Biology subjects

Li, N.

Publications and source records attributed to Li, N..

At least 109 records · Page 6Linked to original sources

bioRxiv2024

A new stegosaur (Dinosauria: Ornithischia) from the Upper Jurassic Qigu Formation of Xinjiang, China and a revision on Chinese stegosaurs phylogeny

Stegosaurs are a small but iconic clade of ornithischian dinosaurs. They and their sister taxa, the ankylosaurs, formed the clade Eurypoda which means broad-footed. Here, we describe a stegosaur from the Upper Jurassic Qigu Formation of Xinjiang, China, based on an associated partial skeleton that includes axial, pectoral girdle, pelvic girdle, limb and armor elements. It can be diagnosed as a new taxon, Angustungui, based on numerous autapomorphies. Some morphologies of Angustungui are more similar to the taxa from Europe, Africa and North America than to those from Asia. Our phylogenetic analysis recovers it as the sister taxon of Loricatosaurus. More importantly, the narrow and claw-shaped ungual of Angustungui proves that Eurypoda, at least stegosaur, has claw-shaped unguals. Besides, we revised the character scores for Chinese stegosaurs based on observations of the specimens.

paleontology↗

bioRxiv2024

Capturing the Hierarchically Assorted Protein-protein Interaction Modules of Mammalian Cell

Proteins are organized into modules by both functions and physical interactions within compartments of an eukaryotic cell. The in vivo chemical crosslinking mass spectrometry (XL-MS) data collected from organelles, the whole cells and tissues are able to provide unique information about both protein-protein interaction (PPI) and the intensity of PPI. In the present study, we have retrieved 55,982 crosslinked peptides (XL-peptides) from the XL-MS databases, out of which 6,356 in vivo PPIs were identified. Introduction of the MONET software into analysis of 4,526 hetero PPIs revealed a total of 402 protein modules, including 15, 58 and 163 stable protein complex(s), condensate-forming protein module(s) and intrinsically disordered region (IDR)-containing protein module(s), respectively. The application of ChatGPT in analysis of these modules unexpectedly identified 4 vesicle-related modules. Together, these modules were assorted into 6 communities (module of modules) and 3 systems (module of communities) hierarchically. The bioinformatic analysis found that the three systems are corresponding to three compartments of eukaryotic cell: nuclei, mitochondria, endoplasmic reticulum (ER), respectively. This study presents a novel and comprehensive biomolecular modulome of a mammalian cell, which captures putative protein compositions of protein complexes, protein condensates and vesicles and provides a hierarchical protein organization and function within compartments of mammalian cell.

bioinformatics↗

bioRxiv2024

Identification and characterization of ugpE required for the full virulence of Streptococcus suis

Streptococcus suis (S. suis) is an emerging zoonotic pathogen that threatens both animal and human health worldwide. UgpE is a protein subunit of the Ugp (uptake of glycerol phosphate) transporter system that is involved in glycerophospholipid synthesis in bacterial membranes. In this study, an ugpE deletion mutant was constructed and the effects of ugpE deletion on cell morphology, biofilm formation, and virulence were investigated. Deletion of ugpE did not affect bacterial growth but impaired cell chain formation and capsular synthesis by downregulating the mRNA levels of the capsular regulon genes cps-2B, cps-2C, and cps-2S. Deletion of ugpE also led to decreased tolerance to heat, oxidative, and acid-base stress. Crystal violet staining and scanning electron microscopy demonstrated ugpE negatively regulated biofilm formation in liquid culture and the rdar biofilm morphotype on agar plates. Moreover, ugpE deletion not only reduced hemolysin activity, survival in whole human blood, and anti-phagocytosis ability against porcine alveolar macrophages (PAM) but also enhanced bacterial adhesion and invasion of human cerebral microvascular endothelial cells (hCMEC/D3) by upregulating the expression of multiple genes associated with cell adhesion. In a mouse infection model, ugpE deletion significantly attenuated virulence and lowered the number of viable bacteria in the blood and major organs, as well as distribution of macrophages. In conclusion, this study identified UgpE as a novel virulence factor that plays a pivotal role in the regulation of virulence and biofilm formation of S. suis.

microbiology↗

bioRxiv2024

The Human T-cell Leukemia Virus capsid protein is a potential drug target

Human T-cell Leukemia Virus type 1 (HTLV-1) is an untreatable retrovirus that causes lethal malignancies and degenerative inflammatory conditions. Effective treatments have been delayed by substantial gaps in our knowledge of the fundamental virology, especially when compared to the closely related virus, HIV. A recently developed and highly effective anti-HIV strategy is to target the virus with drugs that interfere with capsid integrity and interactions with the host. Importantly, the first in class anti-capsid drug approved, lenacapavir, can provide long-acting pre-exposure prophylaxis. Such a property would provide a means to prevent the transmission of HTLV-1, but its capsid has not previously been considered as a drug target. Here we describe the first high-resolution crystal structures of the HTLV-1 capsid protein, define essential lattice interfaces, and identify a previously unknown ligand-binding pocket. We show that this pocket is essential for virus infectivity, providing a potential target for future anti-capsid drug development.

molecular biology↗

bioRxiv2024

Reciprocal regulation of m6A modification and miRNA production machineries via phase separation-dependent and -independent mechanisms

Methyltransferase complex (MTC) deposits N6-adenosine (m6A) onto RNA, whereas microprocessor produces miRNA. Whether and how these two distinct complexes cross-regulate each other has been poorly studied. Here we report that the MTC subunit B (MTB) tends to form insoluble condensates with poor activity, with its level monitored by 20S proteasome. Conversely, the microprocessor component SERRATE (SE) forms liquid-like condensates, which in turn promotes solubility and stability of MTB, leading to increased MTC activity. Consistently, the hypomorphic lines expressing SE variants, defective in MTC interaction or liquid-like phase behavior, exhibit reduced m6A level. Reciprocally, MTC can recruit microprocessor to MIRNA loci, prompting co-transcriptional cleavage of primary miRNA (pri-miRNAs) substrates. Additionally, pri-miRNAs carrying m6A modifications at their single-stranded basal regions are enriched by m6A readers, which retain microprocessor in the nucleoplasm for continuing processing. This reveals an unappreciated mechanism of phase separation in RNA modification and processing through MTC and microprocessor coordination.

plant biology↗

bioRxiv2024

Modulation of antigen delivery and lymph node activation in non-human primates by saponin adjuvant SMNP

Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies in non-human primates (NHPs) comparing the most common clinical adjuvant alum with Saponin/MPLA Nanoparticles (SMNP), a novel ISCOMs-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific germinal center B cell responses, 18-fold higher autologous neutralizing antibody titers, and higher levels of antigen-specific plasma and memory B cells. PET-CT imaging in live NHPs showed that, unlike alum, SMNP promoted rapid antigen accumulation in both proximal and distal lymph nodes (LNs). SMNP also induced strong type I interferon transcriptional signatures, expansion of innate immune cells, and increased antigen presenting cell activation in LNs. These findings indicate that SMNP promotes multiple facets of the early immune response relevant for enhanced immunity to vaccination.

bioengineering↗

bioRxiv2024

MED26-enriched condensates drive erythropoiesis through modulating transcription pausing

The Mediator complex regulates various aspects of hematopoietic development, but whether composition of the Mediator complex undergoes dynamic changes for diversifying transcription and functional outputs is unknown. Here, we found that MED26, a subunit in the core Mediator complex, played a distinctive role in facilitating transcription pausing essential for erythroid development. While most Mediator subunits drastically decreased during this process, MED26 remained relatively abundant. Intriguingly, in the early stages, more than half of MED26 occupancy sites did not co-localize with MED1, a representative Mediator subunit, suggesting these subunits exert context-dependent gene regulation. We revealed that MED26-enriched loci were associated with RNA polymerase pausing. MED26 manifested a markedly preferential recruitment of pausing-related factors, leading to an increase in Pol pausing critical for genome-wide transcription repression during erythropoiesis. Moreover, MED26 exhibited pronounced condensate-forming capability, which was necessary for its function in promoting erythropoiesis and recruiting pausing-related factors. Collectively, this study provides mechanistic insights into the functional coordination of distinct Mediator subunits during development and highlights the switch of transcription condensates towards a MED26 enriched form, which modulates transcription pausing to facilitate transcription repression and erythroid development.

cell biology↗

bioRxiv2024

Early Inflammation and Interferon Signaling Direct Enhanced Intestinal Crypt Regeneration after Proton FLASH Radiotherapy

Ultra-high dose rate ("FLASH") radiotherapy ([≥]40-60 Gy/s) is a promising new radiation modality currently in human clinical trials. Previous studies showed that FLASH proton radiotherapy (FR) improves toxicity of normal tissues compared to standard proton radiotherapy (SR) without compromising anti-tumor effects. Understanding this normal tissue sparing effect may offer insight into how toxicities from cancer therapy can be improved. Here, we show that compared to SR, FR resulted in improved acute weight recovery and survival in mice after whole-abdomen irradiation. Improved morbidity and mortality after FR were associated with greater proliferation of damage-induced epithelial progenitor cells followed by improved tissue regeneration. FR led to the accelerated differentiation of revival stem cells (revSCs), a rare damage-induced stem cell required for intestinal regeneration, and to qualitative and quantitative changes in activity of signaling pathways important for revSC differentiation and epithelial regeneration. Specifically, FR resulted in greater infiltration of macrophages producing TGF-{beta}, a cytokine important for revSC induction, that was coupled to augmented TGF-{beta} signaling in revSCs. In pericryptal fibroblasts, FR resulted in greater type I IFN (IFN-I) signaling, which directly stimulates production of FGF growth factors supporting revSC proliferation. Accordingly, the ability of FR to improve epithelial regeneration and morbidity was dependent on IFN-I signaling. In the context of SR, however, IFN-I had a detrimental effect and promoted toxicity. Thus, a tissue-level signaling network coordinated by differences in IFN-I signaling and involving stromal cells, immune cells, and revSCs underlies the ability of FLASH to improve normal tissue toxicity without compromising anti-tumor efficacy. One Sentence SummaryFLASH radiation improves normal tissue toxicity without compromising anti-tumor efficacy through a stroma, immune, and revSC signaling network coordinated by IFN-I.

cell biology↗

bioRxiv2024

Regulative synthesis of capsular polysaccharides in the pathogenesis of Streptococcus suis

Streptococcus suis (S. suis) is an important zoonotic pathogen causing substantial economic losses in the swine industry. S. suis serotype 2 (SS2) is often isolated from the diseased. S. suis expresses capsular polysaccharide (CPS), a virulence factor crucial for their survival in the blood. However, the role of CPS in the pathogenesis of S. suis is incomplete. Here, we showed a dynamic regulation of CPS in S. suis pathogenesis. In a mouse infection model, an SS2 strain (05ZYH33) was detected in the nasal-associated lymphoid tissue (NALT) and cerebrospinal fluid (CSF) as early as 30 min after intranasal inoculation without bacteremia. Histological analysis revealed that 05ZYH33 in the nasal cavity invaded the olfactory epithelium, resulting in early brain inflammation. Transmission electron microscopy showed that 05ZYH33 isolated from NALT and CSF at early infection time had a thin layer of CPS, and those detected in the blood 5 h post- inoculation showed a much thicker CPS. In addition, adoptive transfer of anti-CPS restricted 05ZYH33 in the blood but not in NALT or CSF. However, an antiserum directed to multiple non-CPS virulence factors (anti-V5) efficiently inhibited 05ZYH33 in NALT, CSF, and blood. Thus, 05ZYH33 colonizes NALT more efficiently without CPS and subsequently invades the meninges through the olfactory nerve system. These findings provide valuable information for the treatment of S. suis infection and the development of vaccines across serotypes of S. suis by targeting CPS-independent immunity.

microbiology↗

bioRxiv2024

Identifying crosstalks among post-translational modifications in lung cancer proteomic data

Post-translational modifications (PTMs) are pivotal in cellular regulations, and their crosstalk is related to various diseases such as cancer. Given the prevalence of PTM crosstalk within close amino acid ranges, identifying peptides with multiple PTMs is essential. However, this task is an NP-hard combinatorial problem with exponential complexity, posing significant challenges for existing analysis methods. Here, we introduce PIPI-C (PTM-Invariant Peptide Identification with a Combinatorial model), a novel search engine that addresses this challenge through a mixed-integer linear programming (MILP) model, thereby overcoming the limitations of existing approaches that struggle with high-order PTM combinations. Rigorous validation across diverse datasets confirms PIPI-Cs superior performance in detecting PTM crosstalks. When applied to over 72 million mass spectra of three human cancers--lung squamous cell carcinoma (LSCC), colorectal adenocarcinoma (COAD), and glioblastoma (GBM)--PIPI-C reveals significantly upregulated PTM crosstalks. In LSCC, 50% of 860 upregulated unique PTM site patterns (UPSPs) (when comparing cancer vs. normal samples) carried at least two PTMs, including literature-supported crosstalks such as di-methylation with trifluoroleucine substitution and amidation with proline-to-valine substitution. Similar findings in COAD and GBM highlight PIPI-Cs utility in uncovering cancer-relevant PTM crosstalk landscapes. Overall, PIPI-C provides a robust mathematical framework for decoding complex PTM patterns, advancing our understanding of PTM-driven cellular processes in diseases.

bioinformatics↗

bioRxiv2024

Clathrin-associated carriers enable recycling through a kiss-and-run mechanism

Endocytosis and recycling control the uptake and retrieval of various materials, including membrane proteins and lipids, in all eukaryotic cells. These processes are crucial for cell growth, organization, function, and environmental communication. However, the mechanisms underlying efficient, fast endocytic recycling remain poorly understood. Here, by utilizing a biosensor and imaged-based screening, we uncover a novel recycling mechanism that couples endocytosis and fast recycling, which we name the clathrin-associated fast endosomal recycling pathway (CARP). Clathrin-associated tubulovesicular carriers containing clathrin, AP1, Arf1, Rab1, and Rab11, while lacking the multimeric retrieval complexes, are generated at subdomains of early endosomes, and then transported along actin to cell surfaces. Unexpectedly, the clathrin-associated recycling carriers undergo partial fusion with the plasma membrane. Subsequently, they are released from the membrane by dynamin and reenter cells. Multiple receptors utilize and modulate CARP for fast recycling following endocytosis. Thus, CARP represents a novel endocytic recycling mechanism with kiss-and-run membrane fusion.

cell biology↗

bioRxiv2024

Human tau promotes Warburg effect-like glycolytic metabolism under acute hyperglycemia conditions through modulating the homeostasis of protein-membrane association

The neurofilaments formed by hyperphosphorylated tau is a hallmark of tau-related neurodegenerative disease, including Alzheimers disease, tau related FTDP-17, Picks disease, et al. However, the biological functions of tau and the physiological significance of its phosphorylation are still not fully understood. By using human tau (441 a.a.) transgenic (hTau) mice in which murine tau has been deleted simultaneously, murine tau knockout (Tau KO) mice and C57BL/6J (C57) mice, unexpectedly, we found that under acute hyperglycemia conditions, JNK but not previously reported GSK-3{beta} mediated tau phosphorylation. Moreover, Akt, the upstream GSK-3{beta} inhibitory kinase, was activated in a tau dependent manner. By comparing the membrane-associated proteome, we found that human tau influenced the homeostasis of protein-membrane association under acute hyperglycemia conditions. Of note, with respect to WT and Tau KO mice, the membrane-association of Krts, TFAM, TRAP1, mTOR et al, were strengthened by human tau. Whereas, the membrane-association of ribosomal proteins Rpls, proteasome proteins Psmds, and mitochondrial proteins, such as COXs, Ndufa1, Mtnt4, et al, were impeded by human tau. In vitro study showed that aerobic glycolysis was promoted in the presence of human tau, which maintained NAD+/NADH ratio. On the other hand, it restricted oxidative phosphorylation level, modulated the activity of SDH, and reduced ROS production upon challenging by high glucose. Furthermore, under acute high glucose conditions, the presence of human tau significantly augmented Akt activation, but inhibited 4EBP phosphorylation simultaneously, indicating that human tau is also involved in regulating the alternative activation of mTORC1/2. In summary, the current study revealed that human tau played an important role in regulating glycolytic metabolism under acute high hyperglycemia conditions, which is similar with the Warburg-effect, through influencing the homeostasis of protein-membrane association.

molecular biology↗

bioRxiv2024

A multi-gene predictive model for the radiation sensitivity of nasopharyngeal carcinoma based on machine learning

BackgroundRadiotherapy resistance is a major obstacle to the long-term survival of nasopharyngeal cancer patients, as it is a primary cause of recurrence and metastasis. Identifying radiotherapy-associated biomarkers can help improve the survival prognosis of nasopharyngeal cancer patients. Consequently, discovering biomarkers associated with radiosensitization is crucial. MethodsWe evaluated 113 combinations of machine learning algorithms and ultimately selected 48 to construct a radiotherapy sensitivity score (NPC-RSS) that can predict radiosensitivity in nasopharyngeal cancer patients. Furthermore, we analyzed the relationship between NPC-RSS and the expression of genes associated with immune and radiotherapy sensitivity profiles. We employed GSEA and ssGSEA to investigate the connection between NPC-RSS and signaling pathways. ResultsWe selected the combined model glmBoost+NaiveBayes, which had the best AUC among 48 models, for our subsequent study. The NPC-RSS, built based on the 18 genes included in this model, can predict the results of the public dataset and the in-house dataset of Zhujiang Hospital, Southern Medical University, with considerable efficiency. The key genes of NPC-RSS are closely associated with immune characteristics, including chemokine and chemokine receptor families, and histocompatibility complex (MHC), and show more active immune processes. Meanwhile, these key genes were significantly associated with the expression of radiosensitization-related genes. Furthermore, GSVA and GSEA analyses demonstrated that different expression levels of key NPC-RSS genes influenced signaling pathways, such as the Wnt/{beta}-catenin signaling pathway, JAK-STAT signaling pathway,NF-kappa B signaling pathway and T cell receptor signaling pathway, which are associated with immunity and disease progression. The consistency of the expression of key genes SMARCA2 and CD9 with NPC-RSS was validated in in-house cell lines. The radiosensitive group, classified according to NPC-RSS, exhibited a more enriched and activated state of immune infiltration compared to the radioresistant group. Moreover, in single-cell samples, NPC-RSS was higher in the radiotherapy-sensitive group, with immune cells playing a predominant role. ConclusionsIn this study, we used machine learning to construct a predictive score, called NPC-RSS, associated with radiosensitivity in nasopharyngeal carcinoma patients; moreover, NPC-RSS is strongly associated with immune characteristics, expression of radiosensitivity-related genes, and signaling pathways related to disease progression. We hope that the NPC-RCC will enable more precise selection of the NPC population of potential beneficiaries of radiation therapy.

bioinformatics↗

bioRxiv2024

A combinatorial neural code for long-term motor memory

Motor skill repertoire can be stably retained over long periods, but the neural mechanism underlying stable memory storage remains poorly understood. Moreover, it is unknown how existing motor memories are maintained as new motor skills are continuously acquired. Here we tracked neural representation of learned actions throughout a significant portion of a mouses lifespan, and we show that learned actions are stably retained in motor memory in combination with context, which protects existing memories from erasure during new motor learning. We used automated home-cage training to establish a continual learning paradigm in which mice learned to perform directional licking in different task contexts. We combined this paradigm with chronic two-photon imaging of motor cortex activity for up to 6 months. Within the same task context, activity driving directional licking was stable over time with little representational drift. When learning new task contexts, new preparatory activity emerged to drive the same licking actions. Learning created parallel new motor memories while retaining the previous memories. Re-learning to make the same actions in the previous task context re-activated the previous preparatory activity, even months later. At the same time, continual learning of new task contexts kept creating new preparatory activity patterns. Context-specific memories, as we observed in the motor system, may provide a solution for stable memory storage throughout continual learning. Learning in new contexts produces parallel new representations instead of modifying existing representations, thus protecting existing motor repertoire from erasure.

neuroscience↗

bioRxiv2024

Biomarker Identification by Proteomic Analysis of Vitreous Humor and Plasma in Diabetic Retinopathy

ImportanceIdentify detectable plasma and/or vitreous signals to potentially predict diabetic retinopathy (DR) progression for earlier disease intervention. ObjectiveTo determine the mediators and potential disease progression biomarkers of DR in vitreous humor (VH) and plasma samples using the SomaScan proteome profiling platform. DesignDifferential expression analysis was conducted on VH and plasma samples using the SomaScan Assay. SettingA non-interventional study conducted to collect and analyze VH and plasma samples from patients with diabetic retinopathy. ParticipantsSamples from DR (60 nonproliferative diabetic retinopathy/NPDR, 60 proliferative diabetic retinopathy/PDR) and 60 control patients were collected. Main outcomes and MeasuresDifferentially expressed proteins between disease and control groups were identified. Pathway enrichment analysis was conducted to identify significantly perturbed pathways in DR. Finally, a random forest model was used to identify predictive biomarkers of disease progression. ResultsSomaScan v3 is a pooled aptamer hybridization assay using 5080 SOMAmers to probe over 4100 proteoforms in VH and plasma samples from 3 groups (control, NPDR, and PDR). The most profound protein content change was observed in the VH samples of PDR patients, while minimal changes were measured in plasma samples, highlighting the regionality of PDR pathogenesis. Many key molecules and molecular pathways such as VEGF-A, erythropoietin, and inflammation-associated proteins implicated in DR were significantly affected in the VH of PDR patients. In addition to the classic pathways (hypoxia, immune response, mTORC1 signaling) known to be involved in PDR, novel signaling pathways, including HEME metabolism and adipogenesis, were identified in VH samples. Application of a machine learning algorithm identified a panel of plasma PDR predictive biomarkers and revealed SCARA5 as the top one based on the largest average Gini decrease in the model. ConclusionOur study identified profound alteration of protein expression and molecular pathways in the VH of PDR patients, supporting the key role of local pathogenic changes in DR progression compared to systemic factors. Although the systemic changes related to DR were small, a few disease progression predictive candidate biomarkers (SCARA5, PTK7, FAM3Band FAM3D) were identified, prompting further investigation. Key PointsQuestion: Are plasma/ vitreous humor (VH) proteins predictive of diabetic retinopathy (DR) progression? Findings: This study identifies substantial protein changes in the VH of proliferative diabetic retinopathy (PDR) patients, while early nonproliferative DR (NPDR) patients show minimal change. We identify multiple proteins linked to angiogenesis, inflammation, immune cells (microglia/macrophage/neutrophil), and leukostasis associated with PDR and reveal a potential plasma panel of disease progression (from NPDR to PDR) biomarkers (SCARA5, PTK7, FAM3B, FAM3D). Meaning: Identified disease progression predictive biomarkers permits potential development of prognostic tools to identify individuals most at risk for PDR progression and offering reduced disease burden by earlier intervention.

physiology↗

bioRxiv2024

Interferon-Inducible Guanylate-Binding Protein 5 Inhibits Replication of Multiple Viruses by Binding to the Oligosaccharyltransferase Complex and Inhibiting Glycoprotein Maturation

Viral infection induces production of type I interferons and expression of interferon-stimulated genes (ISGs) that play key roles in inhibiting viral infection. Here, we show that the ISG guanylate-binding protein 5 (GBP5) inhibits N-linked glycosylation of key proteins in multiple viruses, including SARS-CoV-2 spike protein. GBP5 binds to accessory subunits of the host oligosaccharyltransferase (OST) complex and blocks its interaction with the spike protein, which results in misfolding and retention of spike protein in the endoplasmic reticulum likely due to decreased N-glycan transfer, and reduces the assembly and release of infectious virions. Consistent with these observations, pharmacological inhibition of the OST complex with NGI-1 potently inhibits glycosylation of other viral proteins, including MERS-CoV spike protein, HIV-1 gp160, and IAV hemagglutinin, and prevents the production of infectious virions. Our results identify a novel strategy by which ISGs restrict virus infection and provide a rationale for targeting glycosylation as a broad antiviral therapeutic strategy. HighlightsO_LIThe interferon-stimulated gene GBP5 is induced by SARS-CoV-2 infection in vitro and in vivo. C_LIO_LIER-localized GBP5 restricts N-linked glycosylation of SARS-CoV-2 spike protein, leading to protein misfolding and preventing transport to the Golgi apparatus. C_LIO_LIGBP5 binds to OST complex accessory proteins and potentially blocks access of the catalytic subunit to the spike protein. C_LIO_LIGBP5 inhibits N-glycosylation of key proteins in multiple viruses, including SARS-CoV-2 C_LIO_LIPharmacological inhibition of OST blocks host cell infection by SARS-CoV-2, variants of concern, HIV-1, and IAV. C_LI SignificanceViral infection induces production of type I interferons and expression of interferon-stimulated genes (ISGs) that play key roles in inhibiting viral infection. We found that the interferon-stimulated gene GBP5 is induced by SARS-CoV-2 infection in vitro and in vivo. GBP5 inhibits N-glycosylation of key proteins in multiple viruses, including SARS-CoV-2. Importantly, pharmacological inhibition of Oligosaccharyltransferase (OST) Complex blocks host cell infection by SARS-CoV-2, variants of concern, HIV-1, and IAV, indicating future translational application of our findings.

microbiology↗

bioRxiv2024

Shared pathway-specific network mechanisms of dopamine and deep brain stimulation for the treatment of Parkinson's disease

Deep brain stimulation is a brain circuit intervention that can modulate distinct neural pathways for the alleviation of neurological symptoms in patients with brain disorders. In Parkinsons disease, subthalamic deep brain stimulation clinically mimics the effect of dopaminergic drug treatment, but the shared pathway mechanisms on cortex - basal ganglia networks are unknown. To address this critical knowledge gap, we combined fully invasive neural multisite recordings in patients undergoing deep brain stimulation surgery with normative MRI-based whole-brain connectomics. Our findings demonstrate that dopamine and stimulation exert distinct mesoscale effects through modulation of local neural population activity. In contrast, at the macroscale, stimulation mimics dopamine in its suppression of excessive interregional network synchrony associated with indirect and hyperdirect cortex - basal ganglia pathways. Our results provide a better understanding of the circuit mechanisms of dopamine and deep brain stimulation, laying the foundation for advanced closed-loop neurostimulation therapies.

neuroscience↗

bioRxiv2024

Sox9 marks limbal stem cells and is required for asymmetric cell fate switch in the corneal epithelium

Adult tissues with high cellular turnover require a balance between stem cell renewal and differentiation, yet the mechanisms underlying this equilibrium are unclear. The cornea exhibits a polarized lateral flow of progenitors from the peripheral stem cell niche to the center; attributed to differences in cellular fate. To identify genes that are critical for regulating the asymmetric fates of limbal stem cells and their transient amplified progeny in the central cornea, we utilized an in vivo cell cycle reporter to isolate proliferating basal cells across the anterior ocular surface epithelium and performed single-cell transcriptional analysis. This strategy greatly increased the resolution and revealed distinct basal cell identities with unique expression profiles of structural genes and transcription factors. We focused on Sox9; a transcription factor implicated in stem cell regulation across various organs. Sox9 was found to be differentially expressed between limbal stem cells and their progeny in the central corneal. Lineage tracing analysis confirmed that Sox9 marks long-lived limbal stem cells and conditional deletion led to abnormal differentiation and squamous metaplasia in the central cornea. These data suggest a requirement for Sox9 for the switch to asymmetric fate and commitment toward differentiation, as transient cells exit the limbal niche. By inhibiting terminal differentiation of corneal progenitors and forcing them into perpetual symmetric divisions, we replicated the Sox9 loss-of-function phenotype. Our findings reveal an essential role for Sox9 for the spatial regulation of asymmetric fate in the corneal epithelium that is required to sustain tissue homeostasis.

developmental biology↗