Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: Therapeutic implications for topical treatment of these disorders

Molecular geneticists tend to conceptualize disease pathogenesis from the mutated gene outward, an approach that does not take into account the impact of barrier requirements in determining disease phenotype. An ‘outside-to-inside’ perspective has provided quite different explanations for the ichthyoses, including several of the disorders of distal cholesterol metabolism. Elucidation of responsible pathogenic mechanisms also is pointing to appropriate, pathogenesis (pathway)-based therapeutic strategies. In the case of the lipid metabolic disorders, it takes full advantage of new molecular, genetic and cellular pathogenesis information to correct or bypass the metabolic abnormality. This approach fully exploits the unique accessibility of the skin to a topical approach. Moreover, since it will utilize topical lipids and lipid-soluble, and often generic, lipid-soluble drugs, these treatments should be readily transported across the stratum corneum. If successful, this approach could initiate an entirely new departure for the therapy of the ichthyoses. Finally, because these agents are relatively safe and inexpensive, this form of treatment has the potential to be widely-deployed, even in the developing world

Financing institutional long-term care for the elderly in China: a policy evaluation of new models

A rapid ageing population coupled with changes in family structure has brought about profound implications to social policy in China. Although the past decade has seen a steady increase in public funding to long-term care (LTC), the narrow financing base and vast population have created significant unmet demand, calling for reforms in financing. This paper focuses on the financing of institutional LTC care by examining new models that have emerged from local policy experiments against two policy goals: equity and efficiency. Three emerging models are explored: Social Health Insurance (SHI) in Shanghai, LTC Nursing Insurance (LTCNI) in Qingdao and a means-tested model in Nanjing. A focused systematic narrative review of academic and grey literature is conducted to identify and assess these models, supplemented with qualitative interviews with government officials from relevant departments, care home staff and service users. This paper argues that, although SHI appears to be a convenient solution to fund LTC, this model has led to systematic bias in affordable access among participants of different insurance schemes, and has created a powerful incentive for the over-provision of unnecessary services. The means-tested method has been remarkably constrained by narrow eligibility and insufficiency of funding resources. The LTCNI model is by far the most desirable policy option among the three studied here, but the narrow definition of eligibility has substantively excluded a large proportion of elders in need from access to care, which needs to be addressed in future reforms. This paper proposes three lines of LTC financing reforms for policy-makers: (1) the establishment of a prepaid financing mechanism pooled specifically for LTC costs; (2) the incorporation of more stringent eligibility rules and needs assessment; and (3) reforming the dominant fee-for-service methods in paying LTC service providers

RG running in a minimal UED model in light of recent LHC Higgs mass bounds

We study how the recent ATLAS and CMS Higgs mass bounds affect the renormalization group running of the physical parameters in universal extra dimensions. Using the running of the Higgs self-coupling constant, we derive bounds on the cutoff scale of the extra-dimensional theory itself. We show that the running of physical parameters, such as the fermion masses and the CKM mixing matrix, is significantly restricted by these bounds. In particular, we find that the running of the gauge couplings cannot be sufficient to allow gauge unification at the cutoff scale.Comment: 16 pages, 6 figures, RevTeX4. Final version published in Phys. Lett.

Expression profiling of hypothetical genes in Desulfovibrio vulgaris leads to improved functional annotation

Hypothetical (HyP) and conserved HyP genes account for >30% of sequenced bacterial genomes. For the sulfate-reducing bacterium Desulfovibrio vulgaris Hildenborough, 347 of the 3634 genes were annotated as conserved HyP (9.5%) along with 887 HyP genes (24.4%). Given the large fraction of the genome, it is plausible that some of these genes serve critical cellular roles. The study goals were to determine which genes were expressed and provide a more functionally based annotation. To accomplish this, expression profiles of 1234 HyP and conserved genes were used from transcriptomic datasets of 11 environmental stresses, complemented with shotgun LC–MS/MS and AMT tag proteomic data. Genes were divided into putatively polycistronic operons and those predicted to be monocistronic, then classified by basal expression levels and grouped according to changes in expression for one or multiple stresses. One thousand two hundred and twelve of these genes were transcribed with 786 producing detectable proteins. There was no evidence for expression of 17 predicted genes. Except for the latter, monocistronic gene annotation was expanded using the above criteria along with matching Clusters of Orthologous Groups. Polycistronic genes were annotated in the same manner with inferences from their proximity to more confidently annotated genes. Two targeted deletion mutants were used as test cases to determine the relevance of the inferred functional annotations

Impact of massive neutrinos on the Higgs self-coupling and electroweak vacuum stability

The presence of right-handed neutrinos in the type I seesaw mechanism may lead to significant corrections to the RG evolution of the Higgs self-coupling. Compared to the Standard Model case, the Higgs mass window can become narrower, and the cutoff scale become lower. Naively, these effects decrease with decreasing right-handed neutrino mass. However, we point out that the unknown Dirac Yukawa matrix may impact the vacuum stability constraints even in the low scale seesaw case not far away from the electroweak scale, hence much below the canonical seesaw scale of 10^15 GeV. This includes situations in which production of right-handed neutrinos at colliders is possible. We illustrate this within a particular parametrization of the Dirac Yukawas and with explicit low scale seesaw models. We also note the effect of massive neutrinos on the top quark Yukawa coupling, whose high energy value can be increased with respect to the Standard Model case.Comment: 17 pages, 7 figures, minor revisions, version to appear in JHE

Strain- and Adsorption-Dependent Electronic States and Transport or Localization in Graphene

The chapter generalizes results on influence of uniaxial strain and adsorption on the electron states and charge transport or localization in graphene with different configurations of imperfections (point defects): resonant (neutral) adsorbed atoms either oxygen- or hydrogen-containing molecules or functional groups, vacancies or substitutional atoms, charged impurity atoms or molecules, and distortions. To observe electronic properties of graphene-admolecules system, we applied electron paramagnetic resonance technique in a broad temperature range for graphene oxides as a good basis for understanding the electrotransport properties of other active carbons. Applied technique allowed observation of possible metal-insulator transition and sorption pumping effect as well as discussion of results in relation to the granular metal model. The electronic and transport properties are calculated within the framework of the tight-binding model along with the Kubo-Greenwood quantum-mechanical formalism. Depending on electron density and type of the sites, the conductivity for correlated and ordered adsorbates is found to be enhanced in dozens of times as compared to the cases of their random distribution. In case of the uniaxially strained graphene, the presence of point defects counteracts against or contributes to the band-gap opening according to their configurations. The band-gap behaviour is found to be nonmonotonic with strain in case of a simultaneous action of defect ordering and zigzag deformation. The amount of localized charge carriers (spins) is found to be correlated with the content of adsorbed centres responsible for the formation of potential barriers and, in turn, for the localization effects. Physical and chemical states of graphene edges, especially at a uniaxial strain along one of them, play a crucial role in electrical transport phenomena in graphene-based materials.Comment: 16 pages, 10 figure

Impact of Age and Body Site on Adult Female Skin Surface pH

Background: pH is known as an important parameter in epidermal barrier function and homeostasis. Aim: The impact of age and body site on skin surface pH (pH(SS)) of women was evaluated in vivo. Methods: Time domain dual lifetime referencing with luminescent sensor foils was used for pH(SS) measurements. pH(SS) was measured on the forehead, the temple, and the volar forearm of adult females (n = 97, 52.87 +/- 18.58 years, 20-97 years). Every single measurement contained 2,500 pH values due to the luminescence imaging technique used. Results: pH(SS) slightly increases with age on all three investigated body sites. There are no significant differences in pH(SS) between the three investigated body sites. Conclusion: Adult pH(SS) on the forehead, the temple and the volar forearm increases slightly with age. This knowledge is crucial for adapting medical skin care products. Copyright (C) 2012 S. Karger AG, Base

Fetal Epidermal Differentiation and Barrier Development In Vivo is Accelerated by Nuclear Hormone Receptor Activators1

Nuclear receptors which interact with the retinoid X receptor are involved in the regulation of epidermal differentiation and development. We have recently shown that activators of the peroxisome proliferator-activated receptor and of the farnesoid X-activated receptor accelerate epidermal barrier maturation in fetal rat skin in vitro. In this study we asked whether cutaneous development in utero was affected by peroxisome proliferator-activated receptor or farnesoid X-activated receptor activators, or by an activator of another retinoid X receptor partner, liver X receptor. Activators of the peroxisome proliferator-activated receptor (clofibrate or linoleic acid), farnesoid X-activated receptor (farnesol or juvenile hormone III), or liver X receptor (22R-hydroxycholesterol), were injected into the amniotic fluid of fetal rats on gestational day 17. Fetal epidermal barrier function and morphology was assessed on day 19. Whereas vehicle-treated fetal rats displayed no measurable barrier (transepidermal water loss > 10 mg per cm2 per h), a measurable barrier was induced by the intra-amniotic administration of all activators tested (transepidermal water loss range 4.0–8.5 mg per cm2 per h). By light microscopy, control pups lacked a well-defined stratum corneum, whereas a distinct stratum corneum and a thickened stratum granulosum were present in treated pups. By electron microscopy, the extracellular spaces of the stratum corneum in control pups revealed a paucity of mature lamellar unit structures, whereas these structures filled the stratum corneum interstices in treated pups. Additionally, protein and mRNA levels of loricrin and filaggrin, two structural proteins of stratum corneum, were increased in treated epidermis, as were the activities of two lipid catabolic enzymes critical to stratum corneum function, β-glucocerebrosidase and steroid sulfatase. Finally, peroxisome proliferator-activated receptor-α and -δ and liver X receptor-α and -β mRNAs were detected in fetal epidermis by reverse transcriptase–polymerase chain reaction and northern analyses. The presence of these receptors and the ability of their activators to stimulate epidermal barrier and stratum corneum development suggest a physiologic role for peroxisome proliferator-activated receptor and liver X receptor and their endogenous ligands in the regulation of cutaneous development

The MALATANG Survey : The L GAS-L IR Correlation on Sub-kiloparsec Scale in Six Nearby Star-forming Galaxies as Traced by HCN J = 4 → 3 and HCO + J = 4 → 3

This is an author-created, un-copyedited version of an article published in The Astrophysical Journal. The Version of Record is available online at https://doi.org/10.3847/1538-4357/aac512.We present HCN J = 4→3 and HCO+ J = 4→3 maps of six nearby star-forming galaxies, NGC 253, NGC 1068, IC 342, M82, M83, and NGC 6946, obtained with the James Clerk Maxwell Telescope as part of the MALATANG survey. All galaxies were mapped in the central 2×2 region at 14 (FWHM) resolution (corresponding to linear scales of ∼0.2-1.0 kpc). The LIR-Ldense relation, where the dense gas is traced by the HCN J = 4→3 and the HCO+ J = 4→3 emission, measured in our sample of spatially resolved galaxies is found to follow the linear correlation established globally in galaxies within the scatter. We find that the luminosity ratio, LIR/Ldense, shows systematic variations with LIR within individual spatially resolved galaxies, whereas the galaxy-integrated ratios vary little. A rising trend is also found between LIR/Ldense ratio and the warm-dust temperature gauged by the 70 μm/100 μm flux ratio. We find that the luminosity ratios of IR/HCN (4-3) and IR/HCO+ (4-3), which can be taken as a proxy for the star formation efficiency (SFE) in the dense molecular gas (SFE dense), appear to be nearly independent of the dense gas fraction ( f dense) for our sample of galaxies. The SFE of the total molecular gas (SFEmol) is found to increase substantially with f dense when combining our data with those on local (ultra)luminous infrared galaxies and high-z quasars. The mean LHCN(4-3) LHCO+(4-3) line ratio measured for the six targeted galaxies is 0.9±0.6. No significant correlation is found for the L'HCN(4-3) L'HCO+(4-3) ratio with the star formation rate as traced by L IR, nor with the warm-dust temperature, for the different populations of galaxies.Peer reviewe