Recovery from acidosis is a robust trigger for loss of force in murine hypokalemic periodic paralysis.

Periodic paralysis is an ion channelopathy of skeletal muscle in which recurrent episodes of weakness or paralysis are caused by sustained depolarization of the resting potential and thus reduction of fiber excitability. Episodes are often triggered by environmental stresses, such as changes in extracellular K+, cooling, or exercise. Rest after vigorous exercise is the most common trigger for weakness in periodic paralysis, but the mechanism is unknown. Here, we use knock-in mutant mouse models of hypokalemic periodic paralysis (HypoKPP; NaV1.4-R669H or CaV1.1-R528H) and hyperkalemic periodic paralysis (HyperKPP; NaV1.4-M1592V) to investigate whether the coupling between pH and susceptibility to loss of muscle force is a possible contributor to exercise-induced weakness. In both mouse models, acidosis (pH 6.7 in 25% CO2) is mildly protective, but a return to pH 7.4 (5% CO2) unexpectedly elicits a robust loss of force in HypoKPP but not HyperKPP muscle. Prolonged exposure to low pH (tens of minutes) is required to cause susceptibility to post-acidosis loss of force, and the force decrement can be prevented by maneuvers that impede Cl- entry. Based on these data, we propose a mechanism for post-acidosis loss of force wherein the reduced Cl- conductance in acidosis leads to a slow accumulation of myoplasmic Cl- A rapid recovery of both pH and Cl- conductance, in the context of increased [Cl]in/[Cl]out, favors the anomalously depolarized state of the bistable resting potential in HypoKPP muscle, which reduces fiber excitability. This mechanism is consistent with the delayed onset of exercise-induced weakness that occurs with rest after vigorous activity

The effect of stress on the neuropathogenesis of Theiler's virus-induced demyelination as an animal model of multiple sclerosis

Stressful life events have been associated with the onset and/or exacerbation of multiple sclerosis (MS). To investigate the effects of stress on the pathogenesis of MS, we employed restraint stress (RST) in the TheilerâÂÂs virus-induced demyelination (TVID) model, an animal model for human MS. Intracerebral inoculation of susceptible strain of mice with TheilerâÂÂs murine encephalomyelitis virus (TMEV) results in a biphasic disease â an acute encephalomyelitis and chronic demyelination. The establishment of persistent viral infection is critical in inducing immune-mediated demyelination during the chronic disease. The exposure of mice to RST prior to viral infection produced a stress response as evidenced by elevated circulating corticosterone (CORT). To further study the effect of stress on the immune response to TMEV infection and demyelination, we first examined the cytokine and chemokine response during the acute TMEV infection. We demonstrated that RST down-regulated the virus-induced expression of chemokines, Ltn, IP-10, RANTES, and pro-inflammatory cytokines, TNF, IFN and LT in both the brain and spleen during early infection. Histologically, a decreased pattern of inflammation was observed in the brain of restrained mice as compared to non-restrained mice. The increased viral titer was noted in the CNS of restrained mice and was correlated with the decreased production of pro-inflammatory cytokine, suggesting an impaired immune response by RST. Secondly, the duration of stress on the late demyelination was investigated. Repeated and chronically stressed SJL/J mice developed an early onset of clinical signs and a delayed onset was observed in acutely stressed mice. Both acute and chronic RST suppressed the antibody response to TMEV and stressed displayed a higher incidence of demyelination than non-restrained mice. Axonal loss was also noted in chronic stressed mice. Additionally, RST caused an increased systemic viral infection in extraneural organs during the acute infection and cardiotropic TMEV was isolated from the heart of stressed mice. Taken together, stress resulted in profound immunsuppression during acute infection, which may consequently increase the incidence of demyelination. The present study may be generalized in human MS which is potentially triggered by viral infection

Ultrasound cavitation induced nucleation in metal solidification: an analytical model and validation by real-time experiments

Microstructural refinement of metallic alloys via ultrasonic melt processing (USMP) is an environmentally friendly and promising method. However, so far there has been no report in open literature on how to predict the solidified microstructures and grain size based on the ultrasound processing parameters.In this paper, an analytical model is developed to calculate the cavitation enhanced undercooling and the USMP refined solidification microstructure and grain size for Al-Cu alloys. Ultrafast synchrotron X-ray imaging and tomography techniques were used to collect the real-time experimental data for validating the model and the calculated results. The comparison between modeling and experiments reveal that there exists an effective ultrasound input power intensity for maximizing the grain refinement effects for the Al-Cu alloys, which is in the range of 20-45 MW/m2. In addition, a monotonous increase in temperature during USMP has negative effect on producing new nuclei, deteriorating the benefit of microstructure refinement due to the application of ultrasound

Whole-genome transcription and DNA methylation analysis of peripheral blood mononuclear cells identified aberrant gene regulation pathways in systemic lupus erythematosus

Hypermethylated CpG sites in PBMC of SLE patients comparing normal controls by genome-wide DNA methylation analysis. Three group comparisons, SLE LN+ vs. NC (S3-1), SLE LN− vs. NC (S3-2), and SLE (LN− and LN+) vs. NC (S3-3), were performed to identify hypermethylated DNA CpG sites by fold change (FC) > 1.2 and q value < 5% within each group. The 1813 common hypermethylated sites identified in each of the three group comparisons were then selected and listed in S3-4. (XLSX 814 kb

Long-term BMI change trajectories in Chinese adults and its association with the hazard of type 2 diabetes: evidence from a 20-year China Health and Nutrition Survey.

INTRODUCTION To investigate the relationship between long-term change trajectory in body mass index (BMI) and the hazard of type 2 diabetes among Chinese adults. RESEARCH DESIGN AND METHODS Data were obtained from the China Health and Nutrition Survey (CHNS). Type 2 diabetes was reported by participants themselves in each survey wave. The duration of follow-up was defined as the period from the first visit to the first time self-reported type 2 diabetes, death, or other loss to follow-up from CHNS. The patterns of change trajectories in BMI were derived by latent class trajectory analysis method. The Fine and Gray regression model was used to estimate HRs with corresponding 95% CIs for type 2 diabetes. RESULTS Four patterns of the trajectories of change in BMI were identified among Chinese adults, 42.7% of participants had stable BMI change, 40.8% for moderate BMI gain, 8.9% for substantial BMI gain and 7.7% for weight loss. During the follow-up with mean 11.2 years (158 637 person-years contributed by 14 185 participants), 498 people with type 2 diabetes (3.7%) occurred. Risk of type 2 diabetes was increased by 47% among people who gained BMI more substantially and rapidly (HR: 1.47, 95% CI 1.08 to 2.02, p=0.016) and increased by 20% among those in people with the moderate BMI gain (HR: 1.20, 95% CI 0.98 to 1.48, p=0.078), compared with those with stable BMI change. CONCLUSIONS Long-term substantial gain of BMI was significantly associated with an increased risk of type 2 diabetes in the Chinese adults

A radiative cooling structural material.

Reducing human reliance on energy-inefficient cooling methods such as air conditioning would have a large impact on the global energy landscape. By a process of complete delignification and densification of wood, we developed a structural material with a mechanical strength of 404.3 megapascals, more than eight times that of natural wood. The cellulose nanofibers in our engineered material backscatter solar radiation and emit strongly in mid-infrared wavelengths, resulting in continuous subambient cooling during both day and night. We model the potential impact of our cooling wood and find energy savings between 20 and 60%, which is most pronounced in hot and dry climates