microRNA在亨廷顿病中的研究进展

亨廷顿病(Huntington's disease, HD)是神经退行性疾病(neurodegenerative disorders)中一种单基因遗传病,由亨廷顿基因(the huntingtin gene, HTT)第一个外显子中的CAG三核苷酸序列重复扩增引起,尚无法治愈。HTT编码的蛋白产物被称为亨廷顿蛋白(Huntingtin protein, Htt)。突变亨廷顿蛋白(mutated huntingtin protein, mHtt)容易形成聚集体,具有毒性,导致一系列细胞学异常和神经元功能障碍。microRNA(miRNA)在基因转录后水平调控中起重要作用,其表达的改变与HD病理过程有关,成为治疗HD的潜在生物标志物。近年来,对一些特定miRNA在HD中调控机制及靶基因预测方面的研究可为HD提供潜在的治疗方法。本文就miRNA在HD中的相关研究进展进行综述。     

Factors associated with patient-reported midday fogging in established scleral lens wearers

PurposeTo estimate the prevalence of patient-reported midday fogging and to identify risk factors for midday fogging.MethodA multicenter, cross-sectional study was conducted with an electronic survey that was distributed to scleral lens practitioners. The survey asked them to describe their most recently examined established scleral lens patient. Respondents provided data about patient-reported midday fogging, patient demographic characteristics, indication for lens wear, lens-wearing schedule, lens design, and care products.ResultsOf the 248 survey respondents who indicated whether their patients had midday fogging, 64 (25.8 %) had patients who self-reported such issues. Midday fogging was not associated with demographic characteristics (age, sex, race/ethnicity), indications for scleral lens wear, mean lens diameter (P = .30), haptic design (P = .29), use of a daily cleaner (P = .12), disinfection/storage solution used (P = .71), or filling solution (P = .65). Patients who reported midday fogging more commonly reported redness or irritation associated with scleral lens wear compared with those who did not experience midday fogging (P = .03).ConclusionsPrevalence of midday fogging in this study was similar to previously reported rates. No specific lens design or care product was associated with patient-reported midday fogging. If inflammatory mediators are elevated in the postlens fluid reservoir of patients with midday fogging, as previously described, the redness or irritation associated with scleral lens wear suggests that ocular surface inflammation may be contributing to this phenomenon.     

The Regulatory Functionality of Exosomes Derived from hUMSCs in 3D Culture for Alzheimer's Disease Therapy

Reducing amyloid‐β (Aβ) accumulation could be a potential therapeutic approach for Alzheimer's disease (AD). Particular functional biomolecules in exosomes vested by the microenvironment in which the original cells resided can be transferred to recipient cells to improve pathological conditions. However, there are few reports addressing whether exosomes derived from cells cultured on scaffolds with varying dimension can reduce Aβ deposition or ameliorate cognitive decline for AD therapy. Herein, both 3D graphene scaffold and 2D graphene film are used as the matrix for human umbilical cord mesenchymal stem cell culture, from which the supernatants are obtained to isolate exosomes. The levels of 195 kinds of miRNAs and proteins, including neprilysin, insulin‐degrading enzyme and heat shock protein 70, in 3D‐cultured exosomes (3D‐Exo) are dramatically different from those obtained from 2D culture. Hence, 3D‐Exo could up‐regulate the expression of α‐secretase and down‐regulate the β‐secretase to reduce Aβ production in both AD pathology cells and transgenic mice, through their special cargo. With rescuing Aβ pathology, 3D‐Exo exerts enhanced therapeutic effects on ameliorating the memory and cognitive deficits in AD mice. These findings provide a novel clinical application for scaffold materials and functional exosomes derived from stem cells.     

The Rise of Retinal Organoids for Vision Research

Retinal degenerative diseases lead to irreversible blindness. Decades of research into the cellular and molecular mechanisms of retinal diseases, using either animal models or human cell-derived 2D systems, facilitated the development of several therapeutic interventions. Recently, human stem cell-derived 3D retinal organoids have been developed. These self-organizing 3D organ systems have shown to recapitulate the in vivo human retinogenesis resulting in morphological and functionally similar retinal cell types in vitro. In less than a decade, retinal organoids have assisted in modeling several retinal diseases that were rather difficult to mimic in rodent models. Retinal organoids are also considered as a photoreceptor source for cell transplantation therapies to counteract blindness. Here, we highlight the development and field’s improvements of retinal organoids and discuss their application aspects as human disease models, pharmaceutical testbeds, and cell sources for transplantations.     

Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required.     

Activin A and Cell-Surface GRP78 Are Novel Targetable RhoA Activators for Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of kidney failure. RhoA/Rho-associated protein kinase (ROCK) signaling is a recognized mediator of its pathogenesis, largely through mediating the profibrotic response. While RhoA activation is not feasible due to the central role it plays in normal physiology, ROCK inhibition has been found to be effective in attenuating DKD in preclinical models. However, this has not been evaluated in clinical studies as of yet. Alternate means of inhibiting RhoA/ROCK signaling involve the identification of disease-specific activators. This report presents evidence showing the activation of RhoA/ROCK signaling both in vitro in glomerular mesangial cells and in vivo in diabetic kidneys by two recently described novel pathogenic mediators of fibrosis in DKD, activins and cell-surface GRP78. Neither are present in normal kidneys. Activin inhibition with follistatin and neutralization of cell-surface GRP78 using a specific antibody blocked RhoA activation in mesangial cells and in diabetic kidneys. These data identify two novel RhoA/ROCK activators in diabetic kidneys that can be evaluated for their efficacy in inhibiting the progression of DKD.     

Mast Cell Chymase and Kidney Disease

A sizable part (~2%) of the human genome encodes for proteases. They are involved in many physiological processes, such as development, reproduction and inflammation, but also play a role in pathology. Mast cells (MC) contain a variety of MC specific proteases, the expression of which may differ between various MC subtypes. Amongst these proteases, chymase represents up to 25% of the total proteins in the MC and is released from cytoplasmic granules upon activation. Once secreted, it cleaves the targets in the local tissue environment, but may also act in lymph nodes infiltrated by MC, or systemically, when reaching the circulation during an inflammatory response. MC have been recognized as important components in the development of kidney disease. Based on this observation, MC chymase has gained interest following the discovery that it contributes to the angiotensin-converting enzyme’s independent generation of angiotensin II, an important inflammatory mediator in the development of kidney disease. Hence, progress regarding its role has been made based on studies using inhibitors but also on mice deficient in MC protease 4 (mMCP-4), the functional murine counterpart of human chymase. In this review, we discuss the role and actions of chymase in kidney disease. While initially believed to contribute to pathogenesis, the accumulated data favor a more subtle view, indicating that chymase may also have beneficial actions.     

Automated contact tracing: a game of big numbers in the time of COVID-19

One of the more widely advocated solutions for slowing down the spread of COVID-19 has been automated contact tracing. Since proximity data can be collected by personal mobile devices, the natural proposal has been to use this for automated contact tracing providing a major gain over a manual implementation. In this work, we study the characteristics of voluntary and automated contact tracing and its effectiveness for mapping the spread of a pandemic due to the spread of SARS-CoV-2. We highlight the infrastructure and social structures required for automated contact tracing to work. We display the vulnerabilities of the strategy to inadequate sampling of the population, which results in the inability to sufficiently determine significant contact with infected individuals. Of crucial importance will be the participation of a significant fraction of the population for which we derive a minimum threshold. We conclude that relying largely on automated contact tracing without population-wide participation to contain the spread of the SARS-CoV-2 pandemic can be counterproductive and allow the pandemic to spread unchecked. The simultaneous implementation of various mitigation methods along with automated contact tracing is necessary for reaching an optimal solution to contain the pandemic.