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Prolonged exposure to negative stressors could be harmful if a subject cannot respond appropriately. Strategies evolved to respond to stress, including repetitive displacement behaviours, are important in maintaining behavioural homoeostasis. In rodents, self-grooming is a frequently observed repetitive behaviour believed to contribute to post-stress de-arousal with adaptive value. Here we identified a rat limbic di-synaptic circuit that regulates stress-induced self-grooming with positive affective valence. This circuit links hippocampal ventral subiculum to ventral lateral septum (LSv) and then lateral hypothalamus tuberal nucleus. Optogenetic activation of this circuit triggers delayed but robust excessive grooming with patterns closely resembling those evoked by emotional stress. Consistently, the neural activity of LSv reaches a peak before emotional stress-induced grooming while inhibition of this circuit significantly suppresses grooming triggered by emotional stress. Our results uncover a previously unknown limbic circuitry involved in regulating stress-induced self-grooming and pinpoint a critical role of LSv in this ethologically important behaviour. Self-grooming is a frequently observed repetitive behaviour in rodents that is believed to contribute to post-stress de-arousal. The authors identified a previously unknown limbic circuit that includes the ventral lateral septum in rats and is involved in regulating stress-induced self-grooming.

Iron accumulation in the substantia nigra is recognized as a hallmark of Parkinson’s disease (PD). Therefore, reducing accumulated iron and associated oxidative stress is considered a promising therapeutic strategy for PD. However, current iron chelators have poor membrane permeability and lack cell-type specificity. Here we identified GSK-J4, a histone demethylase inhibitor with the ability to cross blood brain barrier, as a potent iron suppressor. Only a trace amount of GSK-J4 significantly and selectively reduced intracellular labile iron in dopaminergic neurons, and suppressed H 2 O 2 and 6-OHDA-induced cell death in vitro. The iron-suppressive effect was mainly mediated by inducing an increase in the expression of the iron exporter ferroportin-1. In parallel, GSK-J4 rescued dopaminergic neuron loss and motor defects in 6-OHDA-induced PD rats, which was accompanied by reduction of oxidative stress. Importantly, GSK-J4 rescued the abnormal changes of histone methylation, H3K4me3 and H3K27me3 during 6-OHDA treatment although the iron-suppressive and neuroprotective effects were sensitive to H3K4me3 inhibition only. Also, upregulating H3K4me3 increased ferroportin-1 expression and neuroprotection. Taken together, we demonstrate a previously unappreciated action of GSK-J4 on cell-specific iron suppression and neuroprotection via epigenetic mechanism. Compared with conventional iron chelators, this compound has a stronger therapeutic potential for PD.

Fructose consumption induces metabolic syndrome to increase cardiovascular disease risk. Cinnamaldehyde and allopurinol possess anti-oxidative and anti-inflammatory activity to relieve heart injury in metabolic syndrome. But the mechanisms of fructose-induced cardiac injury and cardioprotective effects of cinnamaldehyde and allopurinol are not completely understood. In this study, fructose-fed rats displayed metabolic syndrome with elevated serum ox-LDL, cardiac oxidative stress, inflammation and fibrosis. Scavenger receptor CD36, Toll-like receptor 4 (TLR4), TLR6, IL-1R-associated kinase 4/1 (IRAK4/1), nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, interleukin-1β, transforming growth factor-β (TGF-β), drosophila mothers against DPP homolog (Smad) 2/3 phosphorylation and Smad4 were increased in animal and H9c2 cell models. These pathological processes were further evaluated in ox-LDL or fructose-exposed H9c2 cells pretreated with ROS scavenger and CD36 specific inhibitor, or IRAK1/4 inhibitor and transfected with CD36 , NLRP3 , or IRAK4 / 1 siRNA, demonstrating that NLPR3 inflammasome activation through CD36-mediated TLR4/6-IRAK4/1 signaling may promote cardiac inflammation and fibrosis. Cinnamaldehyde and allopurinol reduced cardiac oxidative stress to suppress NLPR3 inflammasome activation and TGF-β/Smads signaling by inhibiting CD36-mediated TLR4/6-IRAK4/1 signaling under fructose induction. These results suggest that the blockage of CD36-mediated TLR4/6-IRAK4/1 signaling to suppress NLRP3 inflammasome activation by cinnamaldehyde and allopurinol may protect against fructose-induced cardiac inflammation and fibrosis.

Background As populations age, cancer burden becomes increasingly conspicuous. This study quantified the cancer burden of the elderly (≥ 60 years) in China, based on the China Cancer Registry Annual Report to provide epidemiological evidence for cancer prevention and control. Methods Data on cancer cases and deaths among the elderly aged ≥ 60 years were collected from the China Cancer Registry Annual Report, 2008–2019. Potential years of life lost (PYLL) and disability-adjusted life years (DALY) were calculated to analyze fatalities and the non-fatal burden. The time trend was analyzed using the Joinpoint model. Results From 2005 to 2016, the PYLL rate of cancer in the elderly was stable between 45.34‰ and 47.62‰, but the DALY rate for cancer decreased at an average annual rate of 1.18% (95% CI: 0.84–1.52%). The non-fatal cancer burden in the rural elderly was higher than that of the urban elderly. Lung, gastric, liver, esophageal, and colorectal cancers were the main cancers causing the cancer burden in the elderly, and accounted for 74.3% of DALYs. The DALY rate of lung cancer in females in the 60–64 age group increased (annual percentage change [APC] = 1.14%, 95% CI: 0.10–1.82%). Female breast cancer was one of the top five cancers in the 60–64 age group, with DALY rates that also increased (APC = 2.17%, 95% CI: 1.35–3.01%). With increasing age, the burden of liver cancer decreased, while that of colorectal cancer rose. Conclusions From 2005 to 2016, the cancer burden in the elderly in China decreased, mainly reflected in the non-fatal burden. Female breast and liver cancer were a more serious burden in the younger elderly, while colorectal cancer burden was mainly observed in the older elderly.

In 2009, a mysterious illness associated with fever, thrombocytopenia, gastrointestinal symptoms, and leucopenia was seen in rural areas in central China, with an initial case fatality rate of 30%. After extensive investigation, a novel bunyavirus was identified. Between late March and mid-July 2009, an emerging infectious disease, which was identified as the severe fever with thrombocytopenia syndrome (SFTS), was reported in rural areas of Hubei and Henan provinces in Central China. The cause of the illness was unknown. The major clinical symptoms included fever, thrombocytopenia, gastrointestinal symptoms, and leukocytopenia, and there was an unusually high initial case fatality rate of 30%. In June 2009, an investigation was performed to identify whether the disease was caused by Anaplasma phagocytophilum or other pathogens. Although the clinical symptoms were considered to resemble those of human anaplasmosis, 1 neither bacterial DNA nor . . .

Copper is an essential trace element within cells, but it also exerts cytotoxic effects through induction of reactive oxygen species (ROS) production. To determine the mechanisms underlying copper-induced ROS production, we examined the effects of copper sulfate in HeLa cells. Exposure to copper sulfate led to dose-dependent decreases in HeLa cell viability, along with increases in the subG1 and G2/M populations and corresponding decreases in the G1 population. Copper sulfate also increased the levels of apoptosis, senescence, mitochondrial dysfunction, autophagy, ROS, and the expression of several stress proteins, including ATF3, c-Fos, DEC1 (differentiated embryonic chondrocyte gene 1), p21, p53, and HIF-1α (hypoxia-inducible factor 1 alpha). The suppression of copper-induced ROS generation by the ROS scavenger N-acetyl cysteine verified copper’s functional role, while the suppression of copper’s effects by the copper chelator disulfiram, confirmed its specificity. Selective induction of HIF-1α, p53, and phosphorylated ERK proteins by copper was blocked by the knockdown of the transcription factor DEC1, suggesting copper’s effects are mediated by DEC1. In addition to HeLa cells, copper also exerted cytotoxic effects in human endometrial (HEC-1-A) and lung (A549) adenocarcinoma cells, but not in normal human kidney (HEK293) or bronchial (Beas-2B) epithelial cells. These findings shed new light on the functional roles of copper within cells.

Background Candidate genes of neuromuscular junction (NMJ) pathway increased risk of frailty, but the extent and whether can be offset by exercises was unclear. The aim of this study was to investigate the association between aerobic exercises and incident frailty regardless of NMJ pathway‐related genetic risk. Methods A cohort study on participants from Chinese Longitudinal Healthy Longevity Survey was conducted from 2008 to 2011. A total of 7006 participants (mean age of 80.6 ± 10.3 years) without frailty at baseline were interviewed to record aerobic exercise status, and 4053 individuals among them submitted saliva samples. NMJ pathway‐related genes were genotyped and weighted genetic risk scores were constructed. Results During a median follow‐up of 3.1 years (19 634 person‐years), there were 1345 cases (19.2%) of incident frailty. Persistent aerobic exercises were associated with a 26% lesser frailty risk [adjusted hazard ratio (HR) = 0.74, 95% confidence interval (CI) = 0.64–0.85]. This association was stronger in a subgroup of 1552 longevous participants (age between 90 and 111 years, adjusted HR = 0.72, 95% CI = 0.60–0.87). High genetic risk was associated with a 35% increased risk of frailty (adjusted HR = 1.35, 95% CI = 1.16–1.58). Of the participants with high genetic risk and no persistent aerobic exercises, there was a 59% increased risk of frailty (adjusted HR = 1.59, 95% CI = 1.20–2.09). HRs for the risk of frailty increased from the low genetic risk with persistent aerobic exercise to high genetic risk without persistent aerobic exercise (P trend <0.001). Conclusions Both aerobic exercises and NMJ pathway‐related genetic risk were significantly associated with frailty. Persistent aerobic exercises can partly offset NMJ pathway‐related genetic risk to frailty in elderly people.

Distal arthrogryposis (DA) type 2B (DA2B) is an autosomal dominant congenital disorder, characterized by camptodactyly, thumb adduction, ulnar deviation and facial features, including small mouth, down-slanting palpebral fissure and slight nasolabial fold. It has been reported that four genes are associated with DA2B, including troponin I, fast-twitch skeletal muscle isoform, troponin T3, fast skeletal, myosin heavy chain 3 (MYH3) and tropomyosin 2, which are all associated with embryonic limb morphogenesis and skeletal muscle contraction. In the present study, three affected family members and five unaffected individuals were identified through clinical and radiological assessment. Genomic DNA was obtained from the three patients, which then underwent whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and 100 healthy volunteers. Then, the spatial models of embryonic MYH were further constructed. In the clinic, the three patients recruited to the present study were diagnosed with DA2B. Mutation analysis indicated that there was a novel heterogeneous missense mutation c.2506 A>G (p.K836E) in the MYH3 gene among the affected individuals, which was highly conserved and was not identified in the unaffected family members and healthy controls. Furthermore, protein modeling revealed that the altered position interacted with regulatory light chain. Thus, the present study identified a novel pathogenic mutation of the MYH3 gene in a Chinese family with DA2B, which expanded the mutational spectrum of MYH3 and provided additional information regarding the association between mutation locations and different types of DA.

Basal cell carcinoma (BCC) is a frequent malignant tumor of skin cancers with high morbidity. The objective of this study was to identify critical genes and pathways related to the carcinogenesis of BCC and gain more insights into the underlying molecular mechanisms of BCC. The gene expression profiles of GSE7553 and GSE103439 were downloaded from the Gene Expression Omnibus database with 19 tumors and 6 normal skin tissues. Differentially expressed genes (DEGs) were screened between BCC samples and normal tissues, followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Subsequently, protein-protein interaction (PPI) network was constructed for these DEGs, and module analysis was performed. A total of 313 DEGs were obtained. Among them, 222 genes were upregulated and 91 genes were downregulated. Enrichment analysis indicated that the upregulated genes were significantly enriched in cell cycle and mitosis, while the downregulated genes were mainly associated with unsaturated fatty acid metabolic process and cell differentiation. In addition, , , and were identified as the top three hub genes ranked by degrees in the PPI network. Meanwhile, three subnetworks were derived, which indicated that these DEGs were significantly enriched in pathways, including \"cell cycle\", \"extracellular matrix-receptor interaction\", \"basal cell carcinoma\", and \"hedgehog signaling pathway\". The novel critical DEGs and pathways identified in this study may serve pivotal roles in the carcinogenesis of BCC and indicate more molecular targets for the treatment of BCC.