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Cerebral microbleeds (MBs) have been found in patients with cognitive decline. We aimed to examine whether MBs are associated with motor or cognitive decline in patients with Parkinson’s disease (PD). We enrolled 135 PD patients and 34 healthy controls. All participants underwent brain MRI and plasma biomarker assays, including tau, Aβ42, Aβ40, and α-synuclein. PD with dementia (PDD) was operationally defined as Mini-Mental State Examination (MMSE) score < 26 and advanced motor stage was defined as Hoehn-Yahr stage ≥ 3 during “on” status. The association between MBs and disease severity was examined using multivariate logistic regression models. More lobar MBs were observed in PD patients than controls (20.7% vs. 3.3%, p  = 0.031). PDD patients had more lobar MBs (33.3% vs. 15.6%, p  = 0.034), more white matter hyperintensity ( p  = 0.021) and reduced hippocampal volume ( p  = 0.001) than PD with normal cognition. The presence of lobar MB (odds ratio = 2.83 [95% confidence interval 1.04–7.70], p  = 0.042) and severe white matter hyperintensity (3.29 [1.21–8.96], p  = 0.020) was independently associated with PDD after adjusting for vascular risk factors and other confounders. Furthermore, plasma Aβ40 levels were associated the MMSE score ( p  = 0.004) after adjusting for age and sex. Our findings demonstrated that lobar MBs, reduced hippocampal volume, and elevated plasma Aβ40 levels are associated with PDD.

Enzymes involved in epigenetic processes such as methyltransferases or demethylases are becoming highly utilized for their persistent DNA or histone modifying efficacy. Herein, we have developed an optogenetic toolbox fused to the catalytic domain (CD) of DNA-methyltransferase3A (DNMT3A-CD) or Ten-Eleven Dioxygenase-1 (TET1-CD) for loci-specific alteration of the methylation state at the promoter of Ascl1 (Mash1) , a candidate proneuron gene. Optogenetical protein pairs, CRY2 linked to DNMT3A-CD or TET1-CD and CIB1 fused to a Transcription Activator-Like Element (TALE) locating an Ascl1 promoter region, were designed for site specific epigenetic editing. A differentially methylated region at the Ascl1 promoter, isolated from murine dorsal root ganglion (hypermethylated) and striated cells (hypomethylated), was targeted with these optogenetic-epigenetic constructs. Optimized blue-light illumination triggered the co-localization of TALE constructs with DNMT3A-CD or TET1-CD fusion proteins at the targeted site of the Ascl1 promoter. We found that this spatiotemporal association of the fusion proteins selectively alters the methylation state and also regulates gene activity. This proof of concept developed herein holds immense promise for the ability to regulate gene activity via epigenetic modulation with spatiotemporal precision.

Meta‐analyses showed that non‐dipping of nocturnal blood pressure on ambulatory blood pressure monitoring (ABPM) was associated with adverse cardiovascular prognosis. However, these prognostic studies were mainly conducted in Caucasian and Japanese populations. Whether this association applies to Chinese patients remained uninvestigated. A total of 1199 Chinese patients with hypertension undergoing ABPM between January 2012 and December 2014 were recruited retrospectively from five public hypertension referral clinics in Hong Kong. Patients were followed up for a mean 6.42 years for cardiovascular morbidity and mortality and all‐cause mortality. Time to event of different dipping patterns was compared by Kaplan‐Meier curves. Hazard ratios (HR) were obtained by Cox proportional hazard models with patient demographics and confounding factors adjusted in multivariate regression. A total of 163 end point events occurred in the period. Normal dipping was observed in 446 patients (37.2%), non‐dipping in 490 (40.9%), reverse dipping in 161 (13.4%), and extreme dipping in 102 (8.5%). Kaplan‐Meier analyses showed inferior survival in non‐dippers and reverse dippers for total cardiovascular events and coronary events but not cerebrovascular events. After adjusting for confounding factors, Cox regressions showed HRs 1.166 (CI 0.770‐1.764) and 1.173 (CI 0.681‐2.021) in non‐dippers and reverse dippers for total cardiovascular events, and HRs 1.320 (CI 0.814‐2.141) and 1.476 (CI 0.783‐2.784) for coronary events. Nocturnal blood pressure non‐dipping, and to a greater extent reverse dipping, demonstrated adverse cardiovascular prognosis in a cohort of Chinese patients with hypertension in Hong Kong. Further focused studies on cerebrovascular events and reverse dippers were warranted to refine risk stratification.

Background Previous research has demonstrated that atrial fibrillation (AF) ablation improves heart function variably among patients. We proposed that the ANTWERP score, which was validated in a European group of patients with low left ventricular ejection fraction (LVEF) who had AF ablation, would be valid in an Asian group as well. The purpose of the study is to examine how well a new scoring system (the ANTWERP score) can predict heart function improvement after atrial fibrillation ablation in Asian patients with heart failure. Methods A retrospective review was conducted on patients (n = 84) undergoing AF ablation between January 2019 and June 2022. Initial diagnoses for impaired LV systolic function were confirmed by echocardiography. Patients meeting the “2021 Universal Definition of HF” criteria for LVEF recovery were classified as “responders.” Results Similarities were observed between responders and nonresponders regarding comorbidities, AF type, and LVEF, except for the left ventricular internal diameter in diastole. A higher percentage of responders had an ANTWERP score ≤2 (87.8%) compared to those with a score >2 (55.6%). LVEF improvement was notably higher in the former group (+14.8% vs. +9.4%, p = .043). Atrial reverse remodeling and recurrent atrial arrhythmia rates were similar across groups. Conclusion The conclusion of the study was that the ANTWERP score effectively predicted LVEF improvement after atrial fibrillation ablation in the Asian population and that this scoring system could be used to guide clinical decisions and prognosis prediction. Central illustration: The ANTWERP Score in Predicting LVEF Recovery after AF Ablation in the Asian Population.

The transcription factor FliA, also called sigma 28, is a major regulator of bacterial flagellar biosynthesis genes. Growing evidence suggest that in addition to motility, FliA is involved in controlling numerous bacterial behaviors, even though the underlying regulatory mechanism remains unclear. By using a transcriptional fusion to gfp that responds to cyclic (c)-di-GMP, this study revealed a higher c-di-GMP concentration in the fliA deletion mutant of Pseudomonas aeruginosa than in its wild-type strain PAO1. A comparative analysis of transcriptome profiles of P. aeruginosa PAO1 and its fliA deletion mutant revealed an altered expression of several c-di-GMP-modulating enzyme-encoding genes in the fliA deletion mutant. Moreover, the downregulation of PA4367 (bifA), a Glu-Ala-Leu motif-containing phosphodiesterase, in the fliA deletion mutant was confirmed using the β-glucuronidase reporter gene assay. FliA also altered pyocyanin and pyorubin production by modulating the c-di-GMP concentration. Complementing the fliA mutant strain with bifA restored the motility defect and pigment overproduction of the fliA mutant. Our results indicate that in addition to regulating flagellar gene transcription, FliA can modulate the c-di-GMP concentration to regulate the swarming motility and phenazine pigment production in P. aeruginosa.

Neutrophils play essential anti-microbial and inflammatory roles in host defense, however, their activities require tight regulation as dysfunction often leads to detrimental inflammatory and autoimmune diseases. Here we show that the adhesion molecule GPR97 allosterically activates CD177-associated membrane proteinase 3 (mPR3), and in conjugation with several protein interaction partners leads to neutrophil activation in humans. Crystallographic and deletion analysis of the GPR97 extracellular region identified two independent mPR3-binding domains. Mechanistically, the efficient binding and activation of mPR3 by GPR97 requires the macromolecular CD177/GPR97/PAR2/CD16b complex and induces the activation of PAR2, a G protein-coupled receptor known for its function in inflammation. Triggering PAR2 by the upstream complex leads to strong inflammatory activation, prompting anti-microbial activities and endothelial dysfunction. The role of the complex in pathologic inflammation is underscored by the finding that both GPR97 and mPR3 are upregulated on the surface of disease-associated neutrophils. In summary, we identify a PAR2 activation mechanism that directs neutrophil activation, and thus inflammation. The PR3/CD177/GPR97/PAR2/CD16b protein complex, therefore, represents a potential therapeutic target for neutrophil-mediated inflammatory diseases. Activation of neutrophil leukocytes is tightly regulated, and it is important to understand the molecular mechanisms of their response to physiological and pathological stimuli. Here authors show that the adhesion molecule G protein-coupled receptor 97 and its interaction partners play pivotal roles in neutrophil leukocyte activation both in anti-microbial response and in inflammatory diseases.

Sinonasal rhabdomyosarcoma (RMS) is a rare soft tissue malignancy. Due to the limited cases, the clinicopathological features and prognostic factors are still not well understood. This retrospective review included eight patients with sinonasal RMS at our institution between 2004 and 2020. Patient demographics, tumor features, Intergroup Rhabdomyosarcoma Study Group (IRSG) stage and clinical group, treatment strategy, and survival rates were evaluated. Kaplan-Meier analysis and log-rank tests were performed to analyze the possible prognostic factors. We observed a predominance of male sex and alveolar-type tumor in sinonasal RMS. Nasal obstructions and neck masses were the most common symptoms. Patients with pretreatment lactate dehydrogenase (LDH) levels >400 U/l and negative immunohistochemical staining for desmin or MyoD1 had lower survival rates. In patients with sinonasal RMS, pretreatment LDH levels >400 U/l and negative immunohistochemical staining for desmin or MyoD1 may suggest a poor prognosis. These factors can not only contribute to the prediction of prognosis in patients with sinonasal RMS but also facilitate the design of more appropriate treatment strategies.

The ability to analyse online user-generated content related to sentiments (e.g., thoughts and opinions) on products or policies has become a de-facto skillset for many companies and organisations. Besides the challenge of understanding formal textual content, it is also necessary to take into consideration the informal and mixed linguistic nature of online social media languages, which are often coupled with localised slang as a way to express ‘true’ feelings. Due to the multilingual nature of social media data, analysis based on a single official language may carry the risk of not capturing the overall sentiment of online content. While efforts have been made to understand multilingual sentiment analysis based on a range of informal languages, no significant electronic resource has been built for these localised languages. This paper reviews the various current approaches and tools used for multilingual sentiment analysis, identifies challenges along this line of research, and provides several recommendations including a framework that is particularly applicable for dealing with scarce resource languages.

Global DNA de-methylation is thought to occur only during pre-implantation and gametogenesis in mammals. Scalable, cell-wide de-methylation has not been demonstrated beyond totipotent stages. Here, we observed a large scale de-methylation and subsequent re-methylation (CDR) (including 5-methylcytosine (5mC) and 5-hydroxylmethylcytosine (5hmC)) in post-mitotic cerebellar Purkinje cells (PC) through the course of normal development. Through single cell immuno-identification and cell-specific quantitative methylation assays, we demonstrate that the CDR event is an intrinsically scheduled program, occurring in nearly every PC. Meanwhile, cerebellar granule cells and basket interneurons adopt their own DNA methylation program, independent of PCs. DNA de-methylation was further demonstrated at the gene level, on genes pertinent to PC development. The PC, being one of the largest neurons in the brain, may showcase an amplified epigenetic cycle which may mediate stage transformation including cell cycle arrest, vast axonal-dendritic growth, and synaptogenesis at the onset of neuronal specificity. This discovery is a key step toward better understanding the breadth and role of DNA methylation and de-methylation during neural ontology.

The vast amount and diversity of the content shared on social media can pose a challenge for any business wanting to use it to identify potential customers. In this paper, our aim is to investigate the use of both unsupervised and supervised learning methods for target audience classification on Twitter with minimal annotation efforts. Topic domains were automatically discovered from contents shared by followers of an account owner using Twitter Latent Dirichlet Allocation (LDA). A Support Vector Machine (SVM) ensemble was then trained using contents from different account owners of the various topic domains identified by Twitter LDA. Experimental results show that the methods presented are able to successfully identify a target audience with high accuracy. In addition, we show that using a statistical inference approach such as bootstrapping in over-sampling, instead of using random sampling, to construct training datasets can achieve a better classifier in an SVM ensemble. We conclude that such an ensemble system can take advantage of data diversity, which enables real-world applications for differentiating prospective customers from the general audience, leading to business advantage in the crowded social media space.