Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle

Muscle contraction is driven by the molecular machinery of the sarcomere. As phosphorylation is a critical regulator of muscle function, the identification of regulatory kinases is important for understanding sarcomere biology. Pathogenic variants in alpha kinase 3 (ALPK3) cause cardiomyopathy and musculoskeletal disease, but little is known about this atypical kinase. Here we show that ALPK3 is an essential component of the M-band of the sarcomere and define the ALPK3-dependent phosphoproteome. ALPK3 deficiency impaired contractility both in human cardiac organoids and in the hearts of mice harboring a pathogenic truncating Alpk3 variant. ALPK3-dependent phosphopeptides were enriched for sarcomeric components of the M-band and the ubiquitin-binding protein sequestosome-1 (SQSTM1) (also known as p62). Analysis of the ALPK3 interactome confirmed binding to M-band proteins including SQSTM1. In human pluripotent stem cell-derived cardiomyocytes modeling cardiomyopathic ALPK3 mutations, sarcomeric organization and M-band localization of SQSTM1 were abnormal suggesting that this mechanism may underly disease pathogenesis

Overcoming Skin Damage from Pollution via Novel Skincare Strategies.

Urban pollution is one of the main problems encountered worldwide with major impact on public health as well as the environment. Health impact of urban pollution is not limited to respiratory conditions but also encompasses major skin problems including irritation, skin ageing, and skin cancer. Toxic gases and particulate matter are the main pollutants and exhibit extensive local variability. The aforementioned pollutants are small particles that attach to the skin or penetrate into it, enhancing free radicals' production inside the inner skin layers. This urges the need to propose cosmetic products that help prevent and/or minimise pollutants' effects on the skin whether irritation, ageing and cancer. Furthermore, intrinsic and extrinsic factors contributed to skin irritation and ageing. Intrinsic factors are within skin factors and include genetic and physiological characteristics of individuals. Moreover, extrinsic factors comprise environmental factors such as humidity, temperature, and smoke. Subsequently active ingredients with antipollutant properties addressed the intrinsic and extrinsic factors by four mechanisms being: free radical neutralisation, film-forming ability, skin barrier enhancement and fortification. Such ingredients include vitamin A derivatives, vitamin C derivatives, carbohydrates, and plant-based products. Yet, very limited studies have evaluated the effectiveness of the aforementioned active ingredients against irritation or ageing and this should be considered in future work

Anagnostakis. Code generation for packet header intrusion analysis on the IXP1200 network processor

Abstract. We present a software architecture that enables the use of the IXP1200 network processor in packet header analysis for network intrusion detection. The proposed work consists of a simple and efficient run-time infrastructure for managing network processor resources, along with the S2I compiler, a tool that generates efficient C code from highlevel, human readable, intrusion signatures. This approach facilitates the employment of the IXP1200 in network intrusion detection systems while our experimental results demonstrate that provides performance comparable to hand-crafted code.

Kv1.3 Channel Up-Regulation in Peripheral Blood T Lymphocytes of Patients With Multiple Sclerosis

Voltage-gated Kv1.3 potassium channels are key regulators of T lymphocyte activation, proliferation and cytokine production, by providing the necessary membrane hyper-polarization for calcium influx following immune stimulation. It is noteworthy that an accumulating body of in vivo and in vitro evidence links these channels to multiple sclerosis pathophysiology. Here we studied the electrophysiological properties and the transcriptional and translational expression of T lymphocyte Kv1.3 channels in multiple sclerosis, by combining patch clamp recordings, reverse transcription polymerase chain reaction and flow cytometry on freshly isolated peripheral blood T lymphocytes from two patient cohorts with multiple sclerosis, as well as from healthy and disease controls. Our data demonstrate that T lymphocytes in MS, manifest a significant up-regulation of Kv1.3 mRNA, Kv1.3 membrane protein and Kv1.3 current density and therefore of functional membrane channel protein, compared to control groups (p < 0.001). Interestingly, patient sub-grouping shows that Kv1.3 channel density is significantly higher in secondary progressive, compared to relapsing-remitting multiple sclerosis (p < 0.001). Taking into account the tight connection between Kv1.3 channel activity and calcium-dependent processes, our data predict and could partly explain the reported alterations of T lymphocyte function in multiple sclerosis, while they highlight Kv1.3 channels as potential therapeutic targets and peripheral biomarkers for the disease. © Copyright © 2021 Markakis, Charitakis, Beeton, Galani, Repousi, Aggeloglou, Sfikakis, Pennington, Chandy and Poulopoulou

Disparities in spatially variable gene calling highlight the need for benchmarking spatial transcriptomics methods

Abstract Identifying spatially variable genes (SVGs) is a key step in the analysis of spatially resolved transcriptomics data. SVGs provide biological insights by defining transcriptomic differences within tissues, which was previously unachievable using RNA-sequencing technologies. However, the increasing number of published tools designed to define SVG sets currently lack benchmarking methods to accurately assess performance. This study compares results of 6 purpose-built packages for SVG identification across 9 public and 5 simulated datasets and highlights discrepancies between results. Additional tools for generation of simulated data and development of benchmarking methods are required to improve methods for identifying SVGs

Risk and protective factors for atrial fibrillation after cardiac surgery and valvular interventions : an umbrella review of meta-analyses

Objective Postoperative atrial fibrillation (POAF) is a common complication affecting approximately one-third of patients after cardiac surgery and valvular interventions. This umbrella review systematically appraises the epidemiological credibility of published meta-analyses of both observational and randomised controlled trials (RCT) to assess the risk and protective factors of POAF. Methods Three databases were searched up to June 2021. According to established criteria, evidence of association was rated as convincing, highly suggestive, suggestive, weak or not significant concerning observational studies and as high, moderate, low or very low regarding RCTs. Results We identified 47 studies (reporting 61 associations), 13 referring to observational studies and 34 to RCTs. Only the transfemoral transcatheter aortic valve replacement (TAVR) approach was associated with the prevention of POAF and was supported by convincing evidence from meta-analyses of observational data. Two other associations provided highly suggestive evidence, including preoperative hypertension and neutrophil/lymphocyte ratio. Three associations between protective factors and POAF presented a high level of evidence in meta-analyses, including RCTs. These associations included atrial and biatrial pacing and performing a posterior pericardiotomy. Nineteen associations were supported by moderate evidence, including use of drugs such as amiodarone, b-blockers, glucocorticoids and statins and the performance of TAVR compared with surgical aortic valve replacement. Conclusions Our study provides evidence confirming the protective role of amiodarone, b-blockers, atrial pacing and posterior pericardiotomy against POAF as well as highlights the risk of untreated hypertension. Further research is needed to assess the potential role of statins, glucocorticoids and colchicine in the prevention of POAF.Funding Agencies|ALF grants (County Council of Ostergotland) [RO818141]</p

Comparing efficacy and safety in catheter ablation strategies for atrial fibrillation: a network meta-analysis

Background: There is no consensus on the most efficient catheter ablation (CA) strategy for patients with atrial fibrillation (AF). The objective of this study was to compare the efficacy and safety of different CA strategies for AF ablation through network meta-analysis (NMA). Methods: A systematic search of PubMed, Web of Science, and CENTRAL was performed up to October 5th, 2020. Randomized controlled trials (RCT) comparing different CA approaches were included. Efficacy was defined as arrhythmia recurrence after CA and safety as any reported complication related to the procedure during a minimum follow-up time of 6 months. Results: In total, 67 RCTs (n = 9871) comparing 19 different CA strategies were included. The risk of recurrence was significantly decreased compared to pulmonary vein isolation (PVI) alone for PVI with renal denervation (RR: 0.60, CI: 0.38–0.94), PVI with ganglia-plexi ablation (RR: 0.62, CI: 0.41–0.94), PVI with additional ablation lines (RR: 0.8, CI: 0.68–0.95) and PVI in combination with bi-atrial modification (RR: 0.32, CI: 0.11–0.88). Strategies including PVI appeared superior to non-PVI strategies such as electrogram-based approaches. No significant differences in safety were observed. Conclusions: This NMA showed that PVI in combination with additional CA strategies, such as autonomic modulation and additional lines, seem to increase the efficacy of PVI alone. These strategies can be considered in treating patients with AF, since, additionally, no differences in safety were observed. This study provides decision-makers with comprehensive and comparative evidence about the efficacy and safety of different CA strategies. Systematic review registration: PROSPERO registry number: CRD42020169494. © 2022, The Author(s)