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The aim was to evaluate the potential of retinal nerve fiber layer thickness (RNFLT) measured with optical coherence tomography in predicting disease progression in relapsing-remitting multiple sclerosis (RRMS).Analyses were conducted post hoc of this 24-month, phase III, double-blind study, in which RRMS patients were randomized (1:1:1) to once daily oral fingolimod 0.5 mg, 1.25 mg or placebo. The key outcomes were the association between baseline RNFLT and baseline clinical characteristics and clinical/imaging outcomes up to 24 months. Change of RNFLT with fingolimod versus placebo within 24 months and time to retinal nerve fiber layer (RNFL) thinning were evaluated.Altogether 885 patients were included. At baseline, lower RNFLT was correlated with higher Expanded Disability Status Scale score (r = -1.085, p = 0.018), lower brain volume (r = 0.025, p = 0.006) and deep gray matter volume (r = 0.731, p 0.0001), worse visual acuity (r = -19.846, p 0.0001) and longer duration since diagnosis (r = -0.258, p = 0.018). At month 12, low baseline RNFLT (86 μm) versus high baseline RNFLT (≥99 μm) was associated with a greater brain volume loss (percentage change -0.605% vs. -0.315%, p = 0.035) in patients without optic neuritis history. At month 24, low baseline RNFLT versus high baseline RNFLT was associated with a higher number of new or newly enlarged T2 lesions (mean number 4.0 vs. 2.8, p = 0.014) and a higher risk of subsequent RNFL thinning (hazard ratio 2.55; 95% confidence interval 1.84-3.53; p 0.001). The atrophy of the RNFL in the inferior quadrant was alleviated with fingolimod 0.5 mg versus placebo at month 24 (Δ(least squares mean) = 1.8, p = 0.047).Retinal nerve fiber layer thickness could predict disease progression in RRMS.Clinicaltrials.gov identifier: NCT00355134, https://clinicaltrials.gov/ct2/show/NCT00355134.

Diabetic cardiomyopathy (DCM) is currently a progressive and nonstoppable complication in type 2 diabetic patients. Metabolic insults and insulin resistance are involved in its pathogenesis; however, the underlying mechanisms are still not clearly understood. Here we show that calcium dysregulation can be both a cause and a consequence of cardiac insulin resistance that leads to DCM. A western diet induces the development of DCM through at least three phases in mice, among which an early phase depends on impaired Thr484-phosphorylation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) elicited by insulin resistance. Mutation of SERCA2a-Thr484 to a nonphosphorylatable alanine delays calcium re-uptake into the sarcoplasmic reticulum in the cardiomyocytes and decreases cardiac function at the baseline. Importantly, this mutation blunts the early phase of DCM, but has no effect on disease progression in the following phases. Interestingly, impairment of sarcoplasmic reticulum calcium re-uptake caused by the SERCA2a-Thr484 mutation inhibited processing of insulin receptor precursor through FURIN convertase, resulting in cardiac insulin resistance. Collectively, these data reveal a bidirectional relationship between insulin resistance and impairment of calcium homeostasis, which may underlie the early pathogenesis of DCM. Our findings have therapeutic implications for early intervention of DCM.

Background Neuromyelitis optica spectrum disorder (NMOSD) is a chronic inflammatory demyelinating disease of the central nervous system with both a long course and high disability rate. It can cause different degrees of neurological impairment, resulting in the increased perception of stress in the patient. Health-related hardiness is psychological defense against stressors in cases of illness. The study was to investigate the role of health-related hardiness between disability and perceived stress in NMOSD patients and conduct health-related hardiness education for NMOSD patients to observe changes in health-related hardiness and perceived stress.Methods The study investigated disability status, health-related hardiness, and perceived stress in NMOSD patients. The mediating effect of health-related hardiness between disability status and perceived stress was verified. Additionally, health-related hardiness education was used as an intervention to improve the health-related hardiess. The Extended Disability Status Score (EDSS), Health-Related Hardiness Scale (HRHS), and Perceived Stress Scale (PSS) were used to assess patient disability status, health-related hardiness, and perceived stress.Results 128 patients were completed the investigation of HRHS, EDSS and PSS. 69 patients were enrolled in the health-related hardiness education study. NMOSD patients exhibited high levels of perceived stress. Health-related hardiness played a mediating role between disability and perceived stress, with mediating effect accounting for 12.7% of the total effect. After patients received health-related hardiness education, the score of health-related hardiness were significantly elevated and perceived stress scores were significantly lower.Conclusion Health-related hardiness had a partial mediating effect between disability and perceived stress in NMOSD patients. Health-related hardiness education could effectively increase health-related hardiness, as well reducing perceived stress caused by NMOSD.

Figure S1. The promoter CpG island of TRPM3/miR-204 is hypermethylation in CRC cells. A, Target sequences in the promote CpG islands of miR-638 gene used for the DNA methylation analysis. The underlined sequences are regions corresponding to the primers of bisulfite-sequencing PCR (BSP) used. B, Schematic representation of the methylation status of the CpG island (including 42 CpG sites) in the TRPM3 promoter as detected in the indicated CRC cell lines. Circles mark different CpG sites in the analyzed sequence. C, The relative mRNA levels of TRPM3 in CRC cell lines. Normal, a pooled sample of noncancerous tissues (NCTs). D, The relative expression of miR-204-5p in CRC cell lines. E, The TRPM3 mRNA levels in CRC cell lines were positively correlated with those of miR-204-5p. F, Quantitative analysis of miR-204-5p expression in CRC cells treated with DNA methyltransferase inhibitor (5-aza-dC). Following treatment of HCT116 and LoVo cells with 5-aza-dC for 72 hours, the miR-204-5p expression in the treated CRC cells was significantly increased compared with untreated control cells (***P < 0.001).

Figure S3. Ectopic miR-204-5p expression increases the sensitivity of CRC cells to 5-FU and DDP. A, and B, miR-204 overexpression enhanced 5-FU and DDP-induced apoptosis in LoVo (A) and HCT116 (B) cells. Annexin V/PI staining and FACs analysis were performed to detect apoptosis of LoVo and HCT116 cells after administration of 5 μg/mL 5-FU and DDP. The apoptosis levels were determined by the Annexin V positive ratio.

Figure S4. Immunohistochemical staining of RAB22A in the CRC and NCT samples. A, RAB22A protein is mainly localised in the cytoplasm. The scores (0, 1, 2 and 3) are based on the intensity of the brown staining. B, RAB22A protein expression was frequently increased in the tumor tissues compared with the matched NCTs (58.5%) in an independent test cohort of 132 CRC cases.

Figure S2. miR-204-3p showed no significant effect on CRC cell growth. A and B, The expression of miR-204-3p in 6 different CRC cells (A) and tissues (B) was much lower than that of miR-204-5p. C and D, Overexpression of miR-204-3p in LoVo (C) and HCT116 (D) cells did not affect their rates of proliferation. The cell numbers were determined using the Cell Counting Kit-8 assay after transfection. E and F, Inhibition of miR-204-3p in LoVo (E) and HCT116 (F) cells stably expressing miR-204 did not affect their rates of proliferation.

Table S3. Downregulated transcripts in miR-204-5p transfected HCT116 cells

Purpose: miR-204-5p was found to be downregulated in colorectal cancer tissues in our preliminary microarray analyses. However, the function of miR-204-5p in colorectal cancer remains unknown. We therefore investigated the role, mechanism, and clinical significance of miR-204-5p in colorectal cancer development and progression.Experimental Design: We measured the expression of miR-204-5p and determined its correlation with patient prognoses. Ectopic expression in colorectal cancer cells, xenografts, and pulmonary metastasis models was used to evaluate the effects of miR-204-5p on proliferation, migration, and chemotherapy sensitivity. Luciferase assay and Western blotting were performed to validate the potential targets of miR-204-5p after the preliminary screening by a microarray analysis and computer-aided algorithms.Results: miR-204-5p is frequently downregulated in colorectal cancer tissues, and survival analysis showed that the downregulation of miR-204-5p in colorectal cancer was associated with poor prognoses. Ectopic miR-204-5p expression repressed colorectal cancer cell growth both in vitro and in vivo. Moreover, restoring miR-204-5p expression inhibited colorectal cancer migration and invasion and promoted tumor sensitivity to chemotherapy. Mechanistic investigations revealed that RAB22A, a member of the RAS oncogene family, is a direct functional target of miR-204-5p in colorectal cancer. Furthermore, RAB22A protein levels in colorectal cancer tissues were frequently increased and negatively associated with miR-204-5p levels and survival time.Conclusions: Our results demonstrate for the first time that miR-204-5p acts as a tumor suppressor in colorectal cancer through inhibiting RAB22A and reveal RAB22A to be a new oncogene and prognostic factor for colorectal cancer. Clin Cancer Res; 20(23); 6187–99. ©2014 AACR.

Figure S5. The ectopic expression or knockdown of RAB22A in CRC cells. A,The most effective siRNA (siRNA-1) was selected out for further investigation. B, the protein levels of RAB22A were determined by western blotting in LoVo and HCT116 cells transfected with miR-204-5p mimic, RAB22A, siRAB22A or control. Beta-actin served as an internal control.

Supplementary Table S1. Patients' information Supplementary Table S2. Primer sequences Supplementary Figure Legends

Injuries lead to an early systemic inflammatory state with innate immune system activation. Neutrophil extracellular traps (NETs) are a complex of chromatin and proteins released from the activated neutrophils. While initially described as a response to bacterial infections, NETs have also been identified in the sterile post-injury inflammatory state. Peptidylarginine deiminases (PADs) are a group of iso-enzymes that catalyze the conversion of arginine to citrulline, termed citrullination or deimination. PAD2 and PAD4 have been demonstrated to play a role in NET formation through citrullinated histone H3 (CitH3). PAD2 and PAD4 have a variety of substrates with variable organ distribution. Pre-clinical and clinical studies have evaluated the role of PADs and NETs in major trauma, hemorrhage, burns, and traumatic brain injury. NET formation and PAD activation have been shown to contribute to the post-injury inflammatory state leading to a detrimental effect on organ systems. This review describes our current understanding of the of role of PAD and NET formation following injury and burn. This is a new field of study, and the emerging data appears promising for the future development of targeted biomarkers and therapies in trauma.

As the essential content of intelligent animal husbandry, identifying each livestock is the only way to achieve modern and refined scientific husbandry. This paper proposes a sheep face recognition method based on European spatial metrics and realizes noncontact sheep identity recognition by training the network using sheep face image samples in the natural environment. The SheepBase data set was first proposed in this process, which contains 6559 images of Inner Mongolia fine-wool sheep and Sunite sheep. To enhance the diversity of the data, the sheep face images were data-enhanced. Secondly, to solve the problems of more redundant information in the sheep face image and the poor posture and angle of the sheep face, we propose the sheep face detection and correction (SheepFaceRepair) method. This method aims to detect the sheep face area in the image to be recognized and align the sheep face area. On this basis, we offer an open sheep facial recognition network (SheepFaceNet) based on the European spatial metric. This method incorporates the biological identity information features of the sheep face to achieve sheep identity. We also tested the effectiveness of this method in the SheepBase data set. The experimental results show that the method proposed in this paper is much higher than the other methods, and the precision of recognition reaches 89.12%. In addition, we found that integrating the biometrics of the sheep face can effectively improve the network’s recognition capacity.

Cadmium is one of the environmental and occupational pollutants and its potential adverse effects on human health have given rise to substantial concern. Cadmium causes damage to the male reproductive system via induction of germ-cell apoptosis; however, the underlying mechanism of cadmium-induced reproductive toxicity in Leydig cells remains unclear. In this study, twenty mice were divided randomly into four groups and exposed to CdCl2 at concentrations of 0, 0.5, 1.0 and 2.0 mg/kg/day for four consecutive weeks. Testicular injury, abnormal spermatogenesis and apoptosis of Leydig cells were observed in mice. In order to investigate the mechanism of cadmium-induced apoptosis of Leydig cells, a model of mouse Leydig cell line (i.e. TM3 cells) was subjected to treatment with various concentrations of CdCl2. It was found that mitochondrial function was disrupted by cadmium, which also caused a significant elevation in levels of mitochondrial superoxide and cellular ROS. Furthermore, while cadmium increased the expression of mitochondrial fission proteins (DRP1 and FIS1), it reduced the expression of mitochondrial fusion proteins (OPA1 and MFN1). This led to excessive mitochondrial fission, the release of cytochrome c and apoptosis. Conversely, cadmium-induced accumulation of mitochondrial superoxide was decreased by the inhibition of mitochondrial fission through the use of Mdivi-1 (an inhibitor of DRP1). Mdivi-1 also partially prevented the release of cytochrome c from mitochondria to cytosol and attenuated cell apoptosis. Finally, given the accumulation of LC3II and SQSTM1/p62 and the obstruction of Parkin recruitment into damaged mitochondria in TM3 cells, the autophagosome-lysosome fusion was probably inhibited by cadmium. Overall, these findings suggest that cadmium induces apoptosis of mouse Leydig cells via the induction of excessive mitochondrial fission and inhibition of mitophagy.

To investigate the potential associations between household renovation and allergic diseases among preschool children in Wuhan, we conducted a large cross-sectional questionnaire survey among 9455 preschool children aged 3-6 years in Wuhan during November to December 2019. Data on demographics, health status, and home decoration conditions were analysed based on a questionnaire. Compared with tiles/stone/cement floor covering, the use of composite floor significantly increased the risk of diagnosed rhinitis and eczema among children (rhinitis: AOR, 95% CI: 1.36, 1.06-1.73; eczema: AOR, 95% CI: 1.47, 1.17-1.85). Household renovation had significant associations with diagnosed eczema (within 1 year before pregnancy: AOR, 95% CI: 1.34, 1.20-1.50; during pregnancy: AOR, 95% CI: 1.25, 1.08-1.44). This study suggests that use of artificial synthetic materials in home renovation during early childhood and pregnancy may be potential risk factors for childhood asthma, allergic rhinitis, and eczema.

The gut microbiota is a large symbiotic community of anaerobic and facultative aerobic bacteria inhabiting the human intestinal tract, and its activities significantly affect human health. Increasing evidence has suggested that the gut microbiome plays an important role in tumor-related immune regulation. In the tumor microenvironment (TME), the gut microbiome and its metabolites affect the differentiation and function of immune cells regulating the immune evasion of tumors. The gut microbiome can indirectly influence individual responses to various classical tumor immunotherapies, including immune checkpoint inhibitor therapy and adoptive immunotherapy. Microbial regulation through antibiotics, prebiotics, and fecal microbiota transplantation (FMT) optimize the composition of the gut microbiome, improving the efficacy of immunotherapy and bringing a new perspective and hope for tumor treatment.

ObjectiveWe previously identified the independent predictors of recurrent relapse in neuromyelitis optica spectrum disorder (NMOSD) with anti-aquaporin-4 antibody (AQP4-ab) and designed a nomogram to estimate the 1- and 2-year relapse-free probability, using the Cox proportional hazard (Cox-PH) model, assuming that the risk of relapse had a linear correlation with clinical variables. However, whether the linear assumption fits real disease tragedy is unknown. We aimed to employ deep learning and machine learning to develop a novel prediction model of relapse in patients with NMOSD and compare the performance with the conventional Cox-PH model.MethodsThis retrospective cohort study included patients with NMOSD with AQP4-ab in 10 study centers. In this study, 1,135 treatment episodes from 358 patients in Huashan Hospital were employed as the training set while 213 treatment episodes from 92 patients in nine other research centers as the validation set. We compared five models with added variables of gender, AQP4-ab titer, previous attack under the same therapy, EDSS score at treatment initiation, maintenance therapy, age at treatment initiation, disease duration, the phenotype of the most recent attack, and annualized relapse rate (ARR) of the most recent year by concordance index (C-index): conventional Cox-PH, random survival forest (RSF), LogisticHazard, DeepHit, and DeepSurv.ResultsWhen including all variables, RSF outperformed the C-index in the training set (0.739), followed by DeepHit (0.737), LogisticHazard (0.722), DeepSurv (0.698), and Cox-PH (0.679) models. As for the validation set, the C-index of LogisticHazard outperformed the other models (0.718), followed by DeepHit (0.704), DeepSurv (0.698), RSF (0.685), and Cox-PH (0.651) models. Maintenance therapy was calculated to be the most important variable for relapse prediction.ConclusionThis study confirmed the superiority of deep learning to design a prediction model of relapse in patients with AQP4-ab-positive NMOSD, with the LogisticHazard model showing the best predictive power in validation.

Sarcoplasmic/endoplasmic reticulum calcium ATPase SERCA2 mediates calcium re-uptake from the cytosol into sarcoplasmic reticulum, and its dysfunction is a hallmark of heart failure. Multiple factors have been identified to modulate SERCA2 activity, however, its regulation is still not fully understood. Here we identify a Ral-GTPase activating protein RalGAPα1 as a critical regulator of SERCA2 in cardiomyocytes through its downstream target RalA. RalGAPα1 is induced by pressure overload, and its deficiency causes cardiac dysfunction and exacerbates pressure overload-induced heart failure. Mechanistically, RalGAPα1 regulates SERCA2 through direct interaction and its target RalA. Deletion of RalGAPα1 decreases SERCA2 activity and prolongs calcium re-uptake into sarcoplasmic reticulum. GDP-bound RalA, but not GTP-bound RalA, binds to SERCA2 and activates the pump for sarcoplasmic reticulum calcium re-uptake. Overexpression of a GDP-bound RalAS28N mutant in the heart preserves cardiac function in a mouse model of heart failure. Our findings have therapeutic implications for treatment of heart failure.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe neurological inflammatory disease mainly caused by pathogenic aquaporin-4 antibodies (AQP4-IgG). The safety and efficacy of the neonatal Fc receptor antagonist batoclimab addition to conventional intravenous methylprednisolone pulse (IVMP) therapy in patients with NMOSD acute attacks was assessed.In an open-label, dose-escalation phase 1b study, NMOSD patients with acute myelitis and/or optic neuritis received four doses of weekly subcutaneous injections of either 340 mg or 680 mg batoclimab with concurrent IVMP and were followed up for 27 weeks. The primary end-points were safety and tolerability. Secondary end-points included pharmacodynamics and efficacy, with key efficacy assessment at week 4.In total nine NMOSD patients were enrolled, including two and seven in the 340 and 680 mg groups. Five patients had acute myelitis, while the remaining four had unilateral optic neuritis. Batoclimab add-on therapy had an overall good safety profile without serious adverse events. In the 680 mg group, mean immunoglobulin G (IgG) reached its maximum reduction at the last dose (day 22). In the meantime, AQP4-IgG was undetectable in six of seven subjects whose baseline AQP4-IgG titers ranged from 1:32 to 1:320. Expanded Disability Status Scale score was reduced by 1.3 ± 0.4 at week 4 (2.7 ± 1.3) compared with baseline (4.0 ± 1.0).Batoclimab add-on therapy to IVMP is safe and tolerated in patients with NMOSD. Preliminary evidence suggests a beneficial neurological effect. A randomized controlled trial would be needed to prove the efficacy.

Insulin signals through its receptor to recruit insulin receptor substrates (IRS) and phosphatidylinositol 3-kinase (PI3K) to the plasma membrane for production of phosphatidylinositol-3,4,5-trisphosphate (PIP3) from phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], which consequently activates protein kinase B (PKB). How insulin signals transduce from the plasma membrane into the cytoplasm is not clearly understood. Here we show that liquid–liquid phase separation (LLPS) plays a critical role in spatiotemporal control of insulin signaling through regulating multiple components including IRS1. Both protein concentration and insulin stimulation can drive the formation of intracellular IRS1 condensates through LLPS. Components including PI(4,5)P2, p85-PI3K and PDK1 are constitutively present in IRS1 condensates whereas production of PIP3 and recruitment of PKB in them are induced by insulin. Thus, IRS1 condensates function as intracellular signal hubs to mediate insulin signaling, whose formation is impaired in insulin resistant cells. Collectively, these data reveal an important function of LLPS in spatiotemporal control of insulin signaling.

Cadmium (Cd) is a heavy metal that is widely present in modern industrial production. It is a known, highly toxic environmental endocrine disruptor. Long-term exposure to Cd can cause varying degrees of damage to the liver, kidney, and reproductive system of organisms, especially the male reproductive system. This study aimed to explore the mechanism of Cd toxicity in the male reproductive system during puberty. Eighteen healthy 6-week-old male Sprague–Dawley rats were randomly divided into three groups (control group, low-dose group, and high-dose group) according to their body weight, with six in each group. Cd (0, 1, and 3 mg/kg/day) was given by gavage for 28 consecutive days. The results showed that Cd exposure to each dose group caused a decrease in the testicular organ coefficient and sperm count, compared with the control group. Cd exposure resulted in significant changes in testicular morphology in the 3 mg/kg/day Cd group. In the 1 and 3 mg/kg/day Cd groups, serum testosterone decreased and apoptosis of testicular cells increased significantly ( p < 0.05). In addition, compared with the control group, the activity of glutathione peroxidase and superoxide dismutase in each Cd exposure dose group decreased, but the content of malondialdehyde in the high-dose, 3 mg/kg/day Cd treatment group significantly increased ( p < 0.05). Although Cd exposure caused an increase in the messenger RNA (mRNA) levels of Bcl-2, Caspase-3 and Caspase-9 in the testicular tissues ( p < 0.05), Bcl-2 expression was unchanged ( p > 0.05). The expression level of Akt mRNA in testicular tissue of rats in the high-dose 3 mg/kg/day Cd group was increased ( p < 0.05). Our data suggest that Cd affected testosterone levels, and apoptosis was observed in spermatids.

Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160R684X mutation that causes type 2 diabetes. Whether this mutation evolutionarily confers adaptation in Inuit and how it causes metabolic disorders upon dietary changes are unknown due to limitations in human studies. Here, we develop a genetically-modified rat model bearing an orthologous AS160R693X mutation, which mimics human patients exhibiting postprandial hyperglycemia and hyperinsulinemia. Importantly, a sugar-rich diet aggravates metabolic abnormalities in AS160R693X rats. The AS160R693X mutation diminishes a dominant long-variant AS160 without affecting a minor short-variant AS160 in skeletal muscle, which suppresses muscle glucose utilisation but induces fatty acid oxidation. This fuel switch suggests a possible adaptation in Inuit who traditionally had lipid-rich hypoglycemic diets. Finally, induction of the short-variant AS160 restores glucose utilisation in rat myocytes and a mouse model. Our findings have implications for development of precision treatments for patients bearing the AS160R684X mutation.

Background and ObjectivesNeuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the CNS. Three monoclonal antibodies were recently approved as maintenance therapies for aquaporin-4 immunoglobulin G (AQP4-IgG)–seropositive NMOSD (eculizumab, inebilizumab, and satralizumab), prompting the need to consider best practice therapeutic decision-making for this indication. Our objective was to develop validated statements for the management of AQP4-IgG–seropositive NMOSD, through an evidence-based Delphi consensus process, with a focus on recommendations for eculizumab, inebilizumab, and satralizumab.MethodsWe recruited an international panel of clinical experts in NMOSD and asked them to complete a questionnaire on NMOSD management. Panel members received a summary of evidence identified through a targeted literature review and provided free-text responses to the questionnaire based on both the data provided and their clinical experience. Responses were used to generate draft statements on NMOSD-related themes. Statements were voted on over a maximum of 3 rounds; participation in at least 1 of the first 2 rounds was mandatory. Panel members anonymously provided their level of agreement (6-point Likert scale) on each statement. Statements that failed to reach a predefined consensus threshold (≥67%) were revised based on feedback and then voted on in the next round. Final statements were those that met the consensus threshold (≥67%).ResultsThe Delphi panel comprised 24 experts, who completed the Delphi process in November 2021 after 2 voting rounds. In round 1, 23/25 statements reached consensus and were accepted as final. The 2 statements that failed to reach consensus were revised. In round 2, both revised statements reached consensus. Twenty-five statements were agreed in total: 11 on initiation of or switching between eculizumab, inebilizumab, and satralizumab; 3 on monotherapy/combination therapy; 7 on safety and patient population considerations; 3 on biomarkers/patient-reported outcomes; and 1 on research gaps.DiscussionAn established consensus method was used to develop statements relevant to the management of AQP4-IgG–seropositive NMOSD. These international statements will be valuable for informing individualized therapeutic decision-making and could form the basis for standardized practice guidelines.

To investigate the longitudinal microstructural and microvascular changes in patients with myelin oligodendrocyte glycoprotein antibody-associated optic neuritis (MOG-ON) without new attacks.We included 20 eyes of 12 MOG-ON patients without new attacks during the follow-up and 24 eyes of 12 age- and sex-matched healthy controls.The BCVA, retinal vessels and structure were significantly lower in MOG-ON eyes than in healthy eyes(allOngoing deterioration was observed in RNFL thickness and parafoveal and peripapillary vessel density, but not GCIPL thinning, in MOG-ON eyes without a new attack of ON.

Familial clustering of neuromyelitis optica spectrum disorder (NMOSD) was present in Chinese. This study was to investigate the clinical characteristics and genetic background of familial NMOSD.Through questionnaires in four medical centres in 2016-2020, we identified 10 families with NMOSD aggregation. The statistical differences of clinical characteristics between familial and sporadic NMOSD (22 cases and 459 cases) were summarised. The whole-exome sequencing (WES) for seven families (13 cases and 13 controls) was analysed, compared with our previous WES data for sporadic NMOSD (228 cases and 1 400 controls). The family-based and population-based association and linkage analysis were conducted to identify the pathogenetic genes, the variant impacts were predicted.The familial occurrence was 0.87% in Chinese. Familial patients had higher expanded disability status scale score than sporadic patients (p=0.03). The single-nucleotide polymorphism (SNP) rs2252257 in the promoter and enhancer ofMost clinical characteristics of familial NMOSD were indistinguishable from sporadic NMOSD except for the worst episodes severity.

BACKGROUND AND PURPOSE Myelitis is an important clinical component of myelin oligodendrocyte glycoprotein antibody (MOG-ab)-associated disease (MOGAD) and aquaporin-4 antibody (AQP4-ab)-positive neuromyelitis optica spectrum disorder (NMOSD). The aim of this work was to evaluate the differentiating features of myelitis between the two diseases. METHODS Myelitis-related clinical and radiologic data from 130 patients with MOGAD and 125 patients with AQP4-ab-positive NMOSD were retrospectively reviewed and compared. A scoring model was established to differentiate MOG-ab-associated myelitis from AQP4-ab-associated myelitis. RESULTS Overall, 29.2% (38/130) of patients with MOGAD and 66.4% (83/125) of patients with AQP4-ab-positive NMOSD had ever experienced myelitis. Compared with those with NMOSD, patients with MOGAD exhibited a lower frequency of myelitis, either during the first episode (p

Sodium-ion batteries (SIBs) have emerged as one of the most promising candidates for next-generation energy storage systems because sodium is abundant in nature. The practical application of SIBs critically depends on developing robust electrode materials with high specific capacity and long cycling life, developing suitable anode materials is even more challenging. Alloy-type anodes are attractive for their high gravimetric and volumetric specific capacities, demonstrating great potential for high-energy SIBs, however, huge volume swelling hampered their practical application. Given the encouraging breakthroughs on alloy anodes for SIBs, herein, we present a review of the up-to-date progress and works carried out with alloy-based anode materials for SIBs. We review the synthetic strategies and their detailed electrochemical performance. In particular, we extensively reveal the important roles of alloy-based anodes in the development of SIBs. Research progress of alloy-type anodes and their compounds for sodium storage is summarized. Specific efforts to enhance the electrochemical performance of the alloy-based anode materials are discussed. Finally, we proposed multi-component alloys/high-entropy alloys (HEAs) as further research directions for alloy-based anodes.

ObjectivesTo investigate the influence of pregnancy on patients with neuromyelitis optica spectrum disorder (NMOSD) and to identify risk factors that predict pregnancy-related attack.MethodsFrom January 2015 to April 2019, 418 female patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records and identified 110 patients with 136 informative pregnancies, of whom 83 were aquaporin-4 antibody (AQP4-ab)-positive and 21 were myelin oligodendrocyte glycoprotein-antibody-positive. Pregnancy-related attack was defined as an attack that occurred during pregnancy or within 1 year after delivery/abortion. We compared annualised relapse rate (ARR) during 12 months before pregnancy with that during every trimester of pregnancy and after delivery/abortion. Multivariate analyses were used to explore the independent risk factors involved and a nomogram was generated for the prediction of pregnancy-related attack. Thirty-five female patients from 3 other centres formed an external cohort to validate this nomogram.ResultsARR increased significantly during the first trimester after delivery (pConclusionsThe first trimester post partum is a high-risk period for NMOSD recurrence. Patients with younger age, higher AQP4-ab titre and inadequate treatment are at higher risk for pregnancy-related attack.

To determine retinal vessel density in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).Twenty-five patients with MOGAD and 20 healthy participants were enrolled. Patients with MOGAD were divided into myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-positive eyes with a history of optic neuritis (ON; MOG-Ab-ON+ group) or without a history of ON (MOG-Ab-ON- group). Visual function, retinal vessel densities, and thickness were measured.The retinal nerve fiber layer, parafoveal ganglion cell and inner plexiform layers, and vessel densities in the peripapillary and parafoveal areas were significantly decreased in the MOG-Ab-ON+ eyes compared with healthy eyes and MOG-Ab-ON- eyes (all P0.05). An increasing number of ON episodes was associated with greater decreases in these variables (all P0.05). Visual field mean deviation was not significantly decreased in patients with a history of 1 or 2 episodes of ON, although the relative decreases in retinal nerve fiber layer thickness, parafoveal ganglion cell and inner plexiform layer thickness, peripapillary vessel density, and parafoveal vessel density reached 33.1%, 23.2%, 17.0%, and 11.5% (all P0.05), respectively, in eyes with 2 episodes of ON. The mean deviation was significantly correlated with peripapillary vessel density (P0.05) after adjustment for other variables. Best-corrected visual acuity was not significantly correlated with optical coherence tomography variables (all P0.05).MOG-Ab-associated ON was associated with significant decreases in retinal structure and vessel density, without significant deteriorations in visual function. The peripapillary vessel density might predict the visual outcomes in patients with MOG-Ab-associated ON.

Data regarding the efficacy and safety of currently widely available preventive therapies in neuromyelitis optica spectrum disorder (NMOSD) are needed. We compared the efficacy and safety of azathioprine (AZA), mycophenolate mofetil (MMF), and reduced dose of rituximab (RTX) in NMOSD based on a large multicenter retrospective cohort.Patients with aquaporin 4 (AQP4) antibody-positive NMOSD with AZA (n = 167), MMF (n = 131), or RTX (n = 55) as initial preventive treatment were included. The main outcome was the occurrence of relapse after the initiation of immunotherapy. Secondary outcomes were annual relapse rate, disability accumulation, drug persistence, and adverse events.The median follow-up time of the 353 patients was 30.3 months. The regimen of RTX was 100 mg on Day 1 and 500 mg on Day 2, followed by 500 mg every 6 months. The proportions of patients with concomitant steroid therapy at baseline were 96.4%, 95.4%, and 76.4% in the AZA, MMF, and RTX groups. Risk of relapse was significantly reduced in patients treated with RTX compared with those treated with AZA (hazard ratio [HR] = 4.40, 95% confidence interval [CI] = 1.41-13.80, p = 0.011) or MMF (HR = 5.20, 95% CI = 1.60-16.86, p = 0.006) after adjusting for potential confounding variables. Drug discontinuations were less likely on RTX than AZA (HR = 2.22, 95% CI = 1.34-3.66, p = 0.002). RTX exhibited lower incidence of adverse events (32.7%) than AZA (62.3%, p lt; 0.001).We provide Class III evidence that reduced dose of RTX is superior to AZA and MMF as initial treatment to reduce the risk of relapse and is better tolerated than AZA in Chinese patients with AQP4 antibody-positive NMOSD.

BackgroundRecognizing the predictors of disease relapses in patients with anti-aquaporin-4 antibody (AQP4-ab)-positive neuromyelitis optica spectrum disorder (NMOSD) is essential for individualized treatment strategy. We aimed to identify the factors that predicted relapses among patients with AQP4-ab-positive NMOSD, develop outcome prediction models, and validate them in a multicenter validation cohort.MethodsBetween January 2015 and December 2020, 820 patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records, and included 358 AQP4-ab-positive patients with 1135 treatment episodes. Univariate and multivariate analyses were used to explore the predictors of relapse, severe visual or motor disability during follow-up. A model predicting the 1- and 2-year relapse-free probability was developed and validated in an external validation cohort of 92 patients with 213 treatment episodes.ResultsLower serum AQP4-ab titer (< 1:100), higher Expanded Disability Status Scale (EDSS) score at onset (≥ 2.5), and use of intravenous methylprednisolone (IVMP) at the first attack predicted an overall lower annualized relapse rate. Older age (> 48 years), optic neuritis at onset, and higher onset EDSS score (≥ 2.5) significantly increased the risk for blindness, while IVMP at the first attack and maintenance therapy reduced the risk for blindness. Myelitis at onset increased the possibility of motor disability (EDSS ≥ 6.0), severe motor disability or death (EDSS ≥ 8.0), while maintenance therapy reduced these possibilities. Anderson and Gill model identified that the risk factors predicting recurrent relapses under certain treatment status were female gender, high AQP4-ab titer (≥ 1:100), previous attack under same therapy, lower EDSS score at treatment initiation (< 2.5), and no maintenance therapy or oral prednisone lasting less than 6 months. A nomogram using the above factors showed good discrimination and calibration abilities. The concordance indexes in the primary and validation cohort were 0.66 and 0.65, respectively.ConclusionThis study reports the demographic, clinical and therapeutic predictors of relapse, and severe visual or motor disability in NMOSD. Early identification of patients at risk of unfavorable outcomes is of paramount importance to inform treatment decisions.

To describe the clinical features of neuromyelitis optica spectrum disorder (NMOSD) through patient registry in Yangtze River Delta area of China.A total of 502 consecutive patients diagnosed with aquaporin-4 antibody (AQP4-ab)-positive NMOSD were registered between December 2018 to January 2021 in multiple tertiary referral centers within the framework of Yangtze River Delta of China. Their baseline data were reviewed, and follow-up clinical information were collected prospectively.The mean age at onset was 37.3 (range 3-80 years) years and the female-to-male ratio was 8.1:1. The median disease duration was 47 months (interquartile range [IQR] 25-84 months). A total of 1372 attacks of the 502 patients were recorded till the last follow-up, with a median annualized relapse rate of 0.4 (IQR 0.3-0.6). Nearly one-fourth (24.5%, 336/1372) of the attacks had prodromic events, including upper respiratory tract infection (36.3%, 122/336), fever (20.2%, 68/336) and pregnancy-related issues (17.9%, 60/336), etc. Myelitis was the most common attack type throughout the disease course (51.4%, 705/1372), followed by optic neuritis (ON, 43.1%, 592/1372). As for onset phenotype, ON (37.3%, 187/502) prevailed over myelitis (28.3%, 142/502). The median time to first relapse was 12 months (IQR 5-25 months). Patients with brainstem encephalitis at onset were more likely to have other anatomical region involved in subsequent attacks (p 0.001), compared to other onset type. The median serum AQP4-ab titer measured by cell-based assays was 1:100 (IQR 1:32-1:320, range 1:10-1:10,000). The baseline AQP4-ab titer in cerebrospinal fluid (r = 0.542, p0.001), overall ARR (r = 0.232, p0.001) and the EDSS scores at last follow-up (r = 0.119, p = 0.022) significantly correlated with baseline serum AQP4-ab titer. Antinuclear antibodies (48.4%), thyroid peroxidase antibodies (30.7%), and anti-SSA antibodies (26.2%) represented the most frequent concomitant antibodies, while autoimmune thyroid disorders (13.1%, 66/502) and Sjogren's syndrome (10.8%, 54/502) were the most common accompanying autoimmune diseases. Till the last follow-up, 403 patients received preventive treatments. Azathioprine represented the most common initial treatment, mycophenolate mofetil and rituximab was the most common second and third-line treatment, respectively. The EDSS score at the last follow-up ranged from 0 to 8.5 with a median of 2 (IQR 1-3).A comprehensive clinical picture of patients with AQP4-ab-positive NMOSD in Yangtze River Delta area of China was presented. More information on disease tragedy and predictive prognostic factors could be generated through long-term observations.

This study aimed to evaluate the clinical characteristics and prognosis of late onset (≥50 years) neuromyelitis optica spectrum disorder (LO-NMOSD), and compare them with those of early onset (50 years) NMOSD (EO-NMOSD) and NMOSD with various antibody serostatuses.From January 2015 to December 2020, 360 anti-aquaporin 4 antibody (AQP4-ab)-positive and 130 anti-myelin oligodendrocyte glycoprotein antibody (MOG-ab)-positive patients presented to the Huashan Hospital, China. We retrospectively reviewed their medical records, including the Expanded Disability Status Scale (EDSS) score at each visit and the annualized relapse rate (ARR). Prognostic outcomes included the time to first relapse, blindness, motor dysfunction, severe motor dysfunction, and death. Correlations between the age at onset, lesion location, and clinical parameters were analyzed.This study included 122 (24.9%) patients with LO-NMOSD, 101 with AQP4-ab and 21 with MOG-ab. Compared with EO-NMOSD patients, those with LO-NMOSD had higher EDSS scores and more frequent disease onset with transverse myelitis, blindness, motor dysfunction, and severe motor dysfunction. Compared with LO-NMOSD patients with MOG-ab, those with AQP4-ab had a worse prognosis. Age at disease onset had a significantly positive correlation with EDSS score at the last follow-up of all NMOSD patients, but a negative correlation with ARR-1 (ARR excluding the first attack, calculated from disease onset to final follow-up) in NMOSD patients with AQP4-ab.Patients with LO-NMOSD, especially those with AQP4-ab, had a worse prognosis compared with patients with EO-NMOSD. Age at disease onset and antibody serostatus predicted blindness and motor dysfunction.

N6-methylation of adenosine (m6A), a post-transcriptional regulatory mechanism, is the most abundant nucleotide modification in almost all types of RNAs. The biological function of m6A in regulating the expression of oncogenes or tumor suppressor genes has been widely investigated in various cancers. However, recent studies have addressed a new role of m6A modification in the anti-tumor immune response. By modulating the fate of targeted RNA, m6A affects tumor-associated immune cell activation and infiltration in the tumor microenvironment (TME). In addition, m6A-targeting is found to affect the efficacy of classical immunotherapy, which makes m6A a potential target for immunotherapy. Although m6A modification together with its regulators may play the exact opposite role in different tumor types, targeting m6A regulators has been shown to have wide implications in several cancers. In this review, we discussed the link between m6A modification and tumor with an emphasis on the importance of m6A in anti-tumor immune response and immunotherapy.

Antibodies to myelin oligodendrocyte glycoprotein (MOG-ab) and antibodies to aquaporin-4 (AQP4-ab) have been suggested to play roles in commonly separated subsets of patients with neuromyelitis optica spectrum disorder (NMOSD) phenotypes. The aim of this study is to quantitatively delineate and compare the brain lesion distributions of AQP4-ab-positive and MOG-ab-positive patients. Fifty-seven and twenty-eight clinical MRI scans were collected from fifty-two AQP4-ab-positive and twenty-four MOG-ab-positive patients, respectively. T2 lesions were segmented manually on each axial FLAIR image. Probabilistic lesion distribution maps were created for each group after spatial normalization. Lobe-wise and voxel-wise quantitative comparisons of the two distributions were performed. A classification model based on the lesion distribution features was constructed to differentiate the two patient groups. Infratentorial and supratentorial brain lesions were found in both AQP4-ab-positive and MOG-ab-positive patients, with large inter-group overlap mainly in deep white matter (WM). In comparison with those in the AQP4 group, the brain lesions of the MOG-ab-positive patients had a larger size, dispersed distribution, and higher probabilities in the cerebellum, pons, midbrain, and GM and juxtacortical WM in temporal, sublobar, frontal, and parietal lobes. The area under the receiver operating characteristic curve of the lesion-distribution-based classification model was 0.951. MOG-ab-positive and AQP4-ab-positive groups showed similar but quantitatively different brain lesion distributions. These results may help clinicians in considering MOG versus AQP4 in initial diagnosis, and add rationale for sending corresponding serologic testing. • Brain lesion distributions of AQP-ab-positive and MOG-ab-positive NMOSD patients • Larger size, dispersed distribution, higher lesion probabilities in the cerebellum, pons, midbrain, and GM and juxtacortical WM in the MOG group • The lesion-distribution-based classification model differentiates the two groups with AUC = 0.951

Background Several immunosuppressants or monoclonal antibodies have been used as preventive treatment for neuromyelitis optica spectrum disorders (NMOSD); however, the optimal therapies have not been clarified. In this study, we aimed to compare and rank the effectiveness and tolerability of all preventive therapies for NMOSD. Methods Qualified studies were identified in a search of MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov databases. We combined direct and indirect evidence via meta-analyses. The annualized relapse rate (ARR) was defined as the primary outcome. Secondary outcomes included the Expanded Disability Status Scale (EDSS) score and hazard ratios (HR) for the counts of adverse events (AEs). Results We identified one randomized controlled trial (RCT) and five observational studies including a total 631 patients with NMOSD. Among these, the follow-up time ranged from 12 to 40 months. For the primary outcome, rituximab (RTX) was hierarchically superior, with the significant standardized mean difference versus azathioprine (−0.86; 95% confidence interval: −1.60, −0.11). Mycophenolate mofetil (MMF) was ranked the most tolerable therapy, whereas cyclophosphamide was the least tolerable. Conclusion RTX and MMF may be recommended as optimal treatments to prevent relapse in NMOSD. Low-dose cyclosporine A could be a promising alternative therapy.

We aimed to explore the effects of low-dose rituximab (RTX) on circulating T- and B-cell lymphocytes and the improvement of clinical symptoms in refractory myasthenia gravis (MG) patients. Fifteen patients with refractory MG were treated with a low dose of 600 mg RTX and were evaluated by serial-clinical scales, flow cytometry of peripheral blood T and B cells, and antibody titer before and after six months of RTX treatment. The quantitative MG score (QMGS), manual muscle testing (MMT), MG-related activities of daily living (MG-ADL) and MG-specific quality-of-life (QOL) were significantly improved and the average steroid-dosage reduction was 40% (p = .001) in refractory MG patients at six months after RTX infusion. Compared to eighteen non-refractory MG patients and eighteen Healthy controls, our study showed that the frequencies of circulating regulatory B cells (Bregs) and regulatory T cells (Tregs) were significantly lower and the expression of B-cell activating factor receptors (BAFF-Rs) was greater in refractory MG patients without RTX treatment. Importantly, 600-mg RTX was sufficient to deplete B cells and maintain low B-cell counts for up to six months after infusion. Additionally, a low dose of RTX further increased the frequencies of Tregs. Hence, there is an immune imbalance in circulating T- and B-cell lymphocytes in refractory MG patients compared to non-refractory MG patients. We conclude that remarkable T- and B-cell lymphocyte imbalance exists in refractory MG. Low-dose RTX can improve myasthenic symptom and deplete B cells and increase Tregs%.

BackgroundFamilial clustering of neuromyelitis optica spectrum disorder (NMOSD) was present in Chinese. This study was to investigate the clinical characteristics and genetic background of familial NMOSD.MethodsThrough questionnaires in four medical centres in 2016–2020, we identified 10 families with NMOSD aggregation. The statistical differences of clinical characteristics between familial and sporadic NMOSD (22 cases and 459 cases) were summarised. The whole-exome sequencing (WES) for seven families (13 cases and 13 controls) was analysed, compared with our previous WES data for sporadic NMOSD (228 cases and 1 400 controls). The family-based and population-based association and linkage analysis were conducted to identify the pathogenetic genes, the variant impacts were predicted.ResultsThe familial occurrence was 0.87% in Chinese. Familial patients had higher expanded disability status scale score than sporadic patients (p=0.03). The single-nucleotide polymorphism (SNP) rs2252257 in the promoter and enhancer of ubiquitin-specific peptidase USP18 was linked to familial NMOSD (p=7.8E-05, logarithm of the odds (LOD)=3.1), SNPs rs361553, rs2252257 and rs5746523 were related to sporadic NMOSD (p=1.29E-10, 3.45E-07 and 2.01E-09, respectively). Patients with the SNP rs361553 T/T genotype had higher recurrence rate than C/T or C/C genotype (1.22±0.85 vs 0.69±0.57 and 0.81±0.65, p=0.003 and 0.001, respectively). SNPs rs361553 and rs2252257 altered USP18 expression in brain and nerve tissues.ConclusionMost clinical characteristics of familial NMOSD were indistinguishable from sporadic NMOSD except for the worst episodes severity. USP18 with impaired intronic regulatory function contributed to the pathogenesis of NMOSD.

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Rehabilitation treatment may alleviate the disease severity of patients with NMOSD. The reports of rehabilitation exercise for NMOSD during acute phase are rare.To explore the efficacy and safety of rehabilitation exercise in patients with NMOSD during acute phase.This is a prospective cohort study of 36 patients (rehabilitation exercise group, RG) and 37 patients (control group, CG) in whom acute attack of NMOSD involved the spinal cord with EDSS≥4.5 were included. EDSS, American Spinal Injury Association Impairment Scale (AIS) grade, total motor score (TMS), light touch score (LTS), pin prick score (PPS), Berg balance scale (BBS), and Barthel index (BI) were used as outcome measures.During hospitalization, EDSS scores of both groups decreased significantly (P0.05). After treatment, the decline in EDSS was more significant in RG than in CG (P0.05). The change reaching minimal clinically important difference (MCID) was observed in 90% (9/10) of patients in RG and in 27.78% (5/18) of patients in CG in the subgroup with EDSS 4.5-6.0 (MCID, 1.0), which was statistically significant between the groups (P0.05). In the subgroup with EDSS 6.5-10.0 (MCID, 0.5), the proportion of patients with the change that reached MCID was significantly different between CG and RG (P0.05). BBS, TMS, and BI score significantly improved after treatment (P0.001). The improvement ranges of BBS, TMS, and BI scores were more significant in RG than CG (P0.05). AIS grade improvement in RG was significantly higher than in CG. There were no significant changes in LTS and PPS after treatment in either of the groups. In RG, two mild adverse events were recorded.Rehabilitation exercise may improve nervous system function, balance function, and activities of daily living in patients with acute NMOSD, with few adverse reactions.

The outbreak of coronavirus disease 2019 (COVID-19) in December 2019 in Wuhan, China, introduced the third highly pathogenic coronavirus into humans in the 21st century. Scientific advance after the severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic and Middle East respiratory syndrome coronavirus (MERS-CoV) emergence enabled clinicians to understand the epidemiology and pathophysiology of SARS-CoV-2. In this review, we summarize and discuss the epidemiology, clinical features, and virology of and host immune responses to SARS-CoV, MERS-CoV, and SARS-CoV-2 and the pathogenesis of coronavirus-induced acute respiratory distress syndrome (ARDS)., SUMMARY The outbreak of coronavirus disease 2019 (COVID-19) in December 2019 in Wuhan, China, introduced the third highly pathogenic coronavirus into humans in the 21st century. Scientific advance after the severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic and Middle East respiratory syndrome coronavirus (MERS-CoV) emergence enabled clinicians to understand the epidemiology and pathophysiology of SARS-CoV-2. In this review, we summarize and discuss the epidemiology, clinical features, and virology of and host immune responses to SARS-CoV, MERS-CoV, and SARS-CoV-2 and the pathogenesis of coronavirus-induced acute respiratory distress syndrome (ARDS). We especially highlight that highly pathogenic coronaviruses might cause infection-associated hemophagocytic lymphohistiocytosis, which is involved in the immunopathogenesis of human coronavirus-induced ARDS, and also discuss the potential implication of hemophagocytic lymphohistiocytosis therapeutics for combating severe coronavirus infection.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system (CNS) primarily affecting the optic nerves and spinal cord, but also involving other regions of the CNS including the area postrema, periaqueductal gray matter, and hypothalamus. Knowledge related to pediatric manifestations of NMOSD has grown in recent years, particularly in light of newer information regarding the importance of not only antibodies to aquaporin 4 (AQP4-IgG) but also myelin oligodendrocyte glycoprotein (MOG-IgG) in children manifesting clinically with this syndrome. In this review, we describe the current state of the knowledge related to clinical manifestations, diagnosis, and chronic therapies for children with NMOSD, with emphasis on literature that has been published in the last 5 years. Following the review, we propose recommendations for the assessment/follow up clinical care, and treatment of this population.

The sucrose concentration in soybean seed significantly affects the flavor of soybean‐derived products. In this study, an association panel of 178 elite accessions and 33,149 single‐nucleotide polymorphisms (SNPs) was utilized to identify quantitative trait nucleotides (QTNs) of sucrose concentration in soybean seeds by genome‐wide association study (GWAS). Five QTNs (rs2688589, rs29026218, rs5926884, rs6886889, and rs10299216) distributed across five genomic regions in five chromosomes were identified in two or more locations by GWAS. A total of 60 candidate genes near the 200‐kb flanking region of these five identified loci were identified. Three of these genes (Glyma.04G032600, Glyma.04G034600, and Glyma.11G092100) have been reported to be involved in the process of sugar biosynthesis. Based on gene‐based association and haplotype analyses, a total of 35 SNPs from 10 genes associated with sucrose concentration were identified. Of them, Glyma.04G032600 was the only gene that has been reported to be related to sucrose content; the other nine genes were novel and may be associated with sucrose content. These beneficial alleles and candidate genes may be of great value in improving sucrose content in soybean seeds.

Di (2-ethylhexyl) phthalate (DEHP) is a known environmental endocrine disruptor that impairs development of testis and spermatogenesis. This study aims to explore the effects of STAT3/p53 and PI3K-Akt-mTOR signaling pathway on DEHP-induced reproductive toxicity in pubertal male rat. 24 6-week-old male Sprague-Dawley rats were randomly divided into 4 groups (Control, low-dose, middle-dose and high-dose group) and were treated with increasing concentration of DEHP (0, 250, 500, 1000 mg/kg/day) respectively for 28 consecutive days by intragastric administration. Our results showed that DEHP exposure induced obvious morphological changes of testis, decreased organ coefficient of testis and sperm count, and increased testicular cell apoptosis in the 500 and 1000 mg/kg/day DEHP groups (p .05). The serum testosterone decreased in a dose-dependent manner after treatment with DEHP. Furthermore, the exposure of DEHP elevated the levels of oxidative stress accompanied by upregulated expression of p53 and reduced expression of STAT3. In addition, compared with the control group, the expression of PI3K, p-Akt and p-mTOR proteins significantly decreased, whereas the downstream autophagy-related proteins phosphorylated ULK1, Beclin-1, Atg7, LC3-II obviously increased in the 250 mg/kg/day DEHP group (p .05). The expression of p62 was reduced in DEHP-treated groups. Our data indicated that autophagy could be activated to protect testes from DEHP-induced reproductive damage by inhibiting PI3K-Akt-mTOR signaling pathway in the 250 mg/kg/day DEHP group. STAT3/p53-mediated mitochondrial apoptosis pathway might play a major role to cause testis injury and reproductive dysfunction in the 500 and 1000 mg/kg/day DEHP groups.