Toward the End of Time

The null-brane space-time provides a simple model of a big crunch/big bang singularity. A non-perturbative definition of M-theory on this space-time was recently provided using matrix theory. We derive the fermion couplings for this matrix model and study the leading quantum effects. These effects include particle production and a time-dependent potential. Our results suggest that as the null-brane develops a big crunch singularity, the usual notion of space-time is replaced by an interacting gluon phase. This gluon phase appears to constitute the end of our conventional picture of space and time.Comment: 31 pages, reference adde

Pharmacokinetics of quinacrine in the treatment of prion disease

BACKGROUND: Prion diseases are caused by the accumulation of an aberrantly folded isoform of the prion protein, designated PrP(Sc). In a cell-based assay, quinacrine inhibits the conversion of normal host prion protein (PrP(C)) to PrP(Sc )at a half-maximal concentration of 300 nM. While these data suggest that quinacrine may be beneficial in the treatment of prion disease, its penetration into brain tissue has not been extensively studied. If quinacrine penetrates brain tissue in concentrations exceeding that demonstrated for in vitro inhibition of PrP(Sc), it may be useful in the treatment of prion disease. METHODS: Oral quinacrine at doses of 37.5 mg/kg/D and 75 mg/kg/D was administered to mice for 4 consecutive weeks. Plasma and tissue (brain, liver, spleen) samples were taken over 8 weeks: 4 weeks with treatment, and 4 weeks after treatment ended. RESULTS: Quinacrine was demonstrated to penetrate rapidly into brain tissue, achieving concentrations up to 1500 ng/g, which is several-fold greater than that demonstrated to inhibit formation of PrP(Sc )in cell culture. Particularly extensive distribution was observed in spleen (maximum of 100 μg/g) and liver (maximum of 400 μg/g) tissue. CONCLUSIONS: The documented extensive brain tissue penetration is encouraging suggesting quinacrine might be useful in the treatment of prion disease. However, further clarification of the distribution of both intracellular and extracellular unbound quinacrine is needed. The relative importance of free quinacrine in these compartments upon the conversion of normal host prion protein (PrP(C)) to PrP(Sc )will be critical toward its potential benefit

ClpP protease activation results from the reorganization of the electrostatic interaction networks at the entrance pores

Bacterial ClpP is a highly conserved, cylindrical, self-compartmentalizing serine protease required for maintaining cellular proteostasis. Small molecule acyldepsipeptides (ADEPs) and activators of self-compartmentalized proteases 1 (ACP1s) cause dysregulation and activation of ClpP, leading to bacterial cell death, highlighting their potential use as novel antibiotics. Structural changes in Neisseria meningitidis and Escherichia co ClpP upon binding to novel ACP1 and ADEP analogs were probed by X-ray crystallography, methyl-TROSY NMR, and small angle X-ray scattering. ACP1 and ADEP induce distinct conformational changes in the ClpP structure. However, reorganization of electrostatic interaction networks at the ClpP entrance pores is necessary and sufficient for activation. Further activation is achieved by formation of ordered N-terminal axial loops and reduction in the structural heterogeneity of the ClpP cylinder. Activating mutations recapitulate the structural effects of small molecule activator binding. Our data, together with previous findings, provide a structural basis for a unified mechanism of compound-based ClpP activation2CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP306943/2015-8; 420567/2016-099999.004913/2015-092015/15822-1; 2012/01953-9; 2016/05019-0; 2012/50161-8Precision Medicine Initiative (PRiME) at the University of Toronto internal fellowship [PMRF2019-007]; Canadian Institutes of Health Research (CIHR) postdoctoral fellowshipCanadian Institutes of Health Research (CIHR); CNPq-Brazil fellowship [202192/2015-6]; Saskatchewan Health Research Foundation postdoctoral fellowship; Ontario Graduate Scholarship (OGS)Ontario Graduate Scholarship; Department of Biochemistry at the University of Toronto; Centre for Pharmaceutical Oncology (University of Toronto); CIHR Training Program in Protein Folding and Interaction Dynamics: Principles and Diseases fellowshipCanadian Institutes of Health Research (CIHR) [TGF-53910]; University of Toronto Fellowship from the Department of Biochemistry; OGS fellowship; NSERC PGS-D2 fellowship; CIHR Emerging Team Grants from the Institute of Infection and ImmunityCanadian Institutes of Health Research (CIHR) [XNE-86945]; CIHR Project grantCanadian Institutes of Health Research (CIHR) [PJT-148564]; Global Affairs Canada (Canada); CAPES (Brazil)CAPES [99999.004913/2015-09]; NSERCNatural Sciences and Engineering Research Council of Canada [RGPIN-2015-04877, DG-20234]; Canada Research Chairs ProgramCanada Research Chairs; CIHR new investigator programCanadian Institutes of Health Research (CIHR); FAPESPFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2015/15822-1, 2012/01953-9, 2016/05019-0, 2012/50161-8]; CNPqNational Council for Scientific and Technological Development (CNPq) [306943/2015-8, 420567/2016-0]; AbbVie [1097737]; BayerBayer AG [1097737]; Boehringer IngelheimBoehringer Ingelheim [1097737]; Genome Canada through Ontario Genomics Institute GrantGenome Canada [1097737, OGI-055]; GlaxoSmithKlineGlaxoSmithKline [1097737]; JanssenJohnson & Johnson USAJanssen Biotech Inc [1097737]; Lilly CanadaEli Lilly [1097737]; MerckMerck & Company [1097737]; Novartis Research Foundation [1097737]; Ontario Ministry of Economic Development and Innovation [1097737]; PfizerPfizer [1097737]; TakedaTakeda Pharmaceutical Company Ltd [1097737]; Wellcome Trust GrantWellcome Trust [1097737, 092809/Z/10/Z]; Canada Foundation for InnovationCanada Foundation for Innovation; NSERCNatural Sciences and Engineering Research Council of Canada; University of Saskatchewan; Government of Saskatchewan; Western Economic Diversification Canada; National Research Council Canada; CIHRCanadian Institutes of Health Research (CIHR

Non-Supersymmetric String Theory

A class of non-supersymmetric string backgrounds can be constructed using twists that involve space-time fermion parity. We propose a non-perturbative definition of string theory in these backgrounds via gauge theories with supersymmetry softly broken by twisted boundary conditions. The perturbative string spectrum is reproduced, and qualitative effects of the interactions are discussed. Along the way, we find an interesting mechanism for inflation. The end state of closed string tachyon condensation is a highly excited state in the gauge theory which, in all likelihood, does not have a geometric interpretation.Comment: 35 pages, 2 figures; revision adds a computation of the relevant orbifold state

The pancreas anatomy conditions the origin and properties of resident macrophages

We examine the features, origin, turnover, and gene expression of pancreatic macrophages under steady state. The data distinguish macrophages within distinct intrapancreatic microenvironments and suggest how macrophage phenotype is imprinted by the local milieu. Macrophages in islets of Langerhans and in the interacinar stroma are distinct in origin and phenotypic properties. In islets, macrophages are the only myeloid cells: they derive from definitive hematopoiesis, exchange to a minimum with blood cells, have a low level of self-replication, and depend on CSF-1. They express Il1b and Tnfa transcripts, indicating classical activation, M1, under steady state. The interacinar stroma contains two macrophage subsets. One is derived from primitive hematopoiesis, with no interchange by blood cells and alternative, M2, activation profile, whereas the second is derived from definitive hematopoiesis and exchanges with circulating myeloid cells but also shows an alternative activation profile. Complete replacement of islet and stromal macrophages by donor stem cells occurred after lethal irradiation with identical profiles as observed under steady state. The extraordinary plasticity of macrophages within the pancreatic organ and the distinct features imprinted by their anatomical localization sets the base for examining these cells in pathological conditions

A Phase 1 Trial of pharmacologic interactions between transdermal selegiline and a 4-hour cocaine infusion

BackgroundThe selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours.MethodsTwelve nondependent cocaine-experienced subjects received deuterium-labeled cocaine-d5 intravenously (IV) 0.5 mg/kg over 10 minutes followed by 2 mg/kg over 4 hours before and after one week of transdermal selegiline 6 mg/24 hours. Plasma and urine were collected for analysis of selegiline, cocaine, catecholamine and metabolite concentrations. Pharmacodynamic measures were obtained.ResultsSelegiline did not change cocaine pharmacokinetic parameters. Selegiline administration increased phenylethylamine (PEA) urinary excretion and decreased urinary MHPG-sulfate concentration after cocaine when compared to cocaine alone. No serious adverse effects occurred with the combination of selegiline and cocaine, and cocaine-induced physiological effects were unchanged after selegiline. Only 1 peak subjective cocaine effects rating changed, and only a few subjective ratings decreased across time after selegiline.ConclusionNo pharmacological interaction occurred between selegiline and a substantial dose of intravenous cocaine, suggesting the combination will be safe in pharmacotherapy trials. Selegiline produced few changes in subjective response to the cocaine challenge perhaps because of some psychoactive neurotransmitters changing in opposite directions

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

Software for the frontiers of quantum chemistry:An overview of developments in the Q-Chem 5 package

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange–correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear–electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an “open teamware” model and an increasingly modular design