MEK/ERK-mediated phosphorylation of Bim is required to ensure survival of T and B lymphocytes during mitogenic stimulation

Survival and death of lymphocytes are regulated by the balance between pro- and antiapoptotic members of the Bcl-2 family; this is coordinated with the control of cell cycling and differentiation. Bim, a proapoptotic BH3-only member of the Bcl-2 family, can be regulated by MEK/ERK-mediated phosphorylation, which affects its binding to pro-survival Bcl-2 family members and its turnover. We investigated Bim modifications in mouse B and T lymphoid cells after exposure to apoptotic stimuli and during mitogenic activation. Treatment with ionomycin or cytokine withdrawal caused an elevation in Bim(EL), the most abundant Bim isoform. In contrast, in mitogenically stimulated T and B cells, Bim(EL) was rapidly phosphorylated, and its levels declined. Pharmacological inhibitors of MEK/ERK signaling prevented both of these changes in Bim, reduced proliferation, and triggered apoptosis of mitogen-stimulated T and B cells. Loss of Bim prevented this cell killing but did not restore cell cycling. These results show that during mitogenic stimulation of T and B lymphocytes MEK/ERK signaling is critical for two distinct processes, cell survival, mediated (at least in part) through phosphorylation and consequent inhibition of Bim, and cell cycling, which proceeds independently of Bim inactivation.

Detection of Clostridium perfringens type C in pig herds following disease outbreak and subsequent vaccination

Immunisation of sows using Clostridium perfringens type C toxoid vaccines is recommended to prevent necrotising enteritis (NE) on pig breeding farms. Absence of disease, however, oftentimes leads to the false assumption of pathogens being eradicated. The prevalence of C perfringens type C was determined by PCR in faecal samples of piglets and sows in three Swiss pig breeding farms two to four years after implementation of a vaccination programme following disease outbreaks. C perfringens type C could still be detected several years after an outbreak despite absence of NE. In-herd prevalence of the pathogens varied significantly between the farms and was also lower compared with a farm which experienced a recent outbreak. In conclusion, C perfringens type C can be detected on once-affected farms, even in the absence of NE for several years.

Synthesis of (5' S )-5'- C -Alkyl-2'-deoxynucleosides

We describe the synthesis of (5 S )-5- C -butylthymidine ( 5a ), of the (5 S )-5- C -butyl- and the (5 S )-5- C -isopentyl derivatives 16a and 16b of 2-deoxy-5-methylcytidine, as well as of the corresponding cyanoethyl phosphoramidites 9a , b and 14a , b , respectively. Starting from thymidin-5-al 1 , the alkyl chain at C(5) is introduced via Wittig chemistry to selectively yield the ( Z )-olefin derivatives 3a and 3b ( Scheme 2 ). The secondary OH function at C(5) is then introduced by epoxidation followed by regioselective reduction of the epoxy derivatives 4a and 4b with diisobutylaluminium hydride. In the latter step, a kinetic resolution of the diastereoisomer mixture 4a and 4b occurs, yielding the alkylated nucleoside 2a and 2b , respectively, with (5 S )-configuration in high diastereoisomer purity (de=94%). The corresponding 2-deoxy-5-methylcytidine derivatives are obtained from the protected 5-alkylated thymidine derivatives 7a and 7b via known base interconversion processes in excellent yields ( Scheme 3 ). Application of the same strategy to the purine nucleoside 2-deoxyadenine to obtain 5- C -butyl-2-deoxyadenosine 25 proved to be difficult due to the sensitivity of the purine base to hydride-based reducing agents ( Scheme 4 ).

Retrieving the paleoclimatic signal from the deeper part of the EPICA Dome C ice core

An important share of paleoclimatic information is buried within the lowermost layers of deep ice cores. Because improving our records further back in time is one of the main challenges in the near future, it is essential to judge how deep these records remain unaltered, since the proximity of the bedrock is likely to interfere both with the recorded temporal sequence and the ice properties. In this paper, we present a multiparametric study (δD-δ18Oice, δ18Oatm, total air content, CO2, CH4, N2O, dust, high-resolution chemistry, ice texture) of the bottom 60 m of the EPICA (European Project for Ice Coring in Antarctica) Dome C ice core from central Antarctica. These bottom layers were subdivided into two distinct facies: the lower 12 m showing visible solid inclusions (basal dispersed ice facies) and the upper 48 m, which we will refer to as the "basal clean ice facies". Some of the data are consistent with a pristine paleoclimatic signal, others show clear anomalies. It is demonstrated that neither large-scale bottom refreezing of subglacial water, nor mixing (be it internal or with a local basal end term from a previous/initial ice sheet configuration) can explain the observed bottom-ice properties. We focus on the high-resolution chemical profiles and on the available remote sensing data on the subglacial topography of the site to propose a mechanism by which relative stretching of the bottom-ice sheet layers is made possible, due to the progressively confining effect of subglacial valley sides. This stress field change, combined with bottom-ice temperature close to the pressure melting point, induces accelerated migration recrystallization, which results in spatial chemical sorting of the impurities, depending on their state (dissolved vs. solid) and if they are involved or not in salt formation. This chemical sorting effect is responsible for the progressive build-up of the visible solid aggregates that therefore mainly originate "from within", and not from incorporation processes of debris from the ice sheet's substrate. We further discuss how the proposed mechanism is compatible with the other ice properties described. We conclude that the paleoclimatic signal is only marginally affected in terms of global ice properties at the bottom of EPICA Dome C, but that the timescale was considerably distorted by mechanical stretching of MIS20 due to the increasing influence of the subglacial topography, a process that might have started well above the bottom ice. A clear paleoclimatic signal can therefore not be inferred from the deeper part of the EPICA Dome C ice core. Our work suggests that the existence of a flat monotonic ice–bedrock interface, extending for several times the ice thickness, would be a crucial factor in choosing a future "oldest ice" drilling location in Antarctica.

Do new biologics meet the unmet medical need in rheumatoid arthritis? Safety and efficacy of abatacept following B-cell depletion

Sir, anti TNF-α agents (aTNFs) are the most commonly prescribed biological agents in RA. More recently abatacept (ABA), a T-cell costimulation modulator, and rituximab (RTX), a monoclonal antibody directed against CD20, have become available. Observational studies suggest that switching to a new drug class may be more effective in uncontrolled RA than switching to a class of biologics to which the patient had unsuccessfully been exposed [1]. Information about the efficacy and safety of cycling strategies through third-line biologics is lacking. This study aimed to analyse the effectiveness and safety of switching patients to ABA as the third biological class after failure of aTNF plus RTX. The Swiss Clinical Quality Management (SCQM) programme for RA is a longitudinal population-based cohort, which has been approved by the local ethics committees of all participating centres [2]. For this analysis, we collected all the …