Neutrino and axion bounds from the globular cluster M5 (NGC 5904)

The red-giant branch (RGB) in globular clusters is extended to larger brightness if the degenerate helium core loses too much energy in "dark channels." Based on a large set of archival observations, we provide high-precision photometry for the Galactic globular cluster M5 (NGC 5904), allowing for a detailed comparison between the observed tip of the RGB with predictions based on contemporary stellar evolution theory. In particular, we derive 95% confidence limits of $g_{ae}<4.3\times10^{-13}$ on the axion-electron coupling and $\mu_\nu<4.5\times10^{-12}\,\mu_{\rm B}$ (Bohr magneton $\mu_{\rm B}=e/2m_e$) on a neutrino dipole moment, based on a detailed analysis of statistical and systematic uncertainties. The cluster distance is the single largest source of uncertainty and can be improved in the future.Comment: 5 pages, 2 figures, accepted for publication in Physical Review Letter

Vortex fluidics-mediated DNA rescue from formalin-fixed museum specimens.

DNA from formalin-preserved tissue could unlock a vast repository of genetic information stored in museums worldwide. However, formaldehyde crosslinks proteins and DNA, and prevents ready amplification and DNA sequencing. Formaldehyde acylation also fragments the DNA. Treatment with proteinase K proteolyzes crosslinked proteins to rescue the DNA, though the process is quite slow. To reduce processing time and improve rescue efficiency, we applied the mechanical energy of a vortex fluidic device (VFD) to drive the catalytic activity of proteinase K and recover DNA from American lobster tissue (Homarus americanus) fixed in 3.7% formalin for &gt;1-year. A scan of VFD rotational speeds identified the optimal rotational speed for recovery of PCR-amplifiable DNA and while 500+ base pairs were sequenced, shorter read lengths were more consistently obtained. This VFD-based method also effectively recovered DNA from formalin-preserved samples. The results provide a roadmap for exploring DNA from millions of historical and even extinct species

Complete High Temperature Expansions for One-Loop Finite Temperature Effects

We develop exact, simple closed form expressions for partition functions associated with relativistic bosons and fermions in odd spatial dimensions. These expressions, valid at high temperature, include the effects of a non-trivial Polyakov loop and generalize well-known high temperature expansions. The key technical point is the proof of a set of Bessel function identities which resum low temperature expansions into high temperature expansions. The complete expressions for these partition functions can be used to obtain one-loop finite temperature contributions to effective potentials, and thus free energies and pressures.Comment: 9 pages, RevTeX, no figures. To be published in Phys. Rev D. v2 has revised introduction and conclusions, plus a few typographical errors are corrected; v3 corrects one typ

EXPRESSION OF A FUNCTIONAL CHIMERIC lg-MHC CLASS II PROTEIN

composed of the a- and ß-chains of the MHC class I1 I-E molecule fused to antibody V regions derived from anti-human CD4 mAb MT310. Expression vectors were constructed containing the functional, rearranged gene segments coding for the V region domains of the antibody H and L chains in place of the first domains of the complete structural genes of the I-E a- and ß-chains, respectively. Celltsr ansfected with both hybrid genes expressed a stable protein product on the cell surface. The chimeric molecule exhibited the idiotype of the antibody MT310 as shown by binding to the anti-idiotypic mAb 20-46. A protein of the anticipated molecular mass was immunoprecipitated witha nti-mouse IgG antiserum. Furthermore, human soluble CD4 did bind to thetr ansfected cell line, demonstrating that the chimeric protein possessed the binding capacity of the original mAb. Thus, the hybrid molecule retained: 1) the properties of a MHC class I1 protein with regardt o correct chain assembly and transport to the cell surface: as well as 2) the Ag binding capacity of the antibody genes used. Thgee neration of hybrid MHC class I1 molecules with highly specific, non-MHC-restricted bindingc apacities will be useful for studying MHC class 11-mediated effector functions such as selection of the T cell repertoire in thymus of transgenic mice

Fractional diffusion modeling of ion channel gating

An anomalous diffusion model for ion channel gating is put forward. This scheme is able to describe non-exponential, power-law like distributions of residence time intervals in several types of ion channels. Our method presents a generalization of the discrete diffusion model by Millhauser, Salpeter and Oswald [Proc. Natl. Acad. Sci. USA 85, 1503 (1988)] to the case of a continuous, anomalous slow conformational diffusion. The corresponding generalization is derived from a continuous time random walk composed of nearest neighbor jumps which in the scaling limit results in a fractional diffusion equation. The studied model contains three parameters only: the mean residence time, a characteristic time of conformational diffusion, and the index of subdiffusion. A tractable analytical expression for the characteristic function of the residence time distribution is obtained. In the limiting case of normal diffusion, our prior findings [Proc. Natl. Acad. Sci. USA 99, 3552 (2002)] are reproduced. Depending on the chosen parameters, the fractional diffusion model exhibits a very rich behavior of the residence time distribution with different characteristic time-regimes. Moreover, the corresponding autocorrelation function of conductance fluctuations displays nontrivial features. Our theoretical model is in good agreement with experimental data for large conductance potassium ion channels

Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib.

BackgroundEarly detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics.MethodsA nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death.ResultsPlasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk.ConclusionsHeretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264

Gene expression in Leishmania is regulated predominantly by gene dosage

ABSTRACT Leishmania tropica, a unicellular eukaryotic parasite present in North and East Africa, the Middle East, and the Indian subcontinent, has been linked to large outbreaks of cutaneous leishmaniasis in displaced populations in Iraq, Jordan, and Syria. Here, we report the genome sequence of this pathogen and 7,863 identified protein-coding genes, and we show that the majority of clinical isolates possess high levels of allelic diversity, genetic admixture, heterozygosity, and extensive aneuploidy. By utilizing paired genome-wide high-throughput DNA sequencing (DNA-seq) with RNA-seq, we found that gene dosage, at the level of individual genes or chromosomal “somy” (a general term covering disomy, trisomy, tetrasomy, etc.), accounted for greater than 85% of total gene expression variation in genes with a 2-fold or greater change in expression. High gene copy number variation (CNV) among membrane-bound transporters, a class of proteins previously implicated in drug resistance, was found for the most highly differentially expressed genes. Our results suggest that gene dosage is an adaptive trait that confers phenotypic plasticity among natural Leishmania populations by rapid down- or upregulation of transporter proteins to limit the effects of environmental stresses, such as drug selection. IMPORTANCE Leishmania is a genus of unicellular eukaryotic parasites that is responsible for a spectrum of human diseases that range from cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) to life-threatening visceral leishmaniasis (VL). Developmental and strain-specific gene expression is largely thought to be due to mRNA message stability or posttranscriptional regulatory networks for this species, whose genome is organized into polycistronic gene clusters in the absence of promoter-mediated regulation of transcription initiation of nuclear genes. Genetic hybridization has been demonstrated to yield dramatic structural genomic variation, but whether such changes in gene dosage impact gene expression has not been formally investigated. Here we show that the predominant mechanism determining transcript abundance differences (>85%) in Leishmania tropica is that of gene dosage at the level of individual genes or chromosomal somy

C and N Abundances in Stars At the Base of the Red Giant Branch in M5

We present an analysis of a large sample of moderate resolution Keck LRIS spectra of subgiant (V \sim 17.2) and fainter stars in the Galactic globular cluster M5 (NGC 5904) with the goal of deriving C and N abundances. Star-to-star stochastic variations with significant range in both [C/Fe] and [N/Fe] are found at all luminosities extending to the bottom of the RGB at M_V \sim +3. Similar variations in CH appear to be present in the main sequence turnoff spectra. There is no sign of a change in the behavior of C and N with evolutionary stage over the full range in luminosity of the RGB and SGB. The C and N abundances appear strongly anti-correlated, as would be expected from the CN-cycle processing of stellar material. Yet the present stars are considerably fainter than the RGB bump, the point at which deep mixing is believed to set in. On this basis, while the observed abundance pattern is consistent with proton capture nucleosynthesis, we infer that the site of the reactions is likely not within the present sample, but rather in a population of more massive (2 -- 5 M(Sun)) now defunct stars. The range of variation of the N abundances is very large and the sum of C+N increases as C decreases. To reproduce this requires the incorporation not only of CN but also of ON-processed material. Furthermore, the existence of this correlation is quite difficult to reproduce with an external mechanism such as ``pollution'' with material processed in a more massive AGB star, which mechanism is fundamentally stochastic in nature. We therefore suggest that although the internal mixing hypothesis has serious flaws,new theoretical insights are needed and it should not be ruled out yet. (abridged)Comment: Slightly updated version to conform to that accepted by the A

Using hepatitis C prevalence to estimate HIV epidemic potential among people who inject drugs in the Middle East and North Africa.

OBJECTIVES: The objective of this study is to understand the association between HIV and hepatitis C virus (HCV) among people who inject drugs (PWIDs) in the Middle East and North Africa (MENA), and to estimate HIV epidemic potential among PWIDs using HCV prevalence. DESIGN/METHODS: Using data from a systematic review of HIV and HCV among PWID in MENA, we conducted two analyses, stratified by HIV epidemic state: a meta-analysis of the risk ratio of HCV to HIV prevalence (RRHCV/HIV) using DerSimonian-Laird random-effects models, and multivariable linear regression predicting log HIV prevalence. The HCV-HIV association from both analyses was used to estimate HIV prevalence at endemic equilibrium. We compared predicted with current HIV prevalence to classify HIV epidemic potential at country-level as low, medium or high, using predefined criteria. RESULTS: The review identified 88 HCV prevalence measures among PWID in MENA, of which 54 had a paired HIV prevalence measure. The pooled RRHCV/HIV were 16, 4 and 3 in low-level, emerging and established HIV epidemics, respectively. There was a significant linear relationship between HCV and HIV at endemic equilibrium (P = 0.002). The predicted endemic HIV prevalence ranged between 8% (Tunisia) and 22% (Pakistan). Of the nine countries with data, five have high and three medium HIV epidemic potential. Only one country, Pakistan, appears to have reached saturation. CONCLUSION: HCV prevalence could be a predictor of future endemic HIV prevalence. In MENA, we predict that there will be further HIV epidemic growth among PWID. The proposed methodology can identify PWID populations that should be prioritized for HIV prevention interventions