404 research outputs found
Monte Carlo Study of Supernova Neutrino Spectra Formation
The neutrino flux and spectra formation in a supernova core is studied by
using a Monte Carlo code. The dominant opacity contribution for nu_mu and
nu_tau is elastic scattering on nucleons. In addition we switch on or off a
variety of processes which allow for the exchange of energy or the creation and
destruction of neutrino pairs, notably nucleon bremsstrahlung, the e^+ e^- pair
annihilation process and nu_e-bar nu_e -> nu_{mu,tau} nu_{mu,tau}-bar, recoil
and weak magnetism in elastic nucleon scattering, elastic scattering on
electrons and positrons and elastic scattering on electron neutrinos and
anti-neutrinos. The least important processes are neutrino-neutrino scattering
and e^+ e^- annihilation. The formation of the spectra and fluxes of nu_mu is
dominated by the nucleonic processes, i.e. bremsstrahlung and elastic
scattering with recoil, but also nu_e nu_e-bar annihilation and nu_mu e^\pm
scattering contribute significantly. When all processes are included, the
spectral shape of the emitted neutrino flux is always ``pinched,'' i.e. the
width of the spectrum is smaller than that of a thermal spectrum with the same
average energy. In all of our cases we find that the average nu_mu-bar energy
exceeds the average nu_e-bar energy by only a small amount, 10% being a typical
number. Weak magnetism effects cause the opacity of nu_mu to differ slightly
from that of nu_mu-bar, translating into differences of the luminosities and
average energies of a few percent. Depending on the density, temperature, and
composition profile, the flavor-dependent luminosities L_{nu_e}$, L_{nu_e-bar},
and L_{nu_mu} can mutually differ from each other by up to a factor of two in
either direction.Comment: 33 pages, 16 eps-figs, submitted to ApJ. Sections added: weak
magnetism, discussion of different analytic fits to the spectra and detailed
spectral shap
Functional coupling analysis suggests link between the obesity gene FTO and the BDNF-NTRK2 signaling pathway
<p>Abstract</p> <p>Background</p> <p>The Fat mass and obesity gene (FTO) has been identified through genome wide association studies as an important genetic factor contributing to a higher body mass index (BMI). However, the molecular context in which this effect is mediated has yet to be determined. We investigated the potential molecular network for FTO by analyzing co-expression and protein-protein interaction databases, Coxpresdb and IntAct, as well as the functional coupling predicting multi-source database, FunCoup. Hypothalamic expression of FTO-linked genes defined with this bioinformatics approach was subsequently studied using quantitative real time-PCR in mouse feeding models known to affect FTO expression.</p> <p>Results</p> <p>We identified several candidate genes for functional coupling to FTO through database studies and selected nine for further study in animal models. We observed hypothalamic expression of Profilin 2 (Pfn2), cAMP-dependent protein kinase catalytic subunit beta (Prkacb), Brain derived neurotrophic factor (Bdnf), neurotrophic tyrosine kinase, receptor, type 2 (Ntrk2), Signal transducer and activator of transcription 3 (Stat3), and Btbd12 to be co-regulated in concert with Fto. Pfn2 and Prkacb have previously not been linked to feeding regulation.</p> <p>Conclusions</p> <p>Gene expression studies validate several candidates generated through database studies of possible FTO-interactors. We speculate about a wider functional role for FTO in the context of current and recent findings, such as in extracellular ligand-induced neuronal plasticity via NTRK2/BDNF, possibly via interaction with the transcription factor CCAAT/enhancer binding protein β (C/EBPβ).</p
an interim analysis from the prospective GMMG-MM5 trial
We investigated the impact of subcutaneous versus intravenous bortezomib in
the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared
bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide,
and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based
on data from relapsed myeloma, the route of administration for bortezomib was
changed from intravenous to subcutaneous after 314 of 604 patients had been
enrolled. We analyzed 598 patients who received at least one dose of trial
medication. Adverse events were reported more frequently in patients treated
with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates
of grade 2 or more peripheral neuropathy were higher in patients treated with
intravenous bortezomib during the third cycle (intravenous=8%;
subcutaneous=2%, P=0.001). Overall response rates were similar in patients
treated intravenously or subcutaneously. The presence of International Staging
System stage III disease, renal impairment or adverse cytogenetic
abnormalities did not have a negative impact on overall response rates in
either group. To our knowledge this is the largest study to present data
comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma.
We show better tolerance and similar overall response rates for subcutaneous
compared to intravenous bortezomib. The clinical trial is registered at
eudract.ema.europa.eu as n. 2010-019173-16
a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma
Background Despite novel therapeutic agents, most multiple myeloma (MM)
patients eventually relapse. Two large phase III trials have shown
significantly improved response rates (RR) of lenalidomide/dexamethasone
compared with placebo/dexamethasone in relapsed MM (RMM) patients. These
results have led to the approval of lenalidomide for RMM patients and
lenalidomide/dexamethasone has since become a widely accepted second-line
treatment. Furthermore, in RMM patients consolidation with high-dose
chemotherapy plus autologous stem cell transplantation has been shown to
significantly increase progression free survival (PFS) as compared to
cyclophosphamide in a phase III trial. The randomized prospective ReLApsE
trial is designed to evaluate PFS after lenalidomide/dexamethasone induction,
high-dose chemotherapy consolidation plus autologous stem cell transplantation
and lenalidomide maintenance compared with the well-established
lenalidomide/dexamethasone regimen in RMM patients. Methods/Design ReLApsE is
a randomized, open, multicenter phase III trial in a planned study population
of 282 RMM patients. All patients receive three lenalidomide/dexamethasone
cycles and - in absence of available stem cells from earlier harvesting -
undergo peripheral blood stem cell mobilization and harvesting. Subsequently,
patients in arm A continue on consecutive lenalidomide/dexamethasone cycles,
patients in arm B undergo high dose chemotherapy plus autologous stem cell
transplantation followed by lenalidomide maintenance until discontinuation
criteria are met. Therapeutic response is evaluated after the 3rd (arm A + B)
and the 5th lenalidomide/dexamethasone cycle (arm A) or 2 months after
autologous stem cell transplantation (arm B) and every 3 months thereafter
(arm A + B). After finishing the study treatment, patients are followed up for
survival and subsequent myeloma therapies. The expected trial duration is 6.25
years from first patient in to last patient out. The primary endpoint is PFS,
secondary endpoints include overall survival (OS), RR, time to best response
and the influence of early versus late salvage high dose chemotherapy plus
autologous stem cell transplantation on OS. Discussion This phase III trial is
designed to evaluate whether high dose chemotherapy plus autologous stem cell
transplantation and lenalidomide maintenance after lenalidomide/dexamethasone
induction improves PFS compared with the well-established continued
lenalidomide/dexamethasone regimen in RMM patients. Trial registration:
ISRCTN16345835 (date of registration 2010-08-24)
Recommended from our members
Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma
Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target– and tissue-specific manner to mediate heightened expression of a subset of IL-4– and IL-13–responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα–dependent signaling
NS1 Specific CD8(+) T-Cells with Effector Function and TRBV11 Dominance in a Patient with Parvovirus B19 Associated Inflammatory Cardiomyopathy
Background: Parvovirus B19 (B19V) is the most commonly detected virus in endomyocardial biopsies (EMBs) from patients with inflammatory cardiomyopathy (DCMi). Despite the importance of T-cells in antiviral defense, little is known about the role of B19V specific T-cells in this entity.
Methodology and Principal Findings: An exceptionally high B19V viral load in EMBs (115,091 viral copies/mg nucleic acids), peripheral blood mononuclear cells (PBMCs) and serum was measured in a DCMi patient at initial presentation, suggesting B19V viremia. The B19V viral load in EMBs had decreased substantially 6 and 12 months afterwards, and was not traceable in PBMCs and the serum at these times. Using pools of overlapping peptides spanning the whole B19V proteome, strong CD8(+) T-cell responses were elicited to the 10-amico-acid peptides SALKLAIYKA (19.7% of all CD8(+) cells) and QSALKLAIYK (10%) and additional weaker responses to GLCPHCINVG (0.71%) and LLHTDFEQVM (0.06%). Real-time RT-PCR of IFN gamma secretion-assay-enriched T-cells responding to the peptides, SALKLAIYKA and GLCPHCINVG, revealed a disproportionately high T-cell receptor Vbeta (TRBV) 11 expression in this population. Furthermore, dominant expression of type-1 (IFN gamma, IL2, IL27 and Tbet) and of cytotoxic T-cell markers (Perforin and Granzyme B) was found, whereas gene expression indicating type-2 (IL4, GATA3) and regulatory T-cells (FoxP3) was low.
Conclusions: Our results indicate that B19V Ag-specific CD8(+) T-cells with effector function are involved in B19V associated DCMi. In particular, a dominant role of TRBV11 and type-1/CTL effector cells in the T-cell mediated antiviral immune response is suggested. The persistence of B19V in the endomyocardium is a likely antigen source for the maintenance of CD8(+) T-cell responses to the identified epitopes
Guiding principles for determining work shift duration and addressing the effects of work shift duration on performance, safety, and health
The article of record as published may be found at http://dx.doi.org/10.1093/sleep/zsab161Risks associated with fatigue that accumulates during work shifts have historically been managed through working time arrangements that specify fixed maximum durations of work shifts and minimum durations of time off. By themselves, such arrangements are not sufficient to curb risks to performance, safety, and health caused by misalignment between work schedules and the biological regulation of waking alertness and sleep. Science-based approaches for determining shift duration and mitigating associated risks, while addressing operational needs, require: 1) a recognition of the factors contributing to fatigue and fatigue-related risks; 2) an understanding of evidence-based countermeasures that may reduce fatigue and/or fatigue-related risks; and 3) an informed approach to selecting workplace-specific strategies for managing work hours. We propose a series of guiding principles to assist stakeholders with designing a shift duration decision-making process that effectively balances the need to meet operational demands with the need to manage fatigue-related risks.Academy of Sleep Medicine (AASM)Sleep Research Societ
Recommended from our members
Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.
Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes
- …