Clinical features and pathogenicity assessment in patients with HTRA1-autosomal dominant disease.

BACKGROUND: Heterozygous mutations in HTRA1 were recently found to cause autosomal dominant cerebral small vessel disease (CSVD), and it was named HTRA1-autosomal dominant disease (AD-HTRA1) in the consensus recommendations of the European Academy of Neurology. This study aimed to investigate the clinical features of a mutation in HTRA1 and the effect of HTRA1 mutation on white matter hyperintensity (WMH). METHODS: A proband's brain magnetic resonance imaging (MRI) showed multiple lacunar infarctions and multiple WMH in the lateral ventricle, external capsule, frontal lobe and corpus callosum. The proband and family members were tested for CSVD-related genes by next-generation sequencing and the clinical data of the patients were collected. The published literature on AD-HTRA1 was collected, and the clinical characteristics and pathogenicity of the patients were summarized. Combined Annotation Dependent Depletion (CADD) is a tool for scoring the deleteriousness of single-nucleotide variants and insertion/deletion variants in the human genome. The relationship between the degree of WMH and the pathogenicity of the mutation was further analyzed. RESULT: It was found that the proband and her family members had a heterozygous missense mutation of c.854C > T (p.P285L) in the 4 exon of HTRA1 gene. A retrospective analysis of 5 families with c.854C > T mutation found that the patients had an early age of onset, cognitive impairment was more common, and alopecia and spondylosis could be combined at the same time. By univariate analysis, the severity of WMH was found to be significantly associated with the mutated CADD score (p < 0.05, Spearman's rho = 0.266). CONCLUSION: The clinical manifestations of AD-HTRA1 with mutation site c.854C > T (p.P285L) are similar to CARASIL, and brain MRI are mainly moderate or severe WMH and lacunar infarction (LI). WMH are affected by mutation sites. Therefore, our pathogenicity score for mutations can predict the severity of WMH.

From ambiguity to transparency: influence of environmental information disclosure on financial performance in the context of internationalization.

Environmental sustainability is an important strategy for firms to expand market reach and space in pursuit of profitable growth. In the context of internationalization, environment information disclosure (EID) is considered an environmental signal released by a firm to external stakeholders. Using a sample of Chinese construction firms listed in the global Engineering News-Record (ENR), two periods, from 2008 to 2014 and 2015 to 2019, were set up from the perspective of the EID guideline changes. The regression results illustrate a negative relationship between EID and financial performance in the first period. The moderating effect of internationalization on the relationship between EID and financial performance changes from negative to positive over time. Quantile regressions further reveal how EID and internationalization affect firms at different levels of financial performance. This study proposed a periodic contingency perspective to reconcile the changes in the influence of EID on financial performance within the context of internationalization.

Down-regulation of lncRNA GAS5 attenuates neuronal cell injury through regulating miR-9/FOXO3 axis in cerebral ischemic stroke.

Cerebral ischemic stroke is a leading cause of neurological disability worldwide. Previous study reported that long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) was highly expressed in ischemic stroke. However, the mechanism underlying GAS5 in an inflammatory injury during an ischemic stroke remains poorly understood. An in vivo mouse model of middle cerebral artery occlusion (MCAO) and an in vitro cell model of oxygen-glucose deprivation (OGD) were established to induce cerebral ischemic stroke condition. The expressions of GAS5, microRNA-9 (miR-9) and forkhead box O3 (FOXO3) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot analysis, respectively. The neurological injury in vivo was investigated by neurological score and TTC staining. Cell apoptosis and inflammatory injury were analyzed by western blot, flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. The interaction between miR-9 and GAS5 or FOXO3 was explored by luciferase activity, RNA pull-down and RNA immunoprecipitation (RIP) assays. GAS5 expression was enhanced in the cerebral ischemic stroke model. Knockdown of GAS5 attenuated the cerebral infarct, neurological injury, apoptosis and inflammatory injury in the mouse MCAO model. miR-9 was bound to GAS5 and its overexpression inhibited cell apoptosis and inflammatory response in OGD-treated bEnd.3 cells, which was attenuated by GAS5. FOXO3 was a target of miR-9 and its restoration reversed the miR-9-mediated suppression of apoptosis and inflammation. Moreover, GAS5 promoted FOXO3 expression by competitively sponging miR-9. GAS5 knockdown alleviated neuronal cell injury by regulating miR-9/FOXO3, providing a new theoretical foundation for cerebral ischemic stroke.