Cell-specific IL-1R1 regulates the regional heterogeneity of microglial displacement of GABAergic synapses and motor learning ability.

Microglia regulate synaptic function in various ways, including the microglial displacement of the surrounding GABAergic synapses, which provides important neuroprotection from certain diseases. However, the physiological role and underlying mechanisms of microglial synaptic displacement remain unclear. In this study, we observed that microglia exhibited heterogeneity during the displacement of GABAergic synapses surrounding neuronal soma in different cortical regions under physiological conditions. Through three-dimensional reconstruction, in vitro co-culture, two-photon calcium imaging, and local field potentials recording, we found that IL-1ß negatively modulated microglial synaptic displacement to coordinate regional heterogeneity in the motor cortex, which impacted the homeostasis of the neural network and improved motor learning ability. We used the Cre-Loxp system and found that IL-1R1 on glutamatergic neurons, rather than that on microglia or GABAergic neurons, mediated the negative effect of IL-1ß on synaptic displacement. This study demonstrates that IL-1ß is critical for the regional heterogeneity of synaptic displacement by coordinating different actions of neurons and microglia via IL-1R1, which impacts both neural network homeostasis and motor learning ability. It provides a theoretical basis for elucidating the physiological role and mechanism of microglial displacement of GABAergic synapses.

Exploring NK-Cell molecules that impact the immune response and microenvironment in head and neck squamous cell carcinoma.

NK cells play a role in various cancers, but their role in head and neck squamous cell carcinoma (HNSCC) still needs to be explored. All public data are obtained from the Cancer Genome Atlas Program (TCGA) database. All analysis was performed using specific packages in R software. In our study, we quantified the immune microenvironment of HNSCC through multiple algorithms. Next, we identified NK cell-associated genes by quantifying NK cells, including SSNA1, TRIR, PAXX, DPP7, WDR34, EZR, PHLDA1 and ELOVL1. Then, we explored the single-cell expression pattern of these genes in the HNSCC microenvironment. Univariate Cox regression analysis indicated that the EZR, PHLDA1 and ELOVL1 were related to the prognosis of HNSCC patients. Following this, we selected EZR for further analysis. Our results showed that the patients with high EZR expression might have a poor prognosis and worse clinical features. Biological enrichment analysis showed that EZR is associated with many oncogenic pathways and a higher tumour stemness index. Meanwhile, we found that EZR can remodel the immune microenvironment of HNSCC. Moreover, we noticed that EZR could affect the immunotherapy and specific drug sensitivity, making it an underlying clinical target. In summary, our results can improve the understanding of NK cell in HNSCC. Meanwhile, we identified EZR as the underlying clinical target of HNSCC.

Ventral posteromedial nucleus of the thalamus gates the spread of trigeminal neuropathic pain.

BACKGROUND: Widespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking. METHODS: Widespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain. RESULTS: We found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPMGlu) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPMGlu, notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCNGlu). Moreover, VPMGlu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCNGlu in the VPM, the soma of VPMGlu or the terminals of VPMGlu in the pIC all alleviated trigeminal and widespread neuropathic pain. CONCLUSION: These results demonstrate that hyperactive VPMGlu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain.

Observational Insights into Isoprene Secondary Organic Aerosol Formation through the Epoxide Pathway at Three Urban Sites from Northern to Southern China.

Isoprene is the most abundant precursor of global secondary organic aerosol (SOA). The epoxide pathway plays a critical role in isoprene SOA (iSOA) formation, in which isoprene epoxydiols (IEPOX) and/or hydroxymethyl-methyl-α-lactone (HMML) can react with nucleophilic sulfate and water producing isoprene-derived organosulfates (iOSs) and oxygen-containing tracers (iOTs), respectively. This process is complicated and highly influenced by anthropogenic emissions, especially in the polluted urban atmospheres. In this study, we took a 1-year measurement of the paired iOSs and iOTs formed through the IEPOX and HMML pathways at the three urban sites from northern to southern China. The annual average concentrations of iSOA products at the three sites ranged from 14.6 to 36.5 ng m-3. We found that the nucleophilic-addition reaction of isoprene epoxides with water dominated over that with sulfate in the polluted urban air. A simple set of reaction rate constant could not fully describe iOS and iOT formation everywhere. We also found that the IEPOX pathway was dominant over the HMML pathway over urban regions. Using the kinetic data of IEPOX to estimate the reaction parameters of HMML will cause significant underestimation in the importance of HMML pathway. All these findings provide insights into iSOA formation over polluted areas.

Antagonism of histamine H3 receptor promotes angiogenesis following focal cerebral ischemia.

Our previous study showed that H3 receptor antagonists reduced neuronal apoptosis and cerebral infarction in the acute stage after cerebral ischemia, but through an action independent of activation of histaminergic neurons. Because enhanced angiogenesis facilitates neurogenesis and neurological recovery after ischemic stroke, we herein investigated whether antagonism of H3R promoted angiogenesis after brain ischemia. Photothrombotic stroke was induced in mice. We showed that administration of H3R antagonist thioperamide (THIO, 10 mg·kg-1·d-1, i.p., from D1 after cerebral ischemia) significantly improved angiogenesis assessed on D14, and attenuated neurological defects on D28 after cerebral ischemia. Compared with wild-type mice, Hrh3-/- mice displayed more blood vessels in the ischemic boundary zone on D14, and THIO administration did not promote angiogenesis in these knockout mice. THIO-promoted angiogenesis in mice was reversed by i.c.v. injection of H3R agonist immepip, but not by H1 and H2 receptor antagonists, histidine decarboxylase inhibitor α-fluoromethylhistidine, or histidine decarboxylase gene knockout (HDC-/-), suggesting that THIO-promoted angiogenesis was independent of activation of histaminergic neurons. In vascular endothelial cells (bEnd.3), THIO (10-9-10-7 M) dose-dependently facilitated cell migration and tube formation after oxygen glucose deprivation (OGD), and H3R knockdown caused similar effects. We further revealed that H3R antagonism reduced the interaction between H3R and Annexin A2, while knockdown of Annexin A2 abrogated THIO-promoted angiogenesis in bEnd.3 cells after OGD. Annexin A2-overexpressing mice displayed more blood vessels in the ischemic boundary zone, which was reversed by i.c.v. injection of immepip. In conclusion, this study demonstrates that H3R antagonism promotes angiogenesis after cerebral ischemia, which is independent of activation of histaminergic neurons, but related to the H3R on vascular endothelial cells and its interaction with Annexin A2. Thus, H3R antagonists might be promising drug candidates to improve angiogenesis and neurological recovery after ischemic stroke.

Triptolide protects against white matter injury induced by chronic cerebral hypoperfusion in mice.

White matter injury is the major pathological alteration of subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion. It is characterized by progressive demyelination, apoptosis of oligodendrocytes and microglial activation, which leads to impairment of cognitive function. Triptolide exhibits a variety of pharmacological activities including anti-inflammation, immunosuppression and antitumor, etc. In this study, we investigated the effects of triptolide on white matter injury and cognitive impairments in mice with chronic cerebral hypoperfusion induced by the right unilateral common carotid artery occlusion (rUCCAO). We showed that triptolide administration alleviated the demyelination, axonal injury, and oligodendrocyte loss in the mice. Triptolide also improved cognitive function in novel object recognition test and Morris water maze test. In primary oligodendrocytes following oxygen-glucose deprivation (OGD), application of triptolide (0.001-0.1 nM) exerted concentration-dependent protection. We revealed that the protective effect of triptolide resulted from its inhibition of oligodendrocyte apoptosis via increasing the phosphorylation of the Src/Akt/GSK3ß pathway. Moreover, triptolide suppressed microglial activation and proinflammatory cytokines expression after chronic cerebral hypoperfusion in mice and in BV2 microglial cells following OGD, which also contributing to its alleviation of white matter injury. Importantly, mice received triptolide at the dose of 20 µg·kg-1·d-1 did not show hepatotoxicity and nephrotoxicity even after chronic treatment. Thus, our results highlight that triptolide alleviates whiter matter injury induced by chronic cerebral hypoperfusion through direct protection against oligodendrocyte apoptosis and indirect protection by inhibition of microglial inflammation. Triptolide may have novel indication in clinic such as the treatment of chronic cerebral hypoperfusion-induced SIVD.

Novel Caspase-1 inhibitor CZL80 improves neurological function in mice after progressive ischemic stroke within a long therapeutic time-window.

Progressive ischemic stroke (PIS) is featured by progressive neurological dysfunction after ischemia. Ischemia-evoked neuroinflammation is implicated in the progressive brain injury after cerebral ischemia, while Caspase-1, an active component of inflammasome, exaggerates ischemic brain injury. Current Caspase-1 inhibitors are inadequate in safety and druggability. Here, we investigated the efficacy of CZL80, a novel Caspase-1 inhibitor, in mice with PIS. Mice and Caspase-1-/- mice were subjected to photothrombotic (PT)-induced cerebral ischemia. CZL80 (10, 30 mg·kg-1·d-1, i.p.) was administered for one week after PT onset. The transient and the progressive neurological dysfunction (as foot faults in the grid-walking task and forelimb symmetry in the cylinder task) was assessed on Day1 and Day4-7, respectively, after PT onset. Treatment with CZL80 (30 mg/kg) during Day1-7 significantly reduced the progressive, but not the transient neurological dysfunction. Furthermore, we showed that CZL80 administered on Day4-7, when the progressive neurological dysfunction occurred, produced significant beneficial effects against PIS, suggesting an extended therapeutic time-window. CZL80 administration could improve the neurological function even as late as Day43 after PT. In Caspase-1-/- mice with PIS, the beneficial effects of CZL80 were abolished. We found that Caspase-1 was upregulated during Day4-7 after PT and predominantly located in activated microglia, which was coincided with the progressive neurological deficits, and attenuated by CZL80. We showed that CZL80 administration did not reduce the infarct volume, but significantly suppressed microglia activation in the peri-infarct cortex, suggesting the involvement of microglial inflammasome in the pathology of PIS. Taken together, this study demonstrates that Caspase-1 is required for the progressive neurological dysfunction in PIS. CZL80 is a promising drug to promote the neurological recovery in PIS by inhibiting Caspase-1 within a long therapeutic time-window.

HMGB1 in the mPFC governs comorbid anxiety in neuropathic pain.

BACKGROUND: Whether neuroinflammation causes comorbid mood disorders in neuropathic pain remains elusive. Here we investigated the role of high mobility group box 1 protein (HMGB1), a proinflammatory cytokine, in the medial prefrontal cortex (mPFC) in anxiety comorbidity of neuropathic pain. METHODS: Neuropathic pain was induced by partial transection of the infraorbital nerve (p-IONX) or partial sciatic nerve ligation (PSL) in mice and evaluated by measuring nociceptive thresholds to mechanical and heat stimulation. Anxiety-like behaviors were assessed by elevated plus maze, light dark box and open field tests. Aversive or anti-aversive effect was detected by conditioned place preference test. Neuronal activity was evaluated by single-unit and patch clamp recordings. The contribution of mPFC pyramidal neurons to anxiety was further examined by selectively inhibiting them by optogenetics. HMGB1 expression was measured by immunohistochemistry and western blotting. Antagonism of HMGB1 was achieved by injecting anti-HMGB1 monoclonal antibody (mAb) intracerebrally or intraperitoneally. RESULTS: Anxiety-like behaviors were presented earlier after p-IONX than after PSL. HMGB1 expression was upregulated in the mPFC temporally in parallel to anxiety onset, rather than in other regions associated with anxiety. The upregulation of HMGB1 expression and its translocation from the nucleus to cytoplasm in the mPFC occurred predominantly in neurons and were accompanied with activation of microglia and astrocytes. Infusion of anti-HMGB1 mAb into the mPFC during the early and late phases after either p-IONX or PSL alleviated anxiety-like behaviors and aversion without changing pain sensitization, while local infusion of exogenous ds-HMGB1, the proinflammatory form of HMGB1, into the mPFC induced anxiety and aversion but not pain sensitization in naïve mice. In addition to reversing established pain sensitization and anxiety simultaneously, intraperitoneal injection of anti-HMGB1 mAb reduced HMGB1 upregulation and suppressed the hyperexcitability of layer 2/3 pyramidal neurons in the mPFC after p-IONX. Moreover, optogenetic inhibition of mPFC pyramidal neurons alleviated anxiety in p-IONX mice. CONCLUSION: These results demonstrate that HMGB1 in the mPFC drives and maintains anxiety comorbidity in neuropathic pain by increasing the excitability of layer 2/3 pyramidal neurons, and justify antagonism of HMGB1, e.g., neutralization by mAb, as a promising therapeutic strategy for neuropathic pain with anxiety comorbidity.

Melatonin receptor agonist ramelteon attenuates mouse acute and chronic ischemic brain injury.

Melatonin receptors (MTs) are potential drug targets for stroke therapy. Ramelteon is a selective melatonin receptor agonist used to treat insomnia. In this study we investigated whether ramelteon could attenuate cerebral ischemia in mice. Acute focal cerebral ischemia was induced in mice via middle cerebral artery occlusion (MCAO). We found oral administration of ramelteon (3.0 mg/kg) significantly attenuated ischemic injury even when it was given 4 h after the onset of ischemia. We showed that administration of ramelteon (3.0 mg/kg) displayed comparable protective efficacy and length of effective time window as administration of edaravone (10 mg/kg, i.p.), which was used in clinic to treat ischemic stroke. Chronic ischemic brain injury was induced in mice using photothrombosis. Oral administration of ramelteon (3.0 mg · kg-1 · d-1) for 7 days after ischemia significantly attenuated functional deficits for at least 15 days. The neuroprotection of ramelteon was blocked by 4-P-PDOT, a specific MT antagonist. We further revealed that ramelteon significantly inhibited autophagy in the peri-infarct cortex in both the mouse ischemia models via regulating AMPK/mTOR signaling pathway. Intracerebroventricular injection of rapamycin, an autophagy activator, compromised the neuroprotection of ramelteon, suggesting ramelteon might attenuate ischemic injury by counteracting autophagic cell death. These data demonstrate for the first time the potential benefits of ramelteon in the treatment of both acute and chronic ischemic brain injury and provide the rationale for the application of ramelteon in stroke therapy.

[Bioinformatic analysis of differentially expressed genes and Chinese medicine prediction for ulcerative colitis].

The aim of this paper was to analyze the microarray data between ulcerative colitis(UC) patients and healthy people by bioinformatics technology, screen the differentially expressed genes of UC, and predict the potential Chinese medicines for UC. The GSE36807 gene expression profile was downloaded from the gene expression database(GEO) and the differentially expressed(both up-regulated and down-regulated) genes(DEGs) were analyzed by using R language software. The core genes in the DEGs were obtained by using String database, Cytoscape software and its plug-in analysis, and the gene ontology(GO) and Kyoto encyclopedia of genes and genomes(KEGG) were used to analyze the core genes. Moreover, the core genes and the medical ontology information retrieval platform(Coremine Medical) were mapped to each other to screen the traditional Chinese medicines and its active ingredients for treating UC. A total of 648 DEGs were screened, including 397 up-regulated genes and 251 down-regulated genes. Up-regulation of DEGs yielded 15 core genes including CXCL8, IL1 B, MMP9, CXCL1, CXCL10, CXCL9, CXCL2, CXCL5, TIMP1, CXCL11, STAT1,LCN2, IL1 RN, MMP1 and IDO1. Their biological processes and pathways were mainly enriched in interleukins, chemokine ligands and cytokines, chemokine-mediated signaling pathways, and were closely related to inflammatory responses, defense responses, cell chemotaxis, secretory granules, IL17 signaling pathways, Toll-like receptor signaling pathway, NOD-like receptor signaling pathway, and TNF signaling pathway. Potential Chinese medicines for the treatment of UC include Curcumae Longae Rhizoma, Coptidis Rhizoma, Scutellariae Radix, Dendrobii Caulis, Sanguisorbae Radix, Phellodendri Chinensis Cortex, Bletillae Rhizoma and Atractylodis Rhizoma. The analysis of DEGs and core genes could promote our understanding on pathogenesis of UC. This study provides potential gene targets and research ideas for the development of new drugs of Chinese medicine intervention for UC.

Long noncoding RNA TUG1 regulates the development of oral squamous cell carcinoma through sponging miR-524-5p to mediate DLX1 expression as a competitive endogenous RNA.

Long noncoding RNA (lncRNA) exerts a potential regulatory role in tumorigenesis. LncRNA TUG1 expression remains high in oral squamous cell carcinoma (OSCC) tissues. However, its biological mechanism in OSCC remains unknown. In this study, TUG1 expression in OSCC cells was detected by quantitative real-time polymerase chain reaction. Proliferative and migratory potentials of OSCC cells were determined by Cell Counting Kit 8, 5-Ethynyl-2'- deoxyuridine (EdU), and Transwell assay, respectively. We identified the potential target of TUG1 through bioinformatics and dual-luciferase reporter gene assay. Furthermore, their interaction and functions in regulating the development of OSCC were clarified by western blot and RNA immunoprecipitation assay. Our results demonstrated a high expression of TUG1 in OSCC cells. Overexpression of TUG1 markedly accelerated proliferative and migratory potentials of OSCC cells. Besides, TUG1 could positively regulate the expression of distal-less homeobox 1 (DLX1) by competing with miR-524-5p. These results indicated that TUG1 participated in the development of OSCC as a competing endogenous RNA to competitively bind to miR-524-5p and thus mediate DLX1 expression.

hsa_circRNA_100533 regulates GNAS by sponging hsa_miR_933 to prevent oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the head and neck region. Circular RNA (circRNA), as one kind of noncoding RNA, involves in biological processes in diverse cancers. circRNA functions mainly as the microRNA (miRNA) sponge, competitively binding to miRNAs to regulate target gene expressions. However, the expression profiles and roles of circRNAs in OSCC are still unexplored. circRNA microarrays and quantitative real-time polymerase chain reaction was used to identify the hsa_circRNA_100533 downregulated in OSCC tissues and cell lines. Bioinformatics methods were used to predict the interactions among circRNAs, miRNA, and target genes. Based on the luciferase reporter assay and AGO2 RIP assay, we found that hsa_circRNA_100533 binds to miRNAs as a miRNA sponge. hsa_circRNA_100533 inhibited cell proliferation, migration, and promoted cell apoptosis in OSCC cell lines, which could be blocked by hsa-miR-933 overexpression. hsa_circRNA_100533 binds to hsa-miR-933 as a miRNA sponge to regulate GNAS expression, and to modulate cell proliferation, migration, and apoptosis. In summary, the hsa_circRNA_100533-miR-933-GNAS axis affect the proliferation and apoptosis of OSCC cells through the mechanism of competing endogenous RNAs. hsa_circRNA_100533 may function as promising diagnostic biomarkers and effective therapeutic targets for OSCC.

Long non-coding RNA MALAT1 promotes oral squamous cell carcinoma development via microRNA-125b/STAT3 axis.

Oral squamous cell carcinoma (OSCC), as the most common type of oral cancer, is responsible for almost 3% of all malignant tumors worldwide. Non-coding RNAs such as lncRNAs and microRNAs have been involved in many cancers including OSCC. Recently, lncRNA metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) has been reported to play an oncogenic role in OSCC metastasis. However, the underlying mechanism of MALAT1 in regulating OSCC progression remains unclear. The aim of this study was to investigate the specific role of MALAT1 in OSCC development. It was observed that MALAT1 was upregulated in OSCC cell lines. Inhibition of MALAT1 can prevent OSCC proliferation while overexpressing MALAT1 promoted OSCC progression. In addition, bioinformatics search was used to identify that miR-125b was a direct target of MALAT1, which indicated a negative correlation between MALAT1 and miR-125b. Besides these, STAT3 was predicted as a binding target of miR-125b in OSCC. Overexpression of MALAT1 was able to suppress the tumor inhibitory effect of miR-125b mimics via upregulating STAT3. Moreover, the function of MALAT1 in OSCC development was further investigated by using in vivo assays. The established nude mice models revealed that downregulated MALAT1 greatly inhibited OSCC tumor growth and reversely upregualated MALAT1 promoted OSCC development via miR-125b/STAT3 axis, respectively. In conclusion, MALAT1 can function as a competing endogenous RNA (ceRNA) to modulate STAT3 expression by absorbing miR-125b in OSCC and could be used as a novel therapeutic target in OSCC diagnosis and treatment.

Pre-stroke Metformin Treatment is Neuroprotective Involving AMPK Reduction.

Long-term metformin treatment reduces the risk of stroke. However, the effective administration pattern and indications of metformin on acute cerebral ischemia are unclear. To investigate the neuroprotective treatment duration and dosage of metformin on focal ischemia mice and the association of neuroprotection with 5'-adenosine monophosphate-activated protein kinase (AMPK) regulations, male C57BL/6 mice were subjected to permanent or transient middle cerebral artery occlusion (MCAO) and metformin of 3, 10 and 30 mg/kg was intraperitoneally injected 1, 3 or 7 days prior to MCAO, or at the onset, or 1, 3 or 6 h after reperfusion, respectively. Infarct volumes, neurological deficit score, cell apoptosis, both total and phosphorylated AMPK expressions were assessed. Results showed that prolonged pretreatment to 7 days of metformin (10 mg/kg) significantly ameliorated brain infarct, neurological scores and cell apoptosis in permanent MCAO mice. Shorter (3 days or 1 day) or without pretreatment of metformin was not effective, suggesting a pretreatment time window. In transient MCAO mice, metformin showed no neuroprotection even with pretreatment. The expressions of total and phosphorylated AMPK were sharply decreased with effective metformin pretreatments in ischemic brains. Our data provided the first evidence that in acute ischemic injury, a 7-days pretreatment duration of 10 mg/kg metformin is necessary for its neuroprotection, and metformin may not be beneficial in the cases of blood reperfusion.

The efficacy and safety of weekly 35-mg risedronate dosing regimen for Chinese postmenopausal women with osteoporosis or osteopenia: 1-year data.

AIM: Oral risedronate is effective in the treatment of postmenopausal osteoporosis when administered daily, weekly, or monthly. In this 1-year, randomized, double-blind, multicenter study we compared the weekly 35-mg and daily 5-mg risedronate dosing regimens in the treatment of Chinese postmenopausal women with osteoporosis or osteopenia. METHODS: Postmenopausal women with primary osteoporosis or osteopenia were randomly assigned to the weekly group or daily group (n=145 for each) that received oral risedronate 35 mg once a week or 5 mg daily, respectively, for 1 year. The subjects' bone mineral densities (BMDs), bone turnover markers (P1NP and ß-CTX), new vertebral fractures, and adverse events were assessed at baseline and during the treatments. RESULTS: All subjects in the weekly group and 144 subjects in the daily group completed the study. The primary efficacy endpoint after 1 year, ie the mean percent changes in the lumbar spine BMD (95% CI) were 4.87% (3.92% to 5.81%) for the weekly group and 4.35% (3.31% to 5.39%) for the daily group. The incidences of clinical adverse events were 48.3% in the weekly group and 54.2% in the daily group. CONCLUSION: The weekly 35-mg and daily 5-mg risedronate dosing regimens during 1 year of follow-up show similar efficacy in improving BMDs and biochemical markers of bone turnover in Chinese postmenopausal women with osteoporosis or osteopenia. Moreover, the two dosing regimens exhibit similar safety and tolerability.

[Research progress on ubiquitin-specific protease in antiviral immunity].

Ubiquitin-specific protease(USP), which belongs to cysteine protease, is an important member of the deubiquitinating enzyme family(DUB). USP plays an important role in the immune response against viral infections, in which it can regulate the production of type I interferon through various ways to initiate or weaken the antiviral immune response. USP2b, USP3, USP18, USP25, UL36USP and HAUSP play a role of antivirus; while USP4, USP13, USP15 and USP17 negatively regulate antiviral immune response. In this article we review the recent progress on roles of USP family in antiviral immune response.

Serum osteocalcin levels are inversely associated with plasma glucose and body mass index in healthy Chinese women.

AIM: Osteocalcin, a biochemical marker of bone formation, has been suggested to be involved in the regulation of energy metabolism. The aim of this study was to investigate the possible association between serum osteocalcin and markers of glucose and lipid metabolism in a large sample of healthy Chinese women. METHODS: A total of 2032 healthy Chinese women in Shanghai, aged 20-94 (including 1396 discovery-study subjects and 636 postmenopausal women for a reduplication analysis) were recruited. Their serum osteocalcin, calcium and the relevant measurements were analyzed. A Spearman correlation analysis was performed between osteocalcin and the other markers of energy metabolism including triglyceride, total cholesterol, fasting plasma glucose (FPG), serum insulin, body mass index and homeostasis model assessment-insulin resistance. Separate multiple regression analyses were performed with data from the discovery and reduplication subjects to determine whether serum osteocalcin concentration was an independent predictor of the glucose or lipid metabolism markers. RESULTS: For the discovery-study subjects, serum osteocalcin was found to be negatively associated with weight (r=-0.08, P=0.002), BMI (-0.13, P<0.001) and FPG (r=-0.13, P=0.001). Similar results were also found in the reduplication subjects (weight: r=-0.19, P=0.016; BMI: r=-0.23, P=0.003; FPG: r=-0.28, P<0.001). In the multiple regression analysis, serum osteocalcin was revealed as a potential independent predictor for FPG (ß=-0.07 and -0.210 for discovery and reduplication, respectively, P<0.01) and BMI (ß=-0.127 and -0.299 for discovery and reduplication, respectively, P<0.01). CONCLUSION: Serum osteocalcin is negatively associated with weight BMI and FPG in healthy Chinese women. Therefore, osteocalcin might contribute to obesity and diabetes.

Identification of a novel mutation in the CLCN5 gene in a Chinese family with Dent-1 disease.

Dent disease comprises a group of X-linked recessive inherited renal tubular disorders, the symptoms of which include low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, and progressive renal failure. We sought to characterize the clinical manifestations and to identify the mutations associated with this disease in Chinese patients. In total, 155 DNA samples were collected from one affected individual, four of his family members, and 150 healthy donors. All 12 exons and the exon-intron boundaries of the CLCN5 gene were amplified and directly sequenced in this Chinese family. The proband demonstrated osteomalacia, which had resulted in more than 10 fractures, LMWP, and renal failure. A single base 'G' deletion at nucleotide 246 (c. 246delG) was identified in exon 5 of the CLCN5 gene in this patient, resulting in a frame shift mutation (fsX) that changed the Threonine (Thr) residue in position 83 to Proline (Pro). The proband's mother was found to be a carrier of this mutation. The present study suggests that a novel frameshift mutation (c. 246delG) in exon 5 of the CLCN5 gene is responsible for Dent disease in this case. Our findings also expand the known spectrum of CLCN5 mutations.

The role of microglia heterogeneity in synaptic plasticity and brain disorders: Will sequencing shed light on the discovery of new therapeutic targets?

Microglia play a crucial role in interacting with neuronal synapses and modulating synaptic plasticity. This function is particularly significant during postnatal development, as microglia are responsible for removing excessive synapses to prevent neurodevelopmental deficits. Dysregulation of microglial synaptic function has been well-documented in various pathological conditions, notably Alzheimer's disease and multiple sclerosis. The recent application of RNA sequencing has provided a powerful and unbiased means to decipher spatial and temporal microglial heterogeneity. By identifying microglia with varying gene expression profiles, researchers have defined multiple subgroups of microglia associated with specific pathological states, including disease-associated microglia, interferon-responsive microglia, proliferating microglia, and inflamed microglia in multiple sclerosis, among others. However, the functional roles of these distinct subgroups remain inadequately characterized. This review aims to refine our current understanding of the potential roles of heterogeneous microglia in regulating synaptic plasticity and their implications for various brain disorders, drawing from recent sequencing research and functional studies. This knowledge may aid in the identification of pathogenetic biomarkers and potential factors contributing to pathogenesis, shedding new light on the discovery of novel drug targets. The field of sequencing-based data mining is evolving toward a multi-omics approach. With advances in viral tools for precise microglial regulation and the development of brain organoid models, we are poised to elucidate the functional roles of microglial subgroups detected through sequencing analysis, ultimately identifying valuable therapeutic targets.