Beyond insulin: Unraveling the complex interplay of ER stress, oxidative damage, and CFTR modulation in CFRD

\ua9 2024 The Author(s)CF-related diabetes (CFRD) is a prevalent comorbidity in people with Cystic Fibrosis (CF), significantly impacting morbidity and mortality rates. This review article critically evaluates the current understanding of CFRD molecular mechanisms, including the role of CFTR protein, oxidative stress, unfolded protein response (UPR) and intracellular communication. CFRD manifests from a complex interplay between exocrine pancreatic damage and intrinsic endocrine dysfunction, further complicated by the deleterious effects of misfolded CFTR protein on insulin secretion and action. Studies indicate that ER stress and subsequent UPR activation play critical roles in both exocrine and endocrine pancreatic cell dysfunction, contributing to β-cell loss and insulin insufficiency. Additionally, oxidative stress and altered calcium flux, exacerbated by CFTR dysfunction, impair β-cell survival and function, highlighting the significance of antioxidant pathways in CFRD pathogenesis. Emerging evidence underscores the importance of exosomal microRNAs (miRNAs) in mediating inflammatory and stress responses, offering novel insights into CFRD\u27s molecular landscape. Despite insulin therapy remaining the cornerstone of CFRD management, the variability in response to CFTR modulators underscores the need for personalized treatment approaches. The review advocates for further research into non-CFTR therapeutic targets, emphasizing the need to address the multifaceted pathophysiology of CFRD. Understanding the intricate mechanisms underlying CFRD will pave the way for innovative treatments, moving beyond insulin therapy to target the disease\u27s root causes and improve the quality of life for individuals with CF

Maze solvers demystified and some other thoughts

There is a growing interest towards implementation of maze solving in spatially-extended physical, chemical and living systems. Several reports of prototypes attracted great publicity, e.g. maze solving with slime mould and epithelial cells, maze navigating droplets. We show that most prototypes utilise one of two phenomena: a shortest path in a maze is a path of the least resistance for fluid and current flow, and a shortest path is a path of the steepest gradient of chemoattractants. We discuss that substrates with so-called maze-solving capabilities simply trace flow currents or chemical diffusion gradients. We illustrate our thoughts with a model of flow and experiments with slime mould. The chapter ends with a discussion of experiments on maze solving with plant roots and leeches which show limitations of the chemical diffusion maze-solving approach.Comment: This is a preliminary version of the chapter to be published in Adamatzky A. (Ed.) Shortest path solvers. From software to wetware. Springer, 201

Performance Assessment of Pressurized Stairs in High Rise Buildings

Research paper published in the journal Fire Technology, special issue on Smoke Control in Buildings and Tunnels.Pressurized stair cases are an important part of the fire safety strategy of high rise buildings. Long egress times are compensated by creating safe environments within egress staircases allowing the displacement time within those stairs as time where occupants can be considered safe. The main mechanisms by which stairs are ‘‘made safe’’ are by guaranteeing structural protection of the enclosure and by elevating the pressure within the stair to ensure that smoke cannot enter. Despite the critical importance of this element of the fire safety strategy, the analysis and implementation of these systems remain simplified. Simple models have been developed using Bernoulli type formulations that account for static pressure and empirical constants to calculate flows through doors and other leakage areas. Implementation of these systems is even more simplified, consisting mainly of a direct feedback loop that controls a fan output on the basis of a pressure measurement inside the stair. The flow induced by the fan guarantees a minimum pressure. The pressure inside the stair needs to be limited to enable doors to be open, thus pressure dampers are introduced to release airflow in the event the pressure exceeds a specified maximum. Validation of these methodologies was done in the 70s and 80s with very limited field validation in real systems. This study presents an assessment of the performance of pressurized staircases in six high rise buildings. All systems have been designed using a similar methodology but implemented in different ways. In all cases the control mechanism for the fan is a direct feedback loop from a single pressure sensor. The results have been evaluated showing the limitations of the control system in the event of multiple doors being opened and the limitations of the pressure release dampers (as a response mechanism) if the pressure becomes unstable

Calculating WCET Estimates from Timed Traces

© The Author(s) 2015. This article is published with open access at Springerlink.comReal-time systems engineers face a daunting duty: They must ensure that each task in their system can always meet its deadline. To analyse schedulability they must know the worst-case execution time (WCET) of each task. However, determining exact WCETs is practically infeasible in cost-constrained industrial settings involving real-life code and COTS hardware. Static analysis tools that could yield sufficiently tight WCET bounds are often unavailable. As a result, interest in portable analysis approaches like measurement-based timing analysis (MBTA) is growing. We present an approach based on integer linear programming (ILP) for calculating a WCET estimate from a given database of timed execution traces. Unlike previous work, our method specifically aims at reducing overestimation, by means of an automatic classification of code executions into scenarios with differing worst-case behaviour. To ease the integration into existing analysis tool chains, our method is based on the implicit path enumeration technique (IPET). It can thus reuse flow facts from other analysis tools and produces ILP problems that can be solved by off-the-shelf solvers.Peer reviewe

Protein trafficking through the endosomal system prepares intracellular parasites for a home invasion

Toxoplasma (toxoplasmosis) and Plasmodium (malaria) use unique secretory organelles for migration, cell invasion, manipulation of host cell functions, and cell egress. In particular, the apical secretory micronemes and rhoptries of apicomplexan parasites are essential for successful host infection. New findings reveal that the contents of these organelles, which are transported through the endoplasmic reticulum (ER) and Golgi, also require the parasite endosome-like system to access their respective organelles. In this review, we discuss recent findings that demonstrate that these parasites reduced their endosomal system and modified classical regulators of this pathway for the biogenesis of apical organelles

Cultural differences in postnatal quality of life among German-speaking women - a prospective survey in two countries.

Assessment of quality of life after childbirth is an important health-outcome measurement for new mothers and is of special interest in midwifery. The Mother-Generated Index (MGI) is a validated instrument to assess postnatal quality of life. The tool has not been applied for making a cross-cultural comparison before. This study investigated (a) responses to the MGI in German-speaking women in Germany and Switzerland; and (b) associations between MGI scores on the one hand and maternity and midwifery care on the other

Impact of an Early Invasive Strategy versus Conservative Strategy for Unstable Angina and Non-ST Elevation Acute Coronary Syndrome in Patients with Chronic Kidney Disease: A Systematic Review.

BACKGROUND: Clinical practice guidelines support an early invasive approach after NSTE-ACS in patients with chronic kidney disease (CKD). There is no direct randomised controlled trial evidence in the CKD population, and whether the benefit of an early invasive approach is maintained across the spectrum of severity of CKD remains controversial. METHODS: We conducted a systematic review to evaluate the association between an early invasive approach and all-cause mortality in patients with CKD. We searched MEDLINE and EMBASE (1990-May 2015) and article reference lists. Data describing study design, participants, invasive management strategies, renal function, all-cause mortality and risk of bias were extracted. RESULTS: 3,861 potentially relevant studies were identified. Ten studies, representing data on 147,908 individuals with NSTE-ACS met the inclusion criteria. Qualitative heterogeneity in the definitions of early invasive approach, comparison groups and renal dysfunction existed. Meta-analysis of the RCT derived and observational data were generally supportive of an early invasive approach in CKD (RR0.76 (95% CI 0.49-1.17) and RR0.50 (95%CI 0.42-0.59) respectively). Meta-analysis of the observational studies demonstrated a large degree of heterogeneity (I2 79%) driven in part by study size and heterogeneity across various kidney function levels. CONCLUSIONS: The observational data support that an early invasive approach after NSTE-ACS confers a survival benefit in those with early-moderate CKD. Local opportunities for quality improvement should be sought. Those with severe CKD and the dialysis population are high risk and under-studied. Novel and inclusive approaches for CKD and dialysis patients in cardiovascular clinical trials are needed

Folic Acid Supplementation and Spontaneous Preterm Birth: Adding Grist to the Mill?

Nicholas Fisk and colleagues discuss a new study reporting that additional voluntary folic acid supplementation was associated with a major reduction in very preterm births

Prevalence of Childhood Atopic Dermatitis: An Urban and Rural Community-Based Study in Shanghai, China

Background: Atopic dermatitis (AD) is a common inflammatory and chronically relapsing disorder with increasing prevalence. However, little is known about its prevalence in Shanghai, the top metropolitan of China. This study will estimate and compare the prevalence of AD in urban and rural areas in representative samples of 3 to 6-year-old children in Shanghai. Methodology/Principal Findings: A descriptive cross-sectional study was performed. Pre-school children were obtained by cluster sampling from 8 communities in different districts in Shanghai. The main instrument was the core questionnaire module for AD used in the U.K. Working Party’s study. All the data were statistically analyzed by EpiData 3.1 and SPSS16.0. A total of 10436 children completed the study satisfactorily, with a response rate of 95.8%. The prevalence of AD in 3 to 6-year-old children was 8.3 % (Male: 8.5%, Female: 8.2%). The prevalence in urban areas of Shanghai was gradiently and significantly higher than that in rural areas. The highest prevalence was in the core urban area (10.2 % in Xuhui Tianping) vs. the lowest far from the urban areas (4.6 % in Chongming Baozhen). Conclusions/Significance: The prevalence of AD was 8.3 % (95%CI: 7.6%–9.1%) in children aged 3 to 6 in Shanghai. Th