Efeito da qualidade do tratamento durante a lactação sobre o comportamento dos leitões logo após o desmame.

bitstream/item/56394/1/publicacao-490.pdfProjeto/Plano de Ação: 03.08.06.008

O desenvolvimento do comportamento ingestivo e social de leitões lactentes.

bitstream/item/56391/1/publicacao-491.pdfProjeto/Plano de Ação: 01.06.06.001

β\beta-Decay Spectrum, Response Function and Statistical Model for Neutrino Mass Measurements with the KATRIN Experiment

The objective of the Karlsruhe Tritium Neutrino (KATRIN) experiment is to determine the effective electron neutrino mass $m(\nu_\text{e})$ with an unprecedented sensitivity of $0.2\,\text{eV}$ (90\% C.L.) by precision electron spectroscopy close to the endpoint of the $\beta$ decay of tritium. We present a consistent theoretical description of the $\beta$ electron energy spectrum in the endpoint region, an accurate model of the apparatus response function, and the statistical approaches suited to interpret and analyze tritium $\beta$ decay data observed with KATRIN with the envisaged precision. In addition to providing detailed analytical expressions for all formulae used in the presented model framework with the necessary detail of derivation, we discuss and quantify the impact of theoretical and experimental corrections on the measured $m(\nu_\text{e})$. Finally, we outline the statistical methods for parameter inference and the construction of confidence intervals that are appropriate for a neutrino mass measurement with KATRIN. In this context, we briefly discuss the choice of the $\beta$ energy analysis interval and the distribution of measuring time within that range.Comment: 27 pages, 22 figures, 2 table

A influência do ambiente físico e social no bem-estar de leitões desmamados.

bitstream/item/56411/1/publicacao-493.pdfProjeto/Plano de Ação: 01.06.06.001

Monitoring of the operating parameters of the KATRIN Windowless Gaseous Tritium Source

The Karlsruhe Tritium Neutrino (KATRIN) experiment will measure the absolute mass scale of neutrinos with a sensitivity of \m_{\nu} = 200 meV/c$^2$ by high-precision spectroscopy close to the tritium beta-decay endpoint at 18.6 keV. Its Windowless Gaseous Tritium Source (WGTS) is a beta-decay source of high intensity ($10^{11}$/s) and stability, where high-purity molecular tritium at 30 K is circulated in a closed loop with a yearly throughput of 10 kg. To limit systematic effects the column density of the source has to be stabilised at the 0.1% level. This requires extensive sensor instrumentation and dedicated control and monitoring systems for parameters such as the beam tube temperature, injection pressure, gas composition and others. Here we give an overview of these systems including a dedicated Laser-Raman system as well as several beta-decay activity monitors. We also report on results of the WGTS demonstrator and other large-scale test experiments giving proof-of-principle that all parameters relevant to the systematics can be controlled and monitored on the 0.1% level or better. As a result of these works, the WGTS systematics can be controlled within stringent margins, enabling the KATRIN experiment to explore the neutrino mass scale with the design sensitivity.Comment: 32 pages, 13 figures. modification to title, typos correcte

Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing

The anti-FcRH5/CD3 T cell-dependent bispecific antibody (TDB) targets the B cell lineage marker FcRH5 expressed in multiple myeloma (MM) tumor cells. We demonstrate that TDBs trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB kills human plasma cells and patient-derived myeloma cells at picomolar concentrations and results in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys. These data demonstrate the potential for the anti-FcRH5/CD3 TDB, alone or in combination with inhibition of PD-1/PD-L1 signaling, in the treatment of MM and other B cell malignancies.This work was supported by a Sir Henry Dale Fellowship (J.R.J.) jointly funded by the Wellcome Trust and the Royal Society (grant number: 099966/Z/12/Z). PhD studentships (S.A.M. and M.J.H.) were funded by the Wellcome Trust (grant number: 102195/Z/13/Z)

Clinical predictors of response to cognitive-behavioral therapy in pediatric anxiety disorders: the genes for treatment (GxT) study.

OBJECTIVE The Genes for Treatment study is an international, multisite collaboration exploring the role of genetic, demographic, and clinical predictors in response to cognitive-behavioral therapy (CBT) in pediatric anxiety disorders. The current article, the first from the study, examined demographic and clinical predictors of response to CBT. We hypothesized that the child's gender, type of anxiety disorder, initial severity and comorbidity, and parents' psychopathology would significantly predict outcome. METHOD A sample of 1,519 children 5 to 18 years of age with a primary anxiety diagnosis received CBT across 11 sites. Outcome was defined as response (change in diagnostic severity) and remission (absence of the primary diagnosis) at each time point (posttreatment, 3-, 6-, and/or 12-month follow-up) and analyzed using linear and logistic mixed models. Separate analyses were conducted using data from posttreatment and follow-up assessments to explore the relative importance of predictors at these time points. RESULTS Individuals with social anxiety disorder (SoAD) had significantly poorer outcomes (poorer response and lower rates of remission) than those with generalized anxiety disorder (GAD). Although individuals with specific phobia (SP) also had poorer outcomes than those with GAD at posttreatment, these differences were not maintained at follow-up. Both comorbid mood and externalizing disorders significantly predicted poorer outcomes at posttreatment and follow-up, whereas self-reported parental psychopathology had little effect on posttreatment outcomes but significantly predicted response (although not remission) at follow-up. CONCLUSION SoAD, nonanxiety comorbidity, and parental psychopathology were associated with poorer outcomes after CBT. The results highlight the need for enhanced treatments for children at risk for poorer outcomes

Targeting FGFR4 Inhibits Hepatocellular Carcinoma in Preclinical Mouse Models

The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4–FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1). LD1 inhibited: 1) FGF1 and FGF19 binding to FGFR4, 2) FGFR4–mediated signaling, colony formation, and proliferation in vitro, and 3) tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease

The INNs and outs of antibody nonproprietary names

An important step in drug development is the assignment of an International Nonproprietary Name (INN) by the World Health Organization (WHO) that provides healthcare professionals with a unique and universally available designated name to identify each pharmaceutical substance. Monoclonal antibody INNs comprise a –mab suffix preceded by a substem indicating the antibody type, e.g., chimeric (-xi-), humanized (-zu-), or human (-u-). The WHO publishes INN definitions that specify how new monoclonal antibody therapeutics are categorized and adapts the definitions to new technologies. However, rapid progress in antibody technologies has blurred the boundaries between existing antibody categories and created a burgeoning array of new antibody formats. Thus, revising the INN system for antibodies is akin to aiming for a rapidly moving target. The WHO recently revised INN definitions for antibodies now to be based on amino acid sequence identity. These new definitions, however, are critically flawed as they are ambiguous and go against decades of scientific literature. A key concern is the imposition of an arbitrary threshold for identity against human germline antibody variable region sequences. This leads to inconsistent classification of somatically mutated human antibodies, humanized antibodies as well as antibodies derived from semi-synthetic/synthetic libraries and transgenic animals. Such sequence-based classification implies clear functional distinction between categories (e.g., immunogenicity). However, there is no scientific evidence to support this. Dialog between the WHO INN Expert Group and key stakeholders is needed to develop a new INN system for antibodies and to avoid confusion and miscommunication between researchers and clinicians prescribing antibodies

Genome-wide association study of response to cognitive-behavioural therapy in children with anxiety disorders

Background Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. Aims To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980). Method Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. Results No variants passed a genome-wide significance threshold (P = 5×10−8) in either analysis. Four variants met criteria for suggestive significance (P<5×10−6) in association with response post-treatment, and three variants in the 6-month follow-up analysis. Conclusions This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts