TNFα and GM-CSF-induced activation of the CAEV promoter is independent of AP-1

AbstractCaprine arthritis encephalitis virus transcription is under the control of the viral promoter within the long terminal repeat. Previous studies with the closely related maedi visna lentivirus have indicated that viral transcription is dependent upon the AP-1 transcription factor. Other studies have indicated a potential role for the cytokines TNFα and GM-CSF in CAEV pathogenesis by increasing viral loads in infected tissues. The hypotheses that AP-1 transcription factors are necessary for transcriptional activation of the CAEV promoter and that CAEV transcriptional activation results from treatment with the cytokines GM-CSF and TNFα were tested with a stably transduced U937 cell line. Here, we found that TNFα and GM-CSF activated CAEV transcription in U937 cells. However, this activation effect was not blocked by SP600125, an inhibitor of Jun N-terminal kinase. SP600125 effectively prevented Jun phosphorylation in cells subsequently treated with cytokines. The cytokines TNFα and GM-CSF therefore activate CAEV transcription, and this effect occurs independently of AP-1. A set of progressive deletion mutants was utilized to show that TNFα-induced expression depends on an element or elements within the U3 70-bp repeat

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

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

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

Effects of degree and timing of social housing on reversal learning and response to novel objects in dairy calves

Rodents and primates deprived of early social contact exhibit deficits in learning and behavioural flexibility. They often also exhibit apparent signs of elevated anxiety, although the relationship between these effects has not been studied. To investigate whether dairy calves are similarly affected, we first compared calves housed in standard individual pens (n = 7) to those housed in a dynamic group with access to their mothers (n = 8). All calves learned to approach the correct stimulus in a visual discrimination task. Only one individually housed calf was able to re-learn the task when the stimuli were reversed, compared to all but one calf from the group. A second experiment investigated whether this effect might be explained by anxiety in individually housed animals interfering with their learning, and tested varying degrees of social contact in addition to the complex group: pair housing beginning early (approximately 6 days old) and late (6 weeks old). Again, fewer individually reared calves learned the reversal task (2 of 10 or 20%) compared to early paired and grouped calves (16 of 21 or 76% of calves). Late paired calves had intermediate success. Individually housed calves were slower to touch novel objects, but the magnitude of the fear response did not correlate with reversal performance. We conclude that individually housed calves have learning deficits, but these deficits were not likely associated with increased anxiety