Biology subjects

Zhu, X.

Publications and source records attributed to Zhu, X..

At least 235 records · Page 13Linked to original sources

bioRxiv2022

DiffDomain enables identification of structurally reorganized topologically associating domains

Topologically associating domains (TADs) are critical structural units in three-dimensional genome organization of mammalian genome. Dynamic reorganizations of TADs between health and disease states are associated with transcription and other essential genome functions. However, computational methods that can identify reorganized TADs are still in the early stages of development. Here, we present DiffDomain, an algorithm leveraging high-dimensional random matrix theory to identify structurally reorganized TADs using chromatin contact maps. Method comparison using multiple real Hi-C datasets reveals that DiffDomain outperforms alternative methods for FPRs, TPRs, and identifying a new subtype of reorganized TADs. The robustness of DiffDomain and its biological applications are demonstrated by applying on Hi-C data from different cell types and disease states. Identified reorganized TADs are associated with structural variations and changes in CTCF binding sites and other epigenomic changes. By applying to a single-cell Hi-C data from mouse neuronal development, DiffDomain can identify reorganized TADs between cell types with reasonable reproducibility using pseudo-bulk Hi-C data from as few as 100 cells per condition. Moreover, DiffDomain reveals that TADs have differential cell-to-population variability and heterogeneous cell-to-cell variability. Therefore, DiffDomain is a statistically sound method for better comparative analysis of TADs using both Hi-C and single-cell Hi-C data.

bioinformatics↗

bioRxiv2022

An FcRn-targeted mucosal vaccine against SARS-CoV-2 infection and transmission

SARS-CoV-2 and its variants cause COVID-19, which is primarily transmitted through droplets and airborne aerosols. To prevent viral infection and reduce viral spread, vaccine strategies must elicit protective immunity in the airways. FcRn transfers IgG across epithelial barriers; we explore FcRn-mediated respiratory delivery of SARS-CoV-2 spike (S). A monomeric IgG Fc was fused to a stabilized S protein; the resulting S-Fc bound to S-specific antibodies (Ab) and FcRn. A significant increase in Ab responses was observed following the intranasal immunization of mice with S-Fc formulated in CpG as compared to the immunization with S alone or PBS. Furthermore, we intranasally immunize adult or aged mice and hamsters with S-Fc. A significant reduction of virus replication in nasal turbinate, lung, and brain was observed following nasal challenges with SARS-CoV-2, including Delta and Omicron variants. Intranasal immunization also significantly reduced viral transmission between immunized and naive hamsters. Protection was mediated by nasal IgA, serum-neutralizing Abs, tissue-resident memory T cells, and bone marrow S-specific plasma cells. Hence FcRn delivers an S-Fc antigen effectively into the airway and induces protection against SARS-CoV-2 infection and transmission. Based on these findings, FcRn-targeted non-invasive respiratory immunizations are superior strategies for preventing highly contagious respiratory viruses from spreading.

immunology↗

bioRxiv2022

Size-Dependent Transport of Cerebrospinal Fluid Tracers in Mouse Brain Observed by Dynamic Contrast-Enhanced MRI

Recent studies have suggested the glymphatic system as a key mechanism of waste removal in the brain. Dynamic contrast-enhanced MRI (DCE-MRI) using intracisternally administered contrast agents is a promising tool for assessing glymphatic function in the whole brain. In this study, we evaluated the transport kinetics and distribution of three MRI contrast agents with vastly different molecular sizes in mice. Our results demonstrate that oxygen-17 enriched water (H217O), which has direct access to parenchymal tissues via aquaporin-4 water channels, exhibited significantly faster and more extensive transport compared to the two gadolinium-based contrast agents (Gd-DTPA and GadoSpin). Time-lagged correlation and clustering analyses also revealed different transport pathways for Gd-DTPA and H217O. Furthermore, there were significant differences in transport kinetics of the three contrast agents to the lateral ventricles, reflecting the differences in forces that drive solute transport in the brain. These findings suggest the size-dependent transport pathways and kinetics of intracisternal contrast agents and the potential of DCE-MRI for assessing multiple aspects of solute transport in the glymphatic system.

neuroscience↗

bioRxiv2022

Complete functional analysis of type IV pilus components of a reemergent plant pathogen reveals neofunctionalization of paralog genes

Type IV pilus (TFP) is a multifunctional bacterial structure involved in twitching motility, adhesion, biofilm formation, as well as natural competence. Here, by mutagenesis and functional analysis, we dissected the roles of all genes required for TFP biosynthesis and regulation in the reemergent plant pathogenic fastidious prokaryote Xylella fastidiosa. This xylem-limited, insect-transmitted pathogen lives constantly under flow conditions and therefore is highly dependent on TFP for host colonization. In addition, TFP-mediated natural transformation is a process that impacts genomic diversity and environmental fitness. Ten out of the thirty-eight genes analyzed were essential for movement and natural competence. Interestingly, seven sets of paralogs exist, and mutations showed opposing phenotypes, indicating evolutionary neofunctionalization of subunits within TFP. The minor pilin FimT3 was the only protein exclusively required for natural competence. We determined that FimT3 (but not the other two FimT paralogs) is a DNA receptor that is conserved among X. fastidiosa strains and binds DNA non-specifically via an electropositive surface. Among plant pathogens, this gene was also found in the genome of strains of the plant associated Xanthomonadaceae family. Overall, we highlight here the complex regulation of TFP in X. fastidiosa, providing a blueprint to understand TFP in other bacteria living under flow conditions.

microbiology↗

bioRxiv2022

Searching across-cohort relatives via encrypted genotype regression

Explicitly sharing individual level data in genomics studies has many merits comparing to sharing summary statistics, including more strict QCs, common statistical analyses, relative identification and improved statistical power in GWAS, but it is hampered by privacy or ethical constraints. In this study, we developed encG-reg, a regression approach that can detect relatives of various degrees based on encrypted genomic data, which is immune of ethical constraints. The encryption properties of encG-reg are based on the random matrix theory by masking the original genotypic matrix without sacrificing precision of individual-level genotype data. We established a connection between the dimension of a random matrix, which masked genotype matrices, and the required precision of a study for encrypted genotype data. encG-reg has false positive and false negative rates equivalent to sharing original individual level data, and is computationally efficient when searching relatives. We split the UK Biobank into their respective centers, and then encrypted the genotype data. We observed that the relatives estimated using encG-reg was equivalently accurate with the estimation by KING, which is a widely used software but requires original genotype data. In a more complex application, we launched a finely devised multi-center collaboration across 5 research institutes in China, covering 9 cohorts of 54,092 GWAS samples. encG-reg again identified true relatives existing across the cohorts with even different ethnic backgrounds and genotypic qualities. Our study clearly demonstrates that encrypted genomic data can be used for data sharing without loss of information or data sharing barrier. Author SummaryEstimating pairwise genetic relatedness within a single cohort is straightforward. However, in practice, related samples are often distributed across different cohorts, making it challenging to estimate inter-cohort relatedness. In this study, we propose a method called encrypted genotype regression (encG-reg), which provides an unbiased estimation of inter-cohort relatedness using encrypted genotypes. The genotype matrix of each cohort is masked by a random matrix, which acts similarly to a private key in a cryptographic scheme. This masking process produces encrypted genotypes, which are a projection of the original genotype matrix. We derive the expectation and particularly the sampling variance for encG-reg, the latter involves eighth-order moments calculation. encG-reg allows us to accurately identify relatedness across cohorts, even for large-scale biobank data. To demonstrate the efficacy of encG-reg, we verified it in a multi-ethnicity UK Biobank dataset comprising 485,158 samples. For this case, we successfully tracked down to the 1st-degree relatedness (such as full sibs and parent-offspring). Furthermore, we used encG-reg in a collaboration involving 9 Chinese cohorts, encompassing a total of 54,092 samples from 5 genomic centers. It is worth noting that if the number of effective markers is sufficient encG-reg has the potential to detect even more distant degrees of relatedness beyond what we demonstrated.

genetics↗

bioRxiv2022

Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup

BackgroundThe cerebellum critically contributes to higher-order cognitive and emotional functions such fear learning and memory. Prior research on cerebellar volume in PTSD is scant and has neglected neuroanatomical subdivisions of the cerebellum that differentially map on to motor, cognitive, and affective functions. MethodsWe quantified cerebellar lobule volumes using structural magnetic resonance imaging in 4,215 adults (PTSD n= 1640; Control n=2575) across 40 sites from the from the ENIGMA-PGC PTSD working group. Using a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation, we obtained volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum total and subregional volume in PTSD compared to healthy controls. The Benjamini-Hochberg procedure was used to control the false discovery rate (p-FDR < .05). ResultsPTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume. In addition, people with PTSD showed reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), but also the vermis (VI, VIII), flocculonodular lobe (lobule X), and cerebellar white matter (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. ConclusionsThese findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in high-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

neuroscience↗

bioRxiv2022

Synaptojanin1 regulates lysosomal functions in ventral midbrain neurons

A major pathological hallmark of Parkinsons Disease (PD) is the manifestation of Lewy bodies comprised of alpha-synuclein (-syn). The accumulation of -syn enriched protein aggregates is thought to arise from dysfunction in degradation systems within the brain. Recently, missense mutations of SYNJ1 encoding the SAC1 and 5-phosphatase domains have been found in families with hereditary early-onset Parkinsonism. Previous studies showed that Synj1 haploinsufficiency (Synj1+/-) leads to PD-like behavioral and pathological changes in mice, including the accumulation of the autophagy substrate p62 and pathological -syn proteins in the midbrain (MB) and striatum. In this study, we aim to investigate the neuronal degradation pathway using the Synj1+/- MB culture as a model. Our data suggests that autophagy flux and cumulative autophagosome formation is unaltered at baseline in Synj1+/- MB neurons. However, lysosome number is reduced with a similar decrease in lysosomal proteins, including LAMP1, LAMP2, and LAMP2A. Lysosomes are hyperacidified with enhanced enzymatic activity in Synj1+/- MB neurons. Using a combination of light and electron microscopy, we show that lysosomal changes are primarily associated with a lack of SAC1 activity. Consistently, expressing the SYNJ1 R258Q mutant in N2a cells reduces the lysosome number. Interestingly, the lysosomal defects in Synj1+/- neurons does not impact the clearance of exogenously expressed wild-type -syn; however, the clearance of -syn A53T was impaired in the axons of Synj1+/- MB neurons. Taken together, our results suggest axonal vulnerability to lysosomal defects in Synj1 deficient MB neurons. Significance StatementIn the study, Zhu et al. discovered a previously uncharacterized role of Synj1 in regulating lysosomal number, protein, and acidity in ventral midbrain neurons. These alterations are associated with a specific impairment in the clearance of -syn A53T, but not WT -syn in axons, suggesting an essential role of Synj1 in axonal degradative capacity under pathological stress. This work in cultured mammalian neurons complements recent research efforts in Drosophila, C. elegans and zebra fish, and provides a novel insight for the role Synj1 in neuronal autolysosomal function.

neuroscience↗

bioRxiv2022

Iron Chelation Improves Ineffective Erythropoiesis and Iron Overload in Myelodysplastic Syndrome Mice

Myelodysplastic syndrome (MDS) is a heterogeneous group of bone marrow stem cell disorders characterized by ineffective hematopoiesis and cytopenias, most commonly anemia. Red cell transfusion therapy for anemia in MDS results in iron overload, correlating with reduced overall survival. Whether treatment of iron overload benefits MDS patients remains controversial. We evaluate underlying iron-related pathophysiology and the effect of iron chelation using deferiprone on erythropoiesis in NUP98-HOXD13 transgenic mice, a highly penetrant well-established MDS mouse model. Our results characterize an iron overload phenotype with aberrant erythropoiesis in these mice which was reversed by deferiprone-treatment. Serum erythropoietin level decreased while erythroblast erythropoietin receptor expression increased in deferiprone-treated MDS mice. We demonstrate, for the first time, normalized expression of the iron chaperones Pcbp1 and Nco4 and increased ferritin stores in late stage erythroblasts from deferiprone-treated MDS mice, evidence of aberrant iron trafficking in MDS erythroblasts. Importantly, erythroblast ferritin is increased in response to deferiprone, correlating with decreased erythroblast ROS. Finally, we confirmed increased expression of genes involved in iron uptake, sensing, and trafficking in stem and progenitor cells from MDS patients. Taken together, our findings provide evidence that erythroblast-specific iron metabolism is a novel potential therapeutic target to reverse ineffective erythropoiesis in MDS. BRIEF SUMMARYIneffective erythropoiesis in MDS mice correlates with aberrant iron trafficking within bone marrow erythroblasts, consistent with findings in MDS patient progenitors, reversed after iron chelation.

pathology↗

bioRxiv2022

Perturbation of mitochondrial Ca2+ homeostasis activates cross-compartmental proteostatic response in Arabidopsis

Mitochondrial Ca2+ (mtCa2+) homeostasis is essential to mitochondrial functions. However, how mtCa2+ homeostasis is achieved and the consequences of impaired mtCa2+ homeostasis in plants is poorly understood. Here, we demonstrate a critical role for mitochondrial Ca2+ uniporter (MCU) in the control of mtCa2+ uptake for mtCa2+ homeostasis in planta by characterizing MCU mutants and overexpressed plants. Impaired MCU-controlled mtCa2+ homeostasis (iMUCH) in gain-of-function and loss-of-function MCU plants causes the misregulation of mitochondrial gene expression that triggers mitonuclear protein imbalance. Transcriptome integrated with proteomics analysis reveal activation of multiple compartmental UPR gene expression and decrease of cytosolic translation with selective repression of ribosome and RNA modification protein synthesis upon iMUCH. Intriguingly, TOR signalling is not involved in cytosolic translational response to iMUCH, but the reduction of eIF phosphorylation is evident under iMUCH induced mitochondrial stress. Thus, our study unveils the essential functions of MCU proteins for mtCa2+ homeostasis, and the involvement of MCU-controlled mtCa2+ homeostasis in mitochondrial stress dependent regulation of protein synthesis for cellular proteostasis that is connected to plant growth and stress resistance.

plant biology↗

bioRxiv2022

Alternative mRNA polyadenylation bridges mitochondrion-to-nucleus communication in Arabidopsis

Mitochondria produce signals besides energy and metabolites that influence plant growth and fitness. However, how mitochondrial signals are relayed to other cellular compartments is largely unknown. By applying poly(A)-site RNA-sequencing (PAS-seq) to wildtype Arabidopsis seedlings and a mutant in the histone demethylase JMJ30 treated with the mitochondrial electron transfer chain inhibitor antimycin A (AA), we identified a previously undefined mitochondrion-to-nucleus communication pathway by which mitochondrial functional state regulates co-transcriptionally alternative polyadenylation (APA) of nuclear mRNA. We observed a global shortening of 3' untranslated regions (UTRs) as a molecular signature of AA-activated mitochondrial retrograde response (MRR), which contributed in part to translational regulation of auxin response and cell wall biogenesis. JMJ30 regulated AA-induced 3' UTR shortening, resulting in more transcripts with shortened 3' UTRs upon AA treatment in a JMJ30 gain-of-function mutant and overexpression lines. We also report on the JMJ30-interacting protein CPSF30, a cleavage and polyadenylation specificity factor that recruits JMJ30 to modulate H3K27me3 status at its target loci. Our study illustrates how epigenetic modification and APA coordinate mitochondrion-to-nucleus communication to allow cells to rapidly respond to changes in mitochondrial functional state and shape plant growth and fitness. One-sentence summaryEpigenetic modification and APA coordinate mitochondrion-to-nucleus communication to allow cells to rapidly respond to changes in mitochondrial functional state and shape plant growth and fitness.

molecular biology↗

bioRxiv2022

FRIZZLED 2 regulates limb development by mediating both β-catenin-dependent and independent Wnt signaling pathways

Human Robinow Syndrome and omodysplasia, characterized by skeletal limb and craniofacial defects, are associated with mutations in the Wnt receptor FZD2. However, as FZD2 can activate both canonical and non-canonical Wnt pathways, its precise functions and mechanisms of action in limb development are unclear. To address these questions, we generated mice harboring a single nucleotide insertion in the Dishevelled-interacting domain of Fzd2 (Fzd2em1Smill), causing a frameshift mutation similar to the effects of human syndromic FZD2 mutations. Fzd2em1Smill mutant mice had shortened limbs resembling those of Robinow Syndrome and omodysplasia patients. Fzd2em1Smill mutant embryos displayed decreased canonical Wnt signaling in developing limb mesenchyme and disruption of digit chondrocyte elongation and orientation, which is controlled by the WNT5A/PCP pathway. In line with this, we found that tissue-specific disruption of Fzd2 function in limb mesenchyme caused formation of shortened bone elements and was associated with deficiency in both Wnt/{beta}-catenin and WNT5A/PCP signaling. These findings indicate that FZD2 controls limb development by mediating both canonical and non-canonical Wnt pathways and reveal causality of pathogenic FZD2 mutations in Robinow Syndrome and omodysplasia patients. Summary statementHuman FZD2 mutations are associated with limb defects; using genetic mouse models we revealed causality of these mutations and showed that they disrupt both canonical and non-canonical Wnt signaling.

developmental biology↗

bioRxiv2022

Genetic effects of sequence-conserved enhancer-like elements on human complex traits

Non-coding sequences that are evolutionarily conserved and bio-chemically active offer clues to mechanistic interpretations of human genome-wide association studies (GWAS). However, their genetic effects have not been systematically examined across a wide range of human tissues and traits. Here we develop a simple method to identify functional elements exhibiting high levels of human-mouse sequence conservation and enhancer-like biochemical activity, which scales well to 313 epigenomic datasets across 106 tissues and cell types. Combining these elements with 468 GWAS of European (EUR) and East Asian (EAS) ancestries, we identify tissue-specific enrichments of heritability and causal variants for many traits, as well as candidate genes that are functionally relevant to body mass index (BMI) and schizophrenia but were not reported in previous GWAS. Our findings provide a comprehensive assessment of how sequence-conserved enhancer-like elements affect complex traits, and reinforce the importance of integrating evolutionary and biochemical data to elucidate human disease genetics.

genomics↗

bioRxiv2022

Coevolution-based prediction of key allosteric residues for protein function regulation

Allostery is fundamental to many biological processes. Due to the distant regulation nature, how allosteric mutations, modifications and effector binding impact protein function is difficult to forecast. In protein engineering, remote mutations cannot be rationally designed without large scale experimental screen. Allosteric drugs have raised much attention due to their high specificity and possibility of overcoming existing drug-resistant mutations. However, optimization of allosteric compounds remains challenging. Here, we developed a novel computational method KeyAlloSite to predict allosteric site and to identify key allosteric residues (allo-residues) based on the evolutionary coupling model. We found that protein allosteric sites are strongly coupled to orthosteric site compared to non-functional sites. We further inferred key allo-residues by pairwise comparing the difference of evolutionary coupling scores of each residue in the allosteric pocket with the functional site. Our predicted key allo-residues are in accordance with previous experimental studies for typical allosteric proteins like BCR-ABL1, Tar and PDZ3, as well as key cancer mutations. We also showed that KeyAlloSite can be used to predict key allosteric residues distant from the catalytic site that are important for enzyme catalysis. Our study demonstrates that weak coevolutionary couplings contain important information of protein allosteric regulation function. KeyAlloSite can be applied in studying the evolution of protein allosteric regulation, designing and optimizing allosteric drugs, performing functional protein design and enzyme engineering.

biochemistry↗

bioRxiv2022

The Piks allele of the NLR immune receptor Pik breaks the recognition of AvrPik effectors of the rice blast fungus

Arms race co-evolution of plant-pathogen interactions evolved sophisticated recognition mechanisms between host immune receptors and pathogen effectors. Different allelic haplotypes of an immune receptor in host mount distinct recognition against sequence or non-sequence related effectors in pathogens. We report the molecular characterization of the Piks allele of the rice immune receptor Pik against rice blast pathogen, which requires two head-to-head arrayed nucleotide binding site and leucine-rich repeat proteins. Like other Pik genes, both Piks-1 and Piks-2 are necessary and sufficient for Piks-mediated resistance. However, unlike other Pik alleles, Piks does not recognize any known AvrPik variants of M. oryzae. Sequence analysis of the genome of an avirulent isolate V86010 further revealed that its cognate avirulence (Avr) gene most likely has no significant sequence similarity to known AvrPik variants. We conclude that Piks breaks the canonical Pik/AvrPik recognition pattern. Piks-1 and Pikm-1 have only two amino acid differences within the integrated heavy metal-associated (HMA) domain. Pikm-1-HMA interact with AvrPik-A, -D and -E in vitro and in vivo, whereas Piks-1-HMA does not bind any AvrPik variants. Reciprocal exchanges of single amino acid residues between Piks-1 and Pikm-1 further reveal a dynamic recognition mechanism between Piks/Pikm alleles and their respective effectors. Piks-1E229Q/Pikm-1V261A can only activate immunity to AvrPik-D but not to other effectors, indicating that the amino acid change of E to Q at position 229 leads to its gain of a partial recognition spectrum of Pikm. By contrast, Piks-1A261V/Pikm-1Q229E confers immunity to the Piks cognate effector, indicating that the amino acid change of Q to E at position 229 leads to its shifts of the recognition from Pikm to Piks. Intriguingly, binding activities in both Y2H and analytical gel filtration assays are illustrated between Piks-1A261V/Pikm-1Q229E and AvrPik-D. However, it is unable to mount immunity against AvrPik-D, suggesting that biochemical activities based on in vitro and in vivo assays could be insufficient for sustaining biological function of receptor and effector pairs.

plant biology↗

bioRxiv2022

FOXP2 confers oncogenic effects in prostate cancer through activating MET signalling

Identification oncogenes is fundamental to revealing the molecular basis of cancer. Here, we found that FOXP2 is overexpressed in human prostate cancer cells and prostate tumors, but its expression is absent in normal prostate epithelial cells and low in benign prostatic hyperplasia. To date, little is known regarding the link of FOXP2 to prostate cancer. We observed that high FOXP2 expression and frequent amplification are significantly associated with high Gleason score. Ectopic expression of FOXP2 induces malignant transformation of mouse NIH3T3 fibroblasts and human prostate epithelial cell RWPE-1. Conversely, FOXP2 knockdown suppresses the proliferation of prostate cancer cells. Transgenic overexpression of FOXP2 in the mouse prostate causes prostatic intraepithelial neoplasia. Overexpression of FOXP2 aberrantly activates oncogenic MET signalling and inhibitors targeting MET signalling effectively reverts the FOXP2-induced oncogenic phenotype. Additionally, the novel recurrent FOXP2-CPED1 fusion identified in prostate tumors results in high expression of truncated FOXP2, which exhibit a similar capacity for malignant transformation. Together, our data demonstrate for the first time that FOXP2 is an oncogene involved in tumorigenicity of prostate.

cancer biology↗

bioRxiv2022

Intestinal Epithelial Heat Shock Protein 25/27 integrates host and microbial drivers of mucosal restitution following inflammatory injury

Mucosal healing following inflammatory injury is poorly understood and often neglected, despite being the best indicator of long-term outcomes in inflammatory bowel diseases. We report here that the enigmatic small molecular weight heat shock protein, Hsp25 (the human form is Hsp27), plays a vital role in converging microbial and host factors to promote pSTAT3-mediated mucosal healing. In wild type mice, the proximal-to-distal gradient of intestinal epithelial cell (IEC) Hsp25 expression is dependent on microbial cues. Patients with left-sided ulcerative colitis, however, show reduced levels of Hsp27 expression in both uninvolved and involved areas compared to normal colons of non-IBD patients. In mice with global or IEC-specific Hsp25 gene-targeted deletion, impaired mucosal healing with development of hallmarks of chronic disease are observed following DSS-induced or TNBS-induced colitis, whereas mucosal restitution is accelerated in IEC-specific overexpressing Hsp25 transgenic mice. In colonic IECs derived from these murine lines, Hsp25 binds and stabilizes a phospho-STAT3/YAP nuclear complex stimulated by IL-22 to sustain its wound healing gene programming. Thus, our findings provide insight into the mechanism of action of IEC Hsp25/27 in integrating host and microbial drivers of mucosal restitution, which can be leveraged to develop novel approaches for achieving and maintaining remission in complex immune disorders like IBD.

pathology↗

bioRxiv2022

Constraints of vigilance-dependent noradrenergic signaling to mouse cerebellar Bergmann glia

Behavioral state plays an important role in determining astroglia Ca2+ signaling. In particular, locomotion-mediated elevated vigilance has been found to trigger norepinephrine-dependent whole cell Ca2+ elevations in astroglia throughout the brain. For cerebellar Bergmann glia it has recently been found that locomotion-induced transient Ca2+ elevations depend on their 1A-adrenergic receptors. With increasing availability and implementation of locomotion as behavioral parameter it becomes important to understand the constraints of noradrenergic signaling to astroglia. Here we evaluated the effect of speed, duration and interval of locomotion on Ca2+ signals in Bergmann glia as well as cerebellar noradrenergic axon terminals. We found almost no dependence on locomotion speed, but following the initial Ca2+ transient prolonged locomotion events revealed a steady-state Ca2+ elevation. Comparison of time course and recovery of transient Bergmann glia and noradrenergic terminal Ca2+ dynamics suggested that noradrenergic terminal Ca2+ activity determines Bergmann glia Ca2+ activation and does not require noradrenergic receptor desensitization to account for attenuation during prolonged locomotion. Further, analyzing the correlation among Ca2+ dynamics within regions within the field of observation we found that coordinated activity among noradrenergic terminals accounts for fluctuations of steady-state Bergmann glia Ca2+ activity. Together, our findings will help to better understand astroglia Ca2+ dynamics during less controlled awake behavior and may guide the identification of behavioral contexts preferably dependent on astroglia Ca2+ signaling.

neuroscience↗

bioRxiv2022

The adipose-neural axis is critically involved in cardiac arrhythmias

Dysfunction of the sympathetic nervous system and increase of epicardial adipose tissue (EAT) have been independently associated with the occurrence of cardiac arrhythmia. However, their exact roles in triggering arrhythmia remain elusive due to a lack of appropriate human disease models. Here, using the in vitro co-culture system with sympathetic neurons, cardiomyocytes, and adipocytes, we show that adipocyte-derived leptin could activate sympathetic neurons and increase the release of NPY, which in turn trigger arrhythmia of cardiomyocytes by interaction with NPY1R and subsequently enhancing the activity of NCX and CaMKII. The arrhythmic phenotype could be partially blocked by leptin neutralizing antibody, or an inhibitor of NPY1R, NCX or CaMKII. More importantly, increased EAT thickness accompanied with higher leptin/NPY blood levels was detected in atrial fibrillation patients compared to control group. Our study provides the first evidence that adipose-neural axis would contribute to arrhythmogenesis and represent a potential therapeutic target for arrhythmia.

cell biology↗