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Abstract Hyperuricemic nephropathy (HN) is renal injury caused by hyperuricemia (HUA). While sleeve gastrectomy (SG) has shown promise in improving renal injury in patients with obesity-related HN, the mechanisms are not fully understood. This study induced an obesity-combined HN model in male ob/ob mice and measured serum uric acid (SUA), creatinine, and other biochemical indicators 6 weeks post-surgery. Renal histological changes were evaluated through staining techniques, and the study also assessed renal adenosine monophosphate-activated protein kinase (AMPK) and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation levels and urate transporter ABCG2 expression. In vitro experiments involved Nrf2 knockdown in AMPK-activated HK-2 cells and ChIP to confirm Nrf2 binding to the ABCG2 promoter. Results showed that SG reduced SUA levels, serum creatinine, and blood urea nitrogen, increased p-AMPK, p-Nrf2 protein, and ABCG2 expression, and alleviated renal fibrosis and inflammation. In vitro, Nrf2 knockdown down-regulated ABCG2 expression, and ChIP confirmed Nrf2’s role in ABCG2 transcription. The study suggests that SG may improve renal injury in HN mice by modulating the AMPK/Nrf2 pathway and upregulating ABCG2 transcription.

Abstract Lipid droplets (LDs), which are active organelles, derive from the monolayer membrane of the endoplasmic reticulum and encapsulate neutral lipids internally. LD-associated proteins like RAB, those in the PLIN family, and those in the CIDE family participate in LD formation and development, and they are active players in various diseases, organelles, and metabolic processes (i.e., obesity, non-alcoholic fatty liver disease, and autophagy). Our synthesis on existing research includes insights from the formation of LDs to their mechanisms of action, to provide an overview needed for advancing research into metabolic diseases and lipid metabolism.

Abstract Bio-mechanoreceptors capable of micro-motion sensing have inspired mechanics-guided designs of micro-motion sensors in various fields. However, it remains a major challenge for mechanics-guided designs to simultaneously achieve high sensitivity and broadband sensing due to the nature of resonance effect. By mimicking rat vibrissae, here we report a metamaterial mechanoreceptor (MMR) comprised of piezoelectric resonators with distributed zero effective masses featuring a broad range of local resonances, leading to near-infinite sensitivity for micro-motion sensing within a broad bandwidth. We developed a mechanical frequency-division multiplexing mechanism for MMR, in which the measured micro-motion signal is mechanically modulated in non-overlapping frequency bands and reconstructed by a computational multi-channel demodulation approach. The maximum sensitivity of MMR is improved by two orders of magnitude compared to conventional mechanics-guided mechanoreceptors, and its bandwidth with high sensitivity is extendable towards both low-frequency and high-frequency ranges in 0–12 kHz through tuning the local resonance of each individual sensing cell. The MMR is a promising candidate for highly sensitive and broadband micro-motion sensing that was previously inaccessible for mechanics-guided mechanoreceptors, opening pathways towards spatio-temporal sensing, remote-vibration monitoring and smart-driving assistance.

Abstract Background Electroencephalogram (EEG) has emerged as a non-invasive tool to detect the aberrant neuronal activity related to different stages of Alzheimer’s disease (AD). However, the effectiveness of EEG in the precise diagnosis and assessment of AD and its preclinical stage, amnestic mild cognitive impairment (MCI), has yet to be fully elucidated. In this study, we aimed to identify key EEG biomarkers that are effective in distinguishing patients at the early stage of AD and monitoring the progression of AD. Methods A total of 890 participants, including 189 patients with MCI, 330 patients with AD, 125 patients with other dementias (frontotemporal dementia, dementia with Lewy bodies, and vascular cognitive impairment), and 246 healthy controls (HC) were enrolled. Biomarkers were extracted from resting-state EEG recordings for a three-level classification of HC, MCI, and AD. The optimal EEG biomarkers were then identified based on the classification performance. Random forest regression was used to train a series of models by combining participants’ EEG biomarkers, demographic information (i.e., sex, age), CSF biomarkers, and APOE phenotype for assessing the disease progression and individual’s cognitive function. Results The identified EEG biomarkers achieved over 70% accuracy in the three-level classification of HC, MCI, and AD. Among all six groups, the most prominent effects of AD-linked neurodegeneration on EEG metrics were localized at parieto-occipital regions. In the cross-validation predictive analyses, the optimal EEG features were more effective than the CSF + APOE biomarkers in predicting the age of onset and disease course, whereas the combination of EEG + CSF + APOE measures achieved the best performance for all targets of prediction. Conclusions Our study indicates that EEG can be used as a useful screening tool for the diagnosis and disease progression evaluation of MCI and AD.

Abstract Objectives CYLD was a novel causative gene for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. Given the clinical and pathological overlap of FTD and Alzheimer's disease (AD), it is necessary to screen CYLD in AD patients and FTD patients in the Chinese population. Methods In our study, using a targeted sequencing panel, we sequenced the CYLD gene in a large cohort of 2485 participants in the Chinese population, including 1008 AD patients, 105 FTD patients, and 1372 controls. Results In the present study, the average onset age of AD and FTD patients was 66.84 ± 30.42 years old and 60 ± 10.00 years old, respectively. Our study reported three novel CYLD variants: p.Phe288Leu (patient No. 1, AD), p.Tyr485Phe (patients No. 6–9, all AD) and p.Thr951Ala (patient No. 10, AD), plus a previously reported variant: p.Arg397Ser (patient No. 2–5, AD and No. 11, FTD). These variants were absent in our in‐house controls and predicted to be deleterious according to the MutationTaster. The variant carriers were composed of 10 AD patients and one FTD patient, and the average onset age was 61.2 ± 10.9 years. The frequency of CYLD variants in AD was similar to that in FTD, which was 0.99% (10/1008) and 0.95% (1/105), respectively. Interpretation Our finding extended the genotype and phenotype of the CYLD gene and demonstrated that CYLD rare damaging variants may be implicated in AD and FTD pathogenesis.

BackgroundProgressive supranuclear palsy (PSP) is a clinically heterogenous atypical parkinsonian syndrome. Therefore, early recognition and correct diagnosis of PSP is challenging but essential. This study aims to characterize the clinical manifestations, magnetic resonance imaging (MRI), and longitudinal MRI changes of PSP in China.MethodClinical and MRI presentations were compared among 150 cases with PSP. Then the longitudinal MRI changes among 20 patients with PSP were further explored. Additionally, a series of midbrain-based MRI parameters was compared between PSP-P and PD.ResultsThroughout the course of the disease, there were differences in the symptoms of the fall and hand tremor between the PSP-RS and PSP-P. There were significant differences in the six midbrain-based MRI parameters between the PSP-RS and the PSP-P, including hummingbird sign, midbrain diameter, midbrain to pons ratio (MTPR), midbrain area, midbrain area to pons area ratio (Ma/Pa), and midbrain tegmental length (MBTegm). Longitudinal MRI studies revealed that the annual rel.ΔMTPR and rel.Δ (Ma/Pa) for PSP were 5.55 and 6.52%, respectively; additionally, PSP-RS presented a higher decline rate than PSP-P. Moreover, MTPR ≤0.56, midbrain diameter ≤ 0.92, midbrain area ≤ 1.00, and third ventricle width ≤ 0.75 could identify PSP-P from PD.ConclusionPSP-P differs from PSP-RS regarding clinical manifestations, MRI, and longitudinal MRI changes. MRI parameters could be potential imaging markers to identify PSP-P from PD.

BackgroundThis study aimed to investigate the features of autonomic dysfunction (AutD) in a large cohort of patients with neuronal intranuclear inclusion disease (NIID).MethodsA total of 122 patients with NIID and 122 controls were enrolled. All participants completed the Scales for Outcomes in Parkinson’s Disease-Autonomic Questionnaire (SCOPA-AUT) and genetic screening for GGC expanded repeats within the NOTCH2NLC gene. All patients underwent neuropsychological and clinical assessments. SCOPA-AUT was performed to compare AutD between patients and controls. The associations between AutD and disease-related characteristics of NIID were studied.Results94.26% of patients had AutD. Compared with controls, patients had more severe AutD in total SCOPA-AUT, gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor and sexual domains (all p

BackgroundPrevious epidemiological studies have reported controversial results on the relationship between smoking and Alzheimer’s disease (AD). Therefore, we sought to assess the association using Mendelian randomization (MR) analysis.MethodsWe used single nucleotide polymorphisms (SNPs) associated with smoking quantity (cigarettes per day, CPD) from genome-wide association studies (GWAS) of Japanese population as instrumental variables, then we performed two-sample MR analysis to investigate the association between smoking and AD in a Chinese cohort (1,000 AD cases and 500 controls) and a Japanese cohort (3,962 AD cases and 4,074 controls), respectively.ResultsGenetically higher smoking quantity showed no statistical causal association with AD risk (the inverse variance weighted (IVW) estimate in the Chinese cohort: odds ratio (OR) = 0.510, 95% confidence interval (CI) = 0.149–1.744, p = 0.284; IVW estimate in the Japanese cohort: OR = 1.170, 95% confidence interval CI = 0.790–1.734, p = 0.434).ConclusionThis MR study, for the first time in Chinese and Japanese populations, found no significant association between smoking and AD.

ObjectiveNeuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease preferentially affects the optic nerve and the spinal cord. The first attack usually occurs in the third or fourth decade, though patients with disease onset in the fifties or later are not uncommon. This study aimed to investigate the clinical characteristics and prognosis in patients with different age of onset and to explore the correlations between age of onset and clinical characteristics and prognostic outcomes.MethodWe retrospectively reviewed the medical records of 298 NMOSD patients diagnosed according to the 2015 updated version of diagnostic criteria. Patients were divided into early-onset NMOSD (EO-NMOSD) (

Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with aging, environmental, and genetic factors. Amyloid protein precursor (APP) is a known pathogenic gene for familial Alzheimer’s disease (FAD), and now more than 70 APP mutations have been reported, but the genotype-phenotype correlation remains unclear. In this study, we collected clinical data from patients carrying APP mutations defined as pathogenic/likely pathogenic according to the American college of medical genetics and genomics (ACMG) guidelines. Then, we reanalyzed the clinical characteristics and identified genotype-phenotype correlations in APP mutations. Our results indicated that the clinical phenotypes of APP mutations are generally consistent with typical AD despite the fact that they show more non-demented symptoms and neurological symptoms. We also performed genotype-phenotype analysis according to the difference in APP processing caused by the mutations, and we found that there were indeed differences in onset age, behavioral and psychological disorders of dementia (BPSD) and myoclonus.

Background: Genetics plays an important role in progressive supranuclear palsy (PSP) and remains poorly understood. A detailed literature search identified 19 PSP-associated genes: MAPT, LRRK2, LRP10, DCTN1, GRN, NPC1, PARK, TARDBP, TBK1, BSN, GBA, STX6, EIF2AK3, MOBP, DUSP10, SLCO1A2, RUNX2, CXCR4, and APOE. To date, genetic studies on PSP have focused on Caucasian population. The gaps in PSP genetic study on East Asian populations need to be filled. Methods: Exon and flanking regions of the PSP-associated genes were sequenced in 104 patients with PSP and 488 healthy controls. Common variant-based association analysis and gene-based association tests of rare variants were performed using PLINK 1.9 and the sequence kernel association test-optimal, respectively. Additionally, the association of APOE and MAPT genotypes with PSP was evaluated. The above association analyses were repeated among probable PSP patients. Finally, PLINK 1.9 was used to test variants associated with the onset age of PSP. Results: A rare non-pathogenic variant of MAPT (c.425C > T,p.A142V) was detected in a PSP patient. No common variants were significantly associated with PSP. In both the rare-variant and the rare-damaging-variant groups, the combined effect for GBA reached statistical significance (p = 1.43 × 10−3, p = 4.98 × 10−4). The result between APOE, MAPT genotypes and PSP risk were inconsistent across all PSP group and probably PSP group. Conclusions: The pathogenic variant in MAPT were uncommon in PSP patients. Moreover, GBA gene was likely to increase the risk of PSP, and GBA-associated diseases were beyond α-synucleinopathies. The association between APOE, MAPT and PSP is still unclear among the non-Caucasian population.

BackgroundThe Chinese version of the Mini-Mental State Examination (MMSE-C) and the Beijing version of the Montreal Cognitive Assessment (MoCA-BJ) are the most commonly used scales to screen for Alzheimer’s disease (AD) among Chinese patients; however, their consistency varies according to populations and languages. Equivalent conversion of MMSE-C and MoCA-BJ scores is important for meta-analysis.Materials and methodsMMSE-C and MoCA-BJ scoring were performed on the enrolled patients with AD (n = 332). Consistency analysis of MMSE-C and MoCA-BJ scores of patients in the conversion groups was performed. The circle-arc method was used to convert the MMSE-C scores of the conversion groups into MoCA-BJ scores, and the conversion formula was generated. The MMSE-C data of the verification group was converted to MoCA-BJ according to the formula, and the consistency analysis of the original MoCA-BJ of the verification group and the converted MoCA-BJ was performed to verify the conversion model.ResultsThe results of the consistency analysis of MMSE-C and MoCA-BJ in group A showed that the correlation coefficients of the total group, high education years subgroup, medium education years subgroup, and low education years subgroup were 0.905 (P < 0.001), 0.874 (P < 0.001), 0.949 (P < 0.001), and 0.874 (P < 0.001), respectively, with high consistency and statistical significance. After applying the circle-arc method for equivalent conversion, the consistency analysis results of the original and the converted MoCA-BJ of the patients in group B of the total group, high education years subgroup, medium education years subgroup, and low education years subgroup were 0.891 (P < 0.001), 0.894 (P < 0.001), 0.781 (P < 0.001), 0.909 (P < 0.001), respectively, with high consistency and statistical significance.ConclusionWe established and validated a model of MMSE-C and MoCA-BJ score conversion for Chinese patients with AD using the circle-arc method. This model could be useful for multi-centers clinical trials and meta-analysis.

Abstract Neurodegenerative dementias are a group of diseases with highly heterogeneous pathology and complicated etiology. There exist potential genetic component overlaps between different neurodegenerative dementias. Here, 1795 patients with neurodegenerative dementias from South China were enrolled, including 1592 with Alzheimer’s disease (AD), 110 with frontotemporal dementia (FTD), and 93 with dementia with Lewy bodies (DLB). Genes targeted sequencing analysis were performed. According to the American College of Medical Genetics (ACMG) guidelines, 39 pathogenic/likely pathogenic (P/LP) variants were identified in 47 unrelated patients in 14 different genes, including PSEN1, PSEN2, APP, MAPT, GRN, CHCHD10, TBK1, VCP, HTRA1, OPTN, SQSTM1, SIGMAR1, and abnormal repeat expansions in C9orf72 and HTT. Overall, 33.3% (13/39) of the variants were novel, the identified P/LP variants were seen in 2.2% (35/1592) and 10.9% (12/110) of AD and FTD cases, respectively. The overall molecular diagnostic rate was 2.6%. Among them, PSEN1 was the most frequently mutated gene (46.8%, 22/47), followed by PSEN2 and APP. Additionally, the age at onset of patients with P/LP variants (51.4 years), ranging from 30 to 83 years, was ~10 years earlier than those without P/LP variants (p

African swine fever virus (ASFV) represents a serious threat to the global swine industry, and there are no safe or commercially available vaccines. Previous studies have demonstrated that inactivated vaccines do not provide sufficient protection against ASFV and that attenuated vaccines are effective, but raise safety concerns. Here, we first constructed a deletion mutant in which EP153R and EP402R gene clusters were knocked out. Based on the deletion mutant, a further deletion from the MGF_360-12L, MGF_360-13L to MGF_360-14L genes was obtained. The five-genes knockout virus was designated as ASFV-ΔECM3. To investigate the efficacy and safety of the ASFV-ΔECM3 virus as a vaccine candidate, the evaluation of the virus was subsequently carried out in pigs. The results showed that the ASFV-ΔECM3 virus could induce homologous protection against the parental isolate, and no significant clinical signs or viremia were observed. These results show that the contiguous deletion mutant, ASFV-ΔECM3 encompassing the EP153R/EP402R and MGF_360-12L/13L/14L genes, could be a potential live-attenuated vaccine candidate for the prevention of ASFV infection.

Abstract Objective To investigate the impact of rare variants underlying neurodegenerative‐related genes to familial Alzheimer’s disease (AD). Methods We performed targeted sequencing of 277 neurodegenerative‐related genes on probands from 75 Chinese AD families non‐carrying causative mutation of dementia genes. Rare coding variants segregated in families were tested for association in an independent cohort of 506 patients with sporadic AD and 498 cognitively normal controls. East Asians data from the Exome Aggregation Consortium (ExAC) were used as a reference control. Results A novel rare variant, P410S of PLD3 was found in an early‐onset AD family. LRRK2 I2012T, a causative mutation of Parkinson’s disease, was identified in another early‐onset AD family. Missense variants in ABCA7 (P143S and A1507T) and CR1(T239M) were significantly associated with familial AD (P = 0.005437, 0.001383, 0.000549), a missense variant in TREM2(S183C) was significantly associated with AD (P = 0.000396) when compared with the East Asian controls in ExAC database. A non‐frameshift variant in FUS (G223del) was frequent in AD cases and significantly associated with familial AD (P = 0.008). Interpretation Multiple rare coding variants of causal and risk neurodegenerative genes were presented in clinically diagnosed AD families that may confer risk of AD. Our data supported that the clinical, pathological, and genetic architectures of AD, PD, and FTD/ALS may overlapping. We propose that targeted sequencing on neurodegenerative‐related genes is necessary for genetically unclear AD families.

Background: Alzheimer's disease (AD) is the most common type of dementia and has no effective treatment to date. It is essential to develop a minimally invasive blood-based biomarker as a tool for screening the general population, but the efficacy remains controversial. This cross-sectional study aimed to evaluate the ability of plasma biomarkers, including amyloid β (Aβ), total tau (t-tau), and neurofilament light chain (NfL), to detect probable AD in the South Chinese population.Methods: A total of 277 patients with a clinical diagnosis of probable AD and 153 healthy controls with normal cognitive function (CN) were enrolled in this study. The levels of plasma Aβ42, Aβ40, t-tau, and NfL were detected using ultra-sensitive immune-based assays (SIMOA). Lumbar puncture was conducted in 89 patients with AD to detect Aβ42, Aβ40, t-tau, and phosphorylated (p)-tau levels in the cerebrospinal fluid (CSF) and to evaluate the consistency between plasma and CSF biomarkers through correlation analysis. Finally, the diagnostic value of plasma biomarkers was further assessed by constructing a receiver operating characteristic (ROC) curve.Results: After adjusting for age, sex, and the apolipoprotein E (APOE) alleles, compared to the CN group, the plasma t-tau, and NfL were significantly increased in the AD group (p < 0.01, Bonferroni correction). Correlation analysis showed that only the plasma t-tau level was positively correlated with the CSF t-tau levels (r = 0.319, p = 0.003). The diagnostic model combining plasma t-tau and NfL levels, and age, sex, and APOE alleles, showed the best performance for the identification of probable AD [area under the curve (AUC) = 0.89, sensitivity = 82.31%, specificity = 83.66%].Conclusion: Blood biomarkers can effectively distinguish patients with probable AD from controls and may be a non-invasive and efficient method for AD pre-screening.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Archetypal disease-causing mutations are cysteine-affecting variants within the 34 epidermal growth factor-like repeat (EGFr) region of the Notch3 extracellular subunit. Cysteine-sparing variants and variants outside the EGFr coding region associated with CADASIL phenotype have been reported. However, the linkage between untypical variants and CADASIL is unclear. In this study, we investigated the spectrum of NOTCH3 variants in a cohort of 38 probands from unrelated families diagnosed as CADASIL. All coding exons of the NOTCH3 gene were analyzed, and clinical data were retrospectively studied. We identified 23 different NOTCH3 variants including 14 cysteine-affecting pathogenic variants, five cysteine-sparing pathogenic variants, two reported cysteine-sparing variants of unknown significance (VUS), and two novel VUS outside EGFr region. In retrospective studies of clinical data, we found that patients carrying cysteine-sparing pathogenic variants showed later symptom onset (51.36 ± 7.06 vs. 44.96 ± 8.82, p = 0.023) and milder temporal lobe involvement (1.50 ± 1.74 vs. 3.11 ± 2.32, p = 0.027) than patients carrying cysteine-affecting pathogenic variants. Our findings suggested that untypical variants comprise a significant part of NOTCH3 variants and may be associated with a distinctive phenotype.

Background: Vitamin D insufficiency has been considered a risk factor for Alzheimer's disease (AD) in several studies. Recently, four single-nucleotide polymorphisms (SNPs) to be genome-wide significant for 25-hydroxyvitamin D [25(OH)D] were identified to have an association with the risk of AD. These include GC rs2282679 A>C, CYP2R1 rs10741657 T>C, DHCR7 rs12785878 T>C, and CYP24A1 rs6013897 T>A. However, the association between these polymorphisms and AD susceptibility in the Chinese population remains unclear.Methods: A case-control cohort study was conducted in 676 AD patients (mean age at onset was 69.52 ± 10.90 years, male: 39.2%) and 551 healthy controls (mean age was 67.73 ± 6.02 years, male: 44.8%). Genotyping was determined by PCR and SNaPshot sequencing. To determine whether the four SNPs account for risks in AD in Chinese population, multivariate logistic regression models were performed. Stratified analysis was performed based on gender and age of onset of AD, separately. Statistical significance was set at 0.0125 (0.05/4) based on Bonferroni correction.Findings:DHCR7 rs12785878 T>C was found to be significantly associated with an increased risk of early-onset Alzheimer's disease (EOAD) (n = 300, risk allele C, adjusted OR = 1.542, adjusted 95% CI = 1.176–2.023, p = 0.002). There was no statistical significance of the other three SNPs between the two groups.Interpretation: Our results suggested that DHCR7 rs12785878 T>C might be associated with an increased risk of EOAD in the Chinese population, while other polymorphisms related to vitamin D insufficiency might not be. However, due to the limited data in this study, replication studies in a larger sample are required.

The genes involved in the metabolic pathways of amyloid-β (Aβ) and tau proteins significantly influence the etiology of Alzheimer’s disease (AD). Various studies have explored the associations between some of these genes and AD in the Caucasian population; however, researches regarding these associations remain limited in the Chinese population. To systematically evaluate the associations of these genes with AD, we investigated 19 genes involved in the metabolism of Aβ and tau based on previous studies selected using the PubMed database. This study included 372 patients with sporadic late-onset AD (sLOAD) and 345 cognitively healthy individuals from southern China. The results were replicated in the International Genomics of Alzheimer’s Project (IGAP). Protein–protein interactions were determined using the STRING v11 database. We found that a single-nucleotide polymorphism, rs11682128, of BIN1 conferred susceptibility to sLOAD after adjusting for age, sex, and APOE ε4 status and performing the Bonferroni correction {corrected P = 0.000153, odds ratio (OR) [95% confidence interval (CI)] = 1.403 (1.079–1.824)}, which was replicated in the IGAP. Protein–protein interactions indicated that BIN1 was correlated with MAPT. Moreover, rare variants of NEP and FERMT2 (0.0026 < corrected P < 0.05), and the Aβ degradation, tau pathology, and tau phosphatase pathways (0.01 < corrected P < 0.05), were nominally significantly associated with sLOAD. This study suggested that the genes involved in the metabolic pathways of Aβ and tau contributed to the etiology of sLOAD in the southern Han Chinese population.

Amyloid protein deposition is a common mechanism of hereditary amyloidosis (HA) and Alzheimer’s disease (AD). Mutations of gelsolin (GSN), cystatin C (CST3), transthyretin (TTR), and integral membrane protein 2B (ITM2B) genes can lead to HA. But the relationship is unclear between these genes and AD. Genes targeted sequencing (GTS), including GSN, CST3, TTR, and ITM2B, was performed in a total of 636 patients with clinical AD and 365 normal controls from China. As a result, according to American College of Medical Genetics and Genomics (ACMG) guidelines, two novel likely pathogenic frame-shift mutations (GSN:c.1036delA:p.K346fs and GSN:c.8_35del:p.P3fs) were detected in five patients with AD, whose initial symptom was memory decline, accompanied with psychological and behavioral abnormalities later. Interestingly, the patient with K346fs mutation, presented cerebral β-amyloid protein deposition, had an early onset (48 years) and experienced rapid progression, while the other four patients with P3fs mutation had a late onset [(Mean ± SD): 69.50 ± 5.20 years] and a long course of illness [(Mean ± SD): 9.24 ± 4.86 years]. Besides, we also discovered 17 variants of uncertain significance (VUS) in these four genes. To our knowledge, we are the first to report AD phenotype with GSN mutations in patients with AD in the Chinese cohort. Although mutations in the GSN gene are rare, it may explain a small portion of clinically diagnosed AD.

ObjectiveSpinocerebellar ataxia type 3 (SCA3) is the most commonly occurring type of autosomal dominant spinocerebellar ataxia. The present study aims to investigate progressive changes in white matter (WM) fiber in asymptomatic and symptomatic patients with SCA3.MethodsA total of 62 participants were included in this study. Among them, 16 were asymptomatic mutation carriers (pre-SCA3), 22 were SCA3 patients with clinical symptoms, and 24 were normal controls (NC). Group comparison of tract-based spatial statistics was performed to identify microstructural abnormalities at different SCA3 disease stages.ResultsDecreased fractional anisotropy (FA) and increased mean diffusivity (MD) were found in the left inferior cerebellar peduncle and superior cerebellar peduncle (SCP) in the pre-SCA3 group compared with NC. The symptomatic SCA3 group showed brain-wide WM tracts impairment in both supratentorial and infratentorial networks, and the mean FA value of the WM skeleton showed a significantly negative correlation with the International Cooperative Ataxia Rating Scale (ICARS) scores. Specifically, FA of the bilateral posterior limb of the internal capsule negatively correlated with SCA3 disease duration. We also found that FA values in the right medial lemniscus and SCP negatively correlated with ICARS scores, whereas FA in the right posterior thalamic radiation positively correlated with Montreal Cognitive Assessment scores. In addition, MD in the middle cerebellar peduncle, left anterior limb of internal capsule, external capsule, and superior corona radiate positively correlated with ICARS scores in SCA3 patients.ConclusionWM microstructural changes are present even in the asymptomatic stages of SCA3. In individuals in which the disease has progressed to the symptomatic stage, the integrity of WM fibers across the whole brain is affected. Furthermore, abnormalities in WM tracts are closely related to SCA3 disease severity, including movement disorder and cognitive dysfunction. These findings can deepen our understanding of the neural basis of SCA3 dysfunction.

In this paper, we use A-share listed firms between 2002 and 2010 to investigate the relationship between local fiscal distress and the investment efficiency of local SOEs, along with the effect of corporate tax payments on this relationship. We find a positive relationship between the extent of local SOEs’ overinvestment and the fiscal distress of the corresponding local government where the enterprise and this relationship become stronger for firms that pay fewer taxes. The pattern of underinvestment among local SOEs was in contrast, and these relationships do not exist for non-SOEs or central SOEs. Moreover, we find that expanding a firm’s investment scale leads to an increase in total taxes paid, including income and turnover taxes, which further result in more local fiscal revenue. Overall, we conclude that local governments have an incentive to increase fiscal revenue when faced with fiscal distress by raising the investment scale of local SOEs and that the incentives and effects of such interventions appear to be stronger among firms that contribute less to local fiscal revenue.