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Polycystic ovary syndrome (PCOS) is associated with impaired adipose tissue physiology. Elevated brown adipose tissue (BAT) mass or activity has shown potential in the treatment of PCOS. In this study, we aimed to investigate whether BAT-derived exosomes (BAT-Exos), as potential biomarkers of BAT activity, exert similar benefits as BAT in the treatment of PCOS. PCOS was induced in female C57BL/6J mice orally administered 1 mg/kg of letrozole for 21 days. Subsequently, the animals underwent transplantation with BAT or administered BAT-Exos (200 μg) isolated from young healthy mice via the tail vein; healthy female mice were used as controls. The results indicate that BAT-Exos treatment significantly reduced body weight and improved insulin resistance in PCOS mice. In addition, BAT-Exos improved ovulation function by reversing the acyclicity of the estrous cycle, decreasing circulating luteinizing hormone and testosterone, recovering ovarian performance, and improving oocyte quality, leading to a higher pregnancy rate and litter size. Furthermore, western blotting revealed reduced expression of signal transducer and activator of transcription 3 (STAT3) and increased expression of glutathione peroxidase 4 (GPX4) in the ovaries of mice in the BAT-Exos group. To further explore the role of the STAT3/GPX4 signaling pathway in PCOS mice, we treated the mice with an intraperitoneal injection of 5 mg/kg stattic, a STAT3 inhibitor. Consistent with BAT-Exos treatment, the administration of stattic rescued letrozole-induced PCOS phenotypes. These findings suggest that BAT-Exos treatment might be a potential therapeutic strategy for PCOS and that the STAT3/GPX4 signaling pathway is a critical therapeutic target for PCOS., (© 2024 Federation of American Societies for Experimental Biology.)

Background and Purpose: The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear., Experimental Approach: The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like effects of ketamine. Tph2 knockout or depletion of 5-HT by PCPA and 5,7-DHT were used to manipulate the brain 5-HT system. ELISA and fibre photometry recordings were used to measure extracellular 5-HT levels in the brain., Key Results: 60 min after injection, ketamine (10 mg·kg -1 , i.p.) produced rapid antidepressant-like effects and increased brain 5-HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5-HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant-like effects of ketamine were abrogated by PCPA and 5,7-DHT, or by Tph2 knockout. Importantly, NBQX (10 mg·kg -1 , i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5-HT levels and abolished the sustained antidepressant-like effects of ketamine in naïve or CRS-treated mice., Conclusion and Implications: This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant-like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets., (© 2024 British Pharmacological Society.)

Background: Diabetes-associated cognitive impairment (DACI) poses a significant challenge to the self-management of diabetes, markedly elevating the risk of adverse complications. A burgeoning body of evidence implicates microglia as a central player in the pathogenesis of DACI., Methods: We utilized proteomics to identify potential biomarkers in high glucose (HG)-treated microglia, followed by gene knockdown techniques for mechanistic validation in vitro and in vivo., Results: Our proteomic analysis identified a significant upregulation of AKAP8L in HG-treated microglia, with concurrent dysregulation of autophagy and inflammation markers, making AKAP8L a novel biomarker of interest. Notably, the accumulation of AKAP8L was specific to HG-treated microglia, with no observed changes in co-cultured astrocytes or neurons, a pattern that was mirrored in streptozotocin (STZ)-induced diabetic mice. Further studies through co-immunoprecipitation and proximity ligation assay indicated that the elevated AKAP8L in HG-treated microglial cells interacts with the mTORC1. In the STZ mouse model, we demonstrated that both AKAP8L knockdown and rapamycin treatment significantly enhanced cognitive function, as evidenced by improved performance in the Morris water maze, and reduced microglial activation. Moreover, these interventions effectively suppressed mTORC1 signaling, normalized autophagic flux, mitigated neuroinflammation, and decreased pyroptosis., Conclusions: Our findings highlight the critical role of AKAP8L in the development of DACI. By interacting with mTORC1, AKAP8L appears to obstruct autophagic processes and initiate a cascade of neuroinflammatory responses. The identification of AKAP8L as a key mediator in DACI opens up new avenues for potential therapeutic interventions., (© 2024. The Author(s).)

Tuberculous meningitis (TBM) is the most severe complication of tuberculosis (TB) and is associated with high rates of disability and mortality. Mycobacterium tuberculosis (M. tb), the infectious agent of TB, disseminates from the respiratory epithelium, breaks through the blood-brain barrier, and establishes a primary infection in the meninges. Microglia are the core of the immune network in the central nervous system (CNS) and interact with glial cells and neurons to fight against harmful pathogens and maintain homeostasis in the brain through pleiotropic functions. However, M. tb directly infects microglia and resides in them as the primary host for bacillus infections. Largely, microglial activation slows disease progression. The non-productive inflammatory response that initiates the secretion of pro-inflammatory cytokines and chemokines may be neurotoxic and aggravate tissue injuries based on damages caused by M. tb. Host-directed therapy (HDT) is an emerging strategy for modulating host immune responses against diverse diseases. Recent studies have shown that HDT can control neuroinflammation in TBM and act as an adjunct therapy to antibiotic treatment. In this review, we discuss the diverse roles of microglia in TBM and potential host-directed TB therapies that target microglia to treat TBM. We also discuss the limitations of applying each HDT and suggest a course of action for the near future.

TSPO, translocator protein (18 kDa) ligands have demonstrated consistent antidepression and anxiolytic effects in several preclinical studies. This study aimed to examine whether YL-IPA08[N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-ichlorophenyl) -7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, could alleviate anxiety-related behaviors induced by electric shock (ES) and investigate its underlying mechanism. As expected, we showed that chronic treatment with YL-IPA08 significantly reversed anxiety-related behaviors induced by electrical stimulation (0.5 mA, 12 times, duration 1s, interval 10s) exposure. Using the analysis of RNA-sequencing (RNA-seq) technology, it was found that the differential genes associated with the anxiolytic effect of YL-IPA08 were mainly related to synaptic plasticity. Furthermore, YL-IPA08 restored the decreased levels of brain-derived neurotrophic factor (BDNF), synapse-related protein (e.g. synapsin-1 and post-synaptic density95, PSD95), and the number of doublecortin (DCX) + neurons in the hippocampus of post-ES mice. In addition, YL-IPA08 also enhanced the dendritic complexity and dendritic spine density of hippocampal dentate gyrus (DG) granule neurons. Meanwhile, the induction of long-term potentiation (LTP) was significantly enhanced by YL-IPA08. In summary, the findings from the current study showed that YL-IPA08 exerted a clear anxiolytic effect, which might be partially mediated by promoting hippocampal neuroplasticity., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Gamma oscillations have attracted much attention in the field of mood disorders, but their role in depression remains poorly understood. This study aimed to investigate whether gamma oscillations in the medial prefrontal cortex (mPFC) could serve as a predictive biomarker of depression. Chronic restraint stress (CRS) or lipopolysaccharide (LPS) were used to induce depression-like behaviors in mice; local field potentials (LFPs) in the mPFC were recorded by electrophysiological techniques; We found that both CRS and LPS induced significant depression-like behaviors in mice, including increasing immobility durations in the forced swimming test (FST) and tail suspension test (TST) and increasing the latency to feed in the novelty-suppressed feeding test (NSFT). Electrophysiological results suggested that CRS and LPS significantly reduced low and high gamma oscillations in the mPFC. Furthermore, a single injection of ketamine or scopolamine for 24 h significantly increased gamma oscillations and elicited rapid-acting antidepressant-like effects. In addition, fluoxetine treatment for 21 days significantly increased gamma oscillations and elicited antidepressant-like effects. Taken together, our findings suggest that gamma oscillations are strongly associated with depression, yielding new insights into investigating the predictive biomarkers of depression and the time course of antidepressant effects., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Aim: Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG repeats expansion. Cognitive decline contributes to the loss of daily activity in manifest HD. We aimed to examine the cognition status in a Chinese HD cohort and explore factors influencing the diverse cognitive domains., Methods: A total of 205 participants were recruited in the study with the assessment by neuropsychological batteries, including the mini-mental state examination (MMSE), Stroop test, symbol digit modalities test (SDMT), trail making test (TMT), verbal fluency test (VFT), and Hopkins verbal learning test-revised, as well as motor and psychiatric assessment. Pearson correlation and multiple linear regression models were applied to investigate the correlation., Results: Only 41.46% of patients had normal global function first come to our center. There was a significantly difference in MMSE, Stroop test, SDMT, TMT, and VFT across each stage of HD patients (p < .05). Apathy of PBA-s was correlated to MMSE, animal VFT and Stroop-interference tests performance. Severity of motor symptoms, functional capacity, age, and age of motor symptom onset were correlated to all neuropsychological scores, whereas education attainment and diagnostic delay were correlated to most neuropsychological scores except TMT. Severity of motor symptoms, functional capacity, and education attainment showed independent predicting effect (p < .05) in diverse cognitive domains., Conclusion: Cognitive impairment was very common in Chinese HD patients at the first visit and worse in the patients in advanced phase. The severity of motor symptoms and functional capacity were correlated to the diverse cognitive domains., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Cancer-induced bone pain (CIBP) caused by bone metastasis is one of the most prevalent diseases, and current treatments rely primarily on opioids, which have significant side effects. However, recent developments in pharmaceutical science have identified several new mechanisms for CIBP, including the targeted modification of certain ion channels and receptors. Ion channels are transmembrane proteins, which are situated on biological cell membranes, which facilitate passive transport of inorganic ions across membranes. They are involved in various physiological processes, including transmission of pain signals in the nervous system. In recent years, there has been an increasing interest in the role of ion channels in chronic pain, including CIBP. Therefore, in this review, we summarize the current literature on ion channels, related receptors, and drugs and explore the mechanism of CIBP. Targeting ion channels and regulating their activity might be key to treating pain associated with bone cancer and offer new treatment avenues., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lu, Wu and Wei.)

Neuroinflammation contributes to the pathogenesis of depression. Inulin-type oligosaccharides of Morinda officinalis (IOMO) exert antidepressant-like effects in rodents and patients with depression, while the underlying mechanisms remain unclear. This study used chronic restraint stress (CRS) and lipopolysaccharide (LPS) to induce depression-like behaviors in mice. Western blotting and ELISA analysis were used to investigate the effects of IOMO on inflammatory cytokine levels. Immunofluorescence analysis was used to investigate the effects of IOMO on hippocampal NLRP3 inflammasome and microglial cells. The results suggested that 6 weeks of CRS induced significant depression-like behaviors based on the sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST), which were accompanied by increases in the expression of IL-6 and the activation of hippocampal microglial cells. Chronic treatment with IOMO (25 mg/kg, i.g.) for 28 days significantly reversed these depression-like behaviors and inhibited the activation of microglial cells. Furthermore, LPS (0.5 mg/kg, i.p.) also significantly induced depression-like behaviors in the TST, FST, and novelty-suppressed feeding test (NSFT), as well as increased the expression of IL-1β and caspase-1, and activated the microglial cells and the NLRP3 inflammasome in the hippocampus. Treatment with IOMO for 9 days significantly reversed these depression-like behaviors and normalized the LPS-induced activation of the microglial cells and NLRP3 inflammasome. Taken together, these results suggested that IOMO exerted antidepressant-like effects via hippocampal microglial NLRP3 inflammasome mediation followed by caspase-1 inhibition and the production of IL-1β. These findings provide a basis for developing new antidepressants targeting the microglial NLRP3 inflammasome., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The arterial occlusive disease is one of the leading causes of cardiovascular diseases, often requiring revascularization. Lack of suitable small-diameter vascular grafts (SDVGs), infection, thrombosis, and intimal hyperplasia associated with synthetic vascular grafts lead to a low success rate of SDVGs (< 6 mm) transplantation in the clinical treatment of cardiovascular diseases. The development of fabrication technology along with vascular tissue engineering and regenerative medicine technology allows biological tissue-engineered vascular grafts to become living grafts, which can integrate, remodel, and repair the host vessels as well as respond to the surrounding mechanical and biochemical stimuli. Hence, they potentially alleviate the shortage of existing vascular grafts. This paper evaluates the current advanced fabrication technologies for SDVGs, including electrospinning, molding, 3D printing, decellularization, and so on. Various characteristics of synthetic polymers and surface modification methods are also introduced. In addition, it also provides interdisciplinary insights into the future of small-diameter prostheses and discusses vital factors and perspectives for developing such prostheses in clinical applications. We propose that the performance of SDVGs can be improved by integrating various technologies in the near future., (© 2023. The Author(s).)

Objectivve: This study aimed to explore the prevalence and clinical correlates of apathy in amyotrophic lateral sclerosis (ALS) in a cohort of Chinese patients., Methods: A total of 1,013 ALS patients were enrolled in this study. Apathy was recorded during face-to-face interviews using Frontal Behavioral Inventory, and other patient characteristics, including depression, anxiety, and cognitive function, were collected using Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Chinese version of Addenbrooke's Cognitive Examination-revised. Health-related quality of life of ALS patients and their caregivers was also evaluated, and the potential factors associated with apathy were explored using forward binary regression analysis. Survival was analyzed using the Cox proportional hazards model., Results: The prevalence of apathy in all patients was 28.9%. Patients in the late disease stage had a higher prevalence of apathy than those in the early disease stage. Furthermore, patients with apathy had a lower ALS Functional Rating Scale revised (ALSFRS-R) score, higher HDRS score, HARS score and higher proportion of reported problems in the anxiety/depression. Additionally, their caregivers had higher score of depression and higher Zarit-Burden Interview scores. Multivariate regression analysis revealed that apathy in ALS was associated with the onset region ( p  = 0.027), ALSFRS-R score ( p  = 0.007), depression ( p  = 0.001) and anxiety ( p  < 0.001). Apathy had a significant negative effect on survival in ALS patients ( p  = 0.032)., Conclusion: Apathy is relatively common (28.9%) in Chinese patients with ALS. Apathy is related to both the severity of the disease, and the presentation of non-motor symptoms in ALS, such as depression and anxiety disorders. Apathy is an independent prognostic factor for survival and requires early intervention and management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wei, Guo, Li, Yang, Hou, Ou, Lin, Jiang and Shang.)

Social hierarchy greatly impacts physical and mental health, but the relationship between social hierarchy and depression/anxiety and the underlying neural mechanism remain unclear. The present study used the tube test to determine the social hierarchy status of mice and then performed several behavioral tests to evaluate depression-like and anxiety-like behaviors. Electrophysiological techniques were used to record the firing activities of glutamatergic pyramidal neurons and local field potentials in the medial prefrontal cortex (mPFC). The results suggested that the mice in each cage (4 per cage) established a stable social hierarchy after 2 weeks. Subordinate mice displayed significantly fewer pushing and advancing behaviors, and more retreat behaviors compared with dominant mice. Furthermore, subordinate mice had significantly more immobility durations in the TST, but significantly fewer distances, entries, and time into the center in the OFT, as well as significantly less percent of distances, entries, and time into the open arms in the EPMT, compared with dominant mice, which indicated that subordinate mice displayed depression- and anxiety-like behaviors. In addition, chronic restraint stress (CRS) significantly induced depression- and anxiety-like behaviors in mice and altered social dominance behaviors in the tube test. CRS mice displayed significantly fewer pushing and advancing behaviors, and more retreat behaviors compared with control mice. Furthermore, low social rank and CRS significantly decreased the firing of pyramidal neurons and γ-oscillation activity in the mPFC. Taken together, the present study revealed an inverse relationship between social hierarchy and depression/anxiety, and the neural basis underlying this association might be the excitability of pyramidal neurons and γ oscillation in the mPFC. These findings established an important foundation for a depression/anxiety model based on social hierarchy and provided a new avenue for the development of therapies for stress-related mood disorders., Competing Interests: The authors declare that there are no conflicts of interest., (© 2023 The Authors.)

Background: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder (NDS) with unclear pathophysiology and few therapeutic options. Mutations in SOD1 and C9orf72 are the most common in Asian and Caucasian patients with ALS, respectively. Aberrant (microRNAs) miRNAs found in patients with gene-mutated ALS may be involved in the pathogenesis of gene-specific ALS and sporadic ALS (SALS). The aim of this study was to screen for differentially expressed miRNAs from exosomes in patients with ALS and healthy controls (HCs) and to construct a miRNA-based diagnostic model to classify patients and HCs., Methods: We compared circulating exosome-derived miRNAs of patients with ALS and HCs using the following two cohorts: a discovery cohort (three patients with SOD1 -mutated ALS, three patients with C9orf72 -mutated ALS, and three HCs) analyzed by microarray and a validation cohort (16 patients with gene-mutated ALS, 65 patients with SALS, and 61 HCs) confirmed by RT-qPCR. The support vector machine (SVM) model was used to help diagnose ALS using five differentially expressed miRNAs between SALS and HCs., Results: A total of 64 differentially expressed miRNAs in patients with SOD1 -mutated ALS and 128 differentially expressed miRNAs in patients with C9orf72 -mutated ALS were obtained by microarray compared to HCs. Of these, 11 overlapping dysregulated miRNAs were identified in both groups. Among the 14 top-hit candidate miRNAs validated by RT-qPCR, hsa-miR-34a-3p was specifically downregulated in patients with SOD1 -mutated ALS, while hsa-miR-1306-3p was downregulated in ALS patients with both SOD1 and C9orf72 mutations. In addition, hsa-miR-199a-3p and hsa-miR-30b-5p were upregulated significantly in patients with SALS, while hsa-miR-501-3p, hsa-miR-103a-2-5p, and hsa-miR-181d-5p had a trend to be upregulated. The SVM diagnostic model used five miRNAs as features to distinguish ALS from HCs in our cohort with an area under receiver operating characteristic curve (AUC) of 0.80., Conclusion: Our study identified aberrant miRNAs from exosomes of SALS and ALS patients with SOD1 / C9orf72 mutations and provided additional evidence that aberrant miRNAs were involved in the pathogenesis of ALS regardless of the presence or absence of the gene mutation. The machine learning algorithm had high accuracy in predicting the diagnosis of ALS, shedding light on the foundation for the clinical application of blood tests in the diagnosis of ALS, and revealing the pathological mechanisms of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cheng, Gu, Yang, Wei, Cao, Zhang, Shang and Chen.)

This study area was based on the catchment area of the Yaoxianzi ditch located in the arid region of western China. A total of 194 topsoil samples of 0-20 cm depth were collected using the mesh distribution method. The contents of nine heavy metals (Ni, Cu, Zn, As, Ag, Cr, Cd, Hg, and Pb) were determined using ICP-MS. The source and spatial distribution of heavy metals were analyzed using PMF and IDW. Spatial autocorrelation and clustering and outlier analysis were performed using the Spatial Statistical Analysis tool of ArcGIS. The main sources and distribution areas of heavy metals in the soil were obtained through comprehensive analysis. In the study area, the average values of Hg, Ag, Cd, and Pb were 20.48, 3.13, 2.23, and 1.12 times the background values, and the maximum values of Cd, Cu, Pb, and As were 10.92, 5.52, 2.03, and 1.39 times the filter values, respectively. The coefficients of variation of Cu, Cd, Pb, and Hg were ordered as Cu(283.23%)>Cd(224.77%)>Pb(144.40%)>Hg(67.12%) and were closely affected by human activities. The heavy metals in the soil around mining areas came from four main sources:natural parent material (32%), the mixed source of mining activities and transportation (17.1%), the mixed source of industrial activities and atmospheric sedimentation (40.3%), and the mixed source of agricultural activity and putting sandy gravel in farmland (10.6%). Cr and Ni, As and Cu, Hg, and Cd could represent these four sources of heavy metal pollution, respectively. The main sources of soil heavy metal pollution were mining activities and agricultural activities. The heavily contaminated areas were distributed in the mining areas in the south of the study area and in the planting areas in the eastern, central, and northwestern parts of the study area.

Background and Purpose: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese., Methods: In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed., Results: Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction., Conclusions: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD., (© 2022 European Academy of Neurology.)

Background: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers., Methods: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72 . Forty-one ALS-associated genes were analysed., Findings: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72 , FUS , NEK1 , TARDBP and TBK1 . By burden analysis, rare variants in SOD1 , FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition., Conclusions: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The neutrophil-to-lymphocyte ratio (NLR) is considered a robust prognostic biomarker for predicting patient survival outcomes in many diseases. However, it remains unclear whether it can be used as a biomarker for amyotrophic lateral sclerosis (ALS). To correlate NLR with disease progression and survival in sporadic ALS, 1030 patients with ALS between January 2012 and December 2018 were included in this study. These patients were assigned into three groups according to their NLR values: Group 1 (NLR < 2, n = 544 [52.8%]), Group 2 (NLR = 2-3, n = 314 [30.5%]), and Group 3 (NLR > 3, n = 172 [16.7%]). All patients were followed up until April 2020. Patients in Group 3 had a significantly older onset age, a lower score on the Revised ALS Functional Rating Scale, and rapidly progressing disease conditions. Furthermore, faster disease progression rates were associated with higher NLR values (odds ratio = 1.211, 95% confidence interval [CI]: 1.090-1.346, P < 0.001) after adjusting for other risk factors. Compared with Groups 1 and 2, the survival time in Group 3 was significantly shorter (log-rank P = 0.002). The NLR value was considered an independent parameter for the prediction of survival in ALS patients after normalizing for all other potential parameters (hazard ratio [HR] = 1.079, 95% CI: 1.016-1.146, P = 0.014). The effects on ALS survival remained significant when adjusted for treatment (HR = 1.074, 95% CI: 1.012-1.141, P trend = 0.019) or when considering the stratified NLR value (HR = 1.115, 95% CI: 1.009-1.232, P trend = 0.033). Thus, the NLR may help to predict the rate of disease progression and survival in patients with sporadic ALS. The study was approved by the Institutional Ethics Committee of West China Hospital of Sichuan University, China (approval No. 2015 (236)) on December 23, 2015., Competing Interests: None

Ginseng (Panax ginseng C.A. Meyer) is a traditional Oriental herbal drug widely used in East Asia. Its main active ingredients are ginsenosides whose constituents are known to have various pharmacological activities such as anticancer, antinociception, and neuroprotection. The analgesic effects of ginsenosides, such as Rg1, Rg2, and Rb1, as well as compound K, are well known and the analgesic mechanism of action in inflammatory pain models is thought to be the down regulation of pro-inflammatory cytokine expression (TNF-α IL-1β, and IL-6). Several studies have also demonstrated that ginsenosides regulate neuropathic pain through the modulation of estrogen receptors. Recently, an increasing number of pathways have emerged in relation to the antinociceptive effect of ginseng and ginsenosides. Therefore, this review presents our current understanding of the effectiveness of ginseng in chronic pain and how its active constituents regulate nociceptive responses and their mechanisms of action., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Wei and Lu.)

Background and Objectives: Nonmotor symptoms are common in patients with multiple system atrophy (MSA), but there is limited knowledge regarding fatigue in MSA. This study aimed to investigate the frequency and evolution of fatigue and the factors related to fatigue and its progression in patients with MSA at an early stage., Methods: Patients with probable MSA were comprehensively evaluated at both baseline and the 1-year follow-up, including their motor and nonmotor symptoms. Fatigue and anxiety were assessed using the Fatigue Severity Scale (FSS) and Hamilton Anxiety Rating Scale (HARS), respectively. Orthostatic hypotension (OH) was defined as a decrease in the systolic or diastolic blood pressure by at least 30 and 15 mm Hg, respectively. The binary logistic regression model and linear regression model were used to analyze the factors related to fatigue and its progression, respectively., Results: This study enrolled 146 patients with MSA. The frequency of fatigue was 60.3%, 55.1%, and 64.9% in MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C), respectively. The frequency of fatigue and the FSS score in patients with MSA increased from baseline to the 1-year follow-up ( p < 0.05). Young age (odds ratio [OR] 0.939, 95% confidence interval [CI] 0.894-0.987), OH (OR 2.806, 95% CI 1.253-6.286), and high HARS score (OR 1.014, 95% CI 1.035-1.177) were associated with fatigue in MSA. OH was associated with fatigue in MSA-P (OR 3.391, 95% CI 1.066-10.788), while high HARS score was associated with fatigue in MSA-C (OR 1.159, 95% CI 1.043-1.287). In addition, only low FSS scores at baseline were associated with the annual progression rate of FSS scores in MSA, MSA-P, and MSA-C ( p < 0.05). Neurofilament light chain, α-synuclein, glial fibrillary acidic protein, brain-derived neurotrophic factor, and triggering receptor expressed on myeloid cell-2 were not significantly associated with fatigue and its progression in MSA., Discussion: Fatigue was prevalent in early-stage MSA, and it increased and remained persistent over time. This study demonstrated that OH and anxiety were associated with fatigue in patients with MSA., (© 2021 American Academy of Neurology.)

The AD7c-NTP is a promising biomarker for AD diagnosis. However, the exact urinary AD7c-NTP concentration to differentiate AD from the mild cognitive impairment (MCI) remains inconclusive. We enrolled 98 and 90 clinical defined AD and MCI patients, respectively, and access their cognition impairment with Neuropsychiatric Inventory (NPI) and Mental State Examination (MMSE) along with their urinary AD7c-NTP. We demonstrated that urinary AD7c-NTP level in sequence from high to low was AD, MCI, and healthy groups ( P < .01), and the AD7c-NTP was positively and negatively correlated with the NPI and MMSE scores, respectively. Additionally, AD7c-NTP well-matched NPI subscale scores, including agitation, depression, and apathy ( P < .05). Importantly, the optimal cut-off AD7c-NTP level to distinguish the AD and MCI was .94 ng/mL (sensitivity 85.71% & specificity 73.91%). Conclusively, urinary AD7c-NTP could be used for cognition impairment evaluation and differentiated diagnosis of AD and MCI.

Background: Few studies have focused on the cold hand sign (CHS), a red flag symptom, in multiple system atrophy (MSA). Objective: This study aimed to investigate the frequency and correlative factors of CHS in patients with MSA and the impact of its early occurrence on the survival of these patients. Methods: A total of 483 patients with MSA were enrolled in this study, and the motor and non-motor symptoms between patients with MSA with and without CHS were compared. Moreover, patients with disease duration ≤ 3 years at baseline were followed, and the association between CHS and survival of patients with MSA was examined. Results: The frequencies of CHS in patients with MSA were 20, 15.4, and 25.3% in MSA, MSA-parkinsonian subtype (MSA-P), and MSA-cerebellar subtype (MSA-C), respectively. Higher Unified Multiple System Atrophy Rating Scale (UMSARS) scores and higher Non-Motor Symptom Scale (NMSS) scores at baseline were associated with CHS in MSA. CHS was associated with shorter survival after adjusting for baseline diagnosis subtype, age at onset, sex, orthostatic hypotension, disease duration, autonomic onset, UMSARS total score, and NMSS score ( p = 0.001; HR = 3.701; 95% CI = 1.765-7.760). Conclusion: CHS is not rare in patients with MSA. Greater disease severity and more severe non-motor symptoms were associated with CHS in patients with MSA. Patients with early occurrence of CHS had a poor prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cao, Liang, Zhang, Hou, Ou, Wei and Shang.)

Abstract: Studies on the relationship between hospital annualized case volume and in-hospital mortality in patients with subarachnoid hemorrhage (SAH) have shown conflicting results. Therefore, we performed a meta-analysis to further examine this relationship.The authors searched the PubMed and Embase databases from inception through July 2020 to identify studies that assessed the relationship between hospital annualized SAH case volume and in-hospital SAH mortality. Studies that reported in-hospital mortality in SAH patients and an adjusted odds ratio (OR) comparing mortality between low-volume and high-volume hospitals or provided core data to calculate an adjusted OR were eligible for inclusion. No language or human subject restrictions were imposed.Five retrospective cohort studies with 46,186 patients were included for analysis. The pooled estimate revealed an inverse relationship between annualized case volume and in-hospital mortality (OR, 0.53; 95% confidence interval, 0.42-0.68, P < .0001). This relationship was consistent in almost all subgroup analyses and was robust in sensitivity analyses.This meta-analysis confirms an inverse relationship between hospital annualized SAH case volume and in-hospital SAH mortality. Higher annualized case volume was associated with lower in-hospital mortality., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Vascular risk factors have been reported to be associated with cognitive impairment (CI) in the general population, but their role on CI in multiple system atrophy (MSA) is unclear. This study aimed to explore the relationship between vascular risk factors and CI in patients with MSA. Methods: The clinical data and vascular risk factors were collected. The Montreal Cognitive Assessment tool was used to test the cognitive function of patients with MSA. Binary logistic regression was used to analyze the correlation between vascular risk factors and CI. Results: A total of 658 patients with MSA with a mean disease duration of 2.55 ± 1.47 years were enrolled. In MSA patients, hypertension was recorded in 20.2%, diabetes mellitus in 10.3%, hyperlipidemia in 10.2%, smoking in 41.2%, drinking in 34.8%, and obesity in 9.6%. The prevalence of CI in patients with MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C) was 45.0, 45.1, and 44.9%, respectively. In the binary logistic regression model, patients with more than one vascular risk factors were significantly more likely to have CI in MSA (OR = 4.298, 95% CI 1.456-12.691, P = 0.008) and MSA-P (OR = 6.952, 95% CI 1.390-34.774, P = 0.018), after adjusting for age, sex, educational years, disease duration, and total Unified multiple system atrophy rating scale scores. Conclusion: Multiple vascular risk factors had a cumulative impact on CI in MSA. Therefore, the comprehensive management of vascular risk factors in MSA should not be neglected., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Hou, Cao, Wei, Ou, Liu, Lin, Yang, Xiao, Zhao and Shang.)

Objective: This study aimed to explore the prevalence and clinical correlates of pathological laughter and crying (PLC) in patients with amyotrophic lateral sclerosis (ALS). Methods: A total of 1,031 ALS patients were enrolled between August 2012 and August 2019. The PLC was recorded by a face-to-face interview. Other characteristics of patients, including depression, anxiety, cognition, and behavior function, were also evaluated. The potential associated factors of PLC were explored using forward binary regression analysis. Survival was analyzed in groups using propensity score matching (PSM) and Cox proportional hazards models. Results: The prevalence of PLC was 11.4% in all patients at baseline. Bulbar-onset and female patients had higher prevalence of PLC. The multivariate regression analysis indicated that PLC in ALS was associated with bulbar onset ( p < 0.001), late disease stage ( p < 0.001), and higher score in the Hamilton Depression Rating Scale (HDRS) ( p = 0.012). The higher score of HDRS was significantly and independently associated with PLC occurrence in bulbar-onset patients ( p = 0.032). The late disease stage was related to PLC occurrence in spinal-onset patients ( p < 0.001). After comparison with matched pairs by using PSM, PLC at baseline had no impact on survival. Conclusion: PLC was not uncommon in ALS, especially in bulbar-onset and female patients. We highlighted that the emotional state other than cognitive function had possible relationship with PLC in ALS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wei, Ou, Lin, Zhang, Hou, Cao, Chen, Yang and Shang.)

Background: The study aimed to appraise the health-related quality of life (HRQoL) measured by the five-level EuroQol-5 dimensions (EQ-5D-5L) in amyotrophic lateral sclerosis (ALS), and to explore the associations between non-motor symptoms (mood changes, cognitive disturbances and sleep disturbances)., Methods: EQ-5D-5L descriptive scores were converted into a single aggregated "health utility" score. A calibrated visual analog scale (EQ-VAS) was used for self-rating of current health status. Multiple logistic regression analysis was used to explore the factors associated with HRQoL., Results: Among the 547 enrolled ALS patients who were assessed using EQ-5D-5L, the highest frequency of reported problems was with usual activities (76.7%), followed by self-care (68.8%) and anxiety/depression (62.0%). The median health utility score was 0.78 and the median EQ-VAS score was 70. Clinical factors corresponding to differences in the EQ-5D-5L health utility score included age of onset, onset region, the ALS Functional Rating Scale-Revised (ALSFRS-R) score, and King's College stages. Patients with depression, anxiety, and poor sleep had lower health utility scores. Patients with excessive daytime sleepiness and rapid eye movement sleep behavior disorder had lower EQ-VAS scores. Multivariate logistic analysis indicated that ALSFRS-R scores, depression, and anxiety were associated with health utility scores. After adjusting other parameters, ALSFRS-R score, stages, and depression were significantly associated with EQ-VAS scores (P < 0.05)., Conclusion: This study examined HRQoL in ALS patients using the Chinese version of the EQ-5D-5L scale across different stages of the disease. We found that HRQoL is related to disease severity and to mood disturbances. Management of non-motor symptoms may help improve HRQoL in ALS patients., (© 2021. The Author(s).)

Functional and genetic studies have identified association between several Zinc finger (ZNF) proteins and Parkinson's disease (PD). However, most of them were still awaiting further replications, especially in the Asian population. Here, we systematically selected PD-relevant ZNF genes and analyzed the genetic associations between these ZNFs and PD in a large Chinese PD cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated patients with early-onset PD (EOPD, age at onset < 50 years) using whole exome sequencing and evaluated the association between rare variants and EOPD at both allele and gene levels. Totally 91 rare variants were identified in ZNF746, ZNF646, ZNF184, ZNF165, ZND219, and GLIS1. One variant p.R373H in ZNF219 and two variants p.G161D and p.R158H in ZNF746 were significantly associated with EOPD, and gene-based burden analysis showed enrichment of rare variants of ZNF746 in EOPD. Our findings build up the connection between ZNF746 and PD from a genetic perspective for the first time, supplement current understanding for the genetic role of ZNFs in EOPD, and broaden the mutation spectrum in PD.

Background: Helicobacter pylori is a pathogen involved in several gastroduodenal diseases, whose infection mechanisms have not been completely confirmed. To study the specific mechanism of gastropathy caused by H. pylori, we analyzed the gene microarray of gastric mucosa and gastric cells infected by H. pylori through bioinformatics analysis., Methods: We downloaded GSE60427 and GSE74492 from the Gene Expression Omnibus (GEO) database, screened differentially expressed genes (DEGs), and identified the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) through R software. The Search Tool for the Retrieval of Interacting Genes (STRING) was applied to establish a protein-protein interaction (PPI) network and Cytoscape was used to identify the top seven hub genes. Besides, we also constructed the gene-microRNA(gene-miRNA) interaction through the miRTarBase v8.0 database by using the NetworkAnalyst tool., Results: One hundred and fifteen DEGs were screened out, with 54 genes up-regulated and 61 genes down-regulated, among which seven hub genes, including "IGF1R," "APOE," "IRS1," "ATF3," "LCN2," "IL2RG," and "PI3," were considered as the main regulatory proteins in gastric cells when infected by H. pylori., Conclusion: In this study, hub genes and related signal enrichment pathways of gastropathy infected by H. pylori were analyzed through bioinformatics analysis based on the GSE60427 and GSE74492 datasets., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Our aim was to measure the monthly rate of weight loss during 6 months prior to a diagnosis of amyotrophic lateral sclerosis (ALS) and to explore the effect on prognosis., Methods: We enrolled 522 patients free from eating difficulties and with short diagnostic delay between June 2014 to June 2019. The calculating formula for the monthly rate of weight loss=[(weight at baseline-weight at diagnosis)/(weight at baseline*100 %)]/time interval. We employed logistic regression analysis to reveal any association between weight loss and cognitive dysfunction. Survival analysis was performed using the Kaplan-Meier curves and Cox proportional hazard models., Results: Weight loss was observed in 272 patients (52.1 %). Patients with severe weight loss had an older age of onset, a lower ALS Functional Rating Scale-Revised score, a faster disease progression rate, and higher frequencies of executive dysfunction and cognitive decline. The monthly rate of weight loss was associated with executive dysfunction and cognitive decline after adjusting for the emotional state. The stratified monthly rate of weight loss was strongly and independently related to ALS survival after adjusting for confounding factors (HR = 1.473, P trend<0.001). Each upper ladder of the rate of weight loss was correlated with worse survival and a 47.3 % (95 % CI: 25.0-73.6 %) increased risk of mortality., Conclusions: Weight loss is very common in patients with ALS and is associated with poor survival. It is also associated with executive dysfunction and cognitive decline. An important mechanism of weight loss in the early stage of this disease may be hypermetabolism., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Chinese mahogany (Toona sinensis) is a woody plant that is widely cultivated in China and Malaysia. Toona sinensis is important economically, including as a nutritious food source, as material for traditional Chinese medicine and as a high-quality hardwood. However, the absence of a reference genome has hindered in-depth molecular and evolutionary studies of this plant. In this study, we report a high-quality T. sinensis genome assembly, with scaffolds anchored to 28 chromosomes and a total assembled length of 596 Mb (contig N50 = 1.5 Mb and scaffold N50 = 21.5 Mb). A total of 34,345 genes were predicted in the genome after homology-based and de novo annotation analyses. Evolutionary analysis showed that the genomes of T. sinensis and Populus trichocarpa diverged ~99.1-103.1 million years ago, and the T. sinensis genome underwent a recent genome-wide duplication event at ~7.8 million years and one more ancient whole genome duplication event at ~71.5 million years. These results provide a high-quality chromosome-level reference genome for T. sinensis and confirm its evolutionary position at the genomic level. Such information will offer genomic resources to study the molecular mechanism of terpenoid biosynthesis and the formation of flavour compounds, which will further facilitate its molecular breeding. As the first chromosome-level genome assembled in the family Meliaceae, it will provide unique insights into the evolution of members of the Meliaceae., (© 2021 John Wiley & Sons Ltd.)

Background: Camptocormia is common in patients with multiple system atrophy (MSA). The current study was aimed at assessing the frequency of camptocormia and its related factors in MSA patients with different disease durations. Also, the impact of camptocormia on disability was evaluated., Methods: A total of 716 patients were enrolled in the study. They were classified into three groups based on disease duration (≤ 3, 3-5, ≥ 5 years). Specific scales were used to evaluate the motor and non-motor symptoms. Disease severity was assessed using the Unified Multiple System Atrophy Rating Scale (UMSARS). The binary logistic regression model was used to explore the factors related to camptocormia. To analyze the impact of camptocormia on disability in patients with disease duration less than 5 years, propensity score matching (PSM) and stratified Cox regression analysis were used., Results: In the current study, we found that the frequency of camptocormia was 8.9, 19.7 and 19.2% when the disease duration was ≤3, 3-5, ≥ 5 years, respectively. In the disease duration ≤3 years group, we found that MSA-parkinsonian subtype (MSA-P) (OR = 2.043, P = 0.043), higher total UMSARS score (OR = 1.063, P < 0.001), older age of onset (OR = 1.047, P = 0.042), and lower score on the frontal assessment battery (FAB) (OR = 0.899, P = 0.046) were associated with camptocormia. Only greater disease severity was associated with camptocormia in the group of patients with disease duration 3-5 years (OR = 1.494, P = 0.025) and in the group of patients with disease duration ≥5 years (OR = 1.076, P = 0.005). There was no significant impact of camptocormia on disability in patients with a disease duration of < 5 years (HR = 0.687, P = 0.463)., Conclusion: The frequency of camptocormia increased with prolonged disease duration. Disease severity was related to camptocormia at different stages of the disease. The MSA-P subtype, older age of onset, and lower FAB score were associated with camptocormia in the early stage of the disease.

In the management of human immunodeficiency virus (HIV) infection around the world, chronic complications are becoming a new problem along with the prolonged life expectancy. Chronic pain is widespread in HIV infected patients and even affects those with a low viral load undergoing long-term treatment with antiviral drugs, negatively influencing the adherence to disease management and quality of life. A large proportion of chronic pain is neuropathic pain, which defined as chronic pain caused by nervous system lesions or diseases, presenting a series of nervous system symptoms including both positive and negative signs. Injury caused by HIV protein, central and peripheral sensitization, and side effects of antiretroviral therapy lead to neuroinflammation, which is regarded as a maladaptive mechanism originally serving to promote regeneration and healing, constituting the main mechanism of HIV-related neuropathic pain. Gp120, as HIV envelope protein, has been found to be the major toxin that induces neuropathic pain. Particularly, the microglia, releasing numerous pro-inflammatory substances (such as TNFα, IL-1β, and IL-6), not only sensitize the neurons but also are the center part of the crosstalk bridging the astrocytes and oligodendrocytes together forming the central sensitization during HIV infection, which is not discussed detailly in recent reviews. In the meantime, some NRTIs and PIs exacerbate the neuroinflammation response. In this review, we highlight the importance of clarifying the mechanism of HIV-related neuropathic pain, and discuss about the limitation of the related studies as future research directions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lu, Fu, Wei and Zhang.)

Recent genetic studies clearly indicate that variants in several lysosomal genes act as risk factors for idiopathic Parkinson's disease (PD). Variants in the co-activator of glucocerebrosidase gene (GBA) and the four active saposins (Sap A-D) which are encoded by the prosaposin gene (PSAP) are of particular interest; however, their genetic roles in PD are unknown. Whole-exome sequencing and Sanger sequencing were used to assess the genetic etiology of 400 autosomal dominant inherited PD (ADPD) and 300 sporadic PD (SPD) patients. Variants from public databases, including Genome Aggregation Database-East Asian (GnomAD&#95;EAS) and Chinese Millionome Database (CMDB), were used as control groups. Burden analysis based on gene and domains level were performed to investigate the role of rare PSAP variants in PD. Six rare and likely pathogenic variants, located in the Sap A-D domains, were identified and accounted for 0.75% (3/400) of ADPD and 1.33% (4/300) of SPD in the Chinese population. Based on the gene or domain, burden analysis showed that damaging missense variants in SapC had statistical significance on the risk of developing PD. Interestingly, rs4747203, an intronic variant potentially linked to PSAP expression, was associated with reduced risk for PD (p = 8.6e-7 in GnomAD EAS and p = 0.002 in Chinese). Clinically, patients carrying the likely pathogenic variants presented typical PD motor symptoms and responded well to levodopa treatment. Six out of seven patients carrying the likely pathogenic variants of PSAP presented slow disease progression, and none of the patients developed cognitive impairment. Our study expands the spectrum of mutations associated with the risk of developing PD and enhances the understanding of the relationship of the clinical phenotype of PD with PSAP variants.

Objective: The current study was aimed at examining the frequency of and potential factors related to pathological laughter and crying (PLC) in multiple system atrophy (MSA) as well as evaluating the impact of PLC on the survival of patients with early stage MSA., Methods: A total of 465 MSA patients were enrolled in the study. The binary logistic regression model was used to explore the potential factors related to PLC. Altogether, 142 patients in their early stage (disease duration ≤3 years), who were followed up for at least two years, were included in the propensity score matching (PSM) analysis. A Cox regression model was used to analyze the impact of PLC on the survival of patients with early stage MSA., Results: The frequency of PLC was 12.7%, 12.0%, and 13.2% in MSA, MSA-parkinsonian subtype (MSA-P), and MSA-cerebellar type (MSA-C), respectively. The binary logistic regression model indicated that younger age and higher total UMSARS scores were associated with PLC in MSA, MSA-P, and MSA-C patients. Additionally, for patients in the early stage, it was found that PLC was not a predictor for mortality in MSA, as indicated by the multivariate Cox regression model., Conclusion: PLC was not uncommon in patients with MSA, MSA-P, and MSA-C. Younger age and greater disease severity were associated with PLC in MSA, MSA-P, and MSA-C patients. PLC was not a predictor of mortality in patients with MSA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Creatine kinase is a muscle enzyme that has been reported at various levels in different studies involving patients with amyotrophic lateral sclerosis. In the present retrospective case-control study, we included 582 patients with amyotrophic lateral sclerosis and 582 age- and sex-matched healthy controls. All amyotrophic lateral sclerosis participants received treatment in the Department of Neurology, West China Hospital, China, between May 2008 and December 2018. Serum creatine kinase levels in patients with amyotrophic lateral sclerosis were significantly higher than those in healthy controls. Subgroup analysis revealed that serum creatine kinase levels in men were higher than those in women in both amyotrophic lateral sclerosis patients and healthy controls. Compared with patients with bulbar-onset amyotrophic lateral sclerosis, patients with limb-onset amyotrophic lateral sclerosis had higher creatine kinase levels. Spearman's correlation analysis revealed that serum creatine kinase levels were not correlated with body mass index, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, or progression rate. After adjusting for prognostic covariates, higher log creatine kinase values were correlated with higher overall survival in the amyotrophic lateral sclerosis patients. We also investigated the longitudinal changes in serum creatine kinase levels in 81 amyotrophic lateral sclerosis patients; serum creatine kinase levels were decreased at the second blood test, which was sampled at least 6 months after the first blood test. Together, our results suggest that serum creatine kinase levels can be used as an independent factor for predicting the prognosis of amyotrophic lateral sclerosis patients. This study received ethical approval from the Ethics Committee of West China Hospital, China (approval No. 2015(236)) on December 23, 2015., Competing Interests: None

Background: Epidemiological and clinical studies have suggested comorbidity between amyotrophic lateral sclerosis (ALS) and autoimmune disorders. However, little is known about their shared genetic architecture., Methods: To examine the relation between ALS and 10 autoimmune diseases, including asthma, celiac disease (CeD), Crohn's disease (CD), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and ulcerative colitis (UC), and identify shared risk loci, we first estimated the genetic correlation using summary statistics from genome-wide association studies, and then analyzed the genetic enrichment leveraging the conditional false discovery rate statistical method., Results: We identified a significant positive genetic correlation between ALS and CeD, MS, RA, and SLE, as well as a significant negative genetic correlation between ALS and IBD, UC, and CD. Robust genetic enrichment was observed between ALS and CeD and MS, and moderate enrichment was found between ALS and UC and T1D. Thirteen shared genetic loci were identified, among which five were suggestively significant in another ALS GWAS, namely rs3828599 (GPX3), rs3849943 (C9orf72), rs7154847 (G2E3), rs6571361 (SCFD1), and rs9903355 (GGNBP2). By integrating cis-expression quantitative trait loci analyses in Braineac and GTEx, we further identified GGNBP2, ATXN3, and SLC9A8 as novel ALS risk genes. Functional enrichment analysis indicated that the shared risk genes were involved in four pathways including membrane trafficking, vesicle-mediated transport, ER to Golgi anterograde transport, and transport to the Golgi and subsequent modification., Conclusions: Our findings demonstrate a specific genetic correlation between ALS and autoimmune diseases and identify shared risk loci, including three novel ALS risk genes. These results provide a better understanding for the pleiotropy of ALS and have implications for future therapeutic trials.

Background: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson's disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown., Objective: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD., Methods: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal function-related genes and 52 lysosomal storage disorder genes., Results: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2, MCOLN1, LYST, VPS16, and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs., Conclusion: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence.

Background: Sleep disorders are common but under-researched symptoms in patients with multiple system atrophy (MSA). We investigated the frequency and factors associated with sleep-related symptoms in patients with MSA and the impact of sleep disturbances on disease severity., Methods: This cross-sectional study involved 165 patients with MSA. Three sleep-related symptoms, namely Parkinson's disease (PD)-related sleep problems (PD-SP), excessive daytime sleepiness (EDS), and rapid eye movement sleep behavior disorder (RBD), were evaluated using the PD Sleep Scale-2 (PDSS-2), Epworth Sleepiness Scale (ESS), and RBD Screening Questionnaire (RBDSQ), respectively. Disease severity was evaluated using the Unified MSA Rating Scale (UMSARS)., Results: The frequency of PD-SP (PDSS-2 score of ≥18), EDS (ESS score of ≥10), and RBD (RBDSQ score of ≥5) in patients with MSA was 18.8%, 27.3%, and 49.7%, respectively. The frequency of coexistence of all three sleep-related symptoms was 7.3%. Compared with the cerebellar subtype of MSA (MSA-C), the parkinsonism subtype of MSA (MSA-P) was associated with a higher frequency of PD-SP and EDS, but not of RBD. Binary logistic regression revealed that the MSA-P subtype, a higher total UMSARS score, and anxiety were associated with PD-SP; that male sex, a higher total UMSARS score, the MSA-P subtype, and fatigue were associated with EDS; and that male sex, a higher total UMSARS score, and autonomic onset were associated with RBD in patients with MSA. Stepwise linear regression showed that the number of sleep-related symptoms (PD-SP, EDS, and RBD), disease duration, depression, fatigue, and total Montreal Cognitive Assessment score were predictors of disease severity in patients with MSA., Conclusions: Sleep-related disorders were associated with both MSA subtypes and the severity of disease in patients with MSA, indicating that sleep disorders may reflect the distribution and degree of dopaminergic/non-dopaminergic neuron degeneration in MSA., (Copyright © 2020 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

To realize the comprehensive utilization of resources of moutai-flavor vinasse and improve the nitrogen efficiency of yellow soil, a field culture experiment was carried out to study the effects of short-term application of vinasse biochar on nitrogen availability and bacterial community structure diversity in yellow soil of Guizhou by setting 5 biochar dosages of 0% (MB 0 ), 0.5% (MB 0.5 ), 1.0% (MB 1.0 ), 2.0% (MB 2.0 ), and 4.0% (MB 4.0 ). The results showed that the total nitrogen(TN) and nitrate nitrogen(NN) content in the soil increased by 35.79%-365.26% and 122.96%-171.80%, the microbial biomass nitrogen (MBN) content decreased by 34.10%-59.95%, and the AN/TN, NN/TN, and MBN/TN exhibited a decreasing trend with an increase in the amount of biochar applied. The application of vinasse biochar significantly reduced the number of OTU and community richness and diversity of soil bacteria; the influence degree increased with an increase in the application amount of vinasse biochar. In comparison with the MB 0 treatment, the application of biochar significantly changed the soil bacterial community structure. The relative abundance of Bacteroidetes increased by 1.76-2.11 times with an increase in the biochar application. However, the relative abundance of Acidobacteria, Chloroflexi, Gemmatimonadetes, Planctomycetes, Armatimonadetes, Thaumarchaeota, and Nitrospirae decreased to different degrees, with the most significant decrease in the MB 4.0 treatment. The application of vinasse biochar increased the relative abundance of certain soil functional bacteria, such as Streptomyces and Pusillimonas , and simultaneously also decreased the relative abundance of the dominant bacteria, such as Lysobacter and Gemmatimonas . In addition, the redundancy analysis (RDA) showed that the MBN/TN, NN, and MBN were the main cause of soil bacterial community structure change in nitrogen environment factor. The MBN/TN and MBN exhibited a significantly positive correlation with Thaumarchaeota and Nitrospira , which indicated that the short-term application of vinasse biochar can significantly reduce the abundance of ammonia-oxidizing archaea and nitrifying bacteria, inhibit the ammonia-oxidizing effect and nitrification rate of soil, and improve the availability of soil nitrogen. In summary, the short-term application of vinasse biochar can improve nitrogen nutrients, change the structure and diversity of soil bacterial community, and effectively control the risk of soil nitrogen leaching by inhibiting ammonia oxidation and nitrification of soil, to improve the availability of soil nitrogen.

Background: Impaired dopamine metabolism is associated with Parkinson's disease (PD). Considering the overlap in the clinical and pathological characteristics between PD and multiple system atrophy (MSA), we investigated the effect of five potential functional polymorphisms in dopamine metabolism-related genes on disease susceptibility, phenotypes, and responses to dopamine in a large sample of PD and MSA patients. Methods: A total of 1506 PD patients, 496 MSA patients, and 894 healthy controls were included in this study. Five variants (rs6356 in TH , rs921451 in DDC , rs4680 in COMT , rs1799836 in MAOB , and rs1611115 in DBH ) were genotyped in all cases using Sequenom iPLEX Assay technology. Results: After adjusting for gender and age at onset, except for DDC rs921451, which was associated with an increased risk of MSA ( p = 0.001, OR = 1.21), no significant differences were found in genotype distribution or minor allele frequencies for the other four variants between PD and MSA patients and healthy controls. In the subgroup analysis, DDC rs921451 was associated with an increased risk for late-onset PD as well as for PD onset in males ( p = 0.002 [OR = 1.13] p = 0.003 [OR = 1.15], respectively). In addition, patients harboring the risk allele DDC rs921451 required lower levodopa equivalent daily doses of dopaminergic medication than those without the risk allele (52.00 ± 21.31 mg/day, p = 0.015). Conclusion: None of the five candidate functional variants is a major determinant of the risk for PD or MSA. The modified PD phenotypes associated with these variants requires further confirmation., (Copyright © 2020 Chen, Ou, Zhang, Gu, Yuan, Wei, Cao, Zhao, Wu and Shang.)

Objective: In this study, the effect of epithelial cell transformation sequence 2 (ECT2) on the proliferation, invasion and migration of esophageal squamous cell carcinoma (ESCC) was investigated by interfering the expression of ECT2., Patients and Methods: Interfering with the expression level of ECT2 in human squamous cell carcinomas KYSE140 and EC9706 cell lines, the changes of KYSE140 and EC9706 cell proliferation, invasion, and migration were measured using the CCK-8 method, transwell test, and scratch test, respectively. The effects of ECT2 on the Ras homolog gene family, member A-extracellular regulated protein kinases (RhoA-ERK) signaling pathway were also observed., Results: Compared with the control group, the proliferation, migration, and invasion ability of EC9706 and KYSE140 cells after ECT2 knockout were significantly reduced (p <0.05). The knockdown of ECT2 expression in ESCC cell lines suppressed the activation of RhoA-ERK signaling pathway and protein expression of VEGF and MMP9., Conclusions: ECT2 could regulated the expression of VEGF and MMP9 to inhibit cells proliferation, invasion, migration and tumor development through RhoA-ERK signaling pathway. Therefore, ECT2 could be an available marker, and provide a new theoretical basis for the treatment of ESCC.

Objective: It is reported that circular RNA plays an important role in various cancers in recent years. However, there is less investigation reported in lung adenocarcinoma (LUAD) about circRNA. This study aims to explore the role and molecular mechanism of circle RNA FOXP1 in LUAD procession., Patients and Methods: The levels of circFOXP1 and miR-185-5p in LUAD cell lines and LUAD cancer samples were examined by RT-PCR. The functions of circFOXP1 and miR-185-5p at LUAD cells were detected by cell transfection of the overexpression or repression. The A549 and H1299 cell proliferation were detected by MTT assay and colony formation assay. And the cell apoptosis was detected by TUNEL assay. The expression levels WNT1 were measured by Western blot in A549 and H1299 cells. Furthermore, the luciferase assay detected the direct interaction between circFOXP1 and miR-185-5p or miR-185-5p and WNT1., Results: The circFOXP1 expression was increased in LUAD patients and LUAD cell lines. The downregulation of circFOXP1 significantly repressed LUAD cell proliferation and promoted cell apoptosis. Moreover, the luciferase assay results confirmed that circFOXP1 directly interacted with miR-185-5p. Overexpression of miR-185-5p could reverse the effect of circFOXP1 in LUAD cell. Besides, the luciferase results showed that miR-185-5p directly interacted with WNT1. miR-185-5p overexpression inhibited the WNT1 expression, while circFOXP1 repression decreased the WNT1 level in LUAD cell lines. The downregulating WNT1 could reverse the effects of miR-185-5p inhibition in LUAD cell lines. Furthermore, WNT1 was significantly upregulated in LUAD cancer tissues. In addition, circFOXP1 level was negatively correlated with miR-185-5p expression and positively correlated with WNT1 expression in LUAD cancer tissues., Conclusions: These data suggested that circFOXP1 promoted cell proliferation and repressed cell apoptosis in LUAD by regulating miR-185-5p/WNT1 signaling pathway. It provides a novel potential therapeutic agent for the treatment of LUAD.

The global prevalence of nonalcoholic steatohepatitis (NASH) increases incredibly. NASH ends up to advanced liver disease, which is highly threatening to human health. Currently, treatment of NASH is very limited. Acetyl-CoA carboxylases (ACC1/ACC2) are proved as effective drug targets for NASH. We aimed to develop novel ACC inhibitors and evaluate their therapeutic value for NASH prevention. ACC inhibitors were obtained through structure-based drug design, synthesized, screened from ACC enzymatic measurement platform and elucidated in cell culture-based assays and animal models. The lipidome and microbiome analysis were integrated to assess the effects of WZ66 on lipids profiles in liver and plasma as well as gut microbiota in the intestine. WZ66 was identified as a novel ACC1/2 inhibitor. It entered systemic circulation rapidly and could accumulate in liver. WZ66 alleviated NASH-related liver features including steatosis, Kupffer cells and hepatic stellate cells activation in diet-induced obese mice. The triglycerides (TGs) and other lipids including diglycerides (DGs), phosphatidylcholine (PC) and sphingomyelin (SM) were decreased in WZ66-treated mice as evidenced by lipidome analysis in livers. The lipids profiles in plasma were also altered with WZ66 treatment. Plasma TG were moderately increased, while the activation of SREBP1c was not detected. WZ66 also downregulated the abundance of Allobaculum, Mucispirillum and Prevotella genera as well as Mucispirillum schaedleri species in gut microbiota. WZ66 is an ideal lead compound and a potential drug candidate deserving further investigation in the therapeutics of NASH.

Background: Spastic paraplegia type 11 (SPG11) mutations are the most frequent cause of autosomal recessive hereditary spastic paraplegia (ARHSP). We are aiming to identify the causative mutations in SPG11 among families referred to our center with ARHSP in a Chinese population., Methods: Targeted next-generation sequencing was performed on the patients to identify disease-causing mutations. Variants were analyzed according to their predicted pathogenicity and their relevance to the clinical phenotypes. The segregation in the family members was validated by Sanger sequencing., Results: A total of 12 mutations in SPG11 gene from 9 index cases were identified, including 6 frameshift mutations, 3 missense mutations, 1 nonsense mutation, 1 splicing mutation, and 1 intron deletion mutation. In 6 of these patients, the mutations were homozygous, and the other 3 patients carried two compound heterozygous mutations. Six mutations were novel; 2 were classified as pathogenic, 1 were considered as likely pathogenic, and the other 3 were variants of unknown significance. Additionally, 1 missense heterozygous variant we found was also carried by amyotrophic lateral sclerosis (ALS) patient. Clinically and electrophysiologically, some of our ARHSP patients partially shared various features of autosomal-recessive juvenile amyotrophic lateral sclerosis (ARJALS), including combination of both UMN and LMN degeneration., Conclusions: The results contribute to extending of the SPG11 gene mutation spectrum and emphasizing a putative link between ARHSP and ARJALS.

Proinflammatory cytokine such as interleukin (IL)-1β causes inflammation of articular cartilage. In this current study, we explored the chondroprotective effects of long noncoding RNA (lncRNA) MALAT-1 on cell proliferation, apoptosis, and matrix metabolism in IL-1β-induced inflammation in articular chondrocytes. Articular chondrocytes from knee joints of normal rats were isolated and cultured, followed by identification through observation of toluidine blue and COL II immunocytochemical stainings. The proliferation of chondrocytes at passage 2 was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The inflammatory chondrocytes induced by 10 ng/mL IL-1β were observed and identified by toluidine blue and COL II immunocytochemical stainings. pcDNA 3.1 and pcDNA-MALAT-1 were transfected in the chondrocytes. Ultrastructure of chondrocytes was observed by using a transmission electron microscope. The MTT assay was carried out to evaluate chondrocyte viability. Hoechst 33258 staining and flow cytometry were adopted to assess chondrocyte apoptosis. The chondrocytes at passage 2 with the biological characteristics of chondrocytes were used for subsequent experiments. In IL-1β-treated chondrocytes, the growth rate of chondrocytes slowed down, the cells became narrow and long, the vacuoles were seen in the cells, and the morphology of the chondrocytes was irregular. The toluidine blue staining and the immunohistochemical staining of COL II became weaker. In response to IL-1β induction, articular chondrocytes showed reduced MALAT-1 expression; moreover, obvious cartilage injury was observed with decreased chondrocyte viability and Col II expression and elevated chondrocyte apoptosis, MMP-13 expression, and p-JNK expression. With the treatment of pcDNA-MALAT-1, the cartilage injury was alleviated with increased chondrocyte viability and type II collagen (Col II) expression and reduced chondrocyte apoptosis, MMP-13 expression and p-JNK expression. Taken together these results, lncRNA MALAT-1 blocked the activation of the JNK signaling pathway; thereby, IL-1β-induced inflammation in articular chondrocytes was reduced with enhanced chondrocyte proliferation and suppressed chondrocyte apoptosis and extracellular matrix degradation., (© 2019 Wiley Periodicals, Inc.)

Objective: The prevalence of postural deformities in patients with multiple system atrophy (MSA) has varied among previous studies. The objective of our study was to investigate the prevalence of and factors associated with postural deformities in Chinese MSA patients., Methods: A total of 732 MSA patients were consecutively enrolled in the current study. Clinical data including age, sex, age of onset, disease duration, onset symptom and treatment were collected. The Unified Multiple System Atrophy Rating Scale (UMSARS) was used to evaluate the severity of the disease., Results: One hundred and fourteen (15.6%) patients presented with camptocormia. Thirty-one (4.2%) patients manifested with Pisa syndrome. Twenty-four (3.3%) patients presented with antecollis. Patients who exhibited postural deformities were more common among the MSA patients with predominant parkinsonism (MSA-P) (P < 0.05). In addition, MSA patients with postural deformities had a longer disease duration compared to those patients without postural deformities (P < 0.001). After adjusting for disease duration, compared with patients without postural deformities, MSA patients with postural deformities presented with higher score of UMSARS-I (P < 0.001), UMSARS-II (P < 0.001), UMSARS-IV (P < 0.001), and total UMSARS (P < 0.001) scores. The binary logistic regression model indicated that the factors associated with postural deformity in MSA patients were the total UMSARS score (OR = 1.076, P < 0.001) and MSA-P subtype (OR = 3.870, P < 0.001)., Conclusion: Postural deformities were common in Chinese MSA patients. Camptocormia was the most common type of postural deformity, followed by Pisa syndrome and antecollis. The factors associated with postural deformity were the severity of the disease and MSA-P subtype., (Copyright © 2019. Published by Elsevier Ltd.)