Signal peptide peptidases and gamma-secretase: Cousins of the same protease family?

Signal peptide peptidase (SPIP) is an unusual aspartyl protease, which mediates clearance of signal peptides by proteolysis within the endoplasmic reticulum (ER). Like presenilins, which provide the proteolytically active subunit of the,gamma-secretase complex, SPP contains a conserved GxGD motif in its C-terminal domain which is critical for its activity. While SPIP is known to be an aspartyl protease of the GxGD type, several presenilin homologues/SPP-like proteins (PSHs/ SPPL) of unknown function have been identified by database searches. In contrast to SPP and SPPL3, which are both restricted to the endoplasmic reticulum, SPPL2b is targeted through the secretory pathway to endosomes/lysosomes. As suggested by the differential subcellular localization of SPPL2b and SPPL3 distinct phenotypes were found upon antisense gripNA-mediated knockdown in zebrafish. spp and sppl3 knockdowns in zebrafish result in cell death within the central nervous system, whereas reduction of sppl2b expression causes erythrocyte accumulation in an enlarged caudal vein. Moreover, expression of D/A mutants of the putative C-terminal active sites of spp, sppl2, and spp13 produced phenocopies of the respective knockdown phenotypes. These data suggest that all investigated PSHs/SPPLs are members of the novel family of GxGD aspartyl proteases. More recently, it was shown that SPPL2b utilizes multiple intramembrane cleavages to liberate the TNF(x intracellular domain into the cytosol and to release the C-terminal counterpart into the lumen. These findings suggest common principles of intramembrane proteolysis by GxGD type aspartyl proteases. In this article,we will review the similarities of SPPs and gamma-secretase based on recent findings by us and others

The opioid epidemic in rural northern New England: An approach to epidemiologic, policy, and legal surveillance

The opioid crisis presents substantial challenges to public health in New England\u27s rural states, where access to pharmacotherapy for opioid use disorder (OUD), harm reduction, HIV and hepatitis C virus (HCV) services vary widely. We present an approach to characterizing the epidemiology, policy and resource environment for OUD and its consequences, with a focus on eleven rural counties in Massachusetts, New Hampshire and Vermont between 2014 and 2018. We developed health policy summaries and logic models to facilitate comparison of opioid epidemic-related polices across the three states that could influence the risk environment and access to services. We assessed sociodemographic factors, rates of overdose and infectious complications tied to OUD, and drive-time access to prevention and treatment resources. We developed GIS maps and conducted spatial analyses to assess the opioid crisis landscape. Through collaborative research, we assessed the potential impact of available resources to address the opioid crisis in rural New England. Vermont\u27s comprehensive set of policies and practices for drug treatment and harm reduction appeared to be associated with the lowest fatal overdose rates. Franklin County, Massachusetts had good access to naloxone, drug treatment and SSPs, but relatively high overdose and HIV rates. New Hampshire had high proportions of uninsured community members, the highest overdose rates, no HCV surveillance data, and no local access to SSPs. This combination of factors appeared to place PWID in rural New Hampshire at elevated risk. Study results facilitated the development of vulnerability indicators, identification of locales for subsequent data collection, and public health interventions

Characteristic Energy of the Coulomb Interactions and the Pileup of States

Tunneling data on $\mathrm{La_{1.28}Sr_{1.72}Mn_2O_7}$ crystals confirm Coulomb interaction effects through the $\sqrt{\mathrm{E}}$ dependence of the density of states. Importantly, the data and analysis at high energy, E, show a pileup of states: most of the states removed from near the Fermi level are found between ~40 and 130 meV, from which we infer the possibility of universal behavior. The agreement of our tunneling data with recent photoemission results further confirms our analysis.Comment: 4 pages, 4 figures, submitted to PR

Nuclear Ground State Observables and QCD Scaling in a Refined Relativistic Point Coupling Model

We present results obtained in the calculation of nuclear ground state properties in relativistic Hartree approximation using a Lagrangian whose QCD-scaled coupling constants are all natural (dimensionless and of order 1). Our model consists of four-, six-, and eight-fermion point couplings (contact interactions) together with derivative terms representing, respectively, two-, three-, and four-body forces and the finite ranges of the corresponding mesonic interactions. The coupling constants have been determined in a self-consistent procedure that solves the model equations for representative nuclei simultaneously in a generalized nonlinear least-squares adjustment algorithm. The extracted coupling constants allow us to predict ground state properties of a much larger set of even-even nuclei to good accuracy. The fact that the extracted coupling constants are all natural leads to the conclusion that QCD scaling and chiral symmetry apply to finite nuclei.Comment: 44 pages, 13 figures, 9 tables, REVTEX, accepted for publication in Phys. Rev.

Fluids in cosmology

We review the role of fluids in cosmology by first introducing them in General Relativity and then by applying them to a FRW Universe's model. We describe how relativistic and non-relativistic components evolve in the background dynamics. We also introduce scalar fields to show that they are able to yield an inflationary dynamics at very early times (inflation) and late times (quintessence). Then, we proceed to study the thermodynamical properties of the fluids and, lastly, its perturbed kinematics. We make emphasis in the constrictions of parameters by recent cosmological probes.Comment: 34 pages, 4 figures, version accepted as invited review to the book "Computational and Experimental Fluid Mechanics with Applications to Physics, Engineering and the Environment". Version 2: typos corrected and references expande

Product-Group Unification in Type IIB String Thoery

The product-group unification is a model of unified theories, in which masslessness of the two Higgs doublets and absence of dimension-five proton decay are guaranteed by a symmetry. It is based on SU(5) x U(N) (N=2,3) gauge group. It is known that various features of the model are explained naturally, when it is embedded in a brane world. This article describes an idea of how to accommodate all the particles of the model in Type IIB brane world. The GUT-breaking sector is realized by a D3--D7 system, and chiral quarks and leptons arise from intersection of D7-branes. The D-brane configuration can be a geometric realization of the non-parallel family structure of quarks and leptons, an idea proposed to explain the large mixing angles observed in the neutrino oscillation. The tri-linear interaction of the next-to-minimal supersymmetric standard model is obtained naturally in some cases.Comment: 33 pages, 5 figure

Drug allergy

Drug allergy encompasses a spectrum of immunologically-mediated hypersensitivity reactions with varying mechanisms and clinical presentations. This type of adverse drug reaction (ADR) not only affects patient quality of life, but may also lead to delayed treatment, unnecessary investigations, and even mortality. Given the myriad of symptoms associated with the condition, diagnosis is often challenging. Therefore, referral to an allergist experienced in the identification, diagnosis and management of drug allergy is recommended if a drug-induced allergic reaction is suspected. Diagnosis relies on a careful history and physical examination. In some instances, skin testing, graded challenges and induction of drug tolerance procedures may be required

Stress from Uncertainty from Graduation to Retirement—A Population-Based Study of Swiss Physicians

BACKGROUND: Uncertainty shapes many decisions made by physicians everyday. Uncertainty and physicians’ inability to handle it may result in substandard care and unexplained variations in patterns of care. OBJECTIVE: To describe socio-demographic and professional characteristics of reactions to uncertainty among physicians from all specialties, including physicians in training. DESIGN: Cross-sectional postal survey. PARTICIPANT: All physicians practicing in Geneva, Switzerland (n = 1,994). MEASUREMENT: Reaction to medical care uncertainty was measured with the Anxiety Due to Uncertainty and Concern About Bad Outcomes scales. The questionnaire also included items about professional characteristics and work-related satisfaction scales. RESULTS: After the first mailing and two reminders, 1,184 physicians responded to the survey. In univariate analysis, women, junior physicians, surgical specialists, generalist physicians, and physicians with lower workloads had higher scores in both scales. In multivariate models, sex, medical specialty, and workload remained significantly associated with both scales, whereas clinical experience remained associated only with concern about bad outcomes. Higher levels of anxiety due to uncertainty were associated with lower scores of work-related satisfaction, while higher levels of concern about bad outcomes were associated with lower satisfaction scores for patient care, personal rewards, professional relations, and general satisfaction, but not for work-related burden or satisfaction with income-prestige. The negative effect of anxiety due to uncertainty on work-related satisfaction was more important for physicians in training. CONCLUSION: Physicians’ reactions to uncertainty in medical care were associated with several dimensions of work-related satisfaction. Physicians in training experienced the greatest impact of anxiety due to uncertainty on their work-related satisfaction. Incorporating strategies to deal with uncertainty into residency training may be useful

Hypolithic Microbial Community of Quartz Pavement in the High-Altitude Tundra of Central Tibet

The hypolithic microbial community associated with quartz pavement at a high-altitude tundra location in central Tibet is described. A small-scale ecological survey indicated that 36% of quartz rocks were colonized. Community profiling using terminal restriction fragment length polymorphism revealed no significant difference in community structure among a number of colonized rocks. Real-time quantitative PCR and phylogenetic analysis of environmental phylotypes obtained from clone libraries were used to elucidate community structure across all domains. The hypolithon was dominated by cyanobacterial phylotypes (73%) with relatively low frequencies of other bacterial phylotypes, largely represented by the chloroflexi, actinobacteria, and bacteriodetes. Unidentified crenarchaeal phylotypes accounted for 4% of recoverable phylotypes, while algae, fungi, and mosses were indicated by a small fraction of recoverable phylotypes