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Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. To identify additional genetic factors, we analyzed exome sequences in a large cohort of Chinese ALS patients and found a homozygous variant (p.L700P) in PCDHA9 in three unrelated patients. We generated Pcdhα9 mutant mice harboring either orthologous point mutation or deletion mutation. These mice develop progressive spinal motor loss, muscle atrophy, and structural/functional abnormalities of the neuromuscular junction, leading to paralysis and early lethality. TDP-43 pathology is detected in the spinal motor neurons of aged mutant mice. Mechanistically, we demonstrate that Pcdha9 mutation causes aberrant activation of FAK and PYK2 in aging spinal cord, and dramatically reduced NKA-α1 expression in motor neurons. Our single nucleus multi-omics analysis reveals disturbed signaling involved in cell adhesion, ion transport, synapse organization, and neuronal survival in aged mutant mice. Together, our results present PCDHA9 as a potential ALS gene and provide insights into its pathogenesis.

The igfbp family proteins are key regulators of the biological activities of igfs, which play a pivotal role in controlling growth. Growth is highly variable between different fish species and even between growth stages and sexes within the same fish species. For determining the igfbps significantly associated to growth, we identified igfbp genes from the whole-wide genomes of mandarin fish Siniperca chuatsi and big-eye mandarin fish Siniperca kneri, and detected their expression profiles under different growth conditions. The results revealed that: 1) both mandarin fish and big-eye mandarin fish have 10 igfbp family members (igfbp-1a/b, igfbp-2a/b, igfbp-3, igfbp−4, igfbp-5a/b, and igfbp-6a/b), which are highly conserved among igfbp family members; 2) in early development, the expression of igf1 mRNA showed an increasing trend, igfbp-1a/b expression increased significantly with development and the expression trend was strongly similar to that of igf1; 3) variation of body sizes in adult revealed a strong correlation between the serum Gh content and igf1 mRNA expression level in the liver, and the expression levels of hepatic igfbp-2a/b, -4 showed a positive correlation; 4) serum Gh levels and the relative expression of hepatic igf1 mRNA were significantly higher in females than in males, the fold change in igfbp-1a in muscle, -2a, -5a in liver mRNA expression was strongly similar to that of igf1; 5) variation of the interspecific growth showed that the expression of serum Gh and hepatic igf1 mRNA in mandarin fish was significantly higher than that in big-eye mandarin fish. The expression of igfbps mRNA in mandarin fish was significantly higher than that in big-eye mandarin fish, except for igfbp-2a/2b in muscle and igfbp-6a in liver. Taken together, our results suggest that the different effects on growth of mandarin fish are regulated by the actions of different igfbps, where igfbp-1a/b, -2a/b, -4 and -5a may be a candidate for growth rate difference studies. The inherently low expression of Gh, igf1, and igfbps might have contributed to the slow growth of big-eye mandarin fish.

Marine shale reservoirs have experienced intense tectonic movements in southeastern Chongqing, resulting in widely developed folds, faults and bedding slip deformation. The gas content is of a wide range while the organic matter content and thickness are sufficient for shale gas accumulation. Here, we review previous work and present outcrop and core data from 11 shale wells around southeastern Chongqing to analyze and summarize tectonic types and their combinations, as well as their influence on shale gas preservation and enrichment. Fault and bedding slips are prevalent in shale reservoirs, and they apparently influence shale gas content. Bedding slip crush is usually formed at the bottom interval where the total organic content is high from intense horizontal compression. Bedding slip crushing and well-developed high-angle natural fractures form a net fracture system where shale gas is enriched in an anticline structure or lost to air in a syncline structure laterally. Strata dip is the key geological factor that controls bedding slip deformation in shale reservoirs in certain areas. According to the established bedding slip geological model, when bedding slip occurred, the critical strata dips of the lower Silurian Longmaxi Formation were 13.34°, respectively. Bedding slip crushed anticlines without faults and synclines without faults and bedding slip crushing are the two tectonic patterns that are favorable for shale gas preservation and enrichment, which should be the focus of further explorations of lower Paleozoic shale gas in southeastern Chongqing.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by predominant impairment of upper and lower motor neurons. Over 50 TARDBP mutations have been reported in both familial (FALS) and sporadic ALS (SALS). Some mutations in TARDBP, e.g. A382T and G294V, have genetic founder effects in certain geographic regions. However, such prevalence and founder effect have not been reported in Chinese. Methods Whole-exome sequencing (WES) was performed in 16 Chinese FALS patients, followed by Sanger sequencing for the TARDBP p.Gly298Ser mutation (G298S) in 798 SALS patients and 1,325 controls. Haplotype analysis using microsatellites flanking TARDBP was conducted in the G298S-carrying patients and noncarriers. The geographic distribution and phenotypic correlation of the TARDBP mutations reported worldwide were reviewed. Results WES detected the TARDBP G298S mutation in 8 FALS patients, and Sanger sequencing found additional 8 SALS cases, but no controls, carrying this mutation. All the 16 cases came from Southern China, and 7 of these patients shared the 117-286-257-145-246-270 allele for the D1S2736-D1S1151-D1S2667-D1S489-D1S434-D1S2697 markers, which was not found in the 92 non-carrier patients (0/92) (p

Summary: Membraneless condensates, such as stress granules (SGs) and processing bodies (P-bodies), have attracted wide attention due to their unique feature of rapid response to stress without first requiring nuclear feedback. In this study, we identify diaphanous-related formin 3 (DIAPH3), an actin nucleator, as a scaffold protein to initiate liquid-liquid phase separation (LLPS) and form abundant cytosolic phase-separated DIAPH3 granules (D-granules) in mammalian cells such as HeLa, HEK293, and fibroblasts under various stress conditions. Neither mRNAs nor known stress-associated condensate markers, such as G3BP1, G3BP2, and TIA1 for SGs and DCP1A for P-bodies, are detected in D-granules. Using overexpression and knockout of DIAPH3, pharmacological interventions, and optogenetics, we further demonstrate that stress-induced D-granules spatially sequester DIAPH3 within the condensation to inhibit the assembly of actin filaments in filopodia. This study reveals that D-granules formed by LLPS act as a regulatory hub for actin cytoskeletal remodeling in response to stress.

Objectives There is significant burden on caregivers of patients with amyotrophic lateral sclerosis (ALS). However, only a few studies have focused on caregivers, and traditional research methods have obvious shortcomings in dealing with multiple influencing factors. This study was designed to explore influencing factors on caregiver burden among ALS patients and their caregivers from a new perspective.Design Cross-sectional study.Setting The data were collected at an affiliated hospital in Guangzhou, Guangdong, China.Participants Fifty-seven pairs of patients with ALS and their caregivers were investigated by standardised questionnaires.Main outcome measures This study primarily assessed the influencing factor of caregiver burden including age, gender, education level, economic status, anxiety, depression, social support, fatigue, sleep quality and stage of disease through data mining. Statistical analysis was performed using SPSS 24.0, and least absolute shrinkage and selection operator (LASSO) regression model was established by Python 3.8.1 to minimise the effect of multicollinearity.Results According to LASSO regression model, we found 10 variables had weights. Among them, Milano-Torinos (MITOS) stage (0–1) had the highest weight (−12.235), followed by younger age group (−3.198), lower-educated group (2.136), fatigue (1.687) and social support (-0.455). Variables including sleep quality, anxiety, depression and sex (male) had moderate weights in this model. Economic status (common), economic status (better), household (city), household (village), educational level (high), sex (female), age (older) and MITOS stage (2–4) had a weight of zero.Conclusions Our study demonstrates that the severity of ALS patients is the most influencing factor in caregiver burden. Caregivers of ALS patients may suffer less from caregiver burden when the patients are less severe, and the caregivers are younger. Low educational status could increase caregiver burden. Caregiver burden is positively correlated with the degree of fatigue and negatively correlated with social support. Hopefully, more attention should be paid to caregivers of ALS, and effective interventions can be developed to relieve this burden.

BackgroundLimited data exists on the clinical features of patients with amyotrophic lateral sclerosis (ALS) during reproductive ages.ObjectiveOur study characterized the clinical features of ALS and the effects of pregnancy on disease progression in patients with ALS.MethodsWe performed a retrospective study of female patients with ALS in three ALS research centers in southern China from 2009 to 2021. Data regarding fertility status, and clinical and genetic features, were collected. Age-matched male patients with ALS served as controls. The patients were divided into the following two subgroups: patients with symptom onset within 1 year of pregnancy and patients with symptom onset over 1 year group after pregnancy.ResultsA total of 52 female and 52 matched male patients were enrolled. There were no differences in female and male patients in the mean age of symptom onset, the mean baseline ALSFRS-R score, or median reduction of ALSFRS-R score (p > 0.05). The mean age of first pregnancy was 25.57 ± 4.40) years. The mean age of first pregnancy in the over 1 year group was lower than that in the within 1 year group (p= 0.01). There was no difference in the median reduction of ALSFRS-R between the two subgroups. In the univariate analysis, diagnostic delay was highly correlated with the disease progression, with short delay representing rapid progress. No multicollinearity was found among every variable. In addition, 40.38% patients carried ALS-related gene variants. The proportion with gene mutations in the within 1 year group was higher than that in the over 1 year group (p < 0.01). Furthermore, SETX was the most frequently mutated gene in this cohort (16.67%) including 4 uncertain mutation.ConclusionPregnancy and fertility were not associated with disease progression. Diagnostic delay was correlated with disease progression in this cohort. In addition, SETX might be a gene of concern for ALS patients of childbearing age.

SO2, previously known as the product of industrial waste, has recently been proven to be a novel gasotransmitter in the cardiovascular system. It is endogenously produced from the metabolism pathway of sulfur-containing amino acids in mammalians. Endogenous SO2 acts as an important controller in the regulation of many biological processes including cardiovascular physiological and pathophysiological events. Recently, the studies on the regulatory effect of endogenous SO2 on cell apoptosis and its pathophysiological significance have attracted great attention. Endogenous SO2 can regulate the apoptosis of vascular smooth muscle cells, endothelial cells, cardiomyocytes, neuron, alveolar macrophages, polymorphonuclear neutrophils and retinal photoreceptor cells, which might be involved in the pathogenesis of hypertension, pulmonary hypertension, myocardial injury, brain injury, acute lung injury, and retinal disease. Therefore, in the present study, we described the current findings on how endogenous SO2 is generated and metabolized, and we summarized its regulatory effects on cell apoptosis, underlying mechanisms, and pathophysiological relevance.

The slow loris (Genus Nycticebus) is a group of small, nocturnal and venomous primates with a distinctive locomotion mode. The detection of slow loris plays an important role in the subsequent individual identification and behavioral recognition and thus contributes to formulating targeted conservation strategies, particularly in reintroduction and post-release monitoring. However, fewer studies have been conducted on efficient and accurate detection methods of this endangered taxa. The traditional methods to detect the slow loris involve long-term observation or watching surveillance video repeatedly, which would involve manpower and be time consuming. Because humans cannot maintain a high degree of attention for a long time, they are also prone to making missed detections or false detections. Due to these observational challenges, using computer vision to detect slow loris presence and activity is desirable. This article establishes a novel target detection dataset based on monitoring videos of captive Bengal slow loris (N. bengalensis) from the wildlife rescue centers in Xishuangbanna and Pu’er, Yunnan, China. The dataset is used to test two improvement schemes based on the YOLOv5 network: (1) YOLOv5-CBAM + TC, the attention mechanism and deconvolution are introduced; (2) YOLOv5-SD, the small object detection layer is added. The results demonstrate that the YOLOv5-CBAM + TC effectively improves the detection effect. At the cost of increasing the model size by 0.6 MB, the precision rate, the recall rate and the mean average precision (mAP) are increased by 2.9%, 3.7% and 3.5%, respectively. The YOLOv5-CBAM + TC model can be used as an effective method to detect individual slow loris in a captive environment, which helps to realize slow loris face and posture recognition based on computer vision.

The objective of this study was to observe the effects of low-molecular-weight heparin calcium (LMWHC) combined with argatroban on the treatment, vascular endothelial function, inflammatory factors and neurological function in patient with acute cerebral infarction. A total of 80 patients with acute cerebral infarction were randomly divided into 2 groups each of 40 cases, regardless of gender, aged from 55-75 years, who underwent treatment in hospital from January 2018 to December 2020. Each group received routine treatment, in which the treatment group received LMWHC alongwith argatroban. The score of neurological deficit (NIHSS) and serum neurological function, endothelial injury and inflammatory marker levels, and the clinical efficacy after treatment of 14 days were compared between groups. After treatment of 14 days, the vascular endothelial function (NO, ET-1, FMD) and inflammatory factors (hs-CRP, TNF-a, IL-6, MMP-9, Lp-PLA2) in the patients of the treatment group were significantly higher than the control group. NIHSS and serum neurological function (copeptin, NT-proBNP, PAO, S-100B) in the patients of the treatment group were significantly higher than that of the control group (P<0.05). Adverse reaction of LMWHC and argatroban was not found in the course of treatment. We conclude that LMWHC combined with argatroban are safe and effective in the treatment of acute cerebral infarction. [ABSTRACT FROM AUTHOR]