Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases

Physiological reactive oxygen species (ROS) are important regulators of intercellular signal transduction. Oxidative and antioxidation systems maintain a dynamic balance under physiological conditions. Increases in ROS levels destroy the dynamic balance, leading to oxidative stress damage. Oxidative stress is involved in the pathogenesis of aging-related cardiovascular diseases (ACVD), such as atherosclerosis, myocardial infarction, and heart failure, by contributing to apoptosis, hypertrophy, and fibrosis. Oxidative phosphorylation in mitochondria is the main source of ROS. Increasing evidence demonstrates the relationship between ACVD and humanin (HN), an endogenous peptide encoded by mitochondrial DNA. HN protects cardiomyocytes, endothelial cells, and fibroblasts from oxidative stress, highlighting its protective role in atherosclerosis, ischemia–reperfusion injury, and heart failure. Herein, we reviewed the signaling pathways associated with the HN effects on redox signals, including Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2), chaperone-mediated autophagy (CMA), c-jun NH2 terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK), adenosine monophosphate-activated protein kinase (AMPK), and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)-Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3). Furthermore, we discussed the relationship among HN, redox signaling pathways, and ACVD. Finally, we propose that HN may be a candidate drug for ACVD

Cyclic intensive light exposure induces retinal lesions similar to age-related macular degeneration in APPswe/PS1 bigenic mice

<p>Abstract</p> <p>Background</p> <p>Intensive light exposure and beta-amyloid (Aβ) aggregates have been known as a risk factor for macular degeneration and an important component in the pathologic drusen structure involved in this disorder, respectively. However, it is unknown whether Aβ deposition mediates or exacerbates light exposure-induced pathogenesis of macular degeneration. Several studies including the one from us already showed accumulation of Aβ deposits in the retina in Alzheimer's transgenic mice. Using histopathological analysis combined with electroretinographic functional assessment, we investigated the effects of cyclic intensive light exposure (CILE) on the architecture of retina and related function in the APPswe/PS1bigenic mouse.</p> <p>Results</p> <p>Histopathological analysis has found significant loss of outer nuclear layer/photoreceptor outer segment and outer plexiform layer along with abnormal hypo- and hyper-pigmentation in the retinal pigment epithelium (RPE), remarkable choroidal neovascularization (CNV), and exaggerated neuroinflammatory responses in the outer retina of APPswe/PS1 bigenic mice following cyclic intensive light exposure (CILE), whereas controls remained little change contrasted with age-matched non-transgenic littermates. CILE-induced degenerative changes in RPE are further confirmed by transmission electron microcopy and manifest as formation of basal laminar deposits, irregular thickening of Bruch's membrane (BrM), deposition of outer collagenous layer (OCL) in the subretinal space, and vacuolation in the RPE. Immunofluorescence microscopy reveals drusenoid Aβ deposits in RPE as well as neovessels attached which are associated with disruption of RPE integrity and provoked neuroinflammatory response as indicated by markedly increased retinal infiltration of microglia. Moreover, both immunohistochemistry and Western blots detect an induction of vascular endothelial growth factor (VEGF) in RPE, which corroborates increased CNV in the outer retina in the bigenic mice challenged by CILE.</p> <p>Conclusions</p> <p>Our findings demonstrate that degenerative changes in the outer retina in the APPswe/PS1 bigenic mouse induced by CILE are consistent with these in AMD. These results suggest that an Alzheimer's transgenic animal model with accumulation of Aβ deposits might be an alternative animal model for AMD, if combined with other confounding factors such as intensive light exposure for AMD.</p

Effect of delivery mode on postpartum pelvic floor function in primiparous women

Objective To evaluate the pelvic floor functional status of primiparous women undergoing different delivery modes within 2 years postpartum. Methods Primiparous women admitted to the Pelvic Floor Center of Department of Gynecology were enrolled in this study. All participants were divided into the vaginal delivery and cesarean section groups according to the delivery mode. General clinical data were collected. Pelvic Organ Prolapse Quantification （POP-Q），pelvic floor muscle strength and electromyographic analysis were performed. Chronic pelvic pain，urinary and bowel function were evaluated. The Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire -12 （PISQ-12），Incontinence Quality of Life Questionnaire （I-QOL），Pelvic Floor Distress Inventory-20 （PFDI-20），and Self-Rating Depression Scale （SDS） were performed. The differences in pelvic floor anatomy and clinical symptoms in primiparous women were assessed between the vaginal delivery and cesarean section groups. Results A total of 521 primiparous women completed the survey，including 402 cases undergoing vaginal delivery and 119 receiving cesarean section. Primiparous women who underwent vaginal delivery had lower levels of anterior vaginal wall POP-Q，uterine/cervix POP-Q，ClassⅠmuscle strength，ClassⅡmuscle strength， pre-rest， ClassⅠelectromyography，ClassⅡelectromyography，and post-rest compared with those who underwent cesarean section （all P &lt; 0.05）. Moreover，primiparous women who had vaginal delivery were more prone to experiencing stress urinary incontinence （SUI） and lower I-QOL score compared with those receiving cesarean section （both P &lt; 0.05）. In terms of clinical manifestations such as chronic pelvic pain，bowel disorders，sexual dysfunction，and depressive status，there were no significant differences observed between two groups （all P &gt; 0.05）. Conclusions Vaginal delivery may be a risk factor for the increased incidence of postpartum pelvic organ prolapse （POP） and SUI in primiparous women. In clinical practice， early postpartum pelvic floor rehabilitation exercises or interventions should be emphasized for primiparous women，especially for the changes in urinary function

Survey of Automatic Labeling Methods for Topic Models

Topic models are often used in modeling unstructured corpora and discrete data to extract the latent topic. As topics are generally expressed in the form of word lists, it is usually difficult for users to understand the meanings of topics, especially when users lack knowledge in the subject area. Although manually labeling topics can generate more explanatory and easily understandable topic labels, the cost is too high for the method to be feasible. Therefore, research on automatic labeling of topic discovered provides solutions to the problem. Firstly, the currently most popular technique, latent Dirichlet allocation (LDA), is elaborated and analyzed. According to the three different representations of topic labels, based on phrases, abstracts, and pictures, the topic labeling methods are classified into three types. Then, centered on improving the interpretability of topics, with different types of generated topic labels utilized, the relevant research in recent years is sorted out, analyzed, and summarized. The applicable scenarios and usability of different labels are also discussed. Meanwhile, methods are further categorized according to their different characteristics. The focus is placed on the quantitative and qualitative analysis of the abstract topic labels generated through lexical-based, submodular optimization, and graph-based methods. The differences between separate methods with respect to the learning types, technologies used, and data sources are then compared. Finally, the existing problems and trend of development of research on automatic topic labeling are discussed. Based on deep learning, integrating with sentiment analysis, and continuously expanding the applicable scenarios of topic labeling, will be the directions of future development

PERK-Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti-Tumoral Polarization of Microglia

Isocitrate dehydrogenase (IDH) mutation, a known pathologic classifier, initiates metabolic reprogramming in glioma cells and has been linked to the reaction status of glioma-associated microglia/macrophages (GAMs). However, it remains unclear how IDH genotypes contribute to GAM phenotypes. Here, it is demonstrated that gliomas expressing mutant IDH determine M1-like polarization of GAMs, while archetypal IDH induces M2-like polarization. Intriguingly, IDH-mutant gliomas secrete excess cholesterol, resulting in cholesterol-rich, pro-inflammatory GAMs without altering their cholesterol biosynthesis, and simultaneously exhibiting low levels of tumoral cholesterol due to expression remodeling of cholesterol transport molecules, particularly upregulation of ABCA1 and downregulation of LDLR. Mechanistically, a miR-19a/LDLR axis-mediated novel post-transcriptional regulation of cholesterol uptake is identified, modulated by IDH mutation, and influencing tumor cell proliferation and invasion. IDH mutation-induced PERK activation enhances cholesterol export from glioma cells via the miR-19a/LDLR axis and ABCA1/APOE upregulation. Further, a synthetic PERK activator, CCT020312 is introduced, which markedly stimulates cholesterol efflux from IDH wild-type glioma cells, induces M1-like polarization of GAMs, and consequently suppresses glioma cell invasion. The findings reveal an essential role of the PERK/miR-19a/LDLR signaling pathway in orchestrating gliomal cholesterol transport and the subsequent phenotypes of GAMs, thereby highlighting a novel potential target pathway for glioma therapy

Intracytoplasmic sperm injection (ICSI) versus conventional in vitro fertilisation (IVF) in couples with non-severe male infertility (NSMI-ICSI) : protocol for a multicentre randomised controlled trial

Funding This study was supported by National Key Research and Development Program of China (2016YFC1000201; 2018YFC1002104) and the National Science Foundation of China (81730038). The study funders had no rule in the study design, implementation, analysis, manuscript, preparation or decision to submit this article for publication.Peer reviewedPublisher PD

Identification of Heat-Tolerant Genes in Non-Reference Sequences in Rice by Integrating Pan-Genome, Transcriptomics, and QTLs.

The availability of large-scale genomic data resources makes it very convenient to mine and analyze genes that are related to important agricultural traits in rice. Pan-genomes have been constructed to provide insight into the genome diversity and functionality of different plants, which can be used in genome-assisted crop improvement. Thus, a pan-genome comprising all genetic elements is crucial for comprehensive variation study among the heat-resistant and -susceptible rice varieties. In this study, a rice pan-genome was firstly constructed by using 45 heat-tolerant and 15 heat-sensitive rice varieties. A total of 38,998 pan-genome genes were identified, including 37,859 genes in the reference and 1141 in the non-reference contigs. Genomic variation analysis demonstrated that a total of 76,435 SNPs were detected and identified as the heat-tolerance-related SNPs, which were specifically present in the highly heat-resistant rice cultivars and located in the genic regions or within 2 kbp upstream and downstream of the genes. Meanwhile, 3214 upregulated and 2212 downregulated genes with heat stress tolerance-related SNPs were detected in one or multiple RNA-seq datasets of rice under heat stress, among which 24 were located in the non-reference contigs of the rice pan-genome. We then mapped the DEGs with heat stress tolerance-related SNPs to the heat stress-resistant QTL regions. A total of 1677 DEGs, including 990 upregulated and 687 downregulated genes, were mapped to the 46 heat stress-resistant QTL regions, in which 2 upregulated genes with heat stress tolerance-related SNPs were identified in the non-reference sequences. This pan-genome resource is an important step towards the effective and efficient genetic improvement of heat stress resistance in rice to help meet the rapidly growing needs for improved rice productivity under different environmental stresses. These findings provide further insight into the functional validation of a number of non-reference genes and, especially, the two genes identified in the heat stress-resistant QTLs in rice

Lactobacillus acidophilus JCM 1132 Strain and Its Mutant with Different Bacteriocin-Producing Behaviour Have Various In Situ Effects on the Gut Microbiota of Healthy Mice

peer-reviewedThe production of bacteriocin is considered to be a probiotic trait of lactic acid bacteria (LAB). However, not all strains of LAB harbour bacteriocin genes, even within the same species. Moreover, the effects of bacteriocins on the host gut microbiota and on host physiological indicators are rarely studied. This study evaluated the effects of the bacteriocin-producing Lactobacillus acidophilus strain JCM1132 and its non-producing spontaneous mutant, L. acidophilus CCFM720, on the physiological statuses and gut microbiota of healthy mice. Mice that received the bacteriocin-producing strain JCM1132 exhibited reduced water and food intake. Furthermore, the administration of these strains induced significant changes in the compositional abundance of faecal microbiota at the phylum and genus levels, and some of these changes were more pronounced after one week of withdrawal. The effects of CCFM720 treatment on the gut microbiota seemed to favour the prevention of metabolic diseases to some extent. However, individuals that received JCM1132 treatment exhibited weaker inflammatory responses than those that received CCFM720 treatment. Our results indicate that treatment with bacteriocin-producing or non-producing strains can have different effects on the host. Accordingly, this trait should be considered in the applications of LAB