Oral Microbiota and Porphyromonas gingivalis Kgp Genotypes Altered in Parkinson's Disease with Mild Cognitive Impairment.

Cognitive impairment (CI) is a common complication of the non-motor symptoms in Parkinson's disease (PD), including PD with mild cognitive impairment (PD-MCI) and PD dementia. Recent studies reported the oral dysbiosis in PD and CI, respectively. Porphyromonas gingivalis (P. gingivalis), a pathogen of oral dysbiosis, plays an important role in PD, whose lysine-gingipain (Kgp) could lead to AD-type pathologies. No previous study investigated the composition of oral microbiota and role of P. gingivalis in PD-MCI. This study aimed to investigate the differences of oral microbiota composition, P. gingivalis copy number, and Kgp genotypes among PD-MCI, PD with normal cognition (PD-NC) and periodontal status-matched control (PC) groups. The oral bacteria composition, the copy number of P. gingivalis, and the Kgp genotypes in gingival crevicular fluid from PD-MCI, PD-NC, and PC were analyzed using 16S ribosomal RNA sequencing, quantitative real-time PCR, and MseI restriction. We found that the structures of oral microbiota in PD-MCI group were significantly different compared to that in PD-NC and PC group. The relative abundances of Prevotella, Lactobacillus, Megasphaera, Atopobium, and Howardella were negatively correlated with cognitive score. Moreover, there was a significant difference of Kgp genotypes among the three groups. The predominant Kgp genotypes of P. gingivalis in the PD-MCI group were primarily Kgp II, whereas in the PD-NC group, it was mainly Kgp I. The Kgp II correlated with lower MMSE and MoCA scores, which suggested that Kgp genotypes II is related to cognitive impairment in PD.

Investigating gait-responsive somatosensory cueing from a wearable device to improve walking in Parkinson's disease.

Freezing-of-gait (FOG) and impaired walking are common features of Parkinson's disease (PD). Provision of external stimuli (cueing) can improve gait, however, many cueing methods are simplistic, increase task loading or have limited utility in a real-world setting. Closed-loop (automated) somatosensory cueing systems have the potential to deliver personalised, discrete cues at the appropriate time, without requiring user input. Further development of cue delivery methods and FOG-detection are required to achieve this. In this feasibility study, we aimed to test if FOG-initiated vibration cues applied to the lower-leg via wearable devices can improve gait in PD, and to develop real-time FOG-detection algorithms. 17 participants with Parkinson's disease and daily FOG were recruited. During 1 h study sessions, participants undertook 4 complex walking circuits, each with a different intervention: continuous rhythmic vibration cueing (CC), responsive cueing (RC; cues initiated by the research team in response to FOG), device worn with no cueing (NC), or no device (ND). Study sessions were grouped into 3 stages/blocks (A-C), separated by a gap of several weeks, enabling improvements to circuit design and the cueing device to be implemented. Video and onboard inertial measurement unit (IMU) data were analyzed for FOG events and gait metrics. RC significantly improved circuit completion times demonstrating improved overall performance across a range of walking activities. Step frequency was significantly enhanced by RC during stages B and C. During stage C, > 10 FOG events were recorded in 45% of participants without cueing (NC), which was significantly reduced by RC. A machine learning framework achieved 83% sensitivity and 80% specificity for FOG detection using IMU data. Together, these data support the feasibility of closed-loop cueing approaches coupling real-time FOG detection with responsive somatosensory lower-leg cueing to improve gait in PD.

Ergothioneine improves myocardial remodeling and heart function after acute myocardial infarction via S-glutathionylation through the NF-ĸB dependent Wnt5a-sFlt-1 pathway.

Myocardial infarction (MI) remains the leading cause of cardiovascular death worldwide. Studies have shown that soluble fms-like tyrosine kinase-1 (sFlt-1) has a harmful effect on the heart after MI. However, ergothioneine (ERG) has been shown to have protective effects in rats with preeclampsia by reducing circulating levels of sFlt-1. In this study, we aimed to investigate the mechanism by which ERG protects the heart after MI in rats. Our results indicate that treatment with 10 mg/kg ERG for 7 days can improve cardiac function as determined by echocardiography. Additionally, ERG can reduce the size of the damaged area, prevent heart remodeling, fibrosis, and reduce cardiomyocyte death after MI. To explain the mechanism behind the cardioprotective effects of ERG, we conducted several experiments. We observed a significant reduction in the expression of monocyte chemoattractant protein-1 (MCP-1), p65, and p-p65 proteins in heart tissues of ERG-treated rats compared to the control group. ELISA results also showed that ERG significantly reduced plasma levels of sFlt-1. Using Glutaredoxin-1 (GLRX) and CD31 immunofluorescence, we found that GLRX was expressed in clusters in the myocardial tissue surrounding the coronary artery, and ERG can reduce the expression of GLRX caused by MI. In vitro experiments using a human coronary artery endothelial cell (HCAEC) hypoxia model confirmed that ERG can reduce the expression of sFlt-1, GLRX, and Wnt5a. These findings suggest that ERG protects the heart from MI damage by reducing s-glutathionylation through the NF-ĸB-dependent Wnt5a-sFlt-1 pathway.

Three nervous system-specific expressed genes are potential biomarkers for the diagnosis of sporadic amyotrophic lateral sclerosis through a bioinformatic analysis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease in adults. However, ALS, especially sporadic ALS (sALS), is difficult to diagnose due to the lack of biomarkers. RESULTS: We used the bioinformatics technology to find the potential biomarker and we found that two hundred seventy-four DEGs were identified and enrichment analysis showed DEGs were involved in nervous system activity, like axon_guidance and the neurotrophin_signaling_pathway. Five nervous system-specific expressed hub genes were further validated by three GEO datasets. APP, LRRK2, and PSEN1 might be potential diagnostic and prognostic biomarkers of sALS, and NEAT1-miR-373-3p/miR-302c-3p/miR-372-3p-APP, circ_0000002-miR-302d-3p/miR-373-3p-APP and XIST-miR-9-5p/miR-30e-5p/miR-671-5p might be potential ceRNA regulatory pathways. APP SNP analysis showed subjects harboring the minor G allele of rs463946, minor G allele of rs466433 and minor C allele of rs364048 had an increased risk of sALS development. CONCLUSIONS: Our results identified three nervous system-specific expressed hub genes that might be diagnostic and prognostic markers of sALS and APP might be a genetic susceptibility factor contributing to sALS development.

Porphyromonas gingivalis: A key role in Parkinson's disease with cognitive impairment?

Cognitive impairment (CI) is a common complication of Parkinson's disease (PD). The major features of Parkinson's disease with cognitive impairment (PD-CI) include convergence of α-Synuclein (α-Syn) and Alzheimer's disease (AD)-like pathologies, neuroinflammation, and dysbiosis of gut microbiota. Porphyromonas gingivalis (P. gingivalis) is an important pathogen in periodontitis. Recent research has suggested a role of P. gingivalis and its virulence factor in the pathogenesis of PD and AD, in particular concerning neuroinflammation and deposition of α-Synuclein (α-Syn) and amyloid-ß (Aß). Furthermore, in animal models, oral P. gingivalis could cause neurodegeneration through regulating the gut-brain axis, suggesting an oral-gut-brain axis might exist. In this article, we discussed the pathological characteristics of PD-CI and the role of P. gingivalis in them.

Genome-wide identification and expression analysis of the bZIP transcription factor family genes in response to abiotic stress in Nicotiana tabacum L.

BACKGROUND: The basic leucine zipper (bZIP) transcription factor (TF) is one of the largest families of transcription factors (TFs). It is widely distributed and highly conserved in animals, plants, and microorganisms. Previous studies have shown that the bZIP TF family is involved in plant growth, development, and stress responses. The bZIP family has been studied in many plants; however, there is little research on the bZIP gene family in tobacco. RESULTS: In this study, 77 bZIPs were identified in tobacco and named NtbZIP01 through to NtbZIP77. These 77 genes were then divided into eleven subfamilies according to their homology with Arabidopsis thaliana. NtbZIPs were unevenly distributed across twenty-two tobacco chromosomes, and we found sixteen pairs of segmental duplication. We further studied the collinearity between these genes and related genes of six other species. Quantitative real-time polymerase chain reaction analysis identified that expression patterns of bZIPs differed, including in different organs and under various abiotic stresses. NtbZIP49 might be important in the development of flowers and fruits; NtbZIP18 might be an important regulator in abiotic stress. CONCLUSIONS: In this study, the structures and functions of the bZIP family in tobacco were systematically explored. Many bZIPs may play vital roles in the regulation of organ development, growth, and responses to abiotic stresses. This research has great significance for the functional characterisation of the tobacco bZIP family and our understanding of the bZIP family in higher plants.

Ring-like late gadolinium enhancement for predicting ventricular tachyarrhythmias in non-ischaemic dilated cardiomyopathy.

AIMS: Myocardial fibrosis is associated with clinical ventricular tachyarrhythmia (VTA) events in patients with non-ischaemic dilated cardiomyopathy (DCM). Subepicardial or mid-wall ring-like late gadolinium enhancement (LGE) has received increasing attention in recent years. The aim of this study was to investigate the relationship between ring-like LGE and VTAs in DCM. METHODS AND RESULTS: Patients diagnosed with non-ischaemic DCM who underwent cardiac magnetic resonance with LGE imaging at baseline were investigated. The composite outcome was the occurrence of VTAs defined as sustained ventricular tachycardia, ventricular fibrillation/flutter, aborted sudden cardiac death (SCD), SCD, and appropriate implantable cardioverter-defibrillator intervention. The final cohort comprised 157 patients, including 36 (22.9%) in no LGE group, 48 (30.6%) in focal LGE group, 40 (25.5%) in multi-focal LGE group, and 33 (21%) in ring-like LGE group. Ring-like LGE group patients were younger compared to focal and multi-focal LGE group (P < 0.001) with higher left ventricular ejection fraction (33.0% vs. 24.4% vs. 22.1%, P < 0.001). After a median of 13 ± 7 months follow-up, compared to patients with no LGE, the hazard ratios (HRs) with 95% confidence intervals (CIs) for VTAs were 2.90 (0.56-15.06), 5.55 (1.21-25.44), and 11.75 (2.66-51.92) for patients with focal LGE, multi-focal LGE, and ring-like LGE, respectively. After multivariable adjustment, ring-like LGE group remained associated with increased risk of VTAs (adjusted HR 10.00, 95% CI 1.54-64.98; P = 0.016) independent of the global LGE burden. CONCLUSION: The ring-like pattern of LGE is independently associated with an increased risk of VTAs in patients with non-ischaemic DCM.

Remote Ischemic Preconditioning to Prevent Acute Kidney Injury After Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials.

Objective: Randomized controlled trials (RCTs) evaluating the influence of remote ischemic preconditioning (RIPC) on acute kidney injury (AKI) after cardiac surgery showed inconsistent results. We performed a meta-analysis to evaluate the efficacy of RIPC on AKI after cardiac surgery. Methods: Relevant studies were obtained by search of PubMed, Embase, and Cochrane's Library databases. A random-effect model was used to pool the results. Meta-regression and subgroup analyses were used to determine the source of heterogeneity. Results: Twenty-two RCTs with 5,389 patients who received cardiac surgery -2,702 patients in the RIPC group and 2,687 patients in the control group-were included. Moderate heterogeneity was detected (p for Cochrane's Q test = 0.03, I 2 = 40%). Pooled results showed that RIPC significantly reduced the incidence of AKI compared with control [odds ratio (OR): 0.76, 95% confidence intervals (CI): 0.61-0.94, p = 0.01]. Results limited to on-pump surgery (OR: 0.78, 95% CI: 0.64-0.95, p = 0.01) or studies with acute RIPC (OR: 0.78, 95% CI: 0.63-0.97, p = 0.03) showed consistent results. Meta-regression and subgroup analyses indicated that study characteristics, including study design, country, age, gender, diabetic status, surgery type, use of propofol or volatile anesthetics, cross-clamp time, RIPC protocol, definition of AKI, and sample size did not significantly affect the outcome of AKI. Results of stratified analysis showed that RIPC significantly reduced the risk of mild-to-moderate AKI that did not require renal replacement therapy (RRT, OR: 0.76, 95% CI: 0.60-0.96, p = 0.02) but did not significantly reduce the risk of severe AKI that required RRT in patients after cardiac surgery (OR: 0.73, 95% CI: 0.50-1.07, p = 0.11). Conclusions: Current evidence supports RIPC as an effective strategy to prevent AKI after cardiac surgery, which seems to be mainly driven by the reduced mild-to-moderate AKI events that did not require RRT. Efforts are needed to determine the influences of patient characteristics, procedure, perioperative drugs, and RIPC protocol on the outcome.

Exchange proteins directly activated by cAMP mediate cardiac repolarization and arrhythmogenesis during chronic heart failure.

Most sudden cardiac death in chronic heart failure (CHF) is caused by malignant ventricular arrhythmia (VA); however, the molecular mechanism remains unclear. This study aims to explore the effect of exchange proteins directly activated by cAMP (Epac) on VA in CHF and the potential molecular mechanism. Transaortic constriction was performed to prepare CHF guinea pigs. Epac activation model was obtained with 8-pCPT administration. Programmed electrical stimulation (PES) was performed to detect effective refractory period (ERP) or induce VA. Isolated adult cardiomyocytes were treated with 8-pCPT and (or) the Epac inhibitor. Cellular electrophysiology was examined by whole-cell patch clamp. With Epac activation, corrected QT duration was lengthened by 12.6%. The 8-pCPT increased action potential duration (APD) (APD50: 236.9 ± 18.07 ms vs. 328.8 ± 11.27 ms, p < 0.05; APD90: 264.6 ± 18.22 ms vs. 388.6 ± 6.47 ms, p < 0.05) and decreased rapid delayed rectifier potassium (IKr) current (tail current density: 1.1 ± 0.08 pA/pF vs. 0.7 ± 0.03 pA/pF, p < 0.05). PES induced more malignant arrhythmias in the 8-pCPT group than in the control group (3/4 vs. 0/8, p < 0.05). The selective Epac1 inhibitor CE3F4 rescued the drop in IKr after 8-pCPT stimulation (tail current density: 0.5 ± 0.02 pA/pF vs. 0.6 ± 0.03 pA/pF, p < 0.05). In conclusion, Epac1 regulates IKr, APD, and ERP in guinea pigs, which could contribute to the proarrhythmic effect of Epac1 in CHF.

Identification of a novel three-column classification for double-column die-punch fractures of the distal radius.

The present study aimed to classify double-column die-punch fractures of the distal radius according to imaging data, and to evaluate their clinical features. A retrospective analysis of imaging data derived from 498 patients diagnosed with a double-column die-punch fracture of the distal radius was performed. The fractures were divided into those with middle-column avulsion with fracture of the radial-column articular surface (type I), those with middle-column collapse with fracture of the radial-column articular surface (type II), those with middle-column collapse with fracture of epiphysis of the radial column (type III) or mixed-type fractures (type IV). The intra- and inter-observer consistency between assessors was analyzed with kappa statistics. The patients with double-column die-punch fractures of the distal radius were followed up. There were 21 cases of type I fracture, 135 cases of type II fracture, 130 cases of type III fracture and 212 cases of type IV fracture. The intra-observer kappa coefficient ranged from 0.810-0.861, whereas the inter-observer kappa coefficient range was 0.830-0.876, with high consistency. Following 13 months of follow-up, the patients were assessed for functional recovery of the wrist and hand using the Gartland-Werley scoring system. The analysis indicated that in 95.78% of the patients, wrist function was rated as excellent or good (n=477), while in 4.22% of patients it was rated as fair (n=21), mainly due to the development of post-traumatic arthritis of the wrist following inappropriate therapy. All of the cases were type IV and type III fractures. These data demonstrated the application of a novel classification system named the Three-Column Classification, used to classify double-column die-punch fractures of the distal radius. This method reflected the mechanisms and severity of the fractures, conforming to the principle of AO fracture classification. Furthermore, it exhibited high consistency and may provide reference values for clinical diagnosis, treatment and prognostic evaluation.

ß-Arrestin2 regulates the rapid component of delayed rectifier K+ currents and cardiac action potential of guinea pig cardiomyocytes after adrenergic stimulation.

A decrease in the rapid component of delayed rectifier potassium current (IKr) during chronic heart failure (CHF) prolongs action potential (AP), and plays a key role in the pathogenesis of ventricular arrhythmias. ß-Arrestin2 has been shown to restore the inotropic reserve of ß-adrenergic regulation, but little or nothing is known about its effect on intrinsic channel. This study investigated the role of ß-arrestin2 in the regulation of cardiac hERG/IKr potassium channel and AP during chronic adrenergic stimulation. Single left ventricular myocytes were isolated from guinea pig heart, and were transfected with adenovirus encoding ß-arrestin2, or ß-arrestin2 siRNA or an empty adenovirus. Cell cultures containing 10 nM isoproterenol, 1 nM phenylephrine or vehicle alone (control medium) were electro-physiologically examined after 48 h of incubation. Action potential duration at 50 and 90 % of repolarization (APD50 and APD90) were measured using whole-cell patch-clamp recording. Sustained adrenergic stimulation significantly reduced the density of the IKr current (p < 0.001). ß-Arrestin2 expression in cell cultures treated with isoproterenol or phenylephrine was significantly downregulated after adrenergic stimulation (p < 0.001). Overexpression of ß-arrestin2 significantly attenuated isoproterenol or phenylephrine-induced reduction in IKr current. It also prevented the phenylephrine-induced prolongation of AP (p < 0.05 for APD50 and p < 0.001 for APD90), but did not significantly affect AP profile after exposure of the cardiomyocytes to isoproterenol (p > 0.05). Therefore, Increased levels of ß-Arrestin2 weaken dysregulation of IKr current and prevent excessive AP prolongation, making it an effective anti-arrhythmic strategy.