187 research outputs found
Application of realistic effective interactions to the structure of the Zr isotopes
We calculate the low-lying spectra of the zirconium isotopes Z=40 with
neutron numbers from N=52 to N=60 using the 1p1/20g9/2 proton and
2s1d0g7/20h11/2 neutron sub-shells to define the model space. Effective
proton-proton, neutron--neutron and proton-neutron interactions have been
derived using 88Sr as closed core and employing perturbative many-body
techniques. The starting point is the nucleon-nucleon potential derived from
modern meson exchange models. The comprehensive shell-model calculation
performed in this work provides a qualitative reproduction of essential
properties such as the sub-shell closures in 96Zr and 98Zr.Comment: To appear in Phys Rev C, june 2000, 8 figs, Revtex latex styl
Toward a Consistent Description of the PNC Experiments in A=18-21 Nuclei
The experimental PNC results in F, F, Ne and the current
theoretical analysis show a discrepancy . If one interprets the small limit of
the experimentally extracted PNC matrix element for Ne as a destructive
interference between the isoscalar and the isovector contribution, then it is
difficult to understand why the isovector contribution in F is so small
while the isoscalar + isovector contribution in F is relatively large.
In order to understand the origin of this discrepancy a comparison of the
calculated PNC matrix elements was performed. It is shown that the F and
Ne matrix elements contain important contributions from 3
and 4 configuration and that the (0+1) calculations
give distorted results.Comment: REVTEX, 16 pages, 1 postscriptum figure uuencoded and appende
Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease
Loss of intestinal barrier function plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Shedding of intestinal epithelial cells is a potential cause of barrier loss during inflammation. The objectives of the study were (1) to determine whether cell shedding and barrier loss in humans can be detected by confocal endomicroscopy and (2) whether these parameters predict relapse of IBD
Doubly Constrained C-terminal of Roc (COR) Domain-Derived Peptides Inhibit Leucine-Rich Repeat Kinase 2 (LRRK2) Dimerization
Missense mutations along the leucine-rich repeat kinase 2 (LRRK2) protein are a major contributor to Parkinson's Disease (PD), the second most commonly occurring neurodegenerative disorder worldwide. We recently reported the development of allosteric constrained peptide inhibitors that target and downregulate LRRK2 activity through disruption of LRRK2 dimerization. In this study, we designed doubly constrained peptides with the objective of inhibiting C-terminal of Roc (COR)-COR mediated dimerization at the LRRK2 dimer interface. We show that the doubly constrained peptides are cell-permeant, bind wild-type and pathogenic LRRK2, inhibit LRRK2 dimerization and kinase activity, and inhibit LRRK2-mediated neuronal apoptosis, and in contrast to ATP-competitive LRRK2 kinase inhibitors, they do not induce the mislocalization of LRRK2 to skein-like structures in cells. This work highlights the significance of COR-mediated dimerization in LRRK2 activity while also highlighting the use of doubly constrained peptides to stabilize discrete secondary structural folds within a peptide sequence.</p
Shell Model Monte Carlo studies of neutron-rich nuclei in the 1s-0d-1p-0f shells
We demonstrate the feasibility of realistic Shell-Model Monte Carlo (SMMC)
calculations spanning multiple major shells, using a realistic interaction
whose bad saturation and shell properties have been corrected by a newly
developed general prescription. Particular attention is paid to the approximate
restoration of translational invariance. The model space consists of the full
sd-pf shells. We include in the study some well-known T=0 nuclei and several
unstable neutron-rich ones around N=20,28. The results indicate that SMMC can
reproduce binding energies, B(E2) transitions, and other observables with an
interaction that is practically parameter free. Some interesting insight is
gained on the nature of deep correlations. The validity of previous studies is
confirmed.Comment: 22 pages + 7 postscript figure
Microscopic theories of neutrino-^{12}C reactions
In view of the recent experiments on neutrino oscillations performed by the
LSND and KARMEN collaborations as well as of future experiments, we present new
theoretical results of the flux averaged and
cross sections. The approaches used are
charge-exchange RPA, charge-exchange RPA among quasi-particles (QRPA) and the
Shell Model. With a large-scale shell model calculation the exclusive cross
sections are in nice agreement with the experimental values for both reactions.
The inclusive cross section for coming from the decay-in-flight of
is to be compared to the experimental value
of , while the one due to
coming from the decay-at-rest of is which
agrees within experimental error bars with the measured values. The shell model
prediction for the decay-in-flight neutrino cross section is reduced compared
to the RPA one. This is mainly due to the different kind of correlations taken
into account in the calculation of the spin modes and partially due to the
shell-model configuration basis which is not large enough, as we show using
arguments based on sum-rules.Comment: 17 pages, latex, 5 figure
Allosteric Inhibition of Parkinson's-Linked LRRK2 by Constrained Peptides
Leucine-Rich Repeat Kinase 2 (LRRK2) is a large, multidomain protein with dual kinase and GTPase function that is commonly mutated in both familial and idiopathic Parkinson's Disease (PD). While dimerization of LRRK2 is commonly detected in PD models, it remains unclear whether inhibition of dimerization can regulate catalytic activity and pathogenesis. Here, we show constrained peptides that are cell-penetrant, bind LRRK2, and inhibit LRRK2 activation by downregulating dimerization. We further show that inhibited dimerization decreases kinase activity and inhibits ROS production and PD-linked apoptosis in primary cortical neurons. While many ATP-competitive LRRK2 inhibitors induce toxicity and mislocalization of the protein in cells, these constrained peptides were found to not affect LRRK2 localization. The ability of these peptides to inhibit pathogenic LRRK2 kinase activity suggests that disruption of dimerization may serve as a new allosteric strategy to downregulate PD-related signaling pathways.</p
A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus
The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses
Standardizing the classification of skin tears: validity and reliability testing of the International Skin Tear Advisory Panel Classification System in 44 countries
Background: Skin tears are acute wounds that are frequently misdiagnosed and under‐reported. A standardized and globally adopted skin tear classification system with supporting evidence for diagnostic validity and reliability is required to allow assessment and reporting in a consistent way. Objectives:To measure the validity and reliability of the International Skin Tear Advisory Panel (ISTAP) Classification System internationally. Methods: A multicountry study was set up to validate the content of the ISTAP Classification System through expert consultation in a two‐round Delphi procedure involving 17 experts from 11 countries. An online survey including 24 skin tear photographs was conducted in a convenience sample of 1601 healthcare professionals from 44 countries to measure diagnostic accuracy, agreement, inter‐rater reliability and intrarater reliability of the instrument. Results:A definition for the concept of a ‘skin flap’ in the area of skin tears was developed and added to the initial ISTAP Classification System consisting of three skin tear types. The overall agreement with the reference standard was 0·79 [95% confidence interval (CI) 0·79–0·80] and sensitivity ranged from 0·74 (95% CI 0·73–0·75) to 0·88 (95% CI 0·87–0·88). The inter‐rater reliability was 0·57 (95% CI 0·57–0·57). The Cohen's Kappa measuring intrarater reliability was 0·74 (95% CI 0·73–0·75). Conclusions: The ISTAP Classification System is supported by evidence for validity and reliability. The ISTAP Classification System should be used for systematic assessment and reporting of skin tears in clinical practice and research globally.info:eu-repo/semantics/publishedVersio
Social sciences research in neglected tropical diseases 2: A bibliographic analysis
The official published version of the article can be found at the link below.Background
There are strong arguments for social science and interdisciplinary research in the neglected tropical diseases. These diseases represent a rich and dynamic interplay between vector, host, and pathogen which occurs within social, physical and biological contexts. The overwhelming sense, however, is that neglected tropical diseases research is a biomedical endeavour largely excluding the social sciences. The purpose of this review is to provide a baseline for discussing the quantum and nature of the science that is being conducted, and the extent to which the social sciences are a part of that.
Methods
A bibliographic analysis was conducted of neglected tropical diseases related research papers published over the past 10 years in biomedical and social sciences. The analysis had textual and bibliometric facets, and focussed on chikungunya, dengue, visceral leishmaniasis, and onchocerciasis.
Results
There is substantial variation in the number of publications associated with each disease. The proportion of the research that is social science based appears remarkably consistent (<4%). A textual analysis, however, reveals a degree of misclassification by the abstracting service where a surprising proportion of the "social sciences" research was pure clinical research. Much of the social sciences research also tends to be "hand maiden" research focused on the implementation of biomedical solutions.
Conclusion
There is little evidence that scientists pay any attention to the complex social, cultural, biological, and environmental dynamic involved in human pathogenesis. There is little investigator driven social science and a poor presence of interdisciplinary science. The research needs more sophisticated funders and priority setters who are not beguiled by uncritical biomedical promises
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