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Phenotypic heterogeneity within or between families with a same deep-intronic splice-altering variant in the DMD gene has never been systematically analyzed. This study aimed to determine the phenotypic and genetic characteristics of patients with deep-intronic DMD variants.Of 1338 male patients with a suspected dystrophinopathy, 38 were confirmed to have atypical pathogenic DMD variants via our comprehensive genetic testing approach. Of the 38 patients, 30 patients from 22 unrelated families with deep-intronic DMD variants underwent a detailed clinical and imaging assessment.Nineteen different deep-intronic DMD variants were identified in the 30 patients, including 15 with Duchenne muscular dystrophy (DMD), 14 with Becker muscular dystrophy (BMD), and one with X-linked dilated cardiomyopathy. Of the 19 variants, 15 were single-nucleotide variants, 2 were structural variants (SVs), and 2 were pure-intronic large-scale SVs causing aberrant inclusion of other protein-coding genes sequences into the mature DMD transcripts. The trefoil with single fruit sign was observed in 18 patients and the concentric fatty infiltration pattern was observed in 2 patients. Remarkable phenotypic heterogeneity was observed not only in skeletal but also cardiac muscle involvement in 2 families harboring a same deep-intronic variant. Different skeletal muscle involvement between families with a same variant was observed in 4 families. High inter-individual phenotypic heterogeneity was observed within two BMD families and one DMD family.Our study first highlights the variable phenotypic expressivity of deep-intronic DMD variants and demonstrates a new class of deep-intronic DMD variants, i.e., pure-intronic SVs involving other protein-coding genes.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by dysfunction of the upper and lower motor neurons resulting in muscle weakness and wasting. Recently, several studies on ALS patients and ALS animal models indicated that intramuscular toxicity played a role in ALS disease progression; however, the mechanisms driving this are unknown. In this study, we explored the possible dysfunction of lipid metabolism in myocytes associated with ALS. Initially, skeletal muscle from 41 ALS patients, as well as 53 non-ALS control subjects, was investigated, and we identified that lipid droplet accumulation in the muscle fibers of ALS patients was significantly increased, especially in patients with FUS mutations. A myoblast (C2C12) cell line expressing mutant FUS (FUS-K510Q) was able to induce lipid droplet accumulation and mitochondrial dysfunction. Consistently, transgenic flies expressing FUS-K510Q under a muscle-specific driver showed elevated triglyceride levels in the flight muscles, as well as locomotor defects. Biochemical analysis of C2C12 cells and fly muscle tissues showed upregulation of PLIN2, and downregulation of ATGL and CPT1A, indicating inhibition of lipolysis and fatty acid β-oxidation in muscle cells with FUS mutations. Our study provided a potential explanation for the pathogenesis associated with lipid droplets accumulating in skeletal muscle in ALS. Our data also suggested that disordered lipid metabolism and mitochondrial dysfunction play a crucial role in intramuscular toxicity in ALS.

A wound is the pathological change of soft tissue under normal skin caused by various factors, such as collision, contusion, hot crush, avulsion, corrosive chemicals, operations, excessive wound tension after operations, local pressure that cannot be relieved for a long time, liquid immersion, local infection, and rejection reactions caused by allogeneic substances. The skin itself or its underlying soft tissue loses its integrity and continuity, thus losing its normal physiological function. Medical image analysis is a medical term that refers to the interdisciplinary fields of integrated medical imaging, artificial intelligence, digital image processing and analysis, mathematical modeling, and numerical algorithms. According to the time of wound formation, they can be divided into acute and chronic wounds. The common acute wounds include lacerations caused by trauma, surgical incisions, burns, and donor sites formed after skin graft operations. This article mainly studies the role of platelet-rich plasma gel nanocomposites in promoting wound healing. It is proven that ptt-rich plasma gel can significantly promote tissue repair and regeneration and accelerate wound healing in patients with severe burns. The atomic number of the nanocomposite has a better treatment effect on the nanoparticle approach. In this paper, chitosan nanocomposite membrane, nanocomposite algorithm, and the calculation method of enthalpy of formation of high alloy nanomaterials were used to study the role of ptt-rich plasma gel combined chitosan nanocomposite membrane loaded bone marrow stromal cells in promoting wound healing, and its effects were applied to the repair of special site burns, special burns, and different age burns. Good wound repair benefits from the correct treatment of the wound, which directly affects the stability and development of the internal environment. The difference in healing time between the two groups was statistically significant, and the recovery time of the PRP group was 0.001 less than that of the control group. The results showed that the wound healing time of the PRP group was significantly shorter than that of the control group ( P < 0.05 ); after treatment, the content of VEGF in the wound tissue of the two groups increased, especially in the PRP group; the effective rate of the PRP group was 75.0%, which was higher than 68.8% of the control group. It can play an important role in the regulation of expression and the pathophysiological process of wound healing.

Oculopharyngodistal myopathy (OPDM) is a rare adolescent or adult-onset neuromuscular disease that is characterized by progressive ocular, facial, pharyngeal and distal limb muscle weakness. The rimmed vacuoles and intranuclear inclusions in myofibers constitute the pathological hallmark of OPDM. In this review, the latest findings related to the genetic, molecular and clinical features of OPDM, as well as the diagnosis and management are summarized.Four gene mutations, CGG repeats in the 5'-untranslated region of LRP12 , GIPC1 , NOTCH2NLC and RILPL1 have been reported to be disease-causing genes in OPDM, namely OPDM1, OPDM2, OPDM3 and OPDM4, accordingly. So far, limited studies have suggested that CGG repeat expansion within the pathogenic range may play a key role in the pathogenesis of OPDM with the gain-of-function mechanism at the RNA and/or protein level, while repeat expansion over a threshold limit may cause hypermethylation, leading to the transcriptional silencing of the CGG repeats in the expanded allele, which results in the existence of mild phenotype or asymptomatic carriers.Novel gene mutations, possible molecular mechanisms and the clinical features related to different causative genes are discussed in this review. More studies on the exact pathogenic mechanism are needed.

SubHalo Abundance Matching (SHAM) is an empirical method for constructing galaxy catalogues based on high-resolution N-body simulations. We apply SHAM on the UNIT simulation to simulate SDSS BOSS/eBOSS luminous red galaxies (LRGs) within a wide redshift range of 0.2 < $z$ < 1.0. Besides the typical SHAM scatter parameter σ, we include $v$smear and Vceil to take into account the redshift uncertainty and the galaxy incompleteness, respectively. These two additional parameters are critical for reproducing the observed 2PCF multipoles on 5–25$\, h^{-1}\, {\rm Mpc}$. The redshift uncertainties obtained from the best-fitting $v$smear agree with those measured from repeat observations for all SDSS LRGs except for the LOWZ sample. We explore several potential systematics but none of them can explain the discrepancy found in LOWZ. Our explanation is that the LOWZ galaxies might contain another type of galaxies that needs to be treated differently. The evolution of the measured σ and Vceil also reveals that the incompleteness of eBOSS galaxies decreases with the redshift. This is the consequence of the magnitude lower limit applied in eBOSS LRG target selection. Our SHAM also set upper limits for the intrinsic scatter of the galaxy–halo relation, given a complete galaxy sample: σint < 0.31 for LOWZ at 0.2 < $z$ < 0.33, σint < 0.36 for LOWZ at 0.33 < $z$ < 0.43, and σint < 0.46 for CMASS at 0.43 < $z$ < 0.51. The projected 2PCFs of our SHAM galaxies also agree with the observational ones on the 2PCF fitting range.

Neuronal intranuclear inclusion disease (NIID) is a neuromuscular/neurodegenerative disease caused by the expansion of CGG repeats in the 5' untranslated region (UTR) of the

Recent studies indicate that CGG repeat expansions in LRP12, GIPC1, and NOTCH2NLC are associated with oculopharyngodistal myopathy (OPDM) types 1, 2, and 3, respectively. However, some clinicopathologically confirmed OPDM cases continue to have unknown genetic causes. Here, through a combination of long-read whole-genome sequencing (LRS), repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis PCR (AL-PCR), we found that a CGG repeat expansion in the 5' UTR of RILPL1 is associated with familial and simplex OPDM type 4 (OPDM4). The number of repeats ranged from 139 to 197. Methylation analysis indicates that the methylation levels in RILPL1 were unaltered in OPDM4 individuals. Analyses of muscle biopsies suggested that the expanded CGG repeat might be translated into a toxic poly-glycine protein that co-localizes with p62 in intranuclear inclusions. Moreover, analyses suggest that the toxic RNA gain-of-function effects also contributed to the pathogenesis of this disease. Intriguingly, all four types of OPDM have been found to be associated with the CGG repeat expansions located in 5' UTRs. This finding suggests that a common pathogenic mechanism, driven by the CGG repeat expansion, might underlie all cases of OPDM.

Next-generation spectroscopic surveys such as the MegaMapper, MUltiplexed Survey Telescope (MUST), MaunaKea Spectroscopic Explorer (MSE), and Wide Spectroscopic Telescope (WST) are foreseen to increase the number of galaxy/quasar redshifts by an order of magnitude, with hundred millions of spectra that will be measured at $z>2$. We perform a Fisher matrix analysis for these surveys on the baryonic acoustic oscillation (BAO), the redshift-space distortion (RSD) measurement, the non-Gaussianity amplitude $f_{\rm NL}$, and the total neutrino mass $M_\nu$. For BAO and RSD parameters, these surveys may achieve precision at sub-percent level (, Comment: 15 pages, 9 figures

Neuronal intranuclear inclusion disease (NIID) is associated with CGG repeat expansion in the NOTCH2NLC gene. Although pure or dominant peripheral neuropathy has been described as a subtype of NIID in a few patients, most NIID patients predominantly show involvements of the central nervous system (CNS). It is necessary to further explore whether these patients have subclinical peripheral neuropathy.Twenty-eight NIID patients, clinically characterized by CNS-dominant involvements, were recruited from two tertiary hospitals. Standard nerve conduction studies were performed in all patients. Skin and sural nerve biopsies were performed in 28 and 15 patients, respectively. Repeat-primed polymerase chain reaction and amplicon length polymerase chain reaction were used to screen the CGG repeat expansion in NOTCH2NLC.All 28 patients can be diagnosed with NIID based on skin pathological and genetic changes. All patients predominantly showed CNS symptoms mainly characterized by episodic encephalopathy and cognitive impairments, but no clinical symptoms of peripheral neuropathy could be observed initially. Electrophysiological abnormalities were found in 96.4% (27/28) of these patients, indicating that subclinical peripheral neuropathy is common in NIID patients with CNS-dominant type. Electrophysiological and neuropathological studies revealed that demyelinating degeneration was the main pathological pattern in these patients, although mild axonal degeneration was also observed in some patients. No significant association between CGG repeat size and the change of nerve conduction velocity was found in these patients.This study demonstrated that most patients with CNS-dominant NIID had subclinical peripheral neuropathy. Electrophysiological examination should be the routinely diagnostic workflow for every NIID patient.

Neuronal intranuclear inclusion disease (NIID) is a neuromuscular/neurodegenerative disease caused by the expansion of CGG repeats in the 5′ untranslated region (UTR) of the NOTCH2NLC gene. These repeats can be translated into a polyglycine-containing protein, uN2CpolyG, which forms protein inclusions and is toxic in cell models, albeit through an unknown mechanism. Here, we established a transgenic Drosophila model expressing uN2CpolyG in multiple systems, which resulted in progressive neuronal cell loss, locomotor deficiency, and shortened lifespan. Interestingly, electron microscopy revealed mitochondrial swelling both in transgenic flies and in muscle biopsies of individuals with NIID. Immunofluorescence and immunoelectron microscopy showed colocalization of uN2CpolyG with mitochondria in cell and patient samples, while biochemical analysis revealed that uN2CpolyG interacted with a mitochondrial RNA binding protein, LRPPRC (leucine-rich pentatricopeptide repeat motif-containing protein). Furthermore, RNA sequencing (RNA-seq) analysis and functional assays showed down-regulated mitochondrial oxidative phosphorylation in uN2CpolyG-expressing flies and NIID muscle biopsies. Finally, idebenone treatment restored mitochondrial function and alleviated neurodegenerative phenotypes in transgenic flies. Overall, these results indicate that transgenic flies expressing uN2CpolyG recapitulate key features of NIID and that reversing mitochondrial dysfunction might provide a potential therapeutic approach for this disorder.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Pathologically, it is characterized by β-amyloid plaques and neurofibrillary tangles. There are several genes have been found to relate to AD, including the human-specific Notch2 N terminal-like C (NOTCH2NLC) gene. The CGG repeat expansion in NOTCH2NLC has been reported in clinically diagnosed AD patients. However, it has not been reported in pathologically confirmed AD cases. In this study, we detected the NOTCH2NLC CGG repeat expansion in pathologically confirmed AD brain samples by repeat-primed PCR (RP-PCR) and fluorescence amplicon length analysis PCR (AL-PCR). As a result, the intermediate-length CGG repeat expansion in NOTCH2NLC was validated in one out of 39 pathologically confirmed AD cases. Pathologically, p62 positive intranuclear inclusions were observed in wide brain areas, and most inclusions appeared to be presented in the glial cells. In summary, our study found that the intermediate-length CGG repeat expansion in NOTCH2NLC was associated with pathologically confirmed AD. The p62-positive intranuclear inclusions could co-exist with AD neuropathologic changes. These data suggest that the association of NOTCH2NLC CGG repeat expansion with AD may be stronger than in previous studies.

Effective querying of data in the road networks is an important problem in the Internet of vehicles. Aggregate nearest neighbor queries can return the objects that minimizes an aggregate distance function on road networks considering a set of query points in the Internet of vehicles. And ${k}$ aggregate nearest neighbor query ( ${k}$ - ANN) is a complicate version for the basic one. The existing ${k}$ - ANN queries lack effective model to deal with the uncertain data and the existing query methods cannot be applied to solve the problem of ( ${k}$ - ANN) query on uncertain data directly. Therefore, in this paper, a probabilistic threshold ${k}$ - ANN query method based on uncertain Voronoi diagram is proposed. The method includes three phases: processing phase, pruning phase and refinement phase. The processing phase is to compute the minimum covered circle of the query dataset which is prepared for the pruning phase. In pruning phase, the different pruning algorithms are proposed for the corresponding three aggregate function of aggregate nearest neighbor query. The data points that cannot be the result are pruned and the candidate set is obtained. In refinement phase, the sets composed of ${k}$ data points in candidate set whose probabilities are not less than the user-specified threshold are stored into the result set and returned to the user. Experiments are performed to evaluate the effectiveness and superiority of these algorithms on probabilistic threshold k-ANN query.

Background The expansion of GGC repeat in the 5' untranslated region of the NOTCH2NLC has been associated with various neurogenerative disorders of the central nervous system and, more recently, oculopharyngodistal myopathy. This study aimed to report patients with distal weakness with both neuropathic and myopathic features on electrophysiology and pathology who present GGC repeat expansions in the NOTCH2NLC. Methods Whole‐exome sequencing (WES) and long‐read sequencing were implemented to identify the candidate genes. In addition, the available clinical data and the pathological changes associated with peripheral nerve and muscle biopsies were reviewed and studied. Results We identified and validated GGC repeat expansions of NOTCH2NLC in three unrelated patients who presented with progressive weakness predominantly affecting distal lower limb muscles, following negative results in an initial WES. We found intranuclear inclusions with multiple proteins deposits in the nuclei of both myofibers and Schwann cells. The clinical features of these patients are compatible with the diagnosis of distal motor neuropathy and rimmed vacuolar myopathy. Interpretation These phenotypes enrich the class of features associated with NOTCH2NLC‐related repeat expansion disorders (NRED), and provide further evidence that the neurological symptoms of NRED include not only brain, spinal cord, and peripheral nerves damage, but also myopathy, and that overlapping symptoms might exist.

Yi Lu,1 Jiaxi Yu,1 Qiuping Dong,2 Yan Du,3 Zheng Liang1 1Department of Otorhinolaryngology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Department of Cancer Cell Biology, Tianjin’s Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China; 3Department of Operating Theatre, Tianjin Medical University General Hospital, Tianjin, People’s Republic of ChinaCorrespondence: Zheng Liang, Department of Otorhinolaryngology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China, Tel +8618802230827, Email liangzheng01@tmu.edu.cnmailtoPurpose: The involvement of dedicator for cytokinesis 4 (DOCK4), a guanine nucleotide exchange factor for Rac1, in immune infiltration in stomach adenocarcinoma (STAD) remains unclear.Methods: The UALCAN database was used to analyze the expression of the DOCK family. The Kaplan–Meier method and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to assess the prognostic value of the DOCK family in STAD. Furthermore, the correlation between expression of DOCK4 as well as other immune-related marker genes and tumor immune infiltration in STAD was explored using the TIMER and GEPIA websites. Subsequently, the relationship between DOCK4 expression and clinical characteristics was verified using the UALCAN database. Finally, DOCK4 mutation was analyzed via the TIMER2.0 and cBioPortal databases and the DOCK4 protein-protein interaction networks were constructed using the GeneMANIA and STRING websites.Results: DOCK4 was found to be a new prognostic biomarker in STAD. DOCK4 expression in tumors was thoroughly evaluated relative to paracancerous tissues; overexpression of DOCK4 had a negative impact on the prognosis of patients with STAD. DOCK4 was found to be significantly associated with tumor immune infiltration in STAD.Conclusion: In summary, DOCK4 is a potential regulator of the recruitment and regulation of immune-infiltrating cells, thus serving as a valuable prognostic biomarker in STAD.Keywords: DOCK4, stomach adenocarcinoma, immune infiltration, prognostic biomarker, TME

BackgroundGGC repeat expansion in NOTCH2NLC has been recently linked to neuronal intranuclear inclusion disease (NIID) via unknown disease mechanisms. Herein, we explore the genetic origin of the sporadic cases and toxic RNA gain-of-function mechanism in NIID.MethodsMultiple genetic screenings were performed on NIID individuals and their available family members. Methylation status of blood DNA, NOTCH2NLC mRNA level from muscle biopsies and RNA foci from skin biopsies of NIID individuals or asymptomatic carriers were evaluated and compared.ResultsIn two sporadic NIID families, we identified two clinically and pathologically asymptomatic fathers carrying large GGC repeat expansion, above 300 repeats, with offspring repeat numbers of 172 and 148, respectively. Further evaluation revealed that the GGC repeat numbers in the sperm from two asymptomatic fathers were only 63 and 98, respectively. The CpG island in NOTCH2NLC of the asymptomatic carriers was hypermethylated, and accordingly, the NOTCH2NLC mRNA levels were decreased in the asymptomatic fathers. GGC repeat expansion RNA formed RNA foci and sequestered RNA binding proteins into p62 positive intranuclear inclusions in NIID individuals but not in the control or asymptomatic carrier.ConclusionOur study suggested the GGC repeat expansion in NOTCH2NLC might have a disease-causing number ranging from ~41 to ~300 repeats. The contraction of GGC repeat expansion in sperm could be a possible mechanism for the paternal-biased origin in some sporadic or recessive inherited NIID individuals. The toxic RNA gain-of-function mechanism was identified to be involved in the pathogenicity of this disease.

Oculopharyngodistal myopathy (OPDM) is associated with trinucleotide repeat expansions in LRP12 or GIPC1, but the genetic basis of many cases remains unknown. Yu et al. identify GGC repeat expansions in NOTCH2NLC in Chinese patients with OPDM, and provide evidence for possible underlying pathogenic mechanisms., Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ocular, facial, pharyngeal and distal limb muscle involvement. Trinucleotide repeat expansions in LRP12 or GIPC1 were recently reported to be associated with OPDM. However, a significant portion of OPDM patients have unknown genetic causes. In this study, long-read whole-genome sequencing and repeat-primed PCR were performed and we identified GGC repeat expansions in the NOTCH2NLC gene in 16.7% (4/24) of a cohort of Chinese OPDM patients, designated as OPDM type 3 (OPDM3). Methylation analysis indicated that methylation levels of the NOTCH2NLC gene were unaltered in OPDM3 patients, but increased significantly in asymptomatic carriers. Quantitative real-time PCR analysis indicated that NOTCH2NLC mRNA levels were increased in muscle but not in blood of OPDM3 patients. Immunofluorescence on OPDM muscle samples and expressing mutant NOTCH2NLC with (GGC)69 repeat expansions in HEK293 cells indicated that mutant NOTCH2NLC-polyglycine protein might be a major component of intranuclear inclusions, and contribute to toxicity in cultured cells. In addition, two RNA-binding proteins, hnRNP A/B and MBNL1, were both co-localized with p62 in intranuclear inclusions in OPDM muscle samples. These results indicated that a toxic protein gain-of-function mechanism and RNA gain-of-function mechanism may both play a vital role in the pathogenic processes of OPDM3. This study extended the spectrum of NOTCH2NLC repeat expansion-related diseases to a predominant myopathy phenotype presenting as OPDM, and provided evidence for possible pathogenesis of these diseases.

Oculopharyngodistal myopathy (OPDM) is an adult-onset inherited neuromuscular disorder characterized by progressive ptosis, external ophthalmoplegia, and weakness of the masseter, facial, pharyngeal, and distal limb muscles. The myopathological features are presence of rimmed vacuoles (RVs) in the muscle fibers and myopathic changes of differing severity. Inheritance is variable, with either putative autosomal-dominant or autosomal-recessive pattern. Here, using a comprehensive strategy combining whole-genome sequencing (WGS), long-read whole-genome sequencing (LRS), linkage analysis, repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis polymerase chain reaction (AL-PCR), we identified an abnormal GGC repeat expansion in the 5′ UTR of GIPC1 in one out of four families and three sporadic case subjects from a Chinese OPDM cohort. Expanded GGC repeats were further confirmed as the cause of OPDM in an additional 2 out of 4 families and 6 out of 13 sporadic Chinese individuals with OPDM, as well as 7 out of 194 unrelated Japanese individuals with OPDM. Methylation, qRT-PCR, and western blot analysis indicated that GIPC1 mRNA levels were increased while protein levels were unaltered in OPDM-affected individuals. RNA sequencing indicated p53 signaling, vascular smooth muscle contraction, ubiquitin-mediated proteolysis, and ribosome pathways were involved in the pathogenic mechanisms of OPDM-affected individuals with GGC repeat expansion in GIPC1. This study provides further evidence that OPDM is associated with GGC repeat expansions in distinct genes and highly suggests that expanded GGC repeat units are essential in the pathogenesis of OPDM, regardless of the genes in which the expanded repeats are located.

In the cause of working out the challenge of remaining life prediction (RUL) of proton exchange membrane fuel cell (PEMFC) under dynamic operating conditions, this article proposes a PEMFC RUL forecast technique based on the sparse autoencoder (SAE) and deep neural network (DNN). The method extracts the data set from the original experimental data at intervals periods of one hour to realize datum reconstruction. The Gaussian-weighted moving average filter is used to smooth noisy data (voltage and current). The smoothed filtered power output signal of the stack is extracted as an aging indicator. The SAE is used to extract the prediction features automatically, and the DNN is applied to realize the RUL prediction. The proposed method is experimentally verified using 127 369 experimental data. The effectiveness of the novel method is verified by three different training sets and test set configurations. The experimental results reveal that the novel approach has the best prediction effectiveness when the training set length is set to 500 h. At this point, the prediction accuracy can reach 99.68%. The mean absolute error (MAE), mean square error (MSE), and root-mean-square error (RMSE) are minimum values, which are 0.2035, 0.1121, and 0.3348, respectively. The superiority and effectiveness of the proposed approach are further validated by comparison with the K-nearest neighbor and support vector regression machine. The proposed approach can be appropriate for the prediction of the RUL of PEMFC under dynamic conditions.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the dysfunction of upper and lower motor neurons accompanied by muscle weakness and wasting. Recently, several studies on ALS patients and animal models implicated muscle intrinsic toxicity played a role in the disease progression with uncertain mechanisms. In this study, we explored the possible disorder of lipid metabolism in myocytes associated with ALS. Initially, skeletal muscle from 41 ALS patients as well as 53 non-ALS control subjects were investigated, and identified that the accumulation of lipid droplets in the muscle fibers of ALS patients was significantly increased, especially in the patients with FUS mutations. A myoblasts (C2C12) cell model expressing FUS-K510Q mutant induced the accumulation of lipid droplets and mitochondrial dysfunction. Consistently, transgenic flies expressing FUS-K510Q under a muscle-specific driver showed elevated triglyceride levels in flight muscle, as well as locomotor defects. Biochemical analysis of C2C12 cells and fly muscle tissues showed up-regulation of PLIN2, and down-regulation of ATGL and CPT1A, indicating inhibition of lipolysis and fatty acid β-oxidation in muscle cells with FUS mutations. Our study provided a potential explanation for the lipid droplets accumulation in skeletal muscle of ALS. Our data also suggested that lipid metabolism disorder and mitochondrial dysfunction play a crucial role in the muscle intrinsic toxicity of ALS.

BackgroundNeuronal intranuclear inclusion disease (NIID) is a heterogenous neurodegenerative disorder named after its pathological features. It has long been considered a disease of genetic origin. Recently, the GGC repeated expansion in the 5′-untranslated region (5′UTR) of the NOTCH2NLC gene has been found in adult-onset NIID in Japanese individuals. This study was aimed to investigate the causative mutations of NIID in Chinese patients.MethodsFifteen patients with NIID were identified from five academic neurological centres. Biopsied skin samples were analysed by histological staining, immunostaining and electron microscopic observation. Whole-genome sequencing (WGS) and long-read sequencing (LRS) were initially performed in three patients with NIID. Repeat-primed PCR was conducted to confirm the genetic variations in the three patients and the other 12 cases.ResultsOur patients included 14 adult-onset patients and 1 juvenile-onset patient characterised by degeneration of multiple nervous systems. All patients were identified with intranuclear inclusions in the nuclei of fibroblasts, fat cells and ductal epithelial cells of sweat glands. The WGS failed to find any likely pathogenic variations for NIID. The LRS successfully identified that three patients with adult-onset NIID showed abnormalities of GGC expansion in 5′UTR of the NOTCH2NLC gene. The GGC repeated expansion was further confirmed by repeat-primed PCR in seven familial cases and eight sporadic cases.ConclusionOur findings provided evidence that confirmed the GGC repeated expansion in the 5′UTR of the NOTCH2NLC gene is associated with the pathogenesis of NIID. Additionally, the GGC expansion was not only responsible for adult-onset patients, but also responsible for juvenile-onset patients.

As China's first X-ray astronomical satellite, the Hard X-ray Modulation Telescope (HXMT), which was dubbed as Insight-HXMT after the launch on June 15, 2017, is a wide-band (1-250 keV) slat-collimator-based X-ray astronomy satellite with the capability of all-sky monitoring in 0.2-3 MeV. It was designed to perform pointing, scanning and gamma-ray burst (GRB) observations and, based on the Direct Demodulation Method (DDM), the image of the scanned sky region can be reconstructed. Here we give an overview of the mission and its progresses, including payload, core sciences, ground calibration/facility, ground segment, data archive, software, in-orbit performance, calibration, background model, observations and some preliminary results., 29 pages, 40 figures, 6 tables, to appear in Sci. China-Phys. Mech. Astron. arXiv admin note: text overlap with arXiv:1910.04434

Considering the problem that the support vector machine (SVM) algorithm, used in the fault classification of fuel cell systems, is prone to fall into local optimal solution and cannot accurately identify fault categories, a fault classification method based on SVM optimized by cuckoo search (CS) algorithm is proposed. Through the analysis of measured data, the proposed method can effectively identify five fault states, including the leakage of hydrogen, the low pressure of deionized water humidification pumps, deionized ethylene glycol inlet high temperature, signal voltage over-range of deionized ethylene glycol outlet temperature and the low pressure of input air, with classification accuracy up to 93.6%.The advantages of this method are verified by comparing with SVM optimized by traditional grid search (GS) method.

When the robot moves in the room, it’s essential to build a map to guide it. Currently, there is a method to establish the maps in real time called simultaneous localization and mapping. Due to the complexity of the surrounding environment and the influence of the accuracy of sensors on the construction of the map, the correctness of mapping will be greatly affected. This article is based on previous research. This operation uses the algorithm based on robot operating system. We design the algorithms to identify changings between the maps of indoor states and achieve good results.

Neuronal intranuclear inclusion disease (NIID) is a heterogenous neurodegenerative disorder named after its pathological features. It has long been considered a disease of genetic origin. Recently, the GGC repeated expansion in the 5'-untranslated region (5'UTR) of theFifteen patients with NIID were identified from five academic neurological centres. Biopsied skin samples were analysed by histological staining, immunostaining and electron microscopic observation. Whole-genome sequencing (WGS) and long-read sequencing (LRS) were initially performed in three patients with NIID. Repeat-primed PCR was conducted to confirm the genetic variations in the three patients and the other 12 cases.Our patients included 14 adult-onset patients and 1 juvenile-onset patient characterised by degeneration of multiple nervous systems. All patients were identified with intranuclear inclusions in the nuclei of fibroblasts, fat cells and ductal epithelial cells of sweat glands. The WGS failed to find any likely pathogenic variations for NIID. The LRS successfully identified that three patients with adult-onset NIID showed abnormalities of GGC expansion in 5'UTR of theOur findings provided evidence that confirmed the GGC repeated expansion in the 5'UTR of the

Depressive and anxiety symptoms increase the risk of death in patients with Chronic Obstructive Pulmonary Disease (COPD), but the combined effects of the two factors are unknown.To assess the possible interactive effects of depressive and anxiety symptoms on the death of patients with COPD.Prospective data for 7787 Chinese patients with COPD was analyzed and the deaths were recorded. Depressive and anxiety symptoms were evaluated using the Hospital Anxiety and Depression Scale. A product of depressive and anxiety symptoms was added to the logistic regression model to evaluate the multiplicative interaction, and relative excess risk of interaction (RERI), attributable proportion (AP) of interaction, and synergy index (S) were applied to evaluate the additive interaction of the two factors. Bootstrap was used to calculate 95% confidence intervals (CIs) of RERI, AP and S. RERI0, AP0, or S1 indicated biological interaction.After 4 years' follow-up, the cumulative mortality was 20.0%, and the percentages of deaths in patients with depressive and anxiety symptoms were 28.5% and 30.9%, respectively. When adjusting for variables such as age, sex, disease duration, marital status, income, education level, co-morbidity, smoke status, biomass smoke, 6MWD, MRC, BMI and FEV1. the RERI, AP, and S (with 95% CIs) resulted in depression and anxiety scores of 6.54 (1.23-13.79), 0.54 (0.18-0.83), and 2.64 (1.33-4.75) respectively.Interaction effects were found between depressive and anxiety symptoms on the death of patients with COPD. Patients with both depressive and anxiety symptoms have an increased risk of death from COPD.