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Acute kidney injury (AKI), a major health burden, lacks effective therapy. Anti-inflammatory actions of a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13) may provide a new treatment option for AKI. Along with inflammation, oxidative stress is critical for AKI development, yet the impact of ADAMTS13 on oxidative stress in AKI remains to be fully elucidated.We assess recombinant human ADAMTS13 (rhADAMTS13) actions on oxidative stress in a murine ischaemia/reperfusion (IR) model. Antioxidant stress-enzyme activities, renal morphology, kidney function markers and vascular function of isolated afferent arterioles are quantified.rhADAMTS13 provided after IR, reduces blood urea nitrogen (BUN) by 33% and serum creatinine (Scr) by 73% in 24 hours post-IR. rhADAMTS13 reduces BUN (40.03 ± 20.34 mmol/L vs 72.35 ± 18.74 mmol/L, P .01), Scr (75.67 ± 51.19 μmol/L vs 176.17 ± 55.38 μmol/L, P .01) and proteinuria by 41% in 48 hours post-IR as well. Moreover, rhADAMTS13 administration decreases malondialdehyde (MDA) and increases the activity of antioxidant stress enzymes, and attenuates reactive oxygen species production. rhADAMTS13 also upregulates nuclear factor-erythroid-2-related factor 2/haem oxygenase-1, enhances antioxidant enzymes activity and alleviates endothelial dysfunction. Finally, treatment with rhADAMTS13 mitigates severe functional and morphological injury present in IR mice. Extracellular signal-regulated kinase (ERK) phosphorylation is limited by rhADAMTS13 and PPARγ expression is partly restored in ischaemic kidneys. Co-administration of von Willebrand factor (VWF) impairs rhADAMTS13's antioxidant capacity and its protective role in IR.rhADAMTS13 alleviates renal IR injury through antioxidant effects by cleaving VWF.

Visual commonsense reasoning (VCR) task aims at boosting research of cognition-level correlations reasoning. It requires not only a thorough understanding of correlated details of the scene but also the ability to infer correlation with related commonsense knowledge. Existing approaches consider the region-word affinity to perform the semantic alignment between vision and linguistic domains, which neglect the implicit correspondence (e.g. word-scene, region-phrase, and phrase-scene) among visual concepts and linguistic words. Although efforts have been made to deliver promising results in previous work, these methods are still confronted with challenges when comes to make interpretable reasoning. Toward this end, we present a novel hierarchical semantic enhanced directional graph network. To be more specific, we design a Modality Interaction Unit (MIU) module, which captures high-order cross-modal alignment by aggregating the hierarchical vision-language relationships. Afterward, we propose a direction clue-aware graph reasoning (DCGR) module. In this module, valuable entities can be dynamically selected in each reasoning step, according to the importance of these entities. This leads to a more interpretable reasoning procedure. Ultimately, heterogeneous graph attention is introduced to filter the irrelevant parts of the final answers. Extensive experiments have been conducted on the VCR benchmark dataset, which demonstrates that our method can achieve competitive results and better interpretability compared with several state-of-the-art baselines.

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

Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy. X-linked Charcot-Marie-Tooth disease in the GJB1 gene is known as CMTX1. We report a 14 years-old young man with walked unstably, bilateral strephenopodia, severe alopecia and paroxysmal bilateral upper limbs tremor without obvious muscle atrophy. Diagnostic whole-exome sequencing revealed a hemizygote missense mutation c.278 T > A in exon 2 of the GJB1 gene, with lysine at position 93 of the mature protein (p.M93K). This is the first CMT case with alopecia areata reported in the world.

Recent studies found that poor oral hygiene was associated with increased risk of dementia, and the number of oral bacteria significantly increased in the brain tissues of patients with Alzheimer's disease (AD), suggesting that the oral microbiota may play an important role in the pathogenesis of AD. However, the actual composition of oral bacteria communities in patients with AD and whether these oral bacteria are associated with disease severity remain largely unknown. Also, the APOEɛ4 polymorphism is a strong risk factor for sporadic AD, and it would be pertinent to see if the bacterial flora was different in those patients who were APOEɛ4 positive. A total of 78 subjects were recruited in this study, including 39 patients with AD and 39 healthy controls. Saliva was collected from each subject. 16S ribosomal RNA (16S rRNA) sequencing was conducted to analyze the salivary microbiota, and Sanger sequencing was performed to analyze the APOE genotype. There was a significantly lower richness and diversity of saliva microbiota detected in AD patients than healthy controls. The relative abundance of Moraxella, Leptotrichia, and Sphaerochaeta in the saliva of AD patients greatly increased, whereas that of Rothia was significantly reduced. Compared with APOEɛ4 (-) patients, the level of Abiotrophia and Desulfomicrobium was comparatively abundant, while Actinobacillus and Actinomyces decreased significantly in patients carrying the APOEɛ4. No bacteria were found to be associated with the severity of AD. This is the first study to analyze the salivary microorganisms in patients with AD, and we discovered that the composition of salivary microbiome was altered in AD, providing further support for the role of the oral microbiome in AD development.

BACKGROUND Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (SPG1-SPG72). Among autosomal dominant HSP patients, spastic paraplegia 4 (SPG4/SPAST) gene is the most common pathogenic gene, and atlastin-1 (ATL1) is the second most common one. Here we reported a novel ATL1 mutation in a Chinese spastic paraplegia 3A (SPG3A) family, which expands the clinical and genetic spectrum of ATL1 mutations. CASE SUMMARY A 9-year-old boy with progressive spastic paraplegia accompanied by right hearing loss and mental retardation for five years was admitted to our hospital. Past history was unremarkable. The family history was positive, and his grandfather and mother had similar symptoms. Neurological examinations revealed hypermyotonia in his lower limbs, hyperreflexia in knee reflex, bilateral positive Babinski signs and scissors gait. The results of blood routine test, liver function test, blood glucose test, ceruloplasmin test and vitamin test were all normal. The serum lactic acid level was significantly increased. The testing for brainstem auditory evoked potential demonstrated that the right side hearing was impaired while the left was normal. Magnetic resonance imaging showed mild atrophy of the spinal cord. The gene panel test revealed that the proband carried an ATL1 c.752A>G p.Gln251Arg (p.Q251R) mutation, and Sanger sequencing confirmed the existence of family co-segregation. CONCLUSION We reported a novel ATL1 Q251R mutation and a novel clinical phenotype of hearing loss in a Chinese SPG3A family.

African swine fever virus (ASFV) is a large nucleoplasmic DNA virus, in which the genome is around 170–198 kilobases (kb). More than 50 % genes have unknown functions. Here, MGF100-1R gene is chosen to study the primary function and sublocalization. The gene was located at the left variable region of the ASFV genome that belongs to MGF100 families. It located at the cytoplasm without cytotoxic activities. However, it related to induce the transcriptional levels of pro-inflammatory cytokines. A deletion mutant of MGF100-1R gene was constructed based on ASFV Chinese strain GZ201801. The recombinant deletion mutant (ASFV△MGF100-1R) was demonstrated in vitro that the gene is non-essential for virus replication with a similar replication kinetics in bone marrow-derived macrophages (BMDMs) cell cultures when compared to parental virus. In vivo evaluation, ASFV△MGF100-1R was inoculated intramuscularly and led to a similar pathogenesis that caused by the parental ASFV GZ201801, confirming that deletion of MGF100-1R gene from the ASFV genome does not impact virulence.

Learning an effective interaction mechanism is important for Visual Question Answering (VQA). It requires an understanding of both the visual content of images and the textual content of questions. Existing approaches consider both the inter-modal and intra-modal interactions, while neglecting the irrelevant information in the interactions. In this paper, we propose a novel Fine-grained Unbalanced Interaction Network (FUIN) to adaptively capture the most useful information from interactions. It contains a parallel interaction module to model the two-way interactions and a fine-grained adaptive activation module to adaptively activate the interactions for each component according to their specific context. Experimental evaluation results on the benchmark VQA-v2 dataset demonstrate that FUIN achieves state-of-the-art VQA performance, we achieve an overall accuracy of 71.14% on the test-std set.

The method of dynamic mass isolation is utilized in a self-moving precision positioning stage actuated by a piezostack to increase its moving speed. Two prototypes, namely, the referenced stage and the modified stage, have been fabricated. The only difference between the two stages is the flexure hinge manufactured in the modified stage to achieve an efficient dynamic mass isolation method. The step response has been investigated. The modified stage with dynamic mass isolation presents the average displacement of 6.6 µm with the applied step voltage being 55 V. By contrast, the referenced stage without dynamic mass isolation presents the average displacement of 1.6 µm. As a type of quasi-static piezoactuator/motors, the modified stage moves approximately four times faster than the referenced stage under the same driving frequency. By utilizing the dynamic mass isolation method, the modified stage still features the advantages of the referenced stage, such as cost-effective controllers, heavy-load capability, and motion of nanoscale. The concept and technique presented in this study can be applied to precision positioning stages for improved speed performance.

BackgroundRobust studies have focused on blood-based biomarkers for diagnosis of Alzheimer’s disease (AD), while the results were still controversary and failed verified in different cohorts. The aim of this study was to detect the levels of plasma amyloid β (Aβ), total tau (t-tau), and neurofilament light chain (NfL) in patients with AD and cognitive normal (CN) subjects, and clarify their associations with Aβ, t-tau, and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) as well as brain amyloid PET, and calculate the diagnostic efficiency of these characteristics regarding AD.Methods Plasma Aβ42, Aβ40, t-tau and NfL levels were detected by single-molecule array (Simoa) in 379 AD patients and 153 CN subjects. Additionally, lumbar puncture was conducted in 125 AD patients to detect Aβ42, Aβ40, t-tau, and p-tau levels. Brain amyloid PET was performed in 52 AD patients to identify brain amyloid deposition levels. Correlation analysis were performed between plasma biomarkers and typical biomarkers of AD, including CSF core biomarkers and amyloid PET burden. Finally, the diagnostic value of plasma biomarkers was further assessed by receiver operating characteristic (ROC) curve.ResultsCompared with the CN group, plasma Aβ42 and Aβ42/Aβ40 levels were significantly lower in AD patients, while Aβ40, t-tau and NfL levels were higher in AD patients. Among the AD patients, plasma Aβ42 was positively correlated with CSF Aβ42 (r = 0.195, p = 0.03) and Aβ42/Aβ40 (r = 0.208, p = 0.04). Moreover, plasma NfL was positively correlated with age, disease course and severity. The diagnostic model with combined plasma Aβ42, t-tau, and NfL levels controlled for age and APOE genotype showed the best performance to identify AD (area under the curve (AUC) = 0.88, sensitivity = 82.84%, specificity = 81.69%, cutoff value = 0.64).ConclusionsTrends revealed by core biomarkers were generally consistent in AD patients’ plasma and CSF. Combining plasma biomarkers can provide comparatively high AD diagnostic performance.

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.

Background Mutations of APP, PSEN1 and PSEN2 only account for a small portion of familial Alzheimer’s disease (AD), leaving the genetic factors for the rest AD families unexplained. Neurodegenerative diseases have some neuropathological, clinical and genetic crossover. The effect of neurodegenerative genes to familial AD remains unknown. We hypothesized that rare variants of neurodegenerative diseases genes may lead to family aggregation of AD. The aim of the study was to investigate the effect of neurodegenerative genes to familial AD. Methods Targeted sequencing of 277 neurodegenerative disease genes was performed on probands from 75 AD families of Chinese origin. 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 mutation, P410S of PLD3, and a known causative mutation, I2012T of LRRK2 were identified in two early-onset AD families respectively. The p.P143S, rs192694824 in ABCA7 and rs374551420 in CR1 were significantly associated with familial AD (p = 0.005437, 0.001383, 0.000549), the rs200820365 in TREM2 was significantly associated with AD (p = 0.000396) when compared with the East Asian controls in ExAC database. The p. G223del of FUS was frequent in AD cases and significantly associated with familial AD (p = 0.008). Conclusions Our results revealed that rare variants of AD risk genes, FTD/ALS and PD causative genes may lead to family aggregation of AD. We proposed that targeted sequencing on neurodegenerative genes was necessary for genetically unclear AD families.

Accumulation of amyloid β protein (Aβ) due to increased generation and/or impaired degradation plays an important role in Alzheimer's disease (AD) pathogenesis. In this report, we describe the identification of rare coding mutations in the endothelin-converting enzyme 2 (ECE2) gene in 1 late-onset AD family, and additional case-control cohort analysis indicates ECE2 variants associated with the risk of developing AD. The 2 mutations (R186C and F751S) located in the peptidase domain in the ECE2 protein were found to severely impair the enzymatic activity of ECE2 in Aβ degradation. We further evaluated the effect of the R186C mutation in mutant APP-knockin mice. Overexpression of wild-type ECE2 in the hippocampus reduced amyloid load and plaque formation, and improved learning and memory deficits in the AD model mice. However, the effect was abolished by the R186C mutation in ECE2. Taken together, the results demonstrated that ECE2 peptidase mutations contribute to AD pathogenesis by impairing Aβ degradation, and overexpression of ECE2 alleviates AD phenotypes. This study indicates that ECE2 is a risk gene for AD development and pharmacological activation of ECE2 could be a promising strategy for AD treatment.

SNCA, GBA, and VPS35 are three common genes associated with Parkinson’s disease. Previous studies have shown that these three genes may be associated with Alzheimer’s disease (AD). However, it is unclear whether these genes increase the risk of AD in Chinese populations. In this study, we used a targeted gene sequencing panel to screen all the exon regions and the nearby sequences of GBA, SNCA, and VPS35 in a cohort including 721 AD patients and 365 healthy controls from China. The results revealed that neither common variants nor rare variants of these three genes were associated with AD in a Chinese population. These findings suggest that the mutations in GBA, SNCA, and VPS35 are not likely to play an important role in the genetic susceptibility to AD in Chinese populations. The study was approved by the Ethics Committee of Xiangya Hospital, Central South University, China on March 9, 2016 (approval No. 201603198).

Objective The study aimed to investigate the functional alterations of spontaneous brain activity in patients with spastic paraplegia type 4 (SPG4), and the relationship with the severity of spasticity. Methods Twelve patients with SPG4 and ten healthy controls underwent resting-state functional magnetic resonance imaging (rs-fMRI). Amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) were used to characterize regional neural function, and functional connectivity (FC) was used to evaluate the functional integration of the brain network. Results Compared to healthy controls, patients with SPG4 exhibited significantly decreased ReHo values in the medial superior frontal gyrus. ALFF values were lower in left insula and higher in right precentral and superior frontal gyrus of the patient group. Increased ALFF values in the right precentral gyrus negatively correlated with Spastic Paraplegia Rating Scale (SPRS) scores in the patients. The connectivity study showed that the SPG4 patients had one increased FC between the left middle frontal gyrus to the left middle orbitofrontal gyrus, and pairs of decreased FC. Conclusions Our findings confirm that the baseline regional neural activity and interregional connectivity are altered in many brain regions in patients with SPG4, and certain changes are correlated with disease severity, providing potential diagnostic markers for SPG4.

Zearalenone (ZEA) is an estrogenic toxin produced by Fusarium strains, that is widely present in crops, and endangers the reproductive system of animals. Tannic acid (TA) is a natural polyphenolic substance that is widespread in the roots, stems, and leaves of plants, and has special pharmacological activity. This study was designed to investigate the therapeutic effect of TA on ZEA-induced ovarian damage in mice and to explore the molecular mechanism involved. Ninety healthy Kunming female mice were divided into six equal groups. All the groups but the control group were administered daily with ZEA [10 mg/kg body weight (bw)] orally, for 7 days, to induce damage to the reproductive system. Some groups were also administered with TA (50, 100, and 200 mg/bw) for 7 days. Mice were euthanized 24 h later to allow for collection of serum and ovaries. TA can effectively alleviate the appearance of congestion and redness of the ovary, caused by ZEA, and increase the number of healthy growing follicles. Moreover, the estrogen content and the levels of MDA and ROS in the ovaries can be effectively reduced by TA. It can also reduce the apoptosis of ovarian cells, decreases the protein expression of the estrogen receptor, Fas, Fasl, caspase-3, caspase-8, caspase-9, and Bax, and increases the protein expression of Bcl-2. Our study indicates that TA reduces the strong estrogen and oxidative damage induced by ZEA, and these therapeutic effects may be partially mediated by the death receptor and mitochondrial apoptosis signaling pathway.

OBJECTIVE Translocase of outer mitochondrial membrane 40 (TOMM40) encodes translocase of the outer mitochondrial membrane (TOM), which is associated with mitochondrial dysfunction in Alzheimer's disease (AD). TOMM40 rs157581-G has been reported to increase susceptibility to AD. However, the effect of TOMM40 rs157581-G in resting-state functional MRI (rs-fMRI) on AD has not been studied. Therefore, we aimed to investigate the role of TOMM40 rs157581-G on rs-fMRI results in AD patients. METHODS Twenty-four AD patients were divided into two groups based on TOMM40 rs157581-G status, and clinical and imaging data were compared between the groups. RESULTS TOMM40 rs157581-G carriers of AD showed decreased regional homogeneity in the left precuneus and decreased amplitude of low-frequency fluctuations in the bilateral temporal poles compared with noncarriers of AD. TOMM40 rs157581-G carriers of AD also showed increased functional connectivity between the right middle occipital gyrus and the left supramarginal gyrus and decreased connectivity between the left superior occipital gyrus and the right transverse temporal gyrus in comparison with TOMM40 rs157581-G noncarriers. CONCLUSION We analyzed rs-fMRI characteristics of TOMM40 rs157581-G carriers of AD for the first time, which suggest that TOMM40 rs157581-G plays a harmful role in AD patients.

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Intravascular ultrasound (IVUS) has become a useful tool in the detection of coronary artery disease. However, non-uniform rotation distortion (NURD) reduces the image quality. In order to suppress the influence of NURD, a piezoelectric motor that can meet the requirements of IVUS catheters has been proposed. The motor has a diameter of 1 mm and a length of 10 mm using the new polarization direction proposed in the paper. A 45° mirror is fixed on the top of the motor to reflect the ultrasound transmitted from the transducer. The manufacture and drive of the piezoelectric motor is simple, and the maximum speed of the piezoelectric motor can reach 6450 rpm under the voltage of 20Vp-p. The minimum power required by the rotating motor is only 0.038 W, which can be directly driven by the signal generator without a power amplifier. The motor can operate at a low voltage and still has a high and stable speed. Meanwhile, the speed of the motor is controllable and has a satisfactory stability with a maximum angular error of 8°. The images detected by the cooperation of the motor and the ultrasonic transducer are also shown, which indicates that the motor has the rotational stability that meets the imaging requirements and the potential for application in the IVUS catheter to help improve the image quality of the coronary arteries and prevent and help treat potential diseases.

Improved compensation disclosure should increase the efficiency of executive compensation contracts through better benchmarking with peer groups even though managers might try to influence this process through a selective choice of peers. Using a sample of Chinese companies, we find that industry benchmarking is prevalent in China. Moreover, as the regulation for executive compensation disclosure was amended in 2005, executives whose compensation is above the industry average have experienced much smaller pay rises, and executives whose compensation is below the industry average have had much higher pay raises. The results of our study are robust after controlling for various firm and industry characteristics. The results also show that companies controlled by different entities (i.e., central government, local government, or nongovernment) behave very differently in response to enhanced compensation disclosure. These findings highlight the importance of policymakers understanding how different firms react to improved disclosure.

A ring-shaped traveling wave ultrasonic motor with a suspension stator is proposed for improving output power density. Piezoelectric stacks working in d33 mode are involved in the stator, whereas piezoelectric plates employed in classic ring-shaped traveling wave motors often work in d31 mode. Spring-mass systems are used to suspend the stator from the base that supports the motor and provide preload force. The volume of piezoelectric material and the power density of the motor can be easily increased through the suspension structure. Large vibration amplitude of the stator can be generated on the coupling surface. Simulink analysis and finite element analysis are conducted to verify the theory and determine the optimum parameters of the suspension stator with four piezoelectric stacks. The maximum free vibration amplitude of 4.25 µm of the stator is observed, which is nearly 4.7 times of that without suspension. The prototype can work at a maximum no-load speed of 62 rpm and produce a stall torque of 49.5 mN m under a driving signal of 30 Vpp when the mass block is 0.30 g. Furthermore, the higher output power can be expected because more extra stacks can be added in this suspension structure.

The epigenetic modifications during the transdifferentiation of adult stem cells remain to be fully elucidated. In the present study, the histone H3 modifications during the transdifferentiation of rat Thy‑1(+) Lin(‑) bone marrow cells into hepatocytes in vitro were examined, which involved performing hepatocyte growth factor-mediated transdifferentiation of bone marrow Thy-1(+) Lin(‑) cells into hepatic lineage cells. Subsequently, the hepatocyte-specific markers, cytokeratin‑18 (CK‑18), albumin (ALB) and α‑fetoprotein (AFP) were examined by immunofluorescence staining or reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Changes in the key pluripotency factor, octamer‑binding transcription factor 4 (OCT4) and histone modifications, including the dimethylation and acetylation of H3 at lysine 9 (H3K9me2 and H3K9ac), lysine 14 (H3K14me2 and H3K14ac) and lysine 27 (H3K27me2 and H3K27ac), were also investigated by RT-qPCR, immunofluorescence staining or western blot analysis The mRNA expression levels of AFP and ALB were detected in the bone marrow stem cell‑derived hepatic lineage cells on days 7 and 14 following induction, and CK‑18 was detected on day 14 following induction. During the transdifferentiation of the bone marrow Thy‑1(+) Lin(‑) cells into hepatocytes, the mRNA expression of OCT4 was significantly reduced, and the levels of H3K9me2, H3K9ac, H3K14me2, H3K14ac, H3K27me2 and H3K27ac were increased significantly, compared with the levels at baseline (P

Background Spinocerebellar ataxia type 3 (SCA3) and Machado–Joseph disease (MJD) are similar diseases that are often referred to jointly as SCA3/MJD. As the most common autosomal-dominantly inherited subtype of hereditary spastic paraplegia (HSP), HSP4 (or SPG4) has overlapping symptoms with SCA3/MJD, which hinders their diagnoses. Arterial spin labeling (ASL) is a noninvasive, contrast-agent free, magnetic resonance perfusion imaging method used to obtain maps of the cerebral blood flow (CBF). Here, we investigated the diagnostic value of ASL in SCA3/MJD and SPG4 patients. Methods A total of 13 SPG4 cases, 38 SCA3/MJD cases (22 onset patients and 16 genetic abnormality-only patients), and 27 healthy volunteers were examined by ASL. Data were processed to obtain the regional CBF (rCBF) and comparatively studied. Results In the pons, cerebellar dentate nucleus, and cerebellar cortex, rCBF of the onset SCA3/MJD group was significantly lower than that of the normal control group. In the cerebellar dentate nucleus and cerebellar cortex, the rCBF of the non-onset SCA3/MJD group was significantly lower than that of the control group. In the pons and cerebellar cortex, the rCBF of the onset SCA3/MJD group was significantly lower than that of the SPG4 group. Conclusions SCA3/MJD lesions are mainly located in the cerebellum and brainstem. Gray matter and white matter were both involved, although the deep cerebellar nuclei may be the earliest involved region. Cerebellar and brainstem lesions of SCA3/MJD were more severe than those of SPG4. ASL can aid the diagnosis of SCA3/MJD and SPG4.

Hereditary spastic paraplegias (HSP/SPGs) constitute a clinically and genetically heterogeneous group of neurodegenerative disorders. Inheritance of the disease has been reported to be autosomal dominant (AD), autosomal recessive (AR), or X-linked, and isolated cases are often seen in clinical practice [1]. ARHSP accounts for approximately 15–20 % of all types of HSP, almost 52 different loci and 45 genes with AR inheritance have been described, and this number is likely to further increase in the near future [1, 2]. The most frequent ARHSP form associating with thin corpus callosum (TCC), cognitive impairment, and/or white matter abnormalities (WMA) is the SPG11, followed by SPG15, SPG56 (CYP2U1 gene, MIM 609471) and SPG46 (GBA2 gene, MIM 610670) [2–7]. Till now, there is no study about SPG46 or SPG56 mutation in China, and we tried to fill this gap by screening a cohort of 44 Chinese patients which included 23 unrelated probands with ARHSP and 21 sporadic cases presented with mental impairment, TCC or WMA for GBA2 and CYP2U1 gene mutations (Supplementary Table 1). All patients were previously excluded for SPG11, SPG15, SPG5, SPG7 and SPG35 mutations. Mutation analysis of the coding exons and intron–exon boundaries of GBA2 and CYP2U1 genes was performed by Sanger sequencing (Supplementary Table 2). Only a novel homozygous mutation c.2617C[T/p.Arg873Cys in GBA2 gene was detected in a consanguineous ARHSP family (Fig. 1), and no SPG56 mutations were identified. The c.2617C[T/p.Arg873Cys mutation falls in the glucosylceramidase domain of the protein comprising the nonlysosomal b-glycosidase 2 enzyme, and was predicted to result in a nonfunctional enzyme. Compared with 2 % (1/ 46) of a cohort of complicated HSP patients draw from Mediterranean descent [4], the frequency of SPG46 in our samples accounting for 4.35 % (1/23) of ARHSP families, and 2.27 % (1/44) of non-ADHSP patients who were negative for SPG5, SPG7, SPG11 [8], SPG15 and SPG35 [9] mutations. Although validation of these results in a larger number of patients is still needed, SPG46 was suspected to be a rare cause of ARHSP and sporadic cases in China. To date, only five SPG46 families from Tunisia, Turkey, Belgium have been reported [2–7], this is the first SPG46 case detected in China. Similar to the SPG46 patients described so far, his early psychomotor development was normal. He showed progressive difficulties in balance and running in 8 years old, and loss of balance while riding a bicycle at the age of 10. When he was 15 years old, lisp and mental impairment was noted by his relatives. Neurological examination of the patient in 2009 disclosed stiffness in the legs, mild spastic gait (SPRS = 7), positive pyramidal tract signs and mild mental impairment (MMSE = 23). With disease progressed, incoordinate movements, ataxia (Supplementary video) moderate Electronic supplementary material The online version of this article (doi:10.1007/s00415-016-8256-3) contains supplementary material, which is available to authorized users.

To determine the value of diffusion weighted imaging (DWI) in the diagnosis of hereditary spinocerebellar ataxia 3 and the Machado Joseph disease (SCA3/MJD) and hereditary spastic paraplegia 4 (SPG4).We scanned 13 patients with SPG4, 30 patients with SCA3/MJD (21 onset patients and 9 with only genetic abnormalities), and 27 healthy volunteers with DWI. The processing data were apparent diffusion coefficient (ADC). The above data were grouped for comparative study.In the precentral gyrus, posterior limb of the internal capsule, cerebral peduncle, pons, cerebellar cortex and cerebellar white matter, the ADC of onset SCA3/MJD patients increased compared with the control group. The ADC of non-onset SCA3/MJD patients increased only in the cerebellar dentate nucleus compared with the control group. In the cerebellar cortex, the ADC of onset SCA3/MJD patients was significantly higher than the non-onset SCA3/MJD. The ADC of onset SCA3/MJD patients was significantly higher in the posterior limb of the internal capsule, cerebellar cortex, cerebellar white matter and pons than that of SPG4 patients. In the precentral gyrus, the ADC of SPG4 was significantly higher than control.DWI is useful in the diagnosis of SCA3/MJD and SPG4.

Background: Hereditary spastic paraplegias constitute a heterogeneous group of inherited neurodegenerative disorders. To date, there has been no systematic mutation and clinical analysis for a large group of autosomal-dominant hereditary spastic paraplegias in China. Objective: The purpose of this study was to investigate the mutation frequencies and the clinical phenotypes of Chinese spastic paraplegia patients. Methods: Direct sequencing and a multiplex ligation-dependent probe amplification assay were applied to detect the mutations of SPAST and ATL1 in 54 autosomal-dominant hereditary spastic paraplegia probands and 66 isolated cases. Next, mutations in NIPA1, KIF5A, REEP1 and SLC33A1 were detected in the negative patients. Subsets of spastic paraplegia patients were genotyped for the modifying variants. Further, detailed clinical data regarding the genetically diagnosed families were analysed. Results: Altogether, 27 families were diagnosed as SPG4, 3 as SPG3A and 1 as SPG6. No mutations in KIF5A, REEP1 or SLC33A1 were found; 9 SPAST mutations were novel. There was no p.S44L or p.P45Q variant in SPAST and no p.G563A variant in HSPD1 in either the 120 spastic paraplegia patients or the 500 controls. There was a remarkable clinical difference between the SPG4 and non-SPG4 patients and even between genders among the SPG4 patients. Non-penetrance and remarkable gender difference were observed in some SPG4 and SPG3A families. Conclusions: Our data confirm that hereditary spastic paraplegias in China represent a heterogeneous group of genetic neurodegenerative disorders in autosomal-dominant and apparently sporadic forms. Novel genotype-phenotype correlations were established.

Background. Metabolomics studies can quantitatively detect the dynamic metabolic response of living systems.Objective. To detect urinary metabolomics after hepatic ischemia/reperfusion (I/R) injury induced by the Pringle maneuver using gas chromatography-mass spectrometry (GC-MS).Methods. Male Sprague-Dawley rats () were randomly divided into 4 groups (/group): sham operation, day 1, day 3, and day 5. Rats in the day 1, day 3, and day 5 groups underwent the Pringle maneuver. Serum alanine transaminase (ALT) and total bilirubin (TBIL) were measured, and hematoxylin and eosin (HE) staining of the liver tissue was performed. GC-MS was used to detect urinary metabolomics.Results. Compared with the sham group, the serum ALT and TBIL levels at day 1 were significantly elevated () and then decreased and reached close to normal levels at day 5. GC-MS detected 7 metabolites which had similar changes as those of liver tissue revealed by histological examination. Significant differences in lactic acid, pyruvic acid, alanine, serine, and glycerol-3-phosphate were found among the groups (). Principle component analysis showed that 7 metabolites distinguished the day 1 and day 3 groups from the sham group.Conclusions. Noninvasive urinary metabolomic analysis is a potential means for the early detection and diagnosis of hepatic I/R injury.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a potent mitogen and chemotactic factor. HB-EGF attenuates intestinal ischemia/reperfusion injury caused by superior mesenteric artery occlusion. We examined whether HB-EGF offers protection against intestinal congestion/reperfusion (C/R) injury, which is caused by portal triad clamping. Male Sprague-Dawley rats were randomly divided into three equally sized groups: I, sham-operated; II, portal triad clamping (Pringle maneuver); III, II + intraluminal administration of HB-EGF. Compared with sham-operated rats, all rats in group II exhibited significant increases in intestinal histologic injury, pro-inflammatory cytokine expression, myeloperoxidase activity, malonaldehyde levels, and apoptosis indices. Intraluminal administration of HB-EGF in group III significantly reduced these indicators when compared with group II. Clamping of the portal triad followed by reperfusion causes intestinal C/R injury and intraluminal administration of HB-EGF reduces the severity of intestinal C/R injury in rats.

To determine the safety, feasibility and therapeutic effect of in vitro-expanded autologous bone marrow-derived liver stem cells (BMDLSC) transplantation in cirrhotic patients following chronic hepatitis B virus infection.Twelve patients with post-hepatitic cirrhosis and portal hypertension who required splenectomy with periesophagogastric devascularization were included and were divided into two groups. Group I included six patients who received autologous BMDLSC infusion via the hepatic artery after in vitro expansion for 7 days. Group II (control group) included six patients who received normal saline infusion via the same route during splenectomy with periesophagogastric devascularization. The therapeutic effects were compared 3 months later. Patients in Group I were followed-up for 24 months after transplantation.There were no adverse effects during short- and long-term follow-ups. Three months after the operation, patients who received BMDLSC infusion showed better hepatic function than those who received saline infusion (p0.05). Patients in Group I showed stable liver function parameters with no complications during the 24-month follow-up period.Transplantation of in vitro-expanded autologous BMDLSC via the hepatic artery is a safe and effective treatment for decompensated liver cirrhosis.

To investigate the related factors of international cooperative ataxia rating scale (ICARS) and scale for the assessment and rating of ataxia scores (SARA) in patients with spinocerebellar ataxia type 3/Machado-Joseph disease.A total of 126 SCA3/MJD patients were assessed by ICARS and SARA. The relation between ICARS or SARA scores and age of onset, disease duration and CAG repeat size was analyzed.Either the total ICARS or the total SARA score was positively related with the disease duration(r=0.586,P0.05;r=0.643,P0.05). Simple linear regression equations were: Y(1)(total ICARS score)=13.072+2.388 X(2)(disease duration)(F=68.874,P0.05); Y(2)(total SARA score)=4.403+ 0.961 X(2)(disease duration)(F=87.254, P0.05). Either age adjusted the total ICARS score or age adjusted the total SARA score was positively related with CAG repeat size(r=0.328, P0.05; r=0.335, P0.05). Both the ICARS subscores and the SARA subscores were positively related with the disease duration(r=0.257-0.589, P0.05; r=0.432-0.623, P0.05). Both age adjusted ICARS subscores and age adjusted SARA subscores were positively related with CAG repeat size(r=0.263-0.403, P0.05; r=0.189-0.366, P0.05). Analysis of variance showed that the total ICARS score and the total SARA score increased with the disease stage.ICARS and SARA are both reliable and effective scales in assessing the severity of ataxia in patients with SCA3/MJD, and researchers can choose the most suitable scale according to specific requirement.

Background Recent studies suggest that epigenetic factors may play an important role in the pathogenesis of Parkinson’s disease (PD). In our previous work, we sequenced the exomes of sixteen patients from eight Chinese PD families using whole exome sequencing technology, consequently three patients from different pedigrees were found sharing the variant c.1460C > T (rs150689919) in the coding region of the Tet methyl cytosine dioxygenase 1 (TET1) gene. Methods In order to evaluate the possible association between sporadic PD and the single nucleotide polymorphism (SNP) rs150689919 in TET1, a case–control cohort study was conducted in 514 sporadic PD patients and 529 normal controls. Genotyping was determined by PCR and direct sequencing. Statistical significance was analyzed by the Chi-squared test. Results There was no statistical significance in TET1 rs150689919 genotype or allele frequencies between the PD cases and healthy controls, even after being stratified by gender and age at onset. Conclusions Our findings suggest that rs150689919 in TET1 may not be associated with PD in Chinese population. However, due to the limited data in this study, replication studies in larger sample and other populations are required.