Intra- and interspecies interactions between prion proteins and effects of mutations and polymorphisms

Recently, crystallization of the prion protein in a dimeric form was reported. Here we show that native soluble homogenous FLAG-tagged prion proteins from hamster, man and cattle expressed in the baculovirus system are predominantly dimeric. The PrP/PrP interaction was confirmed in Semliki Forest virus-RNA transfected BHK cells co-expressing FLAG- and oligohistidine-tagged human PrP. The yeast two-hybrid system identified the octarepeat region and the C-terminal structured domain (aa90-aa230) of PrP as PrP/PrP interaction domains. Additional octarepeats identified in patients suffering from fCJD reduced (wtPrP versus PrP+90R) and completely abolished (PrP+90R versus PrP+90R) the PrP/PrP interaction in the yeast two-hybrid system. In contrast, the Met/Val polymorphism (aa129), the GSS mutation Pro102Leu and the FFI mutation Asp178Asn did not affect PrP/PrP interactions. Proof of interactions between human or sheep and bovine PrP, and sheep and human PrP, as well as lack of interactions between human or bovine PrP and hamster PrP suggest that interspecies PrP interaction studies in the yeast two-hybrid system may serve as a rapid pre-assay to investigate species barriers in prion diseases

Effective lattice theories for Polyakov loops

We derive effective actions for SU(2) Polyakov loops using inverse Monte Carlo techniques. In a first approach, we determine the effective couplings by requiring that the effective ensemble reproduces the single-site distribution of the Polyakov loops. The latter is flat below the critical temperature implying that the (untraced) Polyakov loop is distributed uniformly over its target space, the SU(2) group manifold. This allows for an analytic determination of the Binder cumulant and the distribution of the mean-field, which turns out to be approximately Gaussian. In a second approach, we employ novel lattice Schwinger-Dyson equations which reflect the SU(2) x SU(2) invariance of the functional Haar measure. Expanding the effective action in terms of SU(2) group characters makes the numerics sufficiently stable so that we are able to extract a total number of 14 couplings. The resulting action is short-ranged and reproduces the Yang-Mills correlators very well.Comment: 27 pages, 8 figures, v2: method refined, chapter and references adde

An upper limit to the secular variation of the gravitational constant from white dwarf stars

A variation of the gravitational constant over cosmological ages modifies the main sequence lifetimes and white dwarf cooling ages. Using an state-of-the-art stellar evolutionary code we compute the effects of a secularly varying G on the main sequence ages and, employing white dwarf cooling ages computed taking into account the effects of a running G, we place constraints on the rate of variation of Newton's constant. This is done using the white dwarf luminosity function and the distance of the well studied open Galactic cluster NGC 6791. We derive an upper bound G'/G ~ -1.8 10^{-12} 1/yr. This upper limit for the secular variation of the gravitational constant compares favorably with those obtained using other stellar evolutionary properties, and can be easily improved if deep images of the cluster allow to obtain an improved white dwarf luminosity function.Comment: 15 pages, 4 figures, accepted for publication in JCA

DC and AC Josephson Effect in a Superconductor-Luttinger Liquid-Superconductor System

We calculate both the DC and the AC Josephson current through a one-dimensional system of interacting electrons, connected to two superconductors by tunnel junctions. We treat the (repulsive) Coulomb interaction in the framework of the one-channel, spin-$1/2$ Luttinger model. The Josephson current is obtained for two geometries of experimental relevance: a quantum wire and a ring. At zero temperature, the critical current is found to decay algebraically with increasing distance $d$ between the junctions. The decay is characterized by an exponent which depends on the strength of the interaction. At finite temperatures $T$, lower than the superconducting transition temperature $T_c$, there is a crossover from algebraic to exponential decay of the critical current as a function of $d$, at a distance of the order of $\hbar v_F/k_B T$. Moreover, the dependence of critical current on temperature shows non-monotonic behavior. If the Luttinger liquid is confined to a ring of circumference $L$, coupled capacitively to a gate voltage and threaded by a magnetic flux, the Josephson current shows remarkable parity effects under the variation of these parameters. For some values of the gate voltage and applied flux, the ring acts as a $\pi$-junction. These features are robust against thermal fluctuations up to temperatures on the order of $\hbar v_F/k_B L$. For the wire-geometry, we have also studied the AC-Josephson effect. The amplitude and the phase of the time-dependent Josephson current are affected by electron-electron interactions. Specifically, the amplitude shows pronounced oscillations as a function of the bias voltage due to the difference between the velocities of spin and charge excitations in the Luttinger liquid. Therefore, the AC Josephson effect can be used as a tool for the observation o

America's Rural Hospitals: A Selective Review of 1980s Research

We review 1980s research on American rural hospitals within the context of a decade of increasing restrictiveness in the reimbursement and operating environments. Areas addressed include rural hospital definitions, organizational and financial performance, and strategic management activities. The latter category consists of hospital closure, diversification and vertical integration, swing-bed conversion, sole community provider designation, horizontal integration and multihospital system affiliation, marketing, and patient retention. The review suggests several research needs, including: developing more meaningful definitions of rural hospitals, engaging in methodologically sound work on the effects of innovative programs and strategic management activities—including conversion of the facility itself—on rural hospital performance, and completing studies of the effects of rural hospital closure or conversion on the health of the communities served.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74857/1/j.1748-0361.1990.tb00682.x.pd

Effect of allopurinol in addition to hypothermia treatment in neonates for hypoxic-ischemic brain injury on neurocognitive outcome (ALBINO): Study protocol of a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III)

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age 65 36 weeks and a birth weight 65 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion: This trial will provide data to assess the efficacy and safety of early postnatal allopurinol in term infants with evolving hypoxic-ischemic encephalopathy. If proven efficacious and safe, allopurinol could become part of a neuroprotective pharmacological treatment strategy in addition to therapeutic hypothermia in children with perinatal asphyxia. Trial registration: NCT03162653, www.ClinicalTrials.gov, May 22, 2017

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes