Detection of Water Vapor in the Photosphere of Arcturus

We report detections of pure rotation lines of OH and H2O in the K1.5 III red-giant star Arcturus (alpha Bootis) using high-resolution, infrared spectra covering the regions 806-822 cm-1 (12.2-12.4 um) and 884-923 cm-1 (10.8-11.3 um). Arcturus is the hottest star yet to show water-vapor features in its disk-averaged spectrum. We argue that the water vapor lines originate from the photosphere, albeit in the outer layers. We are able to predict the observed strengths of OH and H2O lines satisfactorily after lowering the temperature structure of the very outer parts of the photosphere (log tau_500=-3.8 and beyond) compared to a flux-constant, hydrostatic, standard MARCS model photosphere. Our new model is consistently calculated including chemical equilibrium and radiative transfer from the given temperature structure. Possible reasons for a temperature decrease in the outer-most parts of the photosphere and the assumed break-down of the assumptions made in classical model-atmosphere codes are discussed.Comment: To appear in ApJ. See also http://www.astro.uu.se/~ryde/ART

In vivo activity of a mixture of two human monoclonal antibodies (anti-HBs) in a chronic hepatitis B virus carrier chimpanzee

A 35-year-old female hepatitis B virus carrier chimpanzee was infused with one dose of a mixture of human monoclonal antibodies 9H9 and 4-7B (antibodies against hepatitis B virus surface antigen; HBsAg). Blood samples were taken before and up to 3 weeks after infusion. HBsAg and antibodies against HBsAg (anti-HBs) were quantified by radioimmunoassay and enzyme immunoassay. Free anti-HBs was never detected. Thirty min after the start of the infusion the HBsAg level was minimal with maximum loading of the chimpanzee HBsAg with human immunoglobulin. HBsAg complexes could be dissociated by acid treatment. The HBsAg level was completely restored on day 7. Similar results were obtained for the preS1-containing particles that may represent the infectious viral particles in the chimpanzee serum. A mouse monoclonal anti-HBs (HBs.OT40) was found to compete with 9H9 in artificial immune complexes with the pre-treatment HBsAg from the chimpanzee. Used as a conjugate, HBs.OT40 yielded a maximum decrease in the signal in the 30 min sample compared to non-competing anti-HBs conjugates. This indicates binding of HBsAg with 9H9 in the circulation of the chimpanzee. Immune-complexed 4-7B could not be detected by its corresponding 4-7B peptide conjugate, probably due to its low concentration in the complexes. It is concluded that human monoclonal anti-HBs can effectively reduce the level of HBsAg in serum from this chronic carrier. Monoclonals 9H9 and 4-7B may complement each other due to their different mechanisms of inactivation, probably with higher efficiency than that monitored by our HBsAg screening assays

Bcl-2 protein family: Implications in vascular apoptosis and atherosclerosis

Apoptosis has been recognized as a central component in the pathogenesis of atherosclerosis, in addition to the other human pathologies such as cancer and diabetes. The pathophysiology of atherosclerosis is complex, involving both apoptosis and proliferation at different phases of its progression. Oxidative modification of lipids and inflammation differentially regulate the apoptotic and proliferative responses of vascular cells during progression of the atherosclerotic lesion. Bcl-2 proteins act as the major regulators of extrinsic and intrinsic apoptosis signalling pathways and more recently it has become evident that they mediate the apoptotic response of vascular cells in response to oxidation and inflammation either in a provocative or an inhibitory mode of action. Here we address Bcl-2 proteins as major therapeutic targets for the treatment of atherosclerosis and underscore the need for the novel preventive and therapeutic interventions against atherosclerosis, which should be designed in the light of molecular mechanisms regulating apoptosis of vascular cells in atherosclerotic lesions

The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer

available in PMC 2011 February 3.MCL-1 has emerged as a major oncogenic and chemoresistance factor. A screen of stapled peptide helices identified the MCL-1 BH3 domain as selectively inhibiting MCL-1 among the related anti-apoptotic Bcl-2 family members, providing insights into the molecular determinants of binding specificity and a new approach for sensitizing cancer cells to apoptosis.National Institutes of Health (U.S.) (NIH award 5RO1GM084181)National Institutes of Health (U.S.) (NIH grant 5P01CA92625)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F31CA144566)Burroughs Wellcome Fund (Career Award

What are the basic self-monitoring components for cardiovascular risk management?

<p>Abstract</p> <p>Background</p> <p>Self-monitoring is increasingly recommended as a method of managing cardiovascular disease. However, the design, implementation and reproducibility of the self-monitoring interventions appear to vary considerably. We examined the interventions included in systematic reviews of self-monitoring for four clinical problems that increase cardiovascular disease risk.</p> <p>Methods</p> <p>We searched Medline and Cochrane databases for systematic reviews of self-monitoring for: heart failure, oral anticoagulation therapy, hypertension and type 2 diabetes. We extracted data using a pre-specified template for the identifiable components of the interventions for each disease. Data was also extracted on the theoretical basis of the education provided, the rationale given for the self-monitoring regime adopted and the compliance with the self-monitoring regime by the patients.</p> <p>Results</p> <p>From 52 randomized controlled trials (10,388 patients) we identified four main components in self-monitoring interventions: education, self-measurement, adjustment/adherence and contact with health professionals. Considerable variation in these components occurred across trials and conditions, and often components were poorly described. Few trials gave evidence-based rationales for the components included and self-measurement regimes adopted.</p> <p>Conclusions</p> <p>The components of self-monitoring interventions are not well defined despite current guidelines for self-monitoring in cardiovascular disease management. Few trials gave evidence-based rationales for the components included and self-measurement regimes adopted. We propose a checklist of factors to be considered in the design of self-monitoring interventions which may aid in the provision of an evidence-based rationale for each component as well as increase the reproducibility of effective interventions for clinicians and researchers.</p

Mutual Regulation of Bcl-2 Proteins Independent of the BH3 Domain as Shown by the BH3-Lacking Protein Bcl-xAK

The BH3 domain of Bcl-2 proteins was regarded as indispensable for apoptosis induction and for mutual regulation of family members. We recently described Bcl-xAK, a proapoptotic splice product of the bcl-x gene, which lacks BH3 but encloses BH2, BH4 and a transmembrane domain. It remained however unclear, how Bcl-xAK may trigger apoptosis

Shaping a screening file for maximal lead discovery efficiency and effectiveness: elimination of molecular redundancy

High Throughput Screening (HTS) is a successful strategy for finding hits and leads that have the opportunity to be converted into drugs. In this paper we highlight novel computational methods used to select compounds to build a new screening file at Pfizer and the analytical methods we used to assess their quality. We also introduce the novel concept of molecular redundancy to help decide on the density of compounds required in any region of chemical space in order to be confident of running successful HTS campaigns

Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl

Antiapoptotic B-cell lymphoma 2 (Bcl-2) targets the inositol 1,4,5-trisphosphate receptor (IP3R) via its BH4 domain, thereby suppressing IP3R Ca2+-flux properties and protecting against Ca2+-dependent apoptosis. Here, we directly compared IP3R inhibition by BH4-Bcl-2 and BH4-Bcl-Xl. In contrast to BH4-Bcl-2, BH4-Bcl-Xl neither bound the modulatory domain of IP3R nor inhibited IP3-induced Ca2+ release (IICR) in permeabilized and intact cells. We identified a critical residue in BH4-Bcl-2 (Lys17) not conserved in BH4-Bcl-Xl (Asp11). Changing Lys17 into Asp in BH4-Bcl-2 completely abolished its IP3R-binding and -inhibitory properties, whereas changing Asp11 into Lys in BH4-Bcl-Xl induced IP3R binding and inhibition. This difference in IP3R regulation between BH4-Bcl-2 and BH4-Bcl-Xl controls their antiapoptotic action. Although both BH4-Bcl-2 and BH4-Bcl-Xl had antiapoptotic activity, BH4-Bcl-2 was more potent than BH4-Bcl-Xl. The effect of BH4-Bcl-2, but not of BH4-Bcl-Xl, depended on its binding to IP(3)Rs. In agreement with the IP3R-binding properties, the antiapoptotic activity of BH4-Bcl-2 and BH4-Bcl-Xl was modulated by the Lys/Asp substitutions. Changing Lys17 into Asp in full-length Bcl-2 significantly decreased its binding to the IP3R, its ability to inhibit IICR and its protection against apoptotic stimuli. A single amino-acid difference between BH4-Bcl-2 and BH4-Bcl-Xl therefore underlies differential regulation of IP(3)Rs and Ca2+-driven apoptosis by these functional domains. Mutating this residue affects the function of Bcl-2 in Ca2+ signaling and apoptosis

Dynamic Interaction of cBid with Detergents, Liposomes and Mitochondria

The BH3-only protein Bid plays a key role in the induction of mitochondrial apoptosis, but its mechanism of action is still not completely understood. Here we studied the two main activation events of Bid: Caspase-8 cleavage and interaction with the membrane bilayer. We found a striking reversible behaviour of the dissociation-association events between the Bid fragments p15 and p7. Caspase-8 cleavage does not induce per se separation of the two Bid fragments, which remain in a stable complex resembling the full length Bid. Detergents trigger a complete dissociation, which can be fully reversed by detergent removal in a range of protein concentrations from 100 µM down to 500 nM. Incubation of cBid with cardiolipin-containing liposomes leads to partial dissociation of the complex. Only p15 (tBid) fragments are found at the membrane, while p7 shows no tendency to interact with the bilayer, but complete removal of p7 strongly increases the propensity of tBid to become membrane-associated. Despite the striking structural similarities of inactive Bid and Bax, Bid does not form oligomers and reacts differently in the presence of detergents and membranes, highlighting clear differences in the modes of action of the two proteins. The partial dissociation of cBid triggered by the membrane is suggested to depend on the strong and specific interaction between p15 and p7. The reversible disassembly and re-assembly of the cBid molecules at the membrane was as well proven by EPR using spin labeled cBid in the presence of isolated mitochondria. The observed dynamic dissociation of the two Bid fragments could allow the assistance to the pore-forming Bax to occur repeatedly and may explain the proposed “hit-and-run" mode of action of Bid at the bilayer