Likelihood analysis of supersymmetric SU(5) GUTs.

We perform a likelihood analysis of the constraints from accelerator experiments and astrophysical observations on supersymmetric (SUSY) models with SU(5) boundary conditions on soft SUSY-breaking parameters at the GUT scale. The parameter space of the models studied has seven parameters: a universal gaugino mass [Formula: see text], distinct masses for the scalar partners of matter fermions in five- and ten-dimensional representations of SU(5), [Formula: see text] and [Formula: see text], and for the [Formula: see text] and [Formula: see text] Higgs representations [Formula: see text] and [Formula: see text], a universal trilinear soft SUSY-breaking parameter [Formula: see text], and the ratio of Higgs vevs [Formula: see text]. In addition to previous constraints from direct sparticle searches, low-energy and flavour observables, we incorporate constraints based on preliminary results from 13 TeV LHC searches for jets + [Formula: see text] events and long-lived particles, as well as the latest PandaX-II and LUX searches for direct Dark Matter detection. In addition to previously identified mechanisms for bringing the supersymmetric relic density into the range allowed by cosmology, we identify a novel [Formula: see text] coannihilation mechanism that appears in the supersymmetric SU(5) GUT model and discuss the role of [Formula: see text] coannihilation. We find complementarity between the prospects for direct Dark Matter detection and SUSY searches at the LHC.

Supersymmetric dark matter after LHC run 1.

Different mechanisms operate in various regions of the MSSM parameter space to bring the relic density of the lightest neutralino, [Formula: see text], assumed here to be the lightest SUSY particle (LSP) and thus the dark matter (DM) particle, into the range allowed by astrophysics and cosmology. These mechanisms include coannihilation with some nearly degenerate next-to-lightest supersymmetric particle such as the lighter stau [Formula: see text], stop [Formula: see text] or chargino [Formula: see text], resonant annihilation via direct-channel heavy Higgs bosons H / A, the light Higgs boson h or the Z boson, and enhanced annihilation via a larger Higgsino component of the LSP in the focus-point region. These mechanisms typically select lower-dimensional subspaces in MSSM scenarios such as the CMSSM, NUHM1, NUHM2, and pMSSM10. We analyze how future LHC and direct DM searches can complement each other in the exploration of the different DM mechanisms within these scenarios. We find that the [Formula: see text] coannihilation regions of the CMSSM, NUHM1, NUHM2 can largely be explored at the LHC via searches for [Formula: see text] events and long-lived charged particles, whereas their H / A funnel, focus-point and [Formula: see text] coannihilation regions can largely be explored by the LZ and Darwin DM direct detection experiments. We find that the dominant DM mechanism in our pMSSM10 analysis is [Formula: see text] coannihilation: parts of its parameter space can be explored by the LHC, and a larger portion by future direct DM searches.

The pMSSM10 after LHC run 1.

We present a frequentist analysis of the parameter space of the pMSSM10, in which the following ten soft SUSY-breaking parameters are specified independently at the mean scalar top mass scale [Formula: see text]: the gaugino masses [Formula: see text], the first-and second-generation squark masses [Formula: see text], the third-generation squark mass [Formula: see text], a common slepton mass [Formula: see text] and a common trilinear mixing parameter A, as well as the Higgs mixing parameter [Formula: see text], the pseudoscalar Higgs mass [Formula: see text] and [Formula: see text], the ratio of the two Higgs vacuum expectation values. We use the MultiNest sampling algorithm with [Formula: see text]1.2 [Formula: see text] points to sample the pMSSM10 parameter space. A dedicated study shows that the sensitivities to strongly interacting sparticle masses of ATLAS and CMS searches for jets, leptons [Formula: see text][Formula: see text] signals depend only weakly on many of the other pMSSM10 parameters. With the aid of the Atom and Scorpion codes, we also implement the LHC searches for electroweakly interacting sparticles and light stops, so as to confront the pMSSM10 parameter space with all relevant SUSY searches. In addition, our analysis includes Higgs mass and rate measurements using the HiggsSignals code, SUSY Higgs exclusion bounds, the measurements of [Formula: see text] by LHCb and CMS, other B-physics observables, electroweak precision observables, the cold dark matter density and the XENON100 and LUX searches for spin-independent dark matter scattering, assuming that the cold dark matter is mainly provided by the lightest neutralino [Formula: see text]. We show that the pMSSM10 is able to provide a supersymmetric interpretation of [Formula: see text], unlike the CMSSM, NUHM1 and NUHM2. As a result, we find (omitting Higgs rates) that the minimum [Formula: see text] with 18 degrees of freedom (d.o.f.) in the pMSSM10, corresponding to a [Formula: see text] probability of 30.8 %, to be compared with [Formula: see text] in the CMSSM (NUHM1) (NUHM2). We display the one-dimensional likelihood functions for sparticle masses, and we show that they may be significantly lighter in the pMSSM10 than in the other models, e.g., the gluino may be as light as [Formula: see text]1250 [Formula: see text] at the 68 % CL, and squarks, stops, electroweak gauginos and sleptons may be much lighter than in the CMSSM, NUHM1 and NUHM2. We discuss the discovery potential of future LHC runs, [Formula: see text] colliders and direct detection experiments.

The NUHM2 after LHC Run 1.

We make a frequentist analysis of the parameter space of the NUHM2, in which the soft supersymmetry (SUSY)-breaking contributions to the masses of the two Higgs multiplets, [Formula: see text], vary independently from the universal soft SUSY-breaking contributions [Formula: see text] to the masses of squarks and sleptons. Our analysis uses the MultiNest sampling algorithm with over [Formula: see text] points to sample the NUHM2 parameter space. It includes the ATLAS and CMS Higgs mass measurements as well as the ATLAS search for supersymmetric jets + [Formula: see text] signals using the full LHC Run 1 data, the measurements of [Formula: see text] by LHCb and CMS together with other B-physics observables, electroweak precision observables and the XENON100 and LUX searches for spin-independent dark-matter scattering. We find that the preferred regions of the NUHM2 parameter space have negative SUSY-breaking scalar masses squared at the GUT scale for squarks and sleptons, [Formula: see text], as well as [Formula: see text]. The tension present in the CMSSM and NUHM1 between the supersymmetric interpretation of [Formula: see text] and the absence to date of SUSY at the LHC is not significantly alleviated in the NUHM2. We find that the minimum [Formula: see text] with 21 degrees of freedom (dof) in the NUHM2, to be compared with [Formula: see text] in the CMSSM, and [Formula: see text] in the NUHM1. We find that the one-dimensional likelihood functions for sparticle masses and other observables are similar to those found previously in the CMSSM and NUHM1.

Implications of improved Higgs mass calculations for supersymmetric models.

We discuss the allowed parameter spaces of supersymmetric scenarios in light of improved Higgs mass predictions provided by FeynHiggs 2.10.0. The Higgs mass predictions combine Feynman-diagrammatic results with a resummation of leading and subleading logarithmic corrections from the stop/top sector, which yield a significant improvement in the region of large stop masses. Scans in the pMSSM parameter space show that, for given values of the soft supersymmetry-breaking parameters, the new logarithmic contributions beyond the two-loop order implemented in FeynHiggs tend to give larger values of the light CP-even Higgs mass, [Formula: see text], in the region of large stop masses than previous predictions that were based on a fixed-order Feynman-diagrammatic result, though the differences are generally consistent with the previous estimates of theoretical uncertainties. We re-analyse the parameter spaces of the CMSSM, NUHM1 and NUHM2, taking into account also the constraints from CMS and LHCb measurements of [Formula: see text]and ATLAS searches for [Formula: see text] events using 20/fb of LHC data at 8 TeV. Within the CMSSM, the Higgs mass constraint disfavours [Formula: see text], though not in the NUHM1 or NUHM2.

The CMSSM and NUHM1 after LHC Run 1.

We analyze the impact of data from the full Run 1 of the LHC at 7 and 8 TeV on the CMSSM with [Formula: see text] and [Formula: see text] and the NUHM1 with [Formula: see text], incorporating the constraints imposed by other experiments such as precision electroweak measurements, flavour measurements, the cosmological density of cold dark matter and the direct search for the scattering of dark matter particles in the LUX experiment. We use the following results from the LHC experiments: ATLAS searches for events with [Formula: see text] accompanied by jets with the full 7 and 8 TeV data, the ATLAS and CMS measurements of the mass of the Higgs boson, the CMS searches for heavy neutral Higgs bosons and a combination of the LHCb and CMS measurements of [Formula: see text] and [Formula: see text]. Our results are based on samplings of the parameter spaces of the CMSSM for both [Formula: see text] and [Formula: see text] and of the NUHM1 for [Formula: see text] with 6.8[Formula: see text], 6.2[Formula: see text] and 1.6[Formula: see text] points, respectively, obtained using the MultiNest tool. The impact of the Higgs-mass constraint is assessed using FeynHiggs 2.10.0, which provides an improved prediction for the masses of the MSSM Higgs bosons in the region of heavy squark masses. It yields in general larger values of [Formula: see text] than previous versions of FeynHiggs, reducing the pressure on the CMSSM and NUHM1. We find that the global [Formula: see text] functions for the supersymmetric models vary slowly over most of the parameter spaces allowed by the Higgs-mass and the [Formula: see text] searches, with best-fit values that are comparable to the [Formula: see text] for the best Standard Model fit. We provide 95 % CL lower limits on the masses of various sparticles and assess the prospects for observing them during Run 2 of the LHC.

Caspase-independent exposure of aminophospholipids and tyrosine phosphorylation in bicarbonate responsive human sperm cells.

Only capacitated sperm cells are able to fertilize egg cells, and this process is triggered by high levels of bicarbonate. Bicarbonate renders the plasma membrane more fluid, which is caused by protein kinase A (PKA)-mediated alterations in the phospholipid (PL) bilayer. We studied exposure of phosphatidylserine (PS) and phosphatidylethanolamine (PE) in human sperm cells. Surface exposure of PS and PE on sperm cell activation in vitro was found to be bicarbonate dependent and restricted to the apical area of the head plasma membrane. The PL scrambling in bicarbonate-triggered human sperm was not related to apoptosis, because the incubated cells did not show any signs of caspases or degeneration of mitochondria or DNA. The PL scramblase (PLSCR) gene family has been implicated in this nonspecific, bidirectional PL movement. A 25-kDa isoform of PLSCR was identified that was homogeneously distributed in human sperm cells. We propose that compartment-dependent activation of PKA is required for the surface exposure of aminophospholipids at the apical plasma membrane of sperm cells. Bicarbonate-induced PL scrambling appears to be an important event in the capacitation process, because the entire intact scrambling sperm subpopulation showed extensive tyrosine phosphorylation, which was absent in the nonscrambling subpopulation. The proportion of live cells with PL scrambling corresponded with that showing capacitation-specific chlortetracyclin staining.

Dynamics of munc18-1 phosphorylation/dephosphorylation in rat brain nerve terminals.

Munc18-1 is a mammalian member of the SEC1 protein family implicated in neuronal secretion. Its sequence contains several consensus sites for phosphorylation by protein kinase C (PKC), a kinase known to enhance secretion. We have characterized the phosphorylation of the synaptic munc18-1 pool by endogenous, presynaptic PKC-isoforms. In isolated rat brain nerve terminals, munc18-1 was almost completely nonphosphorylated. Its phosphorylation state increased by 250% on inhibition of endogenous phosphatases and by 1500% on additional, direct PKC activation using phorbol esters. K+-evoked depolarization also increased munc18-1 phosphorylation, by 50% within 5 s in a Ca2+-dependent manner. Munc18-1 phosphorylation in nerve terminals was blocked by PKC inhibitors. Activation of endogenous PKC in nerve terminals inhibited the interaction of synaptic munc18-1 with its binding partner syntaxin-1A by 50%. Munc18-1 antisera precipitated 80% of native, brain-derived munc18-1 from salt solutions, but only 12% from synaptosomal lysates, together with 6% synaptic syntaxin-1A/B; these amounts were not changed by PKC activation. In this 12%, the phosphate incorporation per mole of munc18 was four-fold lower than the total pool. We conclude that the synaptic munc18-1 pool can be readily and rapidly phosphorylated by endogenous presynaptic PKC isoforms. A high constitutive phosphatase activity keeps its basal phosphorylation state low so that PKC activation can increase the phosphorylation state dramatically. These phosphorylation dynamics and the effects on the interaction with syntaxin-1A make munc18-1 a prominent candidate to account for PKC-dependent enhancement of secretion.

DOC2 proteins in rat brain: complementary distribution and proposed function as vesicular adapter proteins in early stages of secretion.

DOC2 proteins constitute a novel protein family that may function in secretion and contain a double C2 domain. We have cloned and characterized two DOC2 isoforms in rat brain and studied their interactions with other proteins implicated in secretion. DOC2A was virtually brain specific, DOC2B ubiquitous. Within brain, the isoforms were expressed nonuniformly and complementary within neurons, not astroglia, and copurified with synaptic vesicles. Affinity purification, yeast two-hybrid analysis, and coimmunoprecipitation revealed that DOC2 binds munc18, a protein also implicated in secretion. The first DOC2 C2 domain and most of munc18 are involved in direct interactions. Munc18 may regulate formation of 'core complexes' during vesicle docking, by interacting with syntaxin. We show that DOC2 and syntaxin compete for munc18. Other core complex components shifted the equilibrium between syntaxin-munc18 versus DOC2-munc18. These data suggest that DOC2 proteins are vesicular adapter proteins regulating munc18-syntaxin complexes and herewith synaptic vesicle docking.

Fluorescently labeled phosphatidylinositol transfer protein isoforms (alpha and beta), microinjected into fetal bovine heart endothelial cells, are targeted to distinct intracellular sites.

Upon permeabilization of Swiss mouse 3T3 fibroblasts, an isoform of phosphatidylinositol transfer protein (PI-TP) was preferentially retained, a major part of which was associated with the perinuclear Golgi system (K. J. de Vries, A. Momchilova-Pankova, G. T. Snoek, and K. W. A. Wirtz, Exp. Cell Res. 215, 109-113, 1994). In the present study, the intracellular localization of this isoform (PI-TP beta) and the regular form (PI-TP alpha) was investigated in fetal bovine heart endothelial cells by microinjection of fluorescently labeled analogs followed by confocal laser scanning microscopy. The PI-TP alpha and PI-TP beta used were purified from bovine brain cytosol and covalently labeled with sulfoindocyanine dyes. By this novel method it was found that PI-TP beta was preferentially associated with perinuclear membrane structures whereas PI-TP alpha was predominantly present in the nucleus and in the cytoplasm. This intracellular localization was confirmed by indirect immunofluorescence indicating that the fluorescently labeled PI-TP alpha and PI-TP beta were targeted to the same sites as their endogeneous counterparts.

An isoform of the phosphatidylinositol-transfer protein transfers sphingomyelin and is associated with the Golgi system.

An isoform of the phosphatidylinositol-transfer protein (PI-TP) was identified in the cytosol fraction of bovine brain. This protein, designated PI-TP beta, has an apparent molecular mass of 36 kDa and an isoelectric point of 5.4. The N-terminal amino acid sequence (21 residues) is 90% similar to that of bovine brain PI-TP, henceforth designated PI-TP alpha (molecular mass 35 kDa and pI 5.5). As observed for PI-TP alpha, PI-TP beta has a distinct preference for phosphatidylinositol over phosphatidylcholine. In addition, it expresses a high transfer activity towards sphingomyelin. PI-TP alpha lacks this activity completely. By indirect immunofluorescence we demonstrated that, in Swiss mouse 3T3 fibroblasts, PI-TP beta is preferentially associated with the Golgi system whereas PI-TP alpha is predominantly present in the cytoplasm and the nucleus. In cytosol-depleted HL60 cells, both PI-TP alpha and PI-TP beta were equally effective at reconstituting guanosine 5'-[gamma-thio]triphosphate-mediated phospholipase C beta activity.

A sphingomyelin-transferring protein from chicken liver. Use of pyrene-labeled phospholipid.

A phospholipid transfer protein was purified from chicken liver which, in addition to phosphatidylinositol (PI) and phosphatidylcholine (PC), carries sphingomyelin (SM) between membranes. For comparison, the PI-transfer protein from chicken liver only carries PI and PC. Specificity was established by use of phospholipids that carry a pyrene-labeled acyl chain. Based on the N-terminal sequence and Western blot analysis we conclude that this protein is an isoform of the PI-transfer protein. At increasing length of the pyrene-labeled acyl chain, the isoform expresses a high activity toward SM, a low activity toward PI, and virtually no activity toward PC.

A novel acidic form of the phosphatidylinositol transfer protein is preferentially retained in permeabilized Swiss mouse 3T3 fibroblasts.

By use of indirect immunofluorescence it was shown that phophatidylinositol transfer protein (PI-TP) remains associated with the Golgi system of Swiss mouse 3T3 fibroblasts after permeabilization with streptolysin O. By Western blot analysis it was demonstrated that intact cells contain the phosphatidylinositol-bound form of PI-TP (pI 5.5) and a novel more acidic form of PI-TP (pI 5.4) in approximately equal amounts. After permeabilization, about 50% of the PI-TP was retained in the cells with an enrichment of the pH 5.4 form relative to the pH 5.5 form; the opposite was observed for the PI-TP released into the medium. Subfractionation of cell homogenates by centrifugation provided evidence that a distinct amount of PI-TP is strongly bound to the membrane fraction with the pH 5.4 form more prominently present than the pH 5.5 form.

Environmental regulation of alcohol metabolism in thermotolerant methylotrophic Bacillus strains.

The thermotolerant methylotroph Bacillus sp. C1 possesses a novel NAD-dependent methanol dehydrogenase (MDH), with distinct structural and mechanistic properties. During growth on methanol and ethanol, MDH was responsible for the oxidation of both these substrates. MDH activity in cells grown on methanol or glucose was inversely related to the growth rate. Highest activity levels were observed in cells grown on the C1-substrates methanol and formaldehyde. The affinity of MDH for alcohol substrates and NAD, as well as Vmax, are strongly increased in the presence of a Mr 50,000 activator protein plus Mg(2+)-ions [Arfman et al. (1991) J Biol Chem 266: 3955-3960]. Under all growth conditions tested the cells contained an approximately 18-fold molar excess of (decameric) MDH over (dimeric) activator protein. Expression of hexulose-6-phosphate synthase (HPS), the key enzyme of the RuMP cycle, was probably induced by the substrate formaldehyde. Cells with high MDH and low HPS activity levels immediately accumulated (toxic) formaldehyde when exposed to a transient increase in methanol concentration. Similarly, cells with high MDH and low CoA-linked NAD-dependent acetaldehyde dehydrogenase activity levels produced acetaldehyde when subjected to a rise in ethanol concentration. Problems frequently observed in establishing cultures of methylotrophic bacilli on methanol- or ethanol-containing media are (in part) assigned to these phenomena.

Synthesis of phosphatidylinositol 4,5-bisphosphate in the endoplasmic reticulum of Chinese hamster ovary cells.

We have investigated the intracellular localization and synthesis of phosphatidylinositol 4,5-bisphosphate (PtdInsP2) in Chinese hamster ovary (CHO) cells by analyzing membrane fractions that were obtained by sucrose density gradient centrifugation. After labeling the cells for 24 h with [3H]inositol, the bulk of [3H] PtdInsP2 was found in the plasma membrane fraction, yet this lipid was also distinctly present in the microsomal fraction (20% of total cellular [3H]PtdInsP2). To determine the origin of this microsomal PtdInsP2, gradient fractions from unlabeled CHO cells were incubated with [3H]inositol in the presence of an ATP-generating system. Under these conditions of labeling, [3H]PtdIns was exclusively present in the microsomal fractions and found to be partially converted to [3H] phosphatidylinositol 4-phosphate ([3H]PtdInsP) and phosphatidylinositol 4-phosphate ([3H]PtdInsP) and [3H]PtdInsP2. The ability of microsomes to synthesize PtdInsP and PtdInsP2 was confirmed by assaying the gradient fractions for PtdIns and PtdInsP kinase activity using endogenous substrate and [gamma-32P]ATP. In the presence of exogenous substrate and Triton X-100, PtdInsP kinase activity was particularly high in the plasma membrane fractions. When phosphoinositide synthesis was studied in permeabilized CHO cells under conditions of sustained membrane vesicle flow (Helms, J. B., Karrenbauer, A., Wirtz, K. W. A., Rothman, J. E., and Wieland, F. T. (1990) J. Biol. Chem. 265, 20027-20032), no lag-time could be detected between the synthesis of [3H]PtdIns and the formation of [3H]PtdInsP2. Moreover, when lipid transport pathways were blocked in these permeabilized cells either by omission of membrane-free cytosol, addition of GTP gamma S and brefeldin A, or temperature block, PtdInsP2 formation still occurred at normal levels. These results strongly suggest that PtdInsP2 can be formed at the site of PtdIns synthesis, i.e. the endoplasmic reticulum (ER). The relationship between PtdInsP2, generated in the ER, and PtdInsP2 present in the plasma membrane, remains to be established.

Evaluation of a safe sex campaign regarding AIDS and other sexually transmitted diseases among young people in The Netherlands.

During the summer of 1989 a mass media campaign against the spread of AIDS and other sexually transmitted diseases (STDs) was launched in The Netherlands. The campaign was directed at young people and targeted inappropriate beliefs about the transmission of HIV and STDs. These inappropriate beliefs were considered to function as rationalizations and excuses for individuals and their sexual partners not to take preventive measures. To evaluate the campaign, young people who had noticed the campaign were compared with the ones interviewed at the pre-test. The ones that had not noticed the campaign served as a quasi-experimental control group. The campaign not only reached a sizeable majority of young people, but also succeeded in bringing about some of the desired changes. The risk of HIV infection became personally more relevant to the exposed group and several misconceptions or excuses were less often endorsed. This suggests that a mass media campaign does not have to be restricted to mere attention-raising and increasing factual knowledge, but may be of relevance for other psychosocial processes as well.

AIDS in The Netherlands: the effects of several years of campaigning.

One of the primary aims of acquired immunodeficiency syndrome (AIDS) prevention campaigns in the Netherlands has been to inform the public of the facts about AIDS, thereby stimulating informed, but voluntary action to prevent transmission of the human immunodeficiency virus (HIV). By conducting successive population surveys from April 1987 until October 1989, the effects of this approach were assessed. Twice a year, approximately 1000 respondents, a random sample from the general population, were interviewed about AIDS and safe sex. Additionally, condom sales figures and STD incidences were evaluated. It appears that knowledge about the prevention of HIV transmission with condoms has reached 98% of the sample. During the study, there was an increase in the number of people who expressed an intention to use condoms or who already used them. Behaviour, however, appeared to fall short of intention. The observations were confirmed by condom sales figures and STD incidences. We conclude that the AIDS policy in the Netherlands has had beneficial effects, reflected by several indices.