerequisite for relocating Rim4 into the cytoplasm, where mRNAs protect Rim4 from autophagy. Nonetheless, the underlying mechanism remains unknown. Using genetic, biochemical, and cell imaging approaches, here, we revealed that phosphorylation states regulate Rim4s intracellular interactions with mRNAs and the yeast 14-3-3 proteins Bmh1 and Bmh2. Our data showed that Rim4 forms a heterotrimeric complex with Bmh1 and Bmh2 via multiple phosphorylated sites with the consensus of a PKA kinase target. Remarkably, the Bmh1/2-Rim4 complex excludes mRNAs and is resistant to autophagy. We further found that Cdc14, a conserved cell cycle phosphatase, binds to a canonical Cdc14 docking site (PxL) in Rim4s C-terminal low complexity domain (LCD) to de-phosphorylate Rim4 at multiple sites, resulting in Bmh1/2-Rim4 disassembly. Notably, before meiotic cell divisions, Cdc14 primarily resides in the nucleus, where mRNAs are transcribed. Therefore, Cdc14-triggered Bmh1/2 dissociation facilitates the nuclear Rim4 to target and sequester the nascent mRNAs. In contrast, during the meiotic divisions, Rim4-sequestered mRNAs are released for translation, while Cdc14 mediates Rim4-Bmh1/2 disassembly in the cytoplasm due to its temporary cytoplasmic relocation at the anaphases; subsequently, loss of protection from mRNAs and Bmh1/2 leads to autophagy-mediated Rim4 degradation at this stage. We conclude that phosphorylation states spatiotemporally regulate Rim4s meiotic interactions, subcellular localization, and stability, regulated by Cdc14.

cell biology↗

bioRxiv2022

Stromal resistance to castration-induced prostate regression in a mouse model of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease producing lower urinary tract symptoms related to the enlarged prostate. BPH is pathologically characterized by hyperplastic growth in both epithelial and stromal compartments. Androgen signaling is essential for prostate function and androgen blockade is the second-line medical therapy to relieve symptoms of BPH. Here we examined the prostates of probasin promoter-driven prolactin (Pb-PRL) transgenic mice, a robust model of BPH that spontaneously develops prostate enlargement, to investigate prostate regression in response to surgical castration. Serial ultrasound imaging demonstrated very uniform self-limited growth of Pb-PRL prostate volume that is consistent with the benign, limited cellular proliferation characteristic of BPH and that contrasts with the highly variable, exponential growth of murine prostate cancer models. Castration elicited only a partial reduction in prostate volume, relative to castration-induced regression of the normal prostate gland. The anti-androgen finasteride induced a diminished reduction of Pb-PRL prostate volume versus castration alone. The limited extent of Pb-PRL mouse prostate volume regression correlated with the initial volume of the stromal compartment, suggesting a differential sensitivity to androgen withdrawal of the epithelial and stroma compartments. Indeed, two-dimensional morphometric analyses revealed a distinctly reduced rate of regression for the stromal compartment in Pb-PRL mice. The myofibroblast component of the Pb-PRL prostate stroma appeared normal, but contained more fibroblasts and extracellular collagen deposition. Like normal prostate, the rate of regression of the Pb-PRL prostate was partially dependent on TGF{beta} and TNF signaling, but unlike the normal prostate, the extent of castration-induced regression was not affected by TGF{beta} or TNF blockade. Our studies show that androgen deprivation can effectively reduce the overall volume of hyperplastic prostate, but the stromal compartment is relatively resistant, suggesting additional therapies might be required to offer an effective treatment for the clinical manifestations of BPH.

pathology↗

bioRxiv2022

Large-scale analysis of the N-terminal regulatory elements of the kinase domain in plant receptor-like kinase family

The N-terminal regulatory element of the kinase domain (NRE), which includes juxtamembrane segment (JM) of Receptor-like kinases (RLKs) and the N-terminal extension segment of the kinase domain in RLCKs, is the key component that regulates the activities of RLKs and RLCKs. However, their feature and functions remain largely unexplored. Herein, we perform a systematic analysis of 510,233 NRE sequences in RLKs and RLCKs from 528 plants by integrating information theory and genome-wide analysis to unravel their common characteristics and diversity. Recombinant RLKs are used to explore the structural-functional relationship of the newly-discovered motifs in vitro. Most NRE segments are around 40-80 amino acids, featuring a serine-rich region and a 14-amino-acid motif FSYEELEKATBNFS which harbors a characteristic -helix connecting to the core kinase domain. This -helix suppresses FERONIAs kinase activity. Motif discovery algorithm has identified 29 motifs with known phosphorylation sites highly conserved in RLK and RLCK classes, especially the motif VGPWKpTGLpSGQLQKAFVTGVP in LRR-VI-2 class. The NRE phosphorylation of an LRR-VI-2 member MDIS1 modulates the auto-phosphorylation of its co-receptor MIK1, indicating NREs potential role as a "kinase switch" in RLK activation. Consequently, the characterization of phosphorylatable NRE motifs improves the accuracy in predicting phosphorylatable serines. Altogether, our study provides an enriched and comprehensive dataset to investigate NRE segments from individual RLKs and helps understand the underlying mechanism of action of the RLK signal transduction and kinase activation processes in plant adaptation.

plant biology↗

bioRxiv2022

Moderate High Temperature is Beneficial or Detrimental Depending on Carbon Availability in the Green Alga Chlamydomonas reinhardtii

High temperatures impair plant and algal growth and reduce food and biofuel production, but the underlying mechanisms remain elusive. The unicellular green alga Chlamydomonas reinhardtii is a superior model to study heat responses in photosynthetic cells due to its fast growth rate, many similarities in cellular processes to land plants, simple and sequenced genome, and ample genetic and genomics resources. Chlamydomonas grows in light by photosynthesis and/or with the externally supplied organic carbon source, acetate. Most of the published research about Chlamydomonas heat responses used acetate-containing medium. Understanding how organic carbon sources affect heat responses is important for the algal industry but understudied. We cultivated Chlamydomonas wild-type cultures under highly controlled conditions in photobioreactors at control of 25{degrees}C, moderate high temperature of 35{degrees}C, or acute high temperature of 40{degrees}C with and without constant acetate supply for 1- or 4-days. Our results showed that 35{degrees}C increased algal growth with constant acetate supply but reduced algal growth without sufficient acetate. The overlooked and dynamic effects of 35{degrees}C could be explained by induced carbon metabolism, including acetate uptake and assimilation, glyoxylate cycle, gluconeogenesis pathways, and glycolysis. Acute high temperature at 40{degrees}C for more than 2 days was lethal to algal cultures with and without constant acetate supply. Our research provides insights to understand algal heat responses and help improve thermotolerance in photosynthetic cells. HighlightWe revealed the overlooked, dynamic effects of moderate high temperature in algae depending on carbon availability and demonstrated the importance of carbon metabolism in thermotolerance of photosynthetic cells.

plant biology↗

bioRxiv2022

Inductive biases of neural networks for generalization in spatial navigation

The brain may have evolved a modular architecture for reward-based learning in daily tasks, with circuits featuring functionally specialized modules that match the task structure. We propose that this architecture enables better learning and generalization than architectures with less specialized modules. To test this hypothesis, we trained reinforcement learning agents with various neural architectures on a naturalistic navigation task. We found that the architecture that largely segregates computations of state representation, value, and action into specialized modules enables more efficient learning and better generalization. Behaviors of agents with this architecture also resemble macaque behaviors more closely. Investigating the latent state computations in these agents, we discovered that the learned state representation combines prediction and observation, weighted by their relative uncertainty, akin to a Kalman filter. These results shed light on the possible rationale for the brains modular specializations and suggest that artificial systems can use this insight from neuroscience to improve learning and generalization in natural tasks.

neuroscience↗

bioRxiv2022

Mincle-GSDMD-mediated release of IL-1β containing small extracellular vesicles contributes to ethanol-induced liver injury

Background & AimsMacrophage inducible C-type lectin (Mincle) is expressed on Kupffer cells and senses ethanol-induced danger signals released from dying hepatocytes and promotes IL-1{beta} production. However, it remains unclear what and how ethanol-induced Mincle ligands activate downstream signaling events to mediate IL-1{beta} release and contribute to alcohol-associated liver disease (ALD). In this study, we investigated the association of circulating {beta}-glucosylceramide ({beta}-GluCer), an endogenous Mincle ligand, with severity of ALD and examined the mechanism by which {beta}-GluCer engages Mincle on Kupffer cells to release IL-1{beta} in the absence of cell death and exacerbates ALD. Approach and ResultsConcentrations of {beta}-GluCer were increased in serum of patients with severe AH and correlated with disease severity. Challenge of Kupffer cells with LPS and {beta}-GluCer induced formation of a Mincle and Gsdmd-dependent secretory complex containing chaperoned full-length GSDMD (Hsp90-CDC37-NEDD4) with polyubiquitinated pro-IL-1{beta} and components of the Casp8-NLRP3 inflammasome loaded as cargo in small extracellular vesicles (sEV). Gao-binge ethanol exposure to wild-type, but not Mincle-/- and Gsdmd-/-, mice increased release of IL-1{beta} containing sEVs from liver explant cultures. Myeloid-specific deletion of Gsdmd similarly decreased the formation of sEVs by liver explant cultures and protected mice from ethanol-induced liver injury. sEVs collected from ethanol-fed wild-type, but not Gsdmd-/-, mice promoted injury of cultured hepatocytes and, when injected into wild-type mice, aggravated Gao-binge ethanol-induced liver injury. Conclusion{beta}-GluCer functions as a DAMP activating Mincle-dependent GSDMD-mediated formation and release of IL-1{beta}-containing sEVs, which in turn exacerbate hepatocyte cell death and contribute to the pathogenesis of ALD.

immunology↗