Bimolecular encounters and re-encounters (cage effect) of a spin-labeled analogue of cholestane in a series of n-alkanes: effect of anisotropic exchange integral.

Electron paramagnetic resonance (EPR) spectra of the nitroxide spin probe 3ß-doxyl-5α-cholestane (CSL) are studied as functions of the molar concentration, c, and the temperature, T, in a series of n-alkanes. The results are compared with a similar study of a much smaller spin probe, perdeuterated 2,2,6,6-tetramethyl-4-oxopiperidine-1-oxyl (pDT). The Heisenberg spin exchange (HSE) rate constants, K(ex), of CSL are similar in hexane, octane, and decane and are about one-half of those for pDT in the same solvents. They are also about one-half of the Stokes-Einstein-Perrin prediction. This reduction in HSE efficiency is attributed to an effective steric factor, f(eff), which was evaluated by comparing the results with the Stokes-Einstein-Perrin prediction or with pDT, and it is equal to 0.49 ± 0.03, independent of temperature. The unpaired spin density in CSL is localized near one end of the long molecule, so the exchange integral, J, leading to HSE, is expected to be large in some collisions and small in others; thus, J is modeled by an ideal distribution of values of J = J(0) with probability f and J = 0 with probability (1 - f). Because of rotational and translation diffusion during contact and between re-encounters of the probe, the effective steric factor is predicted to be f(eff) = f(1/2). Estimating the fraction of the surface of CSL with rich spin density yields a theoretical estimate of f(eff) = 0.59 ± 0.08, in satisfactory agreement with experiment. HSE is well described by simple hydrodynamic theory, with only a small dependence on solvent-probe relative sizes at the same value of T/η, where η is the viscosity of the solvent. This result is probably due to a fortuitous interplay between long- and short-range effects that describe diffusion processes over relatively large distances. In contrast, dipole-dipole interactions (DD) as measured by the line broadening, B(dip), and the mean time between re-encounters within the cage, τ(RE), vary significantly with the solvent-probe size ratio at the same value of T/η. For these phenomena, dominated by short-range diffusion, the reciprocal fractional free volume V(0)/V(f) provides a better description of the diffusion. Thus, B(dip) and τ(RE) form common curves when plotted vs V(0)/V(f). As a result, the fractional broadening by DD occurs at an order of magnitude higher values of T/η for CSL compared with pDT.

Prevalence and domains of disability within and outside Appalachian North Carolina: 2013-2016 Behavioral Risk Factor Surveillance System.

BACKGROUND: The health and social conditions of the Appalachian region generally are poorer than in the US overall, and this gap is widening, suggesting disability may be higher in Appalachia. OBJECTIVE: To describe the prevalence of disability overall and by domain in Appalachian and non-Appalachian regions in North Carolina (NC) and describe the characteristics of people with and without disability in each region. METHODS: We conducted a cross-sectional study using data from the NC Behavioral Risk Factor Surveillance System from 2013 to 2016 which assessed disability in five domains: vision, cognitive, mobility, self-care, and independent living. We calculated weighted proportions and age- and sex-adjusted prevalence using direct standardization to the 2010 Census. RESULTS: The prevalence of disability in Appalachian NC was significantly higher than in non-Appalachian NC after standardizing by age and sex (26.6% in Appalachia, 24.1% outside Appalachia, p < 0.001). In both regions, mobility disability was most common and self-care disability was least common. People within Appalachia more frequently reported disability in all domains compared to people outside Appalachia. CONCLUSIONS: More than one in four adults in Appalachian North Carolina experience disability in at least one domain and one in eight experiences disability in multiple domains. The high prevalence of disability should be considered when planning programs and services across the spectrum of public health. Understanding common disability domains present in populations can inform public health agencies and service providers and help them develop programs and messaging that meet the needs of residents in Appalachia and are accessible to people with disabilities.

Oncogenic Rag GTPase signaling enhances B cell activation and drives follicular lymphoma sensitive to pharmacological inhibition of mTOR.

The humoral immune response demands that B cells undergo a sudden anabolic shift and high cellular nutrient levels which are required to sustain the subsequent proliferative burst. Follicular lymphoma (FL) originates from B cells that have participated in the humoral response, and 15% of FL samples harbor point, activating mutations in RRAGC, an essential activator of mTORC1 downstream of the sensing of cellular nutrients. The impact of recurrent RRAGC mutations in B cell function and lymphoma is unexplored. RRAGC mutations, targeted to the endogenous locus in mice, confer a partial insensitivity to nutrient deprivation, but strongly exacerbate B cell responses and accelerate lymphomagenesis, while creating a selective vulnerability to pharmacological inhibition of mTORC1. This moderate increase in nutrient signaling synergizes with paracrine cues from the supportive T cell microenvironment that activates B cells via the PI3K-Akt-mTORC1 axis. Hence, Rragc mutations sustain induced germinal centers and murine and human FL in the presence of decreased T cell help. Our results support a model in which activating mutations in the nutrient signaling pathway foster lymphomagenesis by corrupting a nutrient-dependent control over paracrine signals from the T cell microenvironment.