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"NAGY, L"
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Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independently of pathophysiological changes
BackgroundMyotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardiorespiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown.MethodsEleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12 weeks of cycling can recuperate clinical and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients.RESULTSDM1 was associated with impaired muscle function, fitness, and lung capacity. Cycling evoked several clinical, physical, and metabolic advantages in DM1 patients. We highlight that exercise-induced molecular and cellular alterations in patients do not conform with previously published data in murine models and propose a significant role of mitochondrial function in DM1 pathology. Finally, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity.ConclusionWith no available cures, our data support the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1. Additionally, we provide evidence for the involvement of snoRNAs and other noncoding RNAs in DM1 pathophysiology.Trial registrationThis trial was approved by the HiREB committee (no. 7901) and registered under ClinicalTrials.gov (NCT04187482).FundingNeil and Leanne Petroff. Canadian Institutes of Health Research Foundation (no. 143325).
Journal Article
Real-time observation of cation exchange kinetics and dynamics at the muscovite-water interface
Ion exchange at charged solid–liquid interfaces is central to a broad range of chemical and transport phenomena. Real-time observations of adsorption/desorption at the molecular-scale elucidate exchange reaction pathways. Here we report temporal variation in the distribution of Rb
+
species at the muscovite (001)–water interface during exchange with Na
+
. Time-resolved resonant anomalous X-ray reflectivity measurements at 25 °C reveal that Rb
+
desorption occurs over several tens of seconds during which thermodynamically stable inner-sphere Rb
+
slowly transforms to a less stable outer-sphere Rb
+
. In contrast, Rb
+
adsorption is about twice as fast, proceeding from Rb
+
in the bulk solution to the stable inner-sphere species. The Arrhenius plot of the adsorption/desorption rate constants measured from 9 to 55 °C shows that the pre-exponential factor for desorption is significantly smaller than that for adsorption, indicating that this reduced attempt frequency of cation detachment largely explains the slow cation exchange processes at the interface.
Ion exchange at charged mineral-water interfaces is an important geochemical process, but a molecular-level understanding is still required. Here, the authors probe real-time variations of the interfacial ion exchange dynamics at the muscovite-water interface, providing a general picture of adsorbed ion coverage and speciation.
Journal Article
The surface modification of the silica-coated magnetic nanoparticles and their application in molecular diagnostics of virus infection
The study presents a series of examples of magnetic nanoparticle systems designed for the diagnosis of viral diseases. In this interdisciplinary work, we describe one of the most comprehensive synthetic approaches for the preparation and functionalization of smart nanoparticle systems for rapid and effective RT-PCR diagnostics and isolation of viral RNA. Twelve different organic ligands and inorganic porous silica were used for surface functionalization of the Fe
3
O
4
magnetic core to increase the number of active centres for efficient RNA binding from human swab samples. Different nanoparticle systems with common beads were characterized by HRTEM, SEM, FT-IR, XRD, XPS and magnetic measurements. We demonstrate the application of the fundamental models modified to fit the experimental zero-field cooling magnetization data. We discuss the influence of the nanoparticle shell parameters (morphology, thickness, ligands) on the overall magnetic performance of the systems. The prepared nanoparticles were tested for the isolation of viral RNA from tissue samples infected with hepatitis E virus—HEV and from biofluid samples of SARS-CoV-2 positive patients. The efficiency of RNA isolation was quantified by RT-qPCR method.
Journal Article
Effect of obesity on postoperative complications in ulcerative colitis: A systematic review and meta‐analysis
Background The prevalence of ulcerative colitis (UC) is around 200/100 000 people. Colectomy is required in 7.5%–40% of patients and 58.8%–94% of these operations are elective. Approximately one in two adults with UC are overweight or obese. Objective Our aim was to compare postoperative complications between obese (defined by a body mass index (BMI) over 30 kg/m2) and non‐obese UC patients who underwent total proctocolectomy with ileal pouch‐anal anastomosis (IPAA). Methods Our preregistered protocol can be found on PROSPERO (CRD42022377761). We conducted our search in three databases on the 26th of November 2022. PRISMA 2020 guideline and the Cochrane Handbook were applied. We used the GRADEpro program and the QUIPS tool. We applied a random‐effects model to pool effect sizes. We included cohort and case–control studies investigating UC patients undergoing colectomy with IPAA and reported information on postoperative complications in obese and non‐obese patients. We used mean difference (MD) for continuous variables and calculated odds ratio (OR) with a 95% confidence interval (CI) for dichotomous variables. Results Of the 6870 hits of our systematic search, we included three retrospective cohort studies for analyses involving 4929 patients in our research. Neither the incidence of complications at 30 days after surgery [OR = 1.08; CI: 0.65–1.79] nor the incidence of septic complications [OR = 1.11; CI: 0.85–1.46] had any clinical relevance, except for the length of hospital stay [MD = 0.36; CI:0.04–0.69]. When we assessed the risk of bias, we found that most of the aspects examined had a moderate overall risk. Our results have very low certainty of evidence. Conclusions and Relevance Our findings suggest that obesity defined as BMI over 30 kg/m2 may not associated with an increased risk of higher rates of overall postoperative complications compared to non‐obese patients. Obesity with a cut‐off value of 30 kg/m2 does not appear to be a primary reason for prehabilitation. Our findings from 4929 UC patients suggest that obese patients probably do not differ to a clinically relevant extent from the non‐obese population in the development of postoperative complications following IPAA surgery. Obesity with a cut‐off value of 30 kg/m2 does not appear to be a primary reason for prehabilitation.
Journal Article
Neutrophils actively swell to potentiate rapid migration
While the involvement of actin polymerization in cell migration is well-established, much less is known about the role of transmembrane water flow in cell motility. Here, we investigate the role of water influx in a prototypical migrating cell, the neutrophil, which undergoes rapid, directed movement to sites of injury, and infection. Chemoattractant exposure both increases cell volume and potentiates migration, but the causal link between these processes are not known. We combine single-cell volume measurements and a genome-wide CRISPR screen to identify the regulators of chemoattractant-induced neutrophil swelling, including NHE1, AE2, PI3K-gamma, and CA2. Through NHE1 inhibition in primary human neutrophils, we show that cell swelling is both necessary and sufficient for the potentiation of migration following chemoattractant stimulation. Our data demonstrate that chemoattractant-driven cell swelling complements cytoskeletal rearrangements to enhance migration speed.
Journal Article
Cell confinement reveals a branched-actin independent circuit for neutrophil polarity
Migratory cells use distinct motility modes to navigate different microenvironments, but it is unclear whether these modes rely on the same core set of polarity components. To investigate this, we disrupted actin-related protein 2/3 (Arp2/3) and the WASP-family verprolin homologous protein (WAVE) complex, which assemble branched actin networks that are essential for neutrophil polarity and motility in standard adherent conditions. Surprisingly, confinement rescues polarity and movement of neutrophils lacking these components, revealing a processive bleb-based protrusion program that is mechanistically distinct from the branched actin-based protrusion program but shares some of the same core components and underlying molecular logic. We further find that the restriction of protrusion growth to one site does not always respond to membrane tension directly, as previously thought, but may rely on closely linked properties such as local membrane curvature. Our work reveals a hidden circuit for neutrophil polarity and indicates that cells have distinct molecular mechanisms for polarization that dominate in different microenvironments.
Journal Article
Development Process of TGDI SI Engine Combustion Simulation Model Using Ethanol–Gasoline Blends as Fuel
The Fit for 55 package introduced by the European Union aims to achieve a 55% reduction in greenhouse gas emissions by 2030. In parallel, increasingly stringent exhaust gas regulations have intensified research into alternative fuels. Ethanol presents a promising option due to its compatibility with gasoline, higher octane rating, and lower exhaust emissions compared to conventional gasoline. Additionally, ethanol can be derived from agricultural waste, further enhancing its sustainability. This study examines the impact of two ethanol–gasoline blends (E10, E20) on emissions and performance in a turbocharged gasoline direct injection (TGDI) spark-ignition (SI) engine. The investigation is conducted using three-dimensional computational fluid dynamics (3D CFD) simulations to minimize development time and costs. This paper details the model development process and presents the initial results. The boundary conditions for the simulations are derived from one-dimensional (1D) simulations, which have been validated against experimental data. Subsequently, the simulated performance and emissions results are compared with experimental measurements. The E10 simulations correlated well with experimental measurements, with the largest deviation in cylinder pressure being an RMSE of 1.42. In terms of emissions, HC was underpredicted, while CO was overpredicted compared to the experimental data. For E20, the IMEP was slightly higher at some operating points; however, the deviations were negligible. Regarding emissions, HC and CO emissions were higher with E20, whereas NOx and CO2 emissions were lower.
Journal Article
Synthesis of millimeter-scale ZIF-8 single crystals and their reversible crystal structure changes
Among various metal-organic frameworks (MOFs), the zeolitic imidazole framework (ZIF), constructed by the regular arrangement of 2-methylimidazole and metal ions, has garnered significant attention due to its distinctive crystals and pore structures. Variations in the sizes and shapes of ZIF crystals have been reported by changing the synthesis parameters, such as the molar ratios of organic ligands to metal ions, choice of solvents, and temperatures. Nonetheless, the giant ZIF-8 single crystals beyond the typical range have rarely been reported. Herein, we present the synthesis of millimeter-scale single crystal ZIF-8 using the solvothermal method in N,N-diethylformamide. The resulting 1-mm single crystal is carefully characterized through N
adsorption-desorption isotherms, scanning electron microscopy, and other analytical techniques. Additionally, single-crystal X-ray diffraction is employed to comprehensively investigate the framework's mobility at various temperatures.
Journal Article
Cost-effectiveness of childhood influenza vaccination in England and Wales: Results from a dynamic transmission model
► The economics of vaccinate pre-school age children and/or school age children was assessed. ► Vaccinating 2–18 year olds was estimated to be the most cost-effective policy. ► The mean ICER for this policy was estimated at £251/QALY relative to current practice. ► Paediatric vaccination would appear to be a highly cost-effective intervention.
This study uses a dynamic influenza transmission model to directly compare the cost-effectiveness of various policies of annual paediatric influenza vaccination in England and Wales, varying the target age range and level of coverage. The model accounts for both the protection of those immunised and the indirect protection of the rest of the population via herd immunity. The impact of augmenting current practice with a policy to vaccinate pre-school age children, on their own or with school age children, was assessed in terms of quality adjusted life years and health service costs. Vaccinating 2–18 year olds was estimated to be the most cost-effective policy in an incremental cost-effectiveness analysis, at an assumed annual vaccine uptake rate of 50%. The mean incremental cost-effectiveness ratios for this policy was estimated at £251/QALY relative to current practice. Paediatric vaccination would appear to be a highly cost-effective intervention that directly protects those targeted for vaccination, with indirect protection extending to both the very young and the elderly.
Journal Article