A new perspective on metformin therapy in type 1 diabetes

Metformin is quite frequently used off-label in type 1 diabetes to limit insulin dose requirement. Guidelines recommend that it can improve glucose control in those who are overweight and obese but evidence in support of this is limited. Recently-published findings from the REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) trial suggest that metformin therapy in type 1 diabetes can reduce atherosclerosis progression, weight and LDL-cholesterol levels. This provides a new perspective on metformin therapy in type 1 diabetes and suggests a potential role for reducing the long-term risk of cardiovascular disease

The C291R Tau variant forms different types of protofibrils

Mutations in the MAPT gene can lead to disease-associated variants of tau. However, the pathological mechanisms behind these genetic tauopathies are poorly understood. Here, we characterized the aggregation stages and conformational changes of tau C291R, a recently described MAPT mutation with potential pathogenic functions. The C291R variant of the tau four-repeat domain (tau-K18; a functional fragment with increased aggregation propensity compared with the full-length protein), aggregated into a mix of granular oligomers, amorphous and annular pore-like aggregates, in native-state and heparin-treated reactions as observed using atomic force microscopy (AFM) and negative-stained electron microscopy. On extended incubation in the native-state, tau-K18 C291R oligomers, unlike wild type (WT) tau-K18, aggregated to form protofibrils of four different phenotypes: (1) spherical annular; (2) spherical annular encapsulating granular oligomers; (3) ring-like annular but non-spherical; and (4) linear protofibrils. The ring-like tau-K18 C291R aggregates shared key properties of annular protofibrils previously described for other amyloidogenic proteins, in addition to two unique features: irregular/non-spherical-shaped annular protofibrils, and spherical protofibrils encapsulating granular oligomers. Tau-K18 C291R monomers had a circular dichroism (CD) peak at ~210 nm compared with ~199 nm for tau-K18 WT. These data suggest mutation-enhanced β-sheet propensity. Together, we describe the characterization of tau-K18 C291R, the first genetic mutation substituting a cysteine residue. The aggregation mechanism of tau-K18 C291R appears to involve β-sheet-rich granular oligomers which rearrange to form unique protofibrillar structures

c-Myc induced changes in higher order rDNA structure accompany growth factor stimulation of quiescent cells

Human c-Myc is believed to be a high level coordinator of protein synthesis capacity and cell growth rate, capable of activating transcription by all three nuclear RNA Polymerases. Direct activation of rDNA transcription by c-Myc is functionally conserved in rat cells, despite high divergence in non-coding rDNA sequences, suggesting that this coordinating role is likely to be a general within mammals. Upon re-feeding of starved cells, c-Myc activity enhances the efficiency of RNA Polymerase I and SL1/TIF-1B recruitment to the rDNA and rapidly induces higher order gene loop structures in rDNA chromatin that juxtapose upstream and downstream rDNA sequences. Furthermore c-Myc induced gene-loop formation in rDNA genes occurs independently of rDNA transcription, implying that it may be an early step in the re-programming of quiescent cells as they enter the growth cycle

Sex Industry and Sex Workers in Nevada

Las Vegas has long been known as the symbolic center of the commercial sex industry. Nevada is host to the only legal system of prostitution in the United States. From the early legalization of quickie divorce and marriage to the marketing of its large resorts, sexuality has been a key component of Nevada’s tourist economy. If trends continue, for good or for ill, the sex industry will be an even larger part of the economy in the future. The sex industry refers to all legal and illegal adult businesses that sell sexual products, sexual services, sexual fantasies, and actual sexual contact for profit in the commercial marketplace. The sex industry encompasses an exceedingly wide range of formal and informal, legal and illegal businesses, as well as a wide range of individuals who work in and around the industry. This report will review the context in which sexually oriented commercial enterprises have flourished, discuss general trends in the Nevada sex industry, and make policy recommendations

Random strings and tt-degrees of Turing complete C.E. sets

We investigate the truth-table degrees of (co-)c.e.\ sets, in particular, sets of random strings. It is known that the set of random strings with respect to any universal prefix-free machine is Turing complete, but that truth-table completeness depends on the choice of universal machine. We show that for such sets of random strings, any finite set of their truth-table degrees do not meet to the degree~0, even within the c.e. truth-table degrees, but when taking the meet over all such truth-table degrees, the infinite meet is indeed~0. The latter result proves a conjecture of Allender, Friedman and Gasarch. We also show that there are two Turing complete c.e. sets whose truth-table degrees form a minimal pair.Comment: 25 page

New shifted hybrid inflation

A new shifted hybrid inflationary scenario is introduced which, in contrast to the older one, relies only on renormalizable superpotential terms. This scenario is automatically realized in a concrete extension of the "minimal" supersymmetric Pati-Salam model which naturally leads to a moderate violation of Yukawa unification so that, for mu>0, the predicted b-quark mass is acceptable even with universal boundary conditions. It is shown that this extended model possesses a classically flat "shifted" trajectory which acquires a slope via one-loop radiative corrections and can be used as inflationary path. The constraints from the cosmic background explorer can be met with natural values of the relevant parameters. Also, there is no disastrous production of magnetic monopoles after inflation since the Pati-Salam gauge group is already broken on the "shifted" path. The relevant part of inflation takes place at values of the inflaton field which are not much smaller than the "reduced" Planck scale and, thus, supergravity corrections could easily invalidate inflation. It is, however, shown that inflation can be kept intact provided that an extra gauge singlet with a superheavy vacuum expectation value, which originates from D-terms, is introduced and a specific form of the Kaehler potential is used. Moreover, it is found that, although the supergravity corrections are sizable, the constraints from the cosmic background explorer can again be met by readjusting the values of the parameters which were obtained with global supersymmetry.Comment: 18 pages including 1 figure, uses JHEP3.cls, minor corrections, version to appear in JHE

Inferring evolutionary histories of pathway regulation from transcriptional profiling data

One of the outstanding challenges in comparative genomics is to interpret the evolutionary importance of regulatory variation between species. Rigorous molecular evolution-based methods to infer evidence for natural selection from expression data are at a premium in the field, and to date, phylogenetic approaches have not been well-suited to address the question in the small sets of taxa profiled in standard surveys of gene expression. We have developed a strategy to infer evolutionary histories from expression profiles by analyzing suites of genes of common function. In a manner conceptually similar to molecular evolution models in which the evolutionary rates of DNA sequence at multiple loci follow a gamma distribution, we modeled expression of the genes of an \emph{a priori}-defined pathway with rates drawn from an inverse gamma distribution. We then developed a fitting strategy to infer the parameters of this distribution from expression measurements, and to identify gene groups whose expression patterns were consistent with evolutionary constraint or rapid evolution in particular species. Simulations confirmed the power and accuracy of our inference method. As an experimental testbed for our approach, we generated and analyzed transcriptional profiles of four \emph{Saccharomyces} yeasts. The results revealed pathways with signatures of constrained and accelerated regulatory evolution in individual yeasts and across the phylogeny, highlighting the prevalence of pathway-level expression change during the divergence of yeast species. We anticipate that our pathway-based phylogenetic approach will be of broad utility in the search to understand the evolutionary relevance of regulatory change.Comment: 30 pages, 12 figures, 2 tables, contact authors for supplementary table