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ObjectivesThere 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.DesignCross-sectional study.SettingThe data were collected at an affiliated hospital in Guangzhou, Guangdong, China.ParticipantsFifty-seven pairs of patients with ALS and their caregivers were investigated by standardised questionnaires.Main outcome measuresThis 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.ResultsAccording 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.ConclusionsOur 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.

Klinefelter syndrome (KS) is the most common chromosome aneuploidy and a common cause of infertility in males. KS patients have at least one extra X chromosome, and about 80% of patients have the karyotype 47,XXY. Twenty percent of KS patients have higher-grade aneuploidies (48,XXXY, 48,XXYY, 49,XXXXY) and exert some clinical manifestation different from those with 47,XXY. Here we report the case of a young man who initially presented with diabetic ketosis and foot ulcer and was later diagnosed as having an extremely rare mosaic variant of KS (47,XXY/48,XXXY/49,XXXXY). Clinical and laboratory features are summarized. The patient developed a severe foot ulcer with an 18-month history of diabetes. Learning disability was noted since early childhood. The patient had typical manifestations of KS, including increased height, sparse beard and body hair, and small penis. He also had some characteristic features of patients with additional sex chromosomes, including epicanthal folds, narrow palpebral fissures, prominent elbows, and undescended testicles. Severe myopia and myopic macular degeneration was also found. Lab tests revealed low testosterone and elevated FSH but normal LH levels. Chromosome analysis on lymphocytes revealed an aberration of 47,XXY/48,XXXY/49,XXXXY. This case provides information on KS patients with the extremely rare karyotype 47,XXY/48,XXXY/49,XXXXY, and also emphasizes the importance of considering KS in the differential diagnosis of a sterile male with diabetes.

Prader-Willi Syndrome (PWS) is a rare autosomal dominant disorder on the 15q11.2-q13 chromosome. PWS may impact metabolic, endocrine, and neurologic systems and combine with hypotonia, sleep disturbances, cognitive disability, central adrenal insufficiency, hypothyroidism, hypogonadism, short stature, and other diseases. Here ,we report a PWS patient with secondary diabetes mellitus. Clinical and laboratory features are summarized. The patient had typical manifestations of PWS including almond-shaped eyes, narrow temples, narrow nasal bridge, and short hands and feet. Lab test revealed hypogonadism and growth hormone deficiency. SNP array revealed one copy of chromosome 15 q11.2q13.1 was missing, with a length of about 6.4 mbp. This case emphasizes the importance of considering PWS in the differential diagnosis of an adolescent with diabetes. Antenatal history of neonatal hypotonia and childhood history of feeding disorder are the keys to the diagnosis of PWS.

Background Little is known about the relationship between ubiquilin 1 (UBQLN1) and p53, both of them have been implicated in the development and progression of non-small cell lung cancer (NSCLC). In this study, we aimed to explore the role of loss of UBQLN1 in cell viability and proliferation, and cell apoptosis in human lung adenocarcinoma A549 cells. Methods Cell viability, proliferation, and apoptosis were determined by MTT, BrdU, and TUNEL assays, respectively. Adenoviruses carrying cDNA or siRNA were used to overexpress or silence target protein. Dihydroethidium (DHE) staining was performed to measure the real-time formation of intracellular reactive oxygen species (ROS). The chymotrypsin-like activity of 20S proteasome core was determined by using synthetic fluorogenic peptide substrate. Results UBQLN1 silencing led to a reduction of p53 protein levels and overexpression of p53 reversed the effects of UBQLN1 knockdown (KD) on cell viability, proliferation, and apoptosis. Furthermore, deficiency of UBQLN1 activated autophagy activity but did not affect proteasome activity. Inhibition of autophagy restored p53 protein levels in UBQLN1-KD A549 cells. In addition, UBQLN1 KD markedly inhibited phosphorylation of mammalian target of rapamycin (mTOR) and its downstream ribosomal S6 kinase (S6K). Conclusions Our experiments suggested that the regulation of UBQLN1 on cell viability, proliferation, and apoptosis was mediated by mTOR/autophagy/p53 signaling pathway.

Acute lung injury (ALI) induced by sepsis is characterized by an inflammatory process related to the up‐regulation of inflammatory cytokines and chemokines. In the present study, we explored the role of circC3P1 in sepsis‐induced ALI in vitro and in vivo. The caecal ligation and puncture (CLP)‐induced sepsis model was established through CLP surgery. Forty adult male C57BL/6 mice were randomly assigned into sham, CLP, CLP + vector and CLP + circC3P1 (each n = 10). Primary murine pulmonary microvascular endothelial cells (MPVECs) were transfected with circC3P1 or empty vector 24 hours prior to LPS treatment via Lipofectamine 2000. The expressions of circC3P1, tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6) and IL‐1β were evaluated after 6‐h LPS treatment. Cell apoptosis was evaluated via flow cytometry. The CLP group demonstrated pulmonary morphological abnormalities, increased concentrations of TNF‐α, IL‐6 and IL‐1β in the lung tissue, compared with the sham group. MPVECs treated with LPS significantly elevated TNF‐α, IL‐6 and IL‐1β levels and increased cell apoptosis than that in the control group. The circC3P1 overexpression in sepsis‐induced ALI mice attenuated pulmonary injury, inflammation and apoptosis. Besides, circC3P1 revealed anti‐inflammatory and anti‐apoptotic effect in MPVEC‐treated LPS. CircC3P1 overexpression reduced cell apoptosis and pro‐inflammatory cytokines levels via down‐regulating miR‐21. CircC3P1 attenuated pro‐inflammatory cytokine production and cell apoptosis in ALI induced by sepsis through modulating miR‐21, indicating that circC3P1 is a promising therapeutic biomarker for sepsis‐induced ALI.

Patients with combined phenotypes of Sturge–Weber syndrome and Klippel–Trenaunay syndrome have been reported, though the underlying genetic spectrum in these individuals remains to be elucidated. We reported the patient presenting with Klippel–Trenaunay and Sturge–Weber overlap syndrome in mainland China. Histopathologic study confirmed the hemangioma of vein and capillary. Co‐existence of a novel somatic KRAS c.182_183 delins TC mutation and GNAQ c.548G>A mutation was identified in the affected skin tissue rather than paired peripheral blood. The somatic mutations of GNAQ and KRAS may affect MAPK‐ERK signaling pathway, resulting in endothelial anomaly and blood vessel malformation.

Background: To determine the efficacy and safety of DL-3-n-butylphthalide (NBP) for the treatment of amyotrophic lateral sclerosis (ALS).Methods: A randomized, double-blind, placebo-controlled trial was performed at 19 ALS clinical centers of the Chinese ALS Association. Patients with definite or probable ALS were randomly treated with NBP or placebo for 12 months. The Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score was the primary endpoint and was evaluated every 3 months. Secondary endpoints included survival and tracheotomy incidence, total Medical Research Council (MRC) score, percentage of predicted forced vital capacity (FVC), and clinical global impression scale score assessed using the visual analog scale. Results: Between November 23, 2015 and November 22, 2017, 312 ALS patients were enrolled and randomly allocated to either the NBP group (156 patients) or placebo group (156 patients). Ninety-three patients in the NBP group and 92 patients in the placebo group were included in the primary end point analysis. There was no significant difference in the ALSFRS-R score, total MRC score, or clinical global impression between the two groups after treatment. The NBP group exhibited a mild trend of less decrease in the percentage of predicted FVC between baseline and the 12-month visit than the placebo group (least-squares mean change from baseline ± standard error: -7.34±4.28, 95％CI(-15.24,0.56), p=0.0335). Adverse events were reported in 56.5% of patients in the placebo group and 68.8% of patients in the NBP group (χ2=2.99, P=0.0838). No serious adverse event related to treatment occurred.Conclusion: we found no evidence that NBP improved the ALSFRS-R score in patients with ALS. The results suggest a mild trend in the percentage of predicted FVC decreased slowly in the NBP treatment group than in the placebo group.Trial registration: A Multi-center, Randomized, Double Blinding, Placebo-Controlled Clinical Trial of Dl-3-Butylphthalide in the Treatment of Amyotrophic Lateral Sclerosis, ChiCTR-IPR-15007365, Registered 1 November 2015, http://www.chictr.org.cn/showproj.aspx?proj=12354

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.

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.

(1) Background: The aim of this longitudinal study was to evaluate the association between disease progression according to the Milano–Torino staging (MITOS) system and long-term survival in Chinese patients with amyotrophic lateral sclerosis (ALS). We also examined factors affecting MITOS progression. (2) Methods: Patients were enrolled and underwent follow-up at 6, 12, 18, and 24 months, and their demographic and clinical data, including the Milano–Torino stage, Amyotrophic Lateral Sclerosis Functional Rating Scale—Revised (ALSFRS-R) score and neuropsychiatric data, were evaluated. The sensitivity and specificity of predicting survival outcomes based on MITOS progression and ALSFRS-R score decline from baseline to 6 months were compared. The associations between MITOS progression from baseline to 6 months and survival outcome at 12, 18 and 24 months were examined, and factors associated with disease progression were evaluated with subgroup analyses. (3) Results: Among the 100 patients included, 74% were in stage 0 at baseline, and approximately 95% progressed to a higher stage of the MITOS system at 24 months. MITOS progression from baseline to 6 months and ALSFRS-R decline showed comparable value for predicting survival at 12, 18, and 24 months. MITOS progression from baseline to 6 months is strongly associated with death outcomes. Older age at onset and increased depression and anxiety scores may be related to disease progression. (4) Conclusions: MITOS progression during the early disease course could serve as a prognostic marker of long-term survival and may have utility in clinical trials. Age at onset and diagnosis and neuropsychiatric factors might be associated with disease progression.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of motor neurons. The complex mechanisms underlying ALS are yet to be elucidated, while the lack of disease biomarkers and therapeutic options are associated with the poor prognosis of ALS patients. In this study, we performed bioinformatics analysis to clarify potential mechanisms in sporadic ALS (sALS). We compared three gene expression profiles (GSE18920, GSE56500, and GSE68605) of motor neurons obtained from sALS patients and healthy controls to discover differentially expressed genes (DEGs), and then performed integrated bioinformatics analyses to identify key molecules and pathways underlying sALS. We found that these DEGs were mainly enriched in the structure and functions of extracellular matrix (ECM), while functional enrichment in blood vessel morphogenesis was less correlated with motor neurons. The clustered subnetworks of the constructed protein-protein interaction network for DEGs and the group of selected hub genes were more significantly involved in the organization of collagen-containing ECM. The transcriptional factors database proposed RelA and NF-κB1 from NF-κB family as the key regulators of these hub genes. These results mainly demonstrated the alternations in ECM-related gene expression in motor neurons and suggested the role of NF-κB regulatory pathway in the pathogenesis of sALS.

Background Limb girdle muscular dystrophy type 2Y (LGMD2Y) is a rare subgroup of limb girdle muscular dystrophy featuring limb-girdle weakness, tendon contracture and cardiac involvement. It is caused by the mutation of TOR1AIP1, which encodes nuclear membrane protein LAP1 (lamina-associated polypeptide 1) and comprises heterogeneous phenotypes. The present study reported a patient with a novel homozygous TOR1AIP1 mutation that presented with selective muscle weakness, which further expanded the phenotype of LGMD2Y- and TOR1AIP1-associated nuclear envelopathies. Case presentation A 40-year-old male presented with Achilles tendon contracture and muscle weakness that bothered him from 8 years old. While the strength of his distal and proximal upper limbs was severely impaired, the function of his lower limbs was relatively spared. Muscle pathology showed dystrophic features, and electron microscopy showed ultrastructural abnormalities of disrupted muscle nuclei envelopes. Whole-exome sequencing showed a frameshift mutation in TOR1AIP1 (c.98dupC). Conclusion We reported a novel mild phenotype of LGMD2Y with relatively selective distal upper limb weakness and joint contracture and revealed the heterogeneity of LGDM2Y and the role of the LAP1 isoform by literature review.

The authors have withdrawn this preprint due to author disagreement.

Background Alzheimer’s disease (AD) is ranked as the most prevalent neurodegenerative disease. However, the exact molecular mechanisms underlying pathophysiological alterations in AD remain unclear, especially at the prodromal stage. The decreased proteolytic degradation of Aβ, blood–brain barrier (BBB) disruption, and neuroinflammation are considered to play key roles in the course of AD. Methods Male APPswe/PS1dE9 C57BL/6 J double-transgenic (APP/PS1) mice in the age range from 1 month to 6 months and age-matched wild type mice were used in this study, intending to investigate the expression profiles of Aβ-degrading enzymes for Aβ degradation activities and zonula occludens-1 (zo-1) for BBB integrity at the prodromal stage. Results Our results showed that there were no significant genotype-related alterations in mRNA expression levels of 4 well-characterized Aβ-degrading enzymes in APP/PS1 mice within the ages of 6 months. Interestingly, a significant decrease in zo-1 expression was observed in APP/PS1 mice starting from the age of 5 months, suggesting that BBB disrupt occurs at an early stage. Moreover, treatment of fish oil (FO) for 4 weeks remarkably increased zo-1 expression and significantly inhibited the glial activation and NF-κB activation in APP/PS1 mice. Conclusion The results of our study suggest that FO supplement could be a potential therapeutic early intervention for AD through protecting the BBB integrity and suppressing glial and NF-κB activation.

Background: Our study compares the cosmetic effects, postoperative complications, and quality of life of immediate breast reconstruction with simple prosthesis or prosthesis plus titanium-coated polypropylene mesh (TCPM) after total mastectomy for breast cancer. Methods: In total, 69 patients who underwent total mastectomy, sentinel lymph node biopsy, and immediate prosthetic breast reconstruction from January 2015 to December 2018 in our hospital were selected, and their cosmetic effects, complications, and quality of life after reconstruction were recorded immediately after surgery and 6 months after surgery. Results: Of these 69 patients, 29 were in the simple prosthesis group and 40 in the prosthesis + TCPM group. The incidence of surgical complications was 17.2% in the simple prosthesis group (5/29; including 4 cases of capsular contracture and 1 case of infection) 15.0% in the prosthesis + TCPM group (6/40; 1 case of flap necrosis, 2 cases of poor wound healing, 2 cases of hematomas, and 1 case of inadequate blood supply to nipple). The complications were successfully managed after symptomatic treatment in both groups. No prosthesis loss was noted. The incidence of postoperative complications showed there to be no significant differences between these two groups (P=0.06, χ 2 =0.80). The satisfaction rate of patients on cosmetic effects was 95.0% (38/40) in the prosthesis + TCPM group, significantly higher than that in the simple prosthesis group (75.90%, 22/29) (P=0.05, χ 2 =3.87). The quality of life in the simple prosthesis group at 2 weeks and six months after the operation was significantly lower than that in the prosthesis + TCPM group. The incidence rate of arm pain and fatigue at 2 weeks after operation was significantly higher than that in the prosthesis + TCPM group (P=0.04, χ 2 =4.42). The satisfaction of family life and sexual interest 6 months after the operation was also significantly lower in the simple prosthesis group than in the prosthesis + TCPM group (P=0.03, χ 2 =4.95). Conclusions: Breast reconstruction with prosthesis combined with TCPM does not increase surgical complications and has a good cosmetic effect and high patient satisfaction. Thus, it is a safe and reconstruction method.

Immune escape of breast cancer cells contributes to breast cancer pathogenesis. Tumour microenvironment stresses that disrupt protein homeostasis can produce endoplasmic reticulum (ER) stress. The miRNA‐mediated translational repression of mRNAs has been extensively studied in regulating immune escape and ER stress in human cancers. In this study, we identified a novel microRNA (miR)‐27a‐3p and investigated its mechanistic role in promoting immune evasion. The binding affinity between miR‐27a‐3p and MAGI2 was predicted using bioinformatic analysis and verified by dual‐luciferase reporter assay. Ectopic expression and inhibition of miR‐27a‐3p in breast cancer cells were achieved by transduction with mimics and inhibitors. Besides, artificial modulation of MAGI2 and PTEN was done to explore their function in ER stress and immune escape of cancer cells. Of note, exosomes were derived from cancer cells and co‐cultured with macrophages for mechanistic studies. The experimental data suggested that ER stress biomarkers including GRP78, PERK, ATF6, IRE1α and PD‐L1 were overexpressed in breast cancer tissues relative to paracancerous tissues. Endoplasmic reticulum stress promoted exosome secretion and elevated exosomal miR‐27a‐3p expression. Elevation of miR‐27a‐3p and PD‐L1 levels in macrophages was observed in response to exosomes‐overexpressing miR‐27a‐3p in vivo and in vitro. miR‐27a‐3p could target and negatively regulate MAGI2, while MAGI2 down‐regulated PD‐L1 by up‐regulating PTEN to inactivate PI3K/AKT signalling pathway. Less CD4+, CD8+ T cells and IL‐2, and T cells apoptosis were observed in response to co‐culture of macrophages and CD3+ T cells. Conjointly, exosomal miR‐27a‐3p promotes immune evasion by up‐regulating PD‐L1 via MAGI2/PTEN/PI3K axis in breast cancer.

Long noncoding RNAs (lncRNAs) have been certified as important regulators in tumorigenesis. LncRNA GAS6-AS2 (GAS6-AS2) was a newly identified tumor-related lncRNA, and its dysregulation and oncogenic effects in melanoma and bladder cancer had been reported in previous studies. However, the expression pattern and potential function of GAS6-AS2 in osteosarcoma (OS) have not been investigated. In this study, we identified a novel OS-related lncRNA GAS6-AS2. We found that GAS6-AS2 was distinctly upregulated in both OS specimens and cell lines. Distinct up-regulation of GAS6-AS2 in OS was correlated with advanced clinical stages and shorter survivals. In addition, USF1 could directly bind to the GAS6-AS2 promoter and contribute to its overexpression. Furthermore, GAS6-AS2 knockdown caused tumor suppressive effects via reducing cellular proliferation, migration and invasion, and promoting OS cell apoptosis. Besides, GAS6-AS2 directly bound to miR-934 and downregulated its expression. Mechanistically, GAS6-AS2 positively regulated the expression of BCAT1 through sponging miR-934. Taken together, our data illustrated how GAS6-AS2 played an oncogenic role in OS and might offer a potential therapeutic target for treating OS.

Cerebral microinfarcts have significant effects on the development of geriatric neurological disorders, including vascular dementia and Alzheimer's disease. However, little is known about the pathophysiological mechanisms involved in the evolution of microinfarcts and potential treatment and prevention against these microvascular ischemic lesions. In the present study, the “single cortical microinfarct model” generated via occluding a penetrating arteriole by femtosecond laser ablation and the “multiple diffuse microinfarcts model” induced by unilateral injection of cholesterol crystals through the internal carotid artery were established to investigate the pathophysiological mechanisms underlying the evolution of microinfarcts and the effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on alleviating microinfarct burdens and functional deficits. The occlusion of a single penetrating arteriole led to a distinct cortical microinfarct, which manifested as neuronal loss and occupation of activated glial cells in the ischemic core. Using Fat-1 transgenic mice and fish oil supplements, we demonstrated that both endogenously-generated and exogenously-delivered ω-3 PUFAs significantly inhibited the activation of receptor-interacting serine/threonine protein kinases 1 (RIPK1) and its downstream apoptosis-associated proteins, mitigated cell apoptosis, and anatomically reduced the microinfarct size. The protective effects of ω-3 PUFAs against microinfarcts were further verified in a multiple diffuse microinfarcts model, where ω-3 PUFAs significantly attenuated cell apoptosis as revealed by TUNEL staining, alleviated the diffuse microinfarct burdens and remarkably improved the functional deficits as evidenced by reduced spontaneous anxiety, increased preference for the novel object, and improved hippocampal-based learning and short-term memory. Together, these findings demonstrate that enriched brain ω-3 PUFAs are effective for reducing microinfarct burdens and improving the function deficits, which support the clinical research and application of ω-3 PUFAs in the treatment or prophylaxis in vascular dementia., Highlights • Omega-3 PUFAs inhibit the RIPK1-mediated apoptotic pathways in cortical microinfarcts. • Omega-3 PUFAs contribute to anatomically decreasing microinfarct damage. • Omega-3 PUFAs supplements improve functional deficits in a mouse model with multiple diffuse microinfarcts. Cerebral microinfarct is defined as microscopic vascular occlusion

Due to the indiscriminate use of chemical inputs like pesticides, serious agricultural diffused pollution is arising, not only with the ecological environment damaging, but also with the agriculture sustainable development restricted. It is imperative for China to reduce pesticides use. Under the decentralized production background, farmers’ willingness to reduce pesticides is worth discussing. This paper aims to explore farmers’ willingness to reduce pesticides use based on its determinants analysis. A structured questionnaire was administered to a random sample of 924 farmers in rural China. Binary logistic regression model was used to examine the determinants. The results showed that farmers’ environmental concern, pesticides residues cognition, agro-products quality concern and input controls positively and significantly influence farmers’ willingness to reduce pesticides, while non-agricultural income share influence negatively. Results also reveal that farmers’ self-discipline is more effective than government regulations; enhancing farmers’ self-discipline is important to guide farmers toward environmentally-friend measures in agricultural production. This paper recommended that policy makers take measures to improve farmers’ environmental awareness and strengthen input supervision. Improved effectiveness of pesticides usage is also needed.

Summary Charcot-Marie-Tooth disease type 1A (CMT1A), one of the most frequent inherited peripheral neuropathies, is associated with PMP22 gene duplication. Previous studies of CMT1A mainly relied on rodent models, and it is not yet clear how PMP22 overexpression leads to the phenotype in patients. Here, we generated the human induced pluripotent stem cell (hiPSC) lines from two CMT1A patients as an in vitro cell model. We found that, unlike the normal control cells, CMT1A hiPSCs rarely generated Schwann cells through neural crest stem cells (NCSCs). Instead, CMT1A NCSCs produced numerous endoneurial fibroblast-like cells in the Schwann cell differentiation system, and similar results were obtained in a PMP22-overexpressing iPSC model. Therefore, despite the demyelination-remyelination and/or dysmyelination theory for CMT1A pathogenesis, developmental disabilities of Schwann cells may be considered as an underlying cause of CMT1A. Our results may have important implications for the uncovering of the underlying mechanism and the development of a promising therapeutic strategy for CMT1A neuropathy., Highlights • Modeling CMT1A disease with PMP22 duplication using hiPSC-derived NCSCs • PMP22 duplication may lead to Schwann cell developmental defect of NCSCs • PMP22-overexpressing NCSCs recapitulate the phenotype of CMT1A NCSCs, How PMP22 duplication leads to CMT1A neuropathy remains to be elucidated. In this article, Yao, Li, and colleagues show that neural crest stem cells (NCSCs) derived from CMT1A hiPSCs have developmental disabilities of Schwann cells; in contrast, CMT1A NCSCs generate numerous endoneurial fibroblast-like cells in the Schwann cell differentiation system.

Collateral blood flow as vascular adaptions to focal cerebral ischemia is well recognized. However, few studies directly investigate the dynamics of collateral vessel recruitment in vivo and little is known about the effect of collateral blood flow in different cerebrovascular hierarchy on the neuropathology after focal ischemic stroke. Here, we report that collateral blood flow is critically involved in blood vessel compensations following regional ischemia. We occluded a pial arteriole using femtosecond laser ablating under the intact thinned skull and documented the changes of collateral flow around the surface communication network and between the surface communication network and subsurface microcirculation network using in vivo two photon microscopy imaging. Occlusion of the pial arteriole apparently increased the diameter and collateral blood flow of its leptomeningeal anastomoses, which significantly reduced the cortical infarction size. This result suggests that the collateral flow via surface communicating network connected with leptomeningeal anastomoses could greatly impact on the extent of infarction. We then further occluded the target pial arteriole and all of its leptomeningeal anastomoses. Notably, this type of occlusion led to reversals of blood flow in the penetrating arterioles mainly proximal to the occluded pial arteriole in a direction from the subsurface microcirculation network to surface arterioles. Interesting, the cell death in the area of ischemic penumbra was accelerated when we performed occlusion to cease the reversed blood flow in those penetrating arterioles, suggesting that the collateral blood flow from subsurface microcirculation network exerts protective roles in delaying cell death in the ischemic penumbra. In conclusion, we provide the first experimental evidence that collateral blood vessels at different cerebrovascular hierarchy are endogenously compensatory mechanisms in brain ischemia.

The endoplasmic reticulum (ER)-stress-induced cascade events are implicated in Parkinson’s disease (PD). The discovery of drug candidates to protect dopaminergic (DA) neurons from ER-stress-induced oxidative damage is important to resolve the pathological aspects of PD and modify its progress. In this study, we found that a recently identified unfolded protein response (UPR) modulator, azoramide, showed protective effects on patient induced pluripotent stem cells-derived midbrain DA neurons with the homozygous phospholipase A2 group 6 (PLA2G6) D331Y mutant. A series of PD-related cascade events such as ER stress, abnormal calcium homeostasis, mitochondrial dysfunction, increase of reactive oxygen species, and apoptosis were observed in PLA2G6 D331Y mutant DA neurons, whereas azoramide significantly protected PLA2G6 D331Y mutant DA neurons against these events. The beneficial effects of azoramide were abolished by treatment with a cAMP-response element binding protein (CREB) inhibitor. Our results suggest that azoramide is a potential neuroprotectant against DA neuron damage via restoring ER function and the CREB signaling.

Nanogap plasmonic structures with strong coupling between separated components have different responses to orthogonal-polarized light, giving rise to giant optical chirality. Here, we proposed a three-dimensional (3D) nanostructure that consists of two vertically and twistedly aligned nanogaps, showing the hybridized charge distribution within 3D structures. It is discovered that the structure twisted by 60° exhibits plasmonic coupling behavior with/without gap modes for different circular-polarized plane waves, showing giant chiral response of 60% at the wavelength of 1550 nm. By controlling the disk radius and the insulator layer, the circular dichroism signal can be further tuned between 1538 and 1626 nm.

The present study aimed to screen potential genes associated with metastatic prostate cancer (PCa), in order to improve the understanding of the mechanisms underlying PCa metastasis. The GSE3325 microarray dataset, which was downloaded from the Gene Expression Omnibus database, consists of seven clinically localized PCa samples, six hormone-refractory metastatic PCa samples and six benign prostate tissue samples. The Linear Models for Microarray Data package was used to identify differentially-expressed genes (DEGs) and a hierarchical cluster analysis for DEGs was performed with the pheatmap package. Furthermore, potential functions for the DEGs were predicted by a functional enrichment analysis. Subsequently, microRNAs (miRNAs) potentially involved in the regulation of PCa metastasis were identified by WebGestalt software, and the miRNA-DEG regulatory network was visualized using Cytoscape. In addition, a pathway enrichment analysis for DEGs in the regulatory network was performed. A total of 306 and 2,073 genes were differentially expressed in the clinically localized PCa and the metastatic PCa groups, respectively, as compared with the benign prostate group, of which 174 were differentially expressed in both groups. A number of the DEGs, including CAMK2D and SH3BP4, were significantly enriched in the cell cycle, and others, such as MAF, were associated with the regulation of cell proliferation. Furthermore, some DEGs (CAMK2D and PCDH17) were observed to be regulated by miR-30, whereas others (ADCY2, MAF, SH3BP4 and PCDH17) were modulated by miR-182. Additionally, ADCY2 and CAMK2D were distinctly enriched in the calcium signaling pathway. The present study identified novel DEGs, including ADCY2, CAMK2D, MAF, SH3BP4 and PCDH17, that may be involved in the metastasis of PCa.