Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α1 subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α1–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α1 and β1 subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG. 相似文献
Mesenchymal stem cells (MSCs) transplantation has emerged as a potential therapeutic approach for Alzheimer's disease (AD). However, the poor proliferation capacity and low survival rate of engrafted MSCs in the hostile microenvironment of AD limit their therapeutic efficiency. Lin28B is a conserved RNA-binding protein associated with cell self-renewal and survival. The purpose of the present study was to explore whether lin28B might influence the functions of implanted MSCs and strengthen their neuroprotective potential in AD. A gain-of-function assay was used to upregulate lin28B expression in MSCs by lentiviral transfection. Our in vitro results indicated that lin28B promoted MSCs proliferation and migration, and protected MSCs against Aβ1–42-induced cell death by upregulating insulin-like growth factor-2 (IGF-2). Blockage of IGF-2 partially abrogated the above effects of lin28B. After intracerebroventricular injection into amyloid precursor protein/presenilin 1 mice, implanted MSCs were monitored using bioluminescence imaging. We observed that administration of MSCs transfected with lin28B significantly stimulated their proliferation and prolonged cell retention after delivery. Moreover, administration of the transfected MSCs markedly mitigated cognitive deficits, promoted amyloid plaque clearance, decreased the activation of microglia, and reduced neuronal cell death. The data above confirmed our hypothesis that lin28B is a crucial modulator determining the fate of transplanted MSCs by regulating IGF-2-associated pathways and thereby enhancing their protective effects against AD. 相似文献
Weaning weight is an important economic trait in the meat rabbit industry. Evidence has linked the gut microbiota to health and production performance in rabbits. However, the effect of gut microbiota on meat rabbit weaning weight remains unclear. In this study, we performed 16S rRNA gene sequencing analysis of 135 faecal samples from commercial Ira rabbits. We detected 50 OTUs significantly associated with weaning weight. OTUs that showed positive associations with weaning weight were mostly members of the family Ruminococcaceae which are important in degrading dietary fibres and producing butyrate. On the contrary, OTUs annotated to genera Blautia, Lachnoclostridium and Butyricicoccus correlated with fat deposition were negatively associated with weaning weight. Predicted functional capacity analysis revealed that 91 KOs and 26 KEGG pathways exhibited potential correlations with weaning weight. We found that gut microbiota involved in the metabolism of amino acids, butanoate, energy and monosaccharides affected weaning weight. Additionally, cross-validation analysis indicated that 16.16% of the variation in weaning weight was explained by the gut microbiome. Our findings provide important information to improve weaning weight of meat rabbits by modulating their gut microbiome. 相似文献
Nibea albiflora (yellow drum) is an important seafood fish species in East Asia. We explored the population genetic variation of N. albiflora along the coastal waters of the China Sea using microsatellite markers to facilitate a selective breeding programme that is undertaken in China. A total of 256 alleles were detected at 12 loci in four wild populations. A high level of genetic diversity was observed with the mean number of alleles and the observed and expected heterozygosity in each population ranging from 7.917 to 14.083, 0.701 to 0.764 and 0.765 to 0.841, respectively. Pairwise fixation index (FST) analysis indicated significant but weak genetic differentiation among populations from four localities (FST?=?0.030, P?<?0.01), which was also confirmed by analysis of molecular variance (AMOVA). Significant genetic differentiation was detected between Ningde and the other populations (FST?=?0.047–0.056, P?<?0.01). Structure analysis suggested that N. albiflora within the examined range might be composed of two stocks. The data of the present study revealed high genetic diversity and low genetic differentiation among the N. albiflora populations along the coast of the China Sea. This baseline information could be valuable for future selective breeding programmes of N. albiflora. 相似文献
Prader–Willi syndrome (PWS) is a rare genetic disorder associated with developmental delay, obesity, and neuropsychiatric comorbidities. Limosilactobacillus reuteri (Lactobacillus reuteri, Lact. reuteri) has demonstrated anti-obesity and anti-inflammatory effects in previous studies. In the present study, we aim to evaluate the effects of Lact. reuteri supplementation on body mass index (BMI), social behaviors, and gut microbiota in individuals with PWS. We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 71 individuals with PWS aged 6 to 264 months (64.4 ± 51.0 months). Participants were randomly assigned to either receive daily Lact. reuteri LR-99 probiotic (6 × 1010 colony forming units) or a placebo sachet. Groupwise differences were assessed for BMI, ASQ-3, and GARS-3 at baseline, 6 weeks, and 12 weeks into treatment. Gut microbiome data was analyzed with the QIIME2 software package, and predictive functional profiling was conducted with PICRUSt-2. We found a significant reduction in BMI for the probiotic group at both 6 weeks and 12 weeks relative to the baseline (P < 0.05). Furthermore, we observed a significant improvement in social communication and interaction, fine motor function, and total ASQ-3 score in the probiotics group compared to the placebo group (P < 0.05). Altered gut microbiota was observed in the probiotic group to favor weight loss and improve gut health. The findings suggest a novel therapeutic potential for Lact. reuteri LR-99 probiotic to modulate BMI, social behaviors, and gut microbiota in Prader–Willi syndrome patients, although further investigation is warranted.
Trial registration Chinese Clinical Trial Registry: ChiCTR1900022646
Primary amyloidosis (AL) results from overproduction of unstable monoclonal immunoglobulin light chains (LCs) and the deposition of insoluble fibrils in tissues, leading to fatal organ disease. Glycosaminoglycans (GAGs) are associated with AL fibrils and have been successfully targeted in the treatment of other forms of amyloidosis. We investigated the role of GAGs in LC fibrillogenesis. Ex vivo tissue amyloid fibrils were extracted and examined for structure and associated GAGs. The GAGs were detected along the length of the fibril strand, and the periodicity of heparan sulfate (HS) along the LC fibrils generated in vitro was similar to that of the ex vivo fibrils. To examine the role of sulfated GAGs on AL oligomer and fibril formation in vitro, a κ1 LC purified from urine of a patient with AL amyloidosis was incubated in the presence or absence of GAGs. The fibrils generated in vitro at physiologic concentration, temperature, and pH shared morphologic characteristics with the ex vivo κ1 amyloid fibrils. The presence of HS and over-O-sulfated-heparin enhanced the formation of oligomers and fibrils with HS promoting the most rapid transition. In contrast, GAGs did not enhance fibril formation of a non-amyloidogenic κ1 LC purified from urine of a patient with multiple myeloma. The data indicate that the characteristics of the full-length κ1 amyloidogenic LC, containing post-translational modifications, possess key elements that influence interactions of the LC with HS. These findings highlight the importance of the variable and constant LC regions in GAG interaction and suggest potential therapeutic targets for treatment. 相似文献