An authenticated case of black widow bite

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Irreversible reorganization in a supercooled liquid originates from localised soft modes

The transition of a fluid to a rigid glass upon cooling is a common route of transformation from liquid to solid that embodies the most poorly understood features of both phases1,2,3. From the liquid perspective, the puzzle is to understand stress relaxation in the disordered state. From the perspective of solids, the challenge is to extend our description of structure and its mechanical consequences to materials without long range order. Using computer simulations, we show that the localized low frequency normal modes of a configuration in a supercooled liquid are causally correlated to the irreversible structural reorganization of the particles within that configuration. We also demonstrate that the spatial distribution of these soft local modes can persist in spite of significant particle reorganization. The consequence of these two results is that it is now feasible to construct a theory of relaxation length scales in glass-forming liquids without recourse to dynamics and to explicitly relate molecular properties to their collective relaxation.Comment: Published online: 20 July 2008 | doi:10.1038/nphys1025 Available from http://www.nature.com/nphys/journal/v4/n9/abs/nphys1025.htm

Evaluating the potential for the environmentally sustainable control of foot and mouth disease in Sub-Saharan Africa

Strategies to control transboundary diseases have in the past generated unintended negative consequences for both the environment and local human populations. Integrating perspectives from across disciplines, including livestock, veterinary and conservation sectors, is necessary for identifying disease control strategies that optimise environmental goods and services at the wildlife-livestock interface. Prompted by the recent development of a global strategy for the control and elimination of foot-and-mouth disease (FMD), this paper seeks insight into the consequences of, and rational options for potential FMD control measures in relation to environmental, conservation and human poverty considerations in Africa. We suggest a more environmentally nuanced process of FMD control that safe-guards the integrity of wild populations and the ecosystem dynamics on which human livelihoods depend while simultaneously improving socio-economic conditions of rural people. In particular, we outline five major issues that need to be considered: 1) improved understanding of the different FMD viral strains and how they circulate between domestic and wildlife populations; 2) an appreciation for the economic value of wildlife for many African countries whose presence might preclude the country from ever achieving an FMD-free status; 3) exploring ways in which livestock production can be improved without compromising wildlife such as implementing commodity-based trading schemes; 4) introducing a participatory approach involving local farmers and the national veterinary services in the control of FMD; and 5) finally the possibility that transfrontier conservation might offer new hope of integrating decision-making at the wildlife-livestock interface

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Polyploidization as a Retraction Force in Plant Genome Evolution: Sequence Rearrangements in Triticale

BACKGROUND: Polyploidization is a major evolutionary process in plants where hybridization and chromosome doubling induce enormous genomic stress and can generate genetic and epigenetic modifications. However, proper evaluation of DNA sequence restructuring events and the precise characterization of sequences involved are still sparse. METHODOLOGY/PRINCIPAL FINDINGS: Inter Retrotransposons Amplified Polymorphism (IRAP), Retrotransposons Microsatellite Amplified Polymorphism (REMAP) and Inter Simple Sequence Repeat (ISSR) largely confirmed the absence of any intraspecific variation in wheat, rye and triticale. The comparative analysis of banding profiles between wheat and rye inbred lines revealed 34% of monomorphic (common to both parental species) bands for the ten different primer combinations used. The analysis of triticale plants uncovered nearly 51% of rearranged bands in the polyploid, being the majority of these modifications, due to the loss of rye bands (83%). Sequence analysis of rye fragments absent in triticale revealed for instance homology with hydroxyproline-rich glycoproteins (HRGP), a protein that belongs to a major family of inducible defence response proteins. Conversely, a wheat-specific band absent in triticale comprises a nested structure of copia-like retrotransposons elements, namely Claudia and Barbara. Sequencing of a polyploid-specific band (absent in both parents) revealed a microsatellite related sequence. Cytological studies using Fluorescent In Situ Hybridization (FISH) with REMAP products revealed a widespread distribution of retrotransposon and/or microsatellite flanking sequences on rye chromosomes, with a preferential accumulation in heterochromatic sub-telomeric domains. CONCLUSIONS/SIGNIFICANCE: Here, we used PCR-based molecular marker techniques involving retrotransposons and microsatellites to uncover polyploidization induced genetic restructuring in triticale. Sequence analysis of rearranged genomic fragments either from rye or wheat origin showed these to be retrotransposon-related as well as coding sequences. Further FISH analysis revealed possible chromosome hotspots for sequence rearrangements. The role of chromatin condensation on the origin of genomic rearrangements mediated by polyploidization in triticale is also discussed

Signaling from β1- and β2-adrenergic receptors is defined by differential interactions with PDE4

β1- and β2-adrenergic receptors (βARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by β1AR but not β2AR signaling, and chronic stimulation of the two receptors has opposing effects on myocyte apoptosis and cell survival. Differences in the assembly of macromolecular signaling complexes may explain the distinct biological outcomes. Here, we demonstrate that β1AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a β2AR/β-arrestin/PDE complex reported previously. The β1AR binds a PDE variant, PDE4D8, in a direct manner, and occupancy of the receptor by an agonist causes dissociation of this complex. Conversely, agonist binding to the β2AR is a prerequisite for the recruitment of a complex consisting of β-arrestin and the PDE4D variant, PDE4D5, to the receptor. We propose that the distinct modes of interaction with PDEs result in divergent cAMP signals in the vicinity of the two receptors, thus, providing an additional layer of complexity to enforce the specificity of β1- and β2-adrenoceptor signaling

Case-finding of dementia in general practice and effects of subsequent collaborative care; design of a cluster RCT

<p>Abstract</p> <p>Background</p> <p>In the primary care setting, dementia is often diagnosed relatively late in the disease process. Case finding and proactive collaborative care may have beneficial effects on both patient and informal caregiver by clarifying the cause of cognitive decline and changed behaviour and by enabling support, care planning and access to services.</p> <p>We aim to improve the recognition and diagnosis of individuals with dementia in general practice. In addition to this diagnostic aim, the effects of case finding and subsequent care on the mental health of individuals with dementia and the mental health of their informal carers are explored.</p> <p>Methods and design</p> <p>Design: cluster randomised controlled trial with process evaluation.</p> <p>Participants: 162 individuals ≥ 65 years, in 15 primary care practices, in whom GPs suspect cognitive impairment, but without a dementia diagnosis.</p> <p>Intervention; case finding and collaborative care: 2 trained practice nurses (PNs) invite all patients with suspected cognitive impairment for a brief functional and cognitive screening. If the cognitive tests are supportive of cognitive impairment, individuals are referred to their GP for further evaluation. If dementia is diagnosed, a comprehensive geriatric assessment takes place to identify other relevant geriatric problems that need to be addressed. Furthermore, the team of GP and PN provide information and support.</p> <p>Control: GPs provide care and diagnosis as usual.</p> <p>Main study parameters: after 12 months both groups are compared on: 1) incident dementia (and MCI) diagnoses and 2) patient and caregiver quality of life (QoL-AD; EQ5D) and mental health (MH5; GHQ 12) and caregiver competence to care (SSCQ). The process evaluation concerns facilitating and impeding factors to the implementation of this intervention. These factors are assessed on the care provider level, the care recipient level and on the organisational level.</p> <p>Discussion</p> <p>This study will provide insight into the diagnostic yield and the clinical effects of case finding and collaborative care for individuals with suspected cognitive impairment, compared to usual care. A process evaluation will give insight into the feasibility of this intervention.</p> <p>The first results are expected in the course of 2013.</p> <p>Trial registration</p> <p>NTR3389</p

The molecular pathology of p53 in primitive neuroectodermal tumours of the central nervous system

One hundred and one pre-treatment primary central primitive neuroectodermal tumours were analysed for the expression of p53 protein by immunohistochemistry using the monoclonal antibody DO-7. The staining intensity was classified into four groups: strong, medium, weak and negative and strong staining intensity was associated with the poorest survival. DNA sequencing of the p53 gene was performed in 28 cases representing all four staining groups. Mutations were found in only three of the strong staining tumours suggesting that DNA mutations were not common events and that in the majority of the tumours with over-expressed p53, the protein was likely to be wild-type. Results of immunohistochemistry showed a significantly positive relationship between the expression of p53 and Bax and Bcl-2 proteins, but not Waf-1. Multivariate analyses supported the prognostic value of p53 immunostaining in central primitive neuroectodermal tumours and also of age and gender of patients

Prediction of HIV-1 virus-host protein interactions using virus and host sequence motifs

<p>Abstract</p> <p>Background</p> <p>Host protein-protein interaction networks are altered by invading virus proteins, which create new interactions, and modify or destroy others. The resulting network topology favors excessive amounts of virus production in a stressed host cell network. Short linear peptide motifs common to both virus and host provide the basis for host network modification.</p> <p>Methods</p> <p>We focused our host-pathogen study on the binding and competing interactions of HIV-1 and human proteins. We showed that peptide motifs conserved across 70% of HIV-1 subtype B and C samples occurred in similar positions on HIV-1 proteins, and we documented protein domains that interact with these conserved motifs. We predicted which human proteins may be targeted by HIV-1 by taking pairs of human proteins that may interact via a motif conserved in HIV-1 and the corresponding interacting protein domain.</p> <p>Results</p> <p>Our predictions were enriched with host proteins known to interact with HIV-1 proteins ENV, NEF, and TAT (p-value < 4.26E-21). Cellular pathways statistically enriched for our predictions include the T cell receptor signaling, natural killer cell mediated cytotoxicity, cell cycle, and apoptosis pathways. Gene Ontology molecular function level 5 categories enriched with both predicted and confirmed HIV-1 targeted proteins included categories associated with phosphorylation events and adenyl ribonucleotide binding.</p> <p>Conclusion</p> <p>A list of host proteins highly enriched with those targeted by HIV-1 proteins can be obtained by searching for host protein motifs along virus protein sequences. The resulting set of host proteins predicted to be targeted by virus proteins will become more accurate with better annotations of motifs and domains. Nevertheless, our study validates the role of linear binding motifs shared by virus and host proteins as an important part of the crosstalk between virus and host.</p

First observations of separated atmospheric nu_mu and bar{nu-mu} events in the MINOS detector

The complete 5.4 kton MINOS far detector has been taking data since the beginning of August 2003 at a depth of 2070 meters water-equivalent in the Soudan mine, Minnesota. This paper presents the first MINOS observations of nuµ and [overline nu ]µ charged-current atmospheric neutrino interactions based on an exposure of 418 days. The ratio of upward- to downward-going events in the data is compared to the Monte Carlo expectation in the absence of neutrino oscillations, giving Rup/downdata/Rup/downMC=0.62-0.14+0.19(stat.)±0.02(sys.). An extended maximum likelihood analysis of the observed L/E distributions excludes the null hypothesis of no neutrino oscillations at the 98% confidence level. Using the curvature of the observed muons in the 1.3 T MINOS magnetic field nuµ and [overline nu ]µ interactions are separated. The ratio of [overline nu ]µ to nuµ events in the data is compared to the Monte Carlo expectation assuming neutrinos and antineutrinos oscillate in the same manner, giving R[overline nu ][sub mu]/nu[sub mu]data/R[overline nu ][sub mu]/nu[sub mu]MC=0.96-0.27+0.38(stat.)±0.15(sys.), where the errors are the statistical and systematic uncertainties. Although the statistics are limited, this is the first direct observation of atmospheric neutrino interactions separately for nuµ and [overline nu ]µ