1,427 research outputs found
Heat Shock Protein 70 family members interact with Crimean-Congo hemorrhagic fever virus and Hazara virus nucleocapsid proteins and perform a functional role in the nairovirus replication cycle
The Nairovirus genus of the Bunyaviridae family contains serious human and animal pathogens classified within multiple serogroups and species. Of these serogroups, the Crimean-Congo hemorrhagic fever virus (CCHFV) serogroup comprises sole members CCHFV and Hazara virus (HAZV). CCHFV is an emerging zoonotic virus that causes often-fatal hemorrhagic fever in infected humans for which preventative or therapeutic strategies are not available. In contrast HAZV is non-pathogenic to humans, and thus represents an excellent model to study aspects of CCHFV biology under more accessible biological containment. The three RNA segments that form the nairovirus genome are encapsidated by the viral nucleocapsid protein (N) to form ribonucleoprotein (RNP) complexes that are substrates for RNA synthesis and packaging into virus particles. We used quantitative proteomics to identify cellular interaction partners of CCHFV N, and identified robust interactions with cellular chaperones. These interactions were validated using immunological methods, and the specific interaction between native CCHFV N and cellular chaperones of the HSP70 family was confirmed during live CCHFV infection. Using infectious HAZV we showed for the first time that the nairovirus N-HSP70 association was maintained within both infected cells and virus particles, where N is assembled as RNPs. Reduction of active HSP70 levels in cells using small molecule inhibitors significantly reduced HAZV titres, and a model for chaperone function in the context of high genetic variability is proposed. These results suggest chaperones of the HSP70 family are required for nairovirus replication and thus represent a genetically stable cellular therapeutic target for preventing nairovirus-mediated disease
Functional Polymorphism of the Mu-Opioid Receptor Gene (OPRM1) Influences Reinforcement Learning in Humans
Previous reports on the functional effects (i.e., gain or loss of function), and phenotypic outcomes (e.g., changes in addiction vulnerability and stress response) of a commonly occurring functional single nucleotide polymorphism (SNP) of the mu-opioid receptor (OPRM1 A118G) have been inconsistent. Here we examine the effect of this polymorphism on implicit reward learning. We used a probabilistic signal detection task to determine whether this polymorphism impacts response bias to monetary reward in 63 healthy adult subjects: 51 AA homozygotes and 12 G allele carriers. OPRM1 AA homozygotes exhibited typical responding to the rewarded response—that is, their bias to the rewarded stimulus increased over time. However, OPRM1 G allele carriers exhibited a decline in response to the rewarded stimulus compared to the AA homozygotes. These results extend previous reports on the heritability of performance on this task by implicating a specific polymorphism. Through comparison with other studies using this task, we suggest a possible mechanism by which the OPRM1 polymorphism may confer reduced response to natural reward through a dopamine-mediated decrease during positive reinforcement learning
RECO level \sqrt{s}_{min} and subsystem \sqrt{s}_{min}: improved global inclusive variables for measuring the new physics mass scale in missing energy events at hadron colliders
The variable \sqrt{s}_{min} was originally proposed in arXiv:0812.1042 as a
model-independent, global and fully inclusive measure of the new physics mass
scale in missing energy events at hadron colliders. In the original incarnation
of \sqrt{s}_{min}, however, the connection to the new physics mass scale was
blurred by the effects of the underlying event, most notably initial state
radiation and multiple parton interactions. In this paper we advertize two
improved variants of the \sqrt{s}_{min} variable, which overcome this problem.
First we show that by evaluating the \sqrt{s}_{min} variable at the RECO level,
in terms of the reconstructed objects in the event, the effects from the
underlying event are significantly diminished and the nice correlation between
the peak in the \sqrt{s}_{min}^{(reco)} distribution and the new physics mass
scale is restored. Secondly, the underlying event problem can be avoided
altogether when the \sqrt{s}_{min} concept is applied to a subsystem of the
event which does not involve any QCD jets. We supply an analytic formula for
the resulting subsystem \sqrt{s}_{min}^{(sub)} variable and show that its peak
exhibits the usual correlation with the mass scale of the particles produced in
the subsystem. Finally, we contrast \sqrt{s}_{min} to other popular inclusive
variables such as H_T, M_{Tgen} and M_{TTgen}. We illustrate our discussion
with several examples from supersymmetry, and with dilepton events from top
quark pair production.Comment: 41 pages, 26 figure
Asymmetric Origin for Gravitino Relic Density in the Hybrid Gravity-Gauge Mediated Supersymmetry Breaking
We propose the hybrid gravity-gauge mediated supersymmetry breaking where the
gravitino mass is about several GeV. The strong constraints on supersymmetry
viable parameter space from the CMS and ATLAS experiments at the LHC can be
relaxed due to the heavy colored supersymmetric particles, and it is consistent
with null results in the dark matter (DM) direct search experiments such as
XENON100. In particular, the possible maximal flavor and CP violations from the
relatively small gravity mediation may naturally account for the recent LHCb
anomaly. In addition, because the gravitino mass is around the asymmetric DM
mass, we propose the asymmetric origin of the gravitino relic density and solve
the cosmological coincident problem on the DM and baryon densities \Omega_{\rm
DM}:\Omega_{B}\approx 5:1. The gravitino relic density arises from asymmetric
metastable particle (AMP) late decay. However, we show that there is no AMP
candidate in the minimal supersymmetric Standard Model (SM) due to the robust
gaugino/Higgsino mediated wash-out effects. Interestingly, AMP can be realized
in the well motivated supersymmetric SMs with vector-like particles or
continuous U(1)_R symmetry. Especially, the lightest CP-even Higgs boson mass
can be lifted in the supersymmetric SMs with vector-like particles.Comment: RevTex4, 21 pages, 1 figure, minor corrections, JHEP versio
Asymmetric WIMP dark matter
In existing dark matter models with global symmetries the relic abundance of
dark matter is either equal to that of anti-dark matter (thermal WIMP), or
vastly larger, with essentially no remaining anti-dark matter (asymmetric dark
matter). By exploring the consequences of a primordial asymmetry on the coupled
dark matter and anti-dark matter Boltzmann equations we find large regions of
parameter space that interpolate between these two extremes. Interestingly,
this new asymmetric WIMP framework can accommodate a wide range of dark matter
masses and annihilation cross sections. The present-day dark matter population
is typically asymmetric, but only weakly so, such that indirect signals of dark
matter annihilation are not completely suppressed. We apply our results to
existing models, noting that upcoming direct detection experiments will
constrain a large region of the relevant parameter space.Comment: 32 pages, 6 figures, updated references, updated XENON100 bounds,
typo in figure caption correcte
Electroweak Baryogenesis and Dark Matter with an approximate R-symmetry
It is well known that R-symmetric models dramatically alleviate the SUSY
flavor and CP problems. We study particular modifications of existing
R-symmetric models which share the solution to the above problems, and have
interesting consequences for electroweak baryogenesis and the Dark Matter (DM)
content of the universe. In particular, we find that it is naturally possible
to have a strongly first-order electroweak phase transition while
simultaneously relaxing the tension with EDM experiments. The R-symmetry (and
its small breaking) implies that the gauginos (and the neutralino LSP) are
pseudo-Dirac fermions, which is relevant for both baryogenesis and DM. The
singlet superpartner of the U(1)_Y pseudo-Dirac gaugino plays a prominent role
in making the electroweak phase transition strongly first-order. The
pseudo-Dirac nature of the LSP allows it to behave similarly to a Dirac
particle during freeze-out, but like a Majorana particle for annihilation today
and in scattering against nuclei, thus being consistent with current
constraints. Assuming a standard cosmology, it is possible to simultaneously
have a strongly first-order phase transition conducive to baryogenesis and have
the LSP provide the full DM relic abundance, in part of the allowed parameter
space. However, other possibilities for DM also exist, which are discussed. It
is expected that upcoming direct DM searches as well as neutrino signals from
DM annihilation in the Sun will be sensitive to this class of models.
Interesting collider and Gravity-wave signals are also briefly discussed.Comment: 50 pages, 10 figure
Supersymmetric Monojets at the Large Hadron Collider
Supersymmetric monojets may be produced at the Large Hadron Collider by the
process qg -> squark neutralino_1 -> q neutralino_1 neutralino_1, leading to a
jet recoiling against missing transverse momentum. We discuss the feasibility
and utility of the supersymmetric monojet signal. In particular, we examine the
possible precision with which one can ascertain the neutralino_1-squark-quark
coupling via the rate for monojet events. Such a coupling contains information
on the composition of the neutralino_1 and helps bound dark matter direct
detection cross-sections and the dark matter relic density of the neutralino_1.
It also provides a check of the supersymmetric relation between gauge couplings
and gaugino-quark-squark couplings.Comment: 46 pages, 10 figures. The appendix has been rewritten to correct an
error that appears in all previous versions of the appendix. This error has
no effect on the results in the main body of the pape
Formyl Peptide Receptor as a Novel Therapeutic Target for Anxiety-Related Disorders
Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p-p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface
The crystal structure of the Hazara virus nucleocapsid protein
Background: Hazara virus (HAZV) is a member of the Bunyaviridae family of segmented negative stranded RNA viruses, and shares the same serogroup as Crimean-Congo haemorrhagic fever virus (CCHFV). CCHFV is responsible for fatal human disease with a mortality rate approaching 30 %, which has an increased recent incidence within southern Europe. There are no preventative or therapeutic treatments for CCHFV-mediated disease, and thus CCHFV is classified as a hazard group 4 pathogen. In contrast HAZV is not associated with serious human disease, although infection of interferon receptor knockout mice with either CCHFV or HAZV results in similar disease progression. To characterise further similarities between HAZV and CCHFV, and support the use of HAZV as a model for CCHFV infection, we investigated the structure of the HAZV nucleocapsid protein (N) and compared it to CCHFV N. N performs an essential role in the viral life cycle by encapsidating the viral RNA genome, and thus, N represents a potential therapeutic target. Results: We present the purification, crystallisation and crystal structure of HAZV N at 2.7 Å resolution. HAZV N was expressed as an N-terminal glutathione S-transferase (GST) fusion protein then purified using glutathione affinity chromatography followed by ion-exchange chromatography. HAZV N crystallised in the P212121 space group with unit cell parameters a = 64.99, b = 76.10, and c = 449.28 Å. HAZV N consists of a globular domain formed mostly of alpha helices derived from both the N- and C-termini, and an arm domain comprising two long alpha helices. HAZV N has a similar overall structure to CCHFV N, with their globular domains superposing with an RMSD = 0.70 Å, over 368 alpha carbons that share 59 % sequence identity. Four HAZV N monomers crystallised in the asymmetric unit, and their head-to-tail assembly reveals a potential interaction site between monomers. Conclusions: The crystal structure of HAZV N reveals a close similarity to CCHFV N, supporting the use of HAZV as a model for CCHFV. Structural similarity between the N proteins should facilitate study of the CCHFV and HAZV replication cycles without the necessity of working under containment level 4 (CL-4) conditions
Closing in on Asymmetric Dark Matter I: Model independent limits for interactions with quarks
It is argued that experimental constraints on theories of asymmetric dark
matter (ADM) almost certainly require that the DM be part of a richer hidden
sector of interacting states of comparable mass or lighter. A general requisite
of models of ADM is that the vast majority of the symmetric component of the DM
number density must be removed in order to explain the observed relationship
via the DM asymmetry. Demanding the efficient
annihilation of the symmetric component leads to a tension with experimental
limits if the annihilation is directly to Standard Model (SM) degrees of
freedom. A comprehensive effective operator analysis of the model independent
constraints on ADM from direct detection experiments and LHC monojet searches
is presented. Notably, the limits obtained essentially exclude models of ADM
with mass 1GeV 100GeV annihilating to SM quarks via
heavy mediator states. This motivates the study of portal interactions between
the dark and SM sectors mediated by light states. Resonances and threshold
effects involving the new light states are shown to be important for
determining the exclusion limits.Comment: 18+6 pages, 18 figures. v2: version accepted for publicatio
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