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BackgroundThe aetiology of Alzheimer's disease (AD) is believed to involve environmental exposure and genetic susceptibility. The aim of our present systematic review and meta-analysis was to roundly evaluate the association between AD and its modifiable risk factors.MethodsWe systematically searched PubMed and the Cochrane Database of Systematic Reviews from inception to July 2014, and the references of retrieved relevant articles. We included prospective cohort studies and retrospective case–control studies.Results16 906 articles were identified of which 323 with 93 factors met the inclusion criteria for meta-analysis. Among factors with relatively strong evidence (pooled population >5000) in our meta-analysis, we found grade I evidence for 4 medical exposures (oestrogen, statin, antihypertensive medications and non-steroidal anti-inflammatory drugs therapy) as well as 4 dietary exposures (folate, vitamin E/C and coffee) as protective factors of AD. We found grade I evidence showing that one biochemical exposure (hyperhomocysteine) and one psychological condition (depression) significantly increase risk of developing AD. We also found grade I evidence indicative of complex roles of pre-existing disease (frailty, carotid atherosclerosis, hypertension, low diastolic blood pressure, type 2 diabetes mellitus (Asian population) increasing risk whereas history of arthritis, heart disease, metabolic syndrome and cancer decreasing risk) and lifestyle (low education, high body mass index (BMI) in mid-life and low BMI increasing the risk whereas cognitive activity, current smoking (Western population), light-to-moderate drinking, stress, high BMI in late-life decreasing the risk) in influencing AD risk. We identified no evidence suggestive of significant association with occupational exposures.ConclusionsEffective interventions in diet, medications, biochemical exposures, psychological condition, pre-existing disease and lifestyle may decrease new incidence of AD.

Objective Ovarian cancer (OC) affects nearly 22,000 women annually in the United States and ranks fifth in cancer deaths, largely because of being diagnosed at an advanced stage. Autophagy is the cellular process of self-degrading damaged or degenerate proteins and organelles. Long non-coding RNAs (lncRNAs) are a group of RNA molecules whose transcripts are greater than 200 nt but are not translated into proteins. However, just a small number of autophagy-related lncRNAs have been explored in depth. Methods We used RNA sequencing data from The Cancer Genome Atlas (TCGA) and autophagy datasets to identify dysfunctional autophagy-related lncRNAs and provide potential useful biomarkers for OC diagnosis and prognosis. Results Seventeen differentially expressed lncRNAs (AC010186.3, AC006001.2, LBX2-AS1, SNHG17, AC011445.1, AC083880.1, MIR193BHG, AC025259.3, HCG14, AC007114.1, AC108673.2, USP30-AS1, AC010336.5, LINC01132, AC006333.2, LINC00665 and AC027348.1) were selected as independent prognostic factors for OC patients. Functional annotation of the data was performed through gene set enrichment analysis (GSEA). The results suggested that the high-risk group was mainly enriched in specific tumor-related and metabolism pathways. Conclusion Based on the online databases, we identified novel autophagy-related lncRNAs for the prognosis of ovarian cancer.

ObjectiveWe sought to identify the risk factors for predicting the progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD).MethodsWe searched 6 electronic databases for cohort studies published from January 1966 to March 2015. Eligible studies were required to be relevant to the subject and provide sufficient data for our needs.Results60 cohort studies with 14 821 participants from 16 countries were included in the meta-analysis. The strongest positive associations between risk factors and the progression from MCI to AD were found for abnormal cerebrospinal fluid (CSF), phosphorylated τ (p-τ) (relative risk (RR)=2.43, 95% CI=1.70 to 3.48), abnormal CSF τ/Aβ1–42 (RR=3.77, 95% CI=2.34 to 6.09), hippocampal atrophy (RR=2.59, 95% CI=1.95 to 3.44), medial temporal lobe atrophy (RR=2.11, 95% CI=1.70 to 2.63) and entorhinal atrophy (RR=2.03, 95% CI=1.57 to 2.62). Further positive associations were found for the presence of apolipoprotein E (APOE)ε4ε4 and at least 1 APOEε4 allele, CSF total-τ (t-τ), white matter hyperintensity volume, depression, diabetes, hypertension, older age, female gender, lower mini-mental state examination (MMSE) score and higher AD assessment scale cognitive subscale (ADAS-cog) score. Negative associations were found for high body mass index (RR=0.85, 95% CI=0.76 to 0.96) and higher auditory verbal learning test delay score (RR=0.86, 95% CI=0.77 to 0.96).ConclusionsPatients with MCI with APOEε4, abnormal CSF τ level, hippocampal and medial temporal lobe atrophy, entorhinal atrophy, depression, diabetes, hypertension, older age, female gender, lower MMSE score and higher ADAS-cog score, had a high risk for the progression to AD.

Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson’s disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AA-treated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.

Osteoarthritis (OA) is an ageing‐related disease characterized by articular cartilage degradation and joint inflammation. circRNA has been known to involve in the regulation of multiple inflammatory diseases including OA. However, the mechanism underlying how circRNA regulates OA remains to be elucidated. Here, we report circANKRD36 prevents OA chondrocyte apoptosis and inflammation by targeting miR‐599, which specifically degrades Casz1. We performed circRNA sequencing in normal and OA tissues and found the expression of circANKRD36 is decreased in OA tissues. circANKRD36 is also reduced in IL‐1β–treated human chondrocytes. FACS analysis and Western blot showed that the knockdown of circANKRD36 promotes the apoptosis and inflammation of chondrocytes in IL‐1β stress. We then found miR‐599 to be the target of circANKRD36 and correlate well with circANKRD36 both in vitro and in vivo. By database analysis and luciferase assay, Casz1 was found to be the direct target of miR‐599. Casz1 helps to prevent apoptosis and inflammation of chondrocytes in response to IL‐1β. In conclusion, our results proved circANKRD36 sponge miR‐599 to up‐regulate the expression of Casz1 and thus prevent apoptosis and inflammation in OA.

Background Rhino‐orbito‐cerebral mucormycosis (ROCM) is an opportunistic pathogenic fungal disease caused by the fungus mucor, and it is a life‐threatening fungal infection. The ulceration on the skin of the head and neck, accompanied by rhinitis, headache, orbital inflammation, and eyelid edema, should raise a high suspicion of Mucor infection in diabetic patients with inadequately controlled blood glucose. Case Description The clinical data of a patient with ROCM were analyzed retrospectively, and the clinical features were analyzed. The patient was admitted to the hospital with “diabetic hyperosmotic coma” after presenting with fatigue, poor appetite, and disturbances in consciousness as initial symptoms. After improving relevant examinations, controlling underlying diseases, and administering antifungal treatment, the final clinical outcome was death. Conclusion ROCM is more prevalent in patients with uncontrolled diabetes and varied clinical manifestations. The characteristic feature is an eschar‐like necrosis of the local skin or mucosa. The gold criteria for diagnosis are pathology and fungal culture; imaging examination does not reveal any specific manifestations. Early diagnosis and effective treatment are the keys. Rhino‐orbito‐cerebral mucormycosis is more prevalent in patients with uncontrolled diabetes and varied clinical manifestations. The characteristic feature is an eschar‐like necrosis of the local skin or mucosa. The gold criteria for diagnosis are pathology and fungal culture; imaging examination does not reveal any specific manifestations. Early diagnosis and effective treatment are the keys.

Parkinson’s disease (PD), like many common age-related conditions, has been recognized to have a substantial genetic component. Multiple lines of evidence suggest that Leucine-rich repeat kinase 2 (LRRK2) is a crucial factor to understanding the etiology of PD. LRRK2 is a large, widely expressed, multi-domain and multifunctional protein. LRRK2 mutations are the major cause to inherited and sporadic PD. In this review, we discuss the pathology and clinical features which show diversity and variability of LRRK2-associated PD. In addition, we do a thorough literature review and provide theoretical data for gene counseling. Further, we present the evidence linking LRRK2 to various possible pathogenic mechanism of PD such as α-synuclein, tau, inflammatory response, oxidative stress, mitochondrial dysfunction, synaptic dysfunction as well as autophagy-lysosomal system. Based on the above work, we investigate activities both within GTPase and outside enzymatic regions in order to obtain a potential therapeutic approach to solve the LRRK2 problem.

Background The physiological effects of prone ventilation in ARDS patients have been discussed for a long time but have not been fully elucidated. Electrical impedance tomography (EIT) has emerged as a tool for bedside monitoring of pulmonary ventilation and perfusion, allowing the opportunity to obtain data. This study aimed to investigate the effect of prone positioning (PP) on ventilation–perfusion matching by contrast-enhanced EIT in patients with ARDS. Design Monocenter prospective physiologic study. Setting University medical ICU. Patients Ten mechanically ventilated ARDS patients who underwent PP. Interventions We performed EIT evaluation at the initiation of PP, 3 h after PP initiation and the end of PP during the first PP session. Measurements and main results The regional distribution of ventilation and perfusion was analyzed based on EIT images and compared to the clinical variables regarding respiratory and hemodynamic status. Prolonged prone ventilation improved oxygenation in the ARDS patients. Based on EIT measurements, the distribution of ventilation was homogenized and dorsal lung ventilation was significantly improved by PP administration, while the effect of PP on lung perfusion was relatively mild, with increased dorsal lung perfusion observed. The ventilation–perfusion matched region was found to increase and correlate with the increased PaO 2 /FiO 2 by PP, which was attributed mainly to reduced shunt in the lung. Conclusions Prolonged prone ventilation increased dorsal ventilation and perfusion, which resulted in improved ventilation–perfusion matching and oxygenation. Trial registration : ClinicalTrials.gov, NCT04725227. Registered on 25 January 2021.

Although many cases of genetic adaptations to high elevations have been reported, the processes driving these modifications and the pace of their evolution remain unclear. Many high-elevation adaptations (HEAs) are thought to have arisen in situ as populations rose with growing mountains. In contrast, most high-elevation lineages of the Qinghai-Tibetan Plateau appear to have colonized from low-elevation areas. These lineages provide an opportunity for studying recent HEAs and comparing them with ancestral low-elevation alternatives. Herein, we compare four frogs (three species of Nanorana and a close lowland relative) and four lizards (Phrynocephalus) that inhabit a range of elevations on or along the slopes of the Qinghai-Tibetan Plateau. The sequential cladogenesis of these species across an elevational gradient allows us to examine the gradual accumulation of HEA at increasing elevations. Many adaptations to high elevations appear to arise gradually and evolve continuously with increasing elevational distributions. Numerous related functions, especially DNA repair and energy metabolism pathways, exhibit rapid change and continuous positive selection with increasing elevations. Although the two studied genera are distantly related, they exhibit numerous convergent evolutionary changes, especially at the functional level. This functional convergence appears to be more extensive than convergence at the individual gene level, although we found 32 homologous genes undergoing positive selection for change in both high-elevation groups. We argue that species groups distributed along a broad elevational gradient provide a more powerful system for testing adaptations to high-elevation environments compared with studies that compare only pairs of high-elevation versus low-elevation species.

Objective Chinese Herb QingBai decoction (QBD) has been approved affective in the treatment of IBD patients in clinic. However, the underlying mechanism remains unknown. We aim to investigate the effect of QBD on the mouse model of ulcerative colitis and its possible mechanism. Methods C57/bL mice were given 5% DSS to induce colitis and were divided as QBD and mesalazine group. Weight, faeces and mental status were recorded each day and the histopathological changes (goblet cells etc) of the colon were observed after sacrificed. Fluorescein isothiocyanate‐dextran 4000 was measured to reflect the intestinal mucosal permeability. In addition, cell junction‐related proteins and possible signal pathways were investigated. Results QingBai decoction could significantly alleviate the inflammation and the protection effect of colitis is comparable as those in mesalazine enema group. It was found that the permeability reduced significantly with QBD treatment vs the control group, while no significant difference between the mesalazine and QBD groups. QBD treatment could upregulate the expression of tight junction complex（ZO‐1, claudin‐1 and occludin）and muc‐2 expression. It significantly reduced the production and secretion of serials proinflammatory cytokines (IL‐1β, IL‐6, Kc and TNF‐α) compared with the control group. Meanwhile, NF‐κB and Notch pathways were regulated. Conclusion QingBai decoction can effectively alleviate intestinal inflammation and mucosal barrier function in colitis mice, and the mechanism may be related to the inhibition of inflammatory cascade as well as enhanced mucus layer barrier and mechanical barrier function by NF‐κB and Notch signalling.