Biology subjects

Zheng, C.

Publications and source records attributed to Zheng, C..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

GlioME: A Novel Organoid Model Retaining the Glioma Mi-croenvironment for Personalized Drug Screening and Thera-peutic Evaluation

Glioma is an aggressive brain tumor with a poor prognosis. Establishing an in vitro culture model that closely replicates the cellular composition and microenvironment of the original tumor has been challenging, limiting its clinical applications. Here, we present a novel approach to generate glioma organoids with a microenvironment (GlioME) from patient-derived glioma tissue. These organoids maintain the genetic and epigenetic characteristics of the primary tumor and preserve cell-to-cell interactions within the tumor microenvironment, including resident immune cells. Bulk RNA sequencing, whole exome sequencing, and DNA methylation analysis were used to confirm the molecular similarities between the organoids and primary glioma tissues. Immunofluorescence and flow cytometry were used to assess immune cell viability, comparing GlioME with floating glioma organoids. GlioME exhibited high responsiveness to chemotherapy and targeted therapy, demonstrating its potential for therapeutic screening applications. Notably, GlioME accurately predicted patient response to the recently approved MET inhibitor, vebreltinib. Thus, this organoid model provides a reliable in vitro platform for glioma microenvironment-related research and clinical drug screening.

cancer biology↗

bioRxiv2024

A small molecule enhances arrestin-3 binding to the β2-adrenergic receptor

G protein-coupled receptor (GPCR) signaling is terminated by arrestin binding to a phosphorylated receptor. Binding propensity has been shown to be modulated by stabilizing the pre-activated state of arrestin through point mutations or C-tail truncation. Here, we hypothesize that pre-activated rotated states can be stabilized by small molecules, and this can promote binding to phosphorylation-deficient receptors, which underly a variety of human disorders. We performed virtual screening on druggable pockets identified on pre-activated conformations in Molecular Dynamics trajectories of arrestin-3, and found a compound targeting an activation switch, the back loop at the inter-domain interface. According to our model, consistent with available biochemical and structural data, the compound destabilized the ionic lock between the finger and the back loop, and enabled transition of the gate loop towards the pre-activated state, which stabilizes pre-activated inter-domain rotation. The predicted binding pocket is consistent with saturation-transfer difference NMR data indicating close contact between the piperazine moiety of the compound and C/finger loops. The compound increases in-cell arrestin-3 binding to phosphorylation-deficient and wild-type {beta}2-adrenergic receptor, but not to muscarinic M2 receptor, as verified by FRET and NanoBiT. This study demonstrates that the back loop can be targeted to modulate interaction of arrestin with phosphorylation-deficient GPCRs in a receptor-specific manner.

cell biology↗

bioRxiv2024

Retrotransposon LINE1 trans-regulatory differentiation process maintain embryonic stem cell identity

Long Interspersed Nuclear Elements-1s (LINE1s) are one of the >17% most abundant Retrotransposons in mammalian genomes. LINE1 RNA is high expression during early embryonic development, meanwhile is under tight epigenetic control. Some studies have confirmed LINE1 play a critical role in early embryo development and ESC identity. Previous studies focused on the role of LINE1 in cis-regulation, however, the function of L1 RNA in tans-regulation remains largely unknown. In this study, we performed a high-throughput proximity MARGI (pxMARGI) experiment found transposon LINE1 RNA trans-regulated prefer to young LINE1 subfamily, and in hybrid and non-hybrid two different manner repress ESC to dual progress of 2C-like cells and differentiation. In differentiation process, LINE1 RNA as a scaffold recruit polycomb core subunits combine three core pluripotent factors maintain ESC identity. In 2C process, LINE1 RNA in a sequence-specific manner recruit Kap1 to old L1 subfamily, and recruit ELL3 to RE 5 UTR maintain ESC self-renewal. Our data point to LINE1 transcriptions more detail trans-regulation mechanism to orchestrate developmental progression for the self-renewal of embryonic stem cells (ESCs). LINE1 RNA may be potential biomarker for noninvasive embryo selection.

genomics↗

bioRxiv2024

Continuous sensorimotor transformation enhances robustness of neural dynamics to perturbation in macaque motor cortex

Neural activity in the motor cortex dynamically evolves to plan and generate movement. How motor cortex adapts to dynamic environments or perturbations remains to be fully explored. In this study, we investigated whether dynamic nature of targets in a reach task requires distinct preparatory dynamics in motor cortex and result in varying levels of robustness against disruptions. Two monkeys were trained to perform delayed center-out reaches either to a static target (static condition) or a rotating target that needed to be intercepted (moving condition). Despite nearly identical hand kinematics in both two conditions, responses to the perturbation of intracortical microstimulation (ICMS) differed. In the static condition, ICMS led to prolonged reaction times, particularly when delivered shortly before movement onset and at anterior sites in PMd, aligning with previous findings. Unexpectedly, ICMS reduced reaction times in the moving condition. Furthermore, neural firing rates differed between the static and the moving conditions, with population activity in the latter exhibiting more rapid changes post-perturbation. Spatio-temporal sensorimotor transformation dominated throughout the preparation in the moving condition, while the static condition showed less stable motor intention representation, particularly during the late delay period. An input-driven model replicated the differences in RT-prolonging effect by assuming distinct input control strategy for the static and the moving condition. These findings suggest that input from a moving target to motor cortex can counteract ICMS effects, enabling the motor network to generate appropriate commands more quickly. Lastly, we propose that ICMS may facilitate go cue recognition, providing a potential explanation for the shortened reaction times in the moving condition.

neuroscience↗

bioRxiv2024

Zika virus NS3 drives the assembly of a viroplasm-like structure

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that caused an epidemic in 2015-2016 in the Americas and raised serious global health concerns due to its association with congenital brain developmental defects in infected pregnancies. Upon infection, ZIKV assembles virus particles in a virus-generated toroidal compartment next to the nucleus called the replication factory, or viroplasm, which forms by remodeling the host cell endoplasmic reticulum (ER). How the viral proteins control viroplasm assembly remains unknown. Here we show that the ZIKV non-structural protein 3 (NS3) is sufficient to drive the assembly of a viroplasm-like structure (VLS) in human cells. NS3 encodes a dual-function protease and RNA helicase. The VLS is similar to the ZIKV viroplasm in its assembly near centrosomes at the nuclear periphery, its deformation of the nuclear membrane, its recruitment of ER, Golgi, and dsRNA, and its association with microtubules at its surface. While sufficient to generate a VLS, NS3 is less efficient in several aspects compared to viroplasm formation upon ZIKV infection. We further show that the helicase domain and not the protease domain is required for optimal VLS assembly and dsRNA recruitment. Overall, this work advances our understanding of the mechanism of viroplasm assembly by ZIKV and likely will extend to other flaviviruses. ImportanceThe Zika virus replicates its genome and assembles virus particles in the cytoplasm within the replication organelle, a large virus-induced compartment also called the viroplasm. It does this in part by remodeling the endoplasmic reticulum. However, how the virus directs the host cell to assemble the viroplasm is mostly unknown. This study shows that Zika virus non-structural protein 3 (NS3) is sufficient to assemble a viroplasm-like structures, and indicates that NS3 has a central role in assembling the viroplasm. Understanding how the virus assembles the viroplasm compartment and NS3s role in it should significantly advance our understanding of the cellular mechanisms of virus infection. This study aims to gain more understanding of the Zika virus and its viroplasm along with the molecular mechanisms for viroplasm assembly which might be shared by other viruses.

cell biology↗

bioRxiv2024

TAF1-dependent transcriptional dysregulation underlies multiple sclerosis

A major conceptual and clinical challenge in multiple sclerosis (MS) is understanding the mechanisms that drive the central nervous system (CNS)-resident neuroinflammation and neurodegeneration underneath disease progression. Genome-wide association studies (GWAS) have implicated RNA polymerase II (RNAPII) promoter-proximal pausing in oligodendrocyte pathology, but the causal mechanisms remain unclear. Here we find that the C-terminal region of TAF1, a core component of the general transcription factor TFIID, is underdetected in progressive MS brains, which can be explained by endoproteolysis due to extralysosomal cathepsin B (CTSB). Mice lacking the C-terminal TAF1 domain (Taf1d38) exhibit MS-like brain transcriptomic signature, alongside CNS-resident inflammation, progressive demyelination, and motor disability. Mechanistically, C-terminal TAF1 interacts with MS-linked factors that cooperate to regulate RNAPII pausing, particularly affecting oligodendroglial myelination genes. These findings uncover a previously unrecognized transcriptional mechanism underlying MS progression and establish a tractable in vivo model for therapeutic development.

neuroscience↗

bioRxiv2024

Single-cell analysis of the somatic mutational landscape in human chondrocytes during aging and in osteoarthritis

Somatic mutation is now recognized as a cause of multiple human diseases other than cancer. Osteoarthritis (OA), a highly prevalent age-related disease, has been associated with increased chromosomal abnormalities in articular cartilage of OA patients. Thus far no systematic attempt has been made to characterize the somatic mutational landscape of chondrocytes during normal aging and in affected cartilage of OA patients. Here we used single-cell whole genome sequencing to quantitatively analyze single-nucleotide variants (SNVs) and small insertions and deletions (InDels) in 100 single chondrocytes isolated from the cartilage of hip femoral heads of 17 subjects aged from 26 to 90 years, including 9 OA patients and 8 non-OA donors. Both SNVs and InDels were found to accumulate with age in chondrocytes with a clock-like mutational signature. Surprisingly, the age-related accumulation rate of these mutations was found to be lower in OA chondrocytes compared with chondrocytes from non-OA control subjects.

genomics↗

bioRxiv2024

PRISM: Multiplexed Profiling of RNA In-Situ through Single-round of Imaging in Three-Dimensional Tissue

Spatial RNA imaging has not been widely adopted because conventional fluorescence microscopy is limited to only a few channels, and the cyclic reactions needed to increase multiplexing in techniques such as sequential fluorescence in-situ hybridization (FISH) require sophisticated instrumentation. Here, we introduce Profiling of RNA In-situ through Single-round iMaging (PRISM), a method that expands coding capacity through color intensity grading. Using a radius vector filtering strategy to ensure the distinguishability of codewords in color space, PRISM achieves up to 64-plex color-barcoded RNA imaging in a single imaging round with conventional microscopes. We validate PRISMs versatility across various tissues by generating a 3D atlas of mouse embryonic development from E12.5 to E14.5, a quasi-3D tumor-normal transition landscape of human hepatocellular carcinoma (HCC), and a 3D cell atlas and subcellular RNA localization landscapes of mouse brain. Additionally, we show the critical role of cancer-associated fibroblasts (CAFs) in mediating immune infiltration and immune response heterogeneity within and between tumor microenvironments.

bioengineering↗

bioRxiv2024

A distinct isoform of Msp300/Nesprin organizes the perinuclear microtubule organizing center in adipose cells

In many cell types, disparate non-centrosomal microtubule-organizing centers (ncMTOCs) replace functional centrosomes and serve the unique needs of the cell types in which they are formed. In Drosophila fat body cells (adipocytes), an ncMTOC is organized on the nuclear surface. This perinuclear ncMTOC is anchored by Msp300, encoded by one of two nesprin-encoding genes in Drosophila. Msp300 and the spectraplakin short stop (shot) are co-dependent for localization to the nuclear envelope to generate the ncMTOC where they recruit the microtubule minus-end stabilizer Patronin (CAMSAP). The Msp300 gene is complex, encoding at least eleven isoforms. Here we show that two Msp300 isoforms, Msp300-PE and -PG, are required and only one, Msp300-PE, appears sufficient for generation of the ncMTOC. Loss of Msp300-PE and -PG results in severe loss of localization of shot and Patronin, disruption of the MT array, nuclear mispositioning and loss of endosomal trafficking. Furthermore, upon loss of Msp300-PE and -PG, other isoforms are retained at the nuclear surface despite the loss of nuclear positioning and MT organization, indicating that they are not sufficient to generate the ncMTOC. Msp300-PE has an unusual domain structure including a lack of a KASH domain and very few spectrin repeats and appears therefore to have a highly derived function to generate an ncMTOC on the nuclear surface.

cell biology↗

bioRxiv2024

High IL-1β and IL-18 Levels Associate with Gut Barrier Disruption and Monocyte Activation During Chronic SIV Infection with Long-Term Suppressive Antiretroviral Therapy

HIV-induced persistent immune activation is a key mediator of inflammatory comorbidities such as cardiovascular disease (CVD) and neurocognitive disorders. While a preponderance of data indicate that gut barrier disruption and microbial translocation are drivers of chronic immune activation, the molecular mechanisms of this persistent inflammatory state remain poorly understood. Here, utilizing the nonhuman primate model of HIV infection with suppressive antiretroviral therapy (ART), we investigated activation of inflammasome pathways and their association with intestinal epithelial barrier disruption and CVD pathogenesis. Longitudinal blood samples obtained from rhesus macaques with chronic SIV infection and long-term suppressive ART were evaluated for biomarkers of intestinal epithelial barrier disruption (IEBD), inflammasome activation (IL-1{beta} and IL-18), inflammatory cytokines, and triglyceride (TG) levels. Activated monocyte subpopulations and glycolytic potential were investigated in peripheral blood mononuclear cells (PBMCs). Higher plasma levels of IL-1{beta} and IL-18 were observed following the hallmark increase in IEBD biomarkers, intestinal fatty acid-binding protein (IFABP) and LPS-binding protein (LBP), during the chronic phase of treated SIV infection. Further, significant correlations of plasma IFABP levels with IL-1{beta} and IL-18 were observed between 10-12 months of ART. Higher levels of sCD14, IL-6, and GM-CSF, among other inflammatory mediators, were also observed only during the long-term SIV+ART phase along with a trend of increase in frequencies of activated CD14+CD16+ intermediate monocyte subpopulations. Lastly, we found elevated levels of blood TG and higher glycolytic capacity in PBMCs of chronic SIV-infected macaques with long-term ART. The increase in circulating IL-18 and IL-1{beta} following IEBD and their significant positive correlation with IFABP suggest a connection between gut barrier disruption and inflammasome activation during chronic SIV infection, despite viral suppression with ART. Additionally, the increase in markers of monocyte activation, along with elevated TG and enhanced glycolytic pathway activity, indicates metabolic remodeling that could accelerate CVD pathogenesis. Further research is needed to understand mechanisms by which gut dysfunction and inflammasome activation contribute to HIV-associated CVD and metabolic complications, enabling targeted interventions in people with HIV.

immunology↗

bioRxiv2024

Detection of Nontoxic BoNT/A Levels in Post-Facial Botox Injection Breastmilk using a Multi-technique Approach

BackgroundThe use of cosmetic Botox (Botulinum Neurotoxin Type A, BoNT/A ) has become increasingly prevalent. Particularly after pregnancy, postpartum depression represents one major factor motivating women to use Botox even during the lactation and breastfeeding period. Currently, there is limited understanding of the impact of Botox on lactation and the potential of its active component passing into breastmilk and affecting the infant. MethodsBreastmilk samples were acquired from five women aged between 28 - 45 through a clinic in Suzhou, Jiangsu, P.R. China. Three sample sets ranged from 1 hour to 1 year after facial Botox treatments (64 U), whereas the remaining two sample sets were from women who never received Botox treatment. BoNT/A concentrations in samples were detected using standard Enzyme-Linked Immunosorbent Assay (ELISA), unreduced and reduced Western Blotting, confocal micro-Raman Spectroscopy, and Mass Spectrometry(LC-MS). FindingsFrom ELISA, breastmilk BoNT/A concentrations peaked at 33.4 pg/mL 4 days after Botox injection. BoNT/A concentrations were highest overall in the first week and around two months after injection. While non-reducing polyacrylamide gel electrophoresis (PAGE) showed a protein band of 150 kDa peaking at 48 hours, reduced SDS-PAGE detected a 100 kDa protein first peaking at 72 hours, then re-emerging after 7 days, respectively, and in line with previous observations by others. Interestingly, micro-Raman spectroscopy indicated additional Raman peaks at 6 hours and 48 hours that were not present in other breastmilk samples which were evaluated in this study. However, no clear indication of BoNT/A was detected in Mass Spectrometry (LC-MS). InterpretationThe amount of BoNT/A in breastmilk peaks around 48 hours, and at 2 months after facial injection. Even over a year after injection, BoNT/A can be detected. However, all quantities of BoNT/A detected in this study are highly likely to be safe for infants. Additionally, our study suggests that alternative methods, besides ELISA, may be utilized for the rapid detection of low concentrations of BoNT/A in body fluid samples. FundingDuke Kunshan University Start-Up funds, Duke Kunshan University Undergraduate Studies Signature Work Research Grant, Synear and Wang-Cai Biochemistry grants, and Kunshan Municipal Government research funding. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/595434v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@fcdd11org.highwire.dtl.DTLVardef@11591daorg.highwire.dtl.DTLVardef@11ab30eorg.highwire.dtl.DTLVardef@1e19311_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIBoNT/A was detected in the breastmilk of 3 women after facial Botox injections of 64 U. C_LIO_LIToxin levels peaked in the first week and at around 2 months after injection. C_LIO_LIAll detected levels (up to 33.40 pg/mL) were significantly below the lethal dose for newborns. C_LI

molecular biology↗

bioRxiv2024

MBL-1/Muscleblind regulates neuronal differentiation and controls the splicing of a terminal selector in Caenorhabditis elegans

The muscleblind family of mRNA splicing regulators is conserved across species and regulate the development of muscles and the nervous system. However, how Muscleblind proteins regulate neuronal fate specification and neurite morphogenesis at the single-neuron level is not well understood. In this study, we found that the C. elegans Muscleblind/MBL-1 promotes axonal growth in the touch receptor neurons (TRNs) by regulating microtubule stability and polarity. Transcriptomic analysis identified dozens of MBL-1-controlled splicing events in genes related to neuronal differentiation or microtubule functions. Among the MBL-1 targets, the LIM-domain transcription factor mec-3 is the terminal selector for the TRN fate and induces the expression of many TRN terminal differentiation genes. MBL-1 promotes the splicing of the mec-3 long isoform, which are essential for TRN fate specification, and inhibits the short isoforms that have much weaker activities in activating downstream genes. MBL-1 promotes mec-3 splicing through three "YGCU(U/G)Y" motifs located downstream of the included exon, which is similar to the mechanisms used by mammalian Muscleblind and suggests a deeply conserved context-dependency of the splicing regulation. Interestingly, the expression of mbl-1 in the TRNs is dependent on the mec-3 long isoform, indicating a positive feedback loop between the splicing regulator and the terminal selector. Finally, through a forward genetic screen, we found that MBL-1 promotes neurite growth partly by inhibiting the DLK-1/p38 MAPK pathway. In summary, our study provides mechanistic understanding of the role of Muscleblind in regulating cell fate specification and neuronal morphogenesis.

developmental biology↗

bioRxiv2024

Dynamic Gamma Modulation of Hippocampal Place Cells Predominates Development of Theta Sequences

The experience-dependent spatial cognitive process requires sequential organization of hippocampal neural activities by theta rhythm, which develops to represent highly compressed information for rapid learning. However, how the theta sequences were developed in a finer time scale within theta cycles remains unclear. In this study, we found that sweep-ahead structure of theta sequences developing with exploration was predominantly dependent on a relatively large proportion of FG-cells, i.e. a subset of place cells dominantly phase-locked to fast gamma rhythms. These ensembles integrated compressed spatial information by cells consistently firing at precessing slow gamma phases within the theta cycle. Accordingly, the sweep-ahead structure of FG-cell sequences was positively correlated with the intensity of slow gamma phase precession, in particular during early development of theta sequences. These findings highlight the dynamic network-modulation by fast and slow gamma in the development of theta sequences which may further facilitate memory encoding and retrieval.

neuroscience↗

bioRxiv2024

In-depth investigation of the mechanisms of high and low residual feed intake regulating hens during the late laying period via liver and gut microbiota.

Residual feed intake (RFI) is a more accurate indicator of feed efficiency than the feed conversion ratio (FCR) and is widely used to measure the efficiency of livestock and poultry feed utilization. Typically, Low RFI (LRFI) implies higher feed conversion efficiency, while high RFI (HRFI) indicates lower feed conversion efficiency. This study systematically explored the differences between high and low RFI and the function of the liver and cecum microbes of hens during the late laying period by multiple-omics techniques and further explored the interaction among microorganisms, the function of tissues and organs, and body metabolism. The results showed that the length and mass of the digestive organs in the LRFI group were higher than those in the HRFI group as well as the chest width. Additionally, the key genes and metabolites regulating RFI in hens during the late laying phase were found to be ADCY2, ADCY8, CCKAR, ACSS2, FABP1, FABP4, and LysoPI (18:2(9Z,12Z)/0:0) in the liver. The levels of AST, HDL-C and ACTH in the serum were considered candidate markers influencing RFI. By conducting a microbiome-metabolome association analysis, we have identified the dominant and beneficial microbial community in the gut of LRFI groups, such as Oscillospirales, Ruminococcaceae, and Butyricicoccaceae, which offers a theoretical basis for understanding how the gut microbiota regulates RFI. These results will provide a scientific basis for the molecular mechanism of RFI phenotypic variation in late laying hens.

microbiology↗

bioRxiv2024

Editing of endogenous tubulins reveals varying effects of tubulin posttranslational modifications on axonal growth and regeneration

Tubulin posttranslational modifications (PTMs) modulate the dynamic properties of microtubules and their interactions with other proteins. However, the effects of tubulin PTMs were often revealed indirectly through the deletion of modifying enzymes or the overexpression of tubulin mutants. In this study, we directly edited the endogenous tubulin loci to install PTM-mimicking or -disabling mutations and studied their effects on microtubule stability, neurite outgrowth, axonal regeneration, cargo transport, and sensory functions in the touch receptor neurons of Caenorhabditis elegans. We found that the status of {beta}-tubulin S172 phosphorylation and K252 acetylation strongly affected microtubule dynamics, neurite growth, and regeneration, whereas -tubulin K40 acetylation had little influence. Polyglutamylation and detyrosination in the tubulin C-terminal tail had more subtle effects on microtubule stability likely by modulating the interaction with kinesin-13. Overall, our study systematically assessed and compared several tubulin PTMs for their impacts on neuronal differentiation and regeneration and established an in vivo platform to test the function of tubulin PTMs in neurons.

cell biology↗

bioRxiv2024

Beige adipose tissue-derived extracellular vesicles: a potent metabolic regulator and a novel remedy for nonalcoholic fatty liver disease

Adipose tissue (AT) is an essential metabolic and endocrine organ, which are categorized into the white adipose tissue (WAT) and the brown adipose tissue (BAT), as well as the beige adipose tissue (BeAT) that derives from WAT browning. Notably, extracellular vesicles (EVs), especially tissue-produced EVs, have been recognized to be critical players in multiple physiological and pathophysiological settings and provide efficient strategy for disease treatment. However, little is known about the BeAT-derived EVs (BeEVs). In this study, we induced BeEV formation by cold stimulation and extracted EVs from three kinds of AT via enzyme digestion combined with gradient centrifugation. The isolated BeEVs possess typical morphological, structural and marker characteristics of EVs. Proteomics analysis further demonstrated that the BeEVs hold a distinct protein profile while are enriched with multiple metabolic regulatory proteins. Importantly, systemic injection of BeEVs into mice improved metabolic dysfunction in a nonalcoholic fatty liver disease (NAFLD) model induced by high-fat diet (HFD). Moreover, we demonstrated that the BeEVs alleviated liver steatosis via decreasing the lipogenesis. These findings promote the understanding of AT-EVs and shed light on the isolation, identification and applications of BeEVs as a potent metabolic regulator and novel remedy for metabolic diseases.

cell biology↗

bioRxiv2023

Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease that targets mature oligodendrocytes (MOLs) and their myelin. MOLs are transcriptionally heterogeneous and can transition to immune-like states in the context of MS. However, the intricacies of their dynamics throughout disease progression remain poorly understood. Here, we employed simultaneous single-cell multiome ATAC and RNA sequencing targeting oligodendroglia (OLGs) from the experimental autoimmune encephalomyelitis (EAE) MS mouse model at different stages of the disease course. We found that the transition to immune OLG states appear already at the early stages of EAE and persist to the late stages of the disease. Interestingly, transcription factor activity suggested immunosuppression in MOLs at early stages of EAE and we also observed a transitory activation of a regenerative program in MOLs at this stage. Importantly, different MOLs exhibit a differential responsiveness to EAE, with MOL2 exhibiting a stronger transcriptional immune response than MOL5/6. Moreover, we observed divergent responses at the epigenetic level of MOL2 and MOL5/6 during disease evolution. Thus, our single-cell multiomic resource highlights dynamic and distinct responses of OLG subpopulations to the evolving environment in EAE, which might modulate their response to regenerative therapeutic interventions in MS.

neuroscience↗

bioRxiv2023

In vitro antimicrobial mechanism of diacerein and potential to reverse MRSE resistance to β-lactams

Staphylococcus epidermidis is the most common pathogens causing ocular infection. With the increase of drug resistance rate, it poses a new challenge to anti-infection treatment. In this study, we analyzed the drug resistance of S. epidermidis isolated from the eye in the past 5 years to guide empirical antibiotics treatment. Then, the MIC and MBC of diacerein against MRSE were detected, and continuous induced resistance experiments confirmed that MRSE not easily induce resistance to diacerein. In addition, it was observed that diacerein induced MRSE cell lysis, increased membrane permeability and resulted in intracellular ROS accumulation. Diacerein does not have toxic effects to HCEC at effective bacteriostatic concentrations. The results of checkerboard assay indicated that the combination of diacerein and {beta}-lactams had additive effect on MRSE. We also observed that diacerein may reverse MRSE resistance to {beta}-lactam drugs by affecting the active efflux system. In conclusion, our results provide strong evidence for the high therapeutic potential of diacerein against MRSE.

microbiology↗