Regulation of nitric oxide signaling by formation of a distal receptor-ligand complex.

The binding of nitric oxide (NO) to the heme cofactor of heme-nitric oxide/oxygen binding (H-NOX) proteins can lead to the dissociation of the heme-ligating histidine residue and yield a five-coordinate nitrosyl complex, an important step for NO-dependent signaling. In the five-coordinate nitrosyl complex, NO can reside on either the distal or proximal side of the heme, which could have a profound influence over the lifetime of the in vivo signal. To investigate this central molecular question, we characterized the Shewanella oneidensis H-NOX (So H-NOX)-NO complex biophysically under limiting and excess NO conditions. The results show that So H-NOX preferably forms a distal NO species with both limiting and excess NO. Therefore, signal strength and complex lifetime in vivo will be dictated by the dissociation rate of NO from the distal complex and the rebinding of the histidine ligand to the heme

Health effects in fish of long-term exposure to effluents from wastewater treatment works

The effects of simple mixtures of chemicals, with similar mechanisms of action, can be predicted using the concentration addition model (CA). The ability of this model to predict the estrogenic effects of more complex mixtures such as effluent discharges, however, has yet to be established. Effluents from 43 U.K. wastewater treatment works were analyzed for the presence of the principal estrogenic chemical contaminants, estradiol, estrone, ethinylestradiol, and nonylphenol. The measured concentrations were used to predict the estrogenic activity of each effluent, employing the model of CA, based on the relative potencies of the individual chemicals in an in vitro recombinant yeast estrogen screen (rYES) and a short-term (14-day) in vivo rainbow trout vitellogenin induction assay. Based on the measured concentrations of the four chemicals in the effluents and their relative potencies in each assay, the calculated in vitro and in vivo responses compared well and ranged between 3.5 and 87 ng/L of estradiol equivalents (E2 EQ) for the different effluents. In the rYES, however, the measured E2 EQ concentrations in the effluents ranged between 0.65 and 43 ng E2 EQ/L, and they varied against those predicted by the CA model. Deviations in the estimation of the estrogenic potency of the effluents by the CA model, compared with the measured responses in the rYES, are likely to have resulted from inaccuracies associated with the measurement of the chemicals in the extracts derived from the complex effluents. Such deviations could also result as a consequence of interactions between chemicals present in the extracts that disrupted the activation of the estrogen response elements in the rYES. E2 EQ concentrations derived from the vitellogenic response in fathead minnows exposed to a series of effluent dilutions were highly comparable with the E2 EQ concentrations derived from assessments of the estrogenic potency of these dilutions in the rYES. Together these data support the use of bioassays for determining the estrogenic potency of WwTW effluents, and they highlight the associated problems for modeling approaches that are reliant on measured concentrations of estrogenic chemicals

Glucose enhancement of memory is modulated by trait anxiety in healthy adolescent males

Glucose administration is associated with memory enhancement in healthy young individuals under conditions of divided attention at encoding. While the specific neurocognitive mechanisms underlying this ‘glucose memory facilitation effect’ are currently uncertain, it is thought that individual differences in glucoregulatory efficiency may alter an individual’s sensitivity to the glucose memory facilitation effect. In the present study, we sought to investigate whether basal hypothalamic–pituitary–adrenal axis function (itself a modulator of glucoregulatory efficiency), baseline self-reported stress and trait anxiety influence the glucose memory facilitation effect. Adolescent males (age range = 14–17 years) were administered glucose and placebo prior to completing a verbal episodic memory task on two separate testing days in a counter-balanced, within-subjects design. Glucose ingestion improved verbal episodic memory performance when memory recall was tested (i) within an hour of glucose ingestion and encoding, and (ii) one week subsequent to glucose ingestion and encoding. Basal hypothalamic–pituitary–adrenal axis function did not appear to influence the glucose memory facilitation effect; however, glucose ingestion only improved memory in participants reporting relatively higher trait anxiety. These findings suggest that the glucose memory facilitation effect may be mediated by biological mechanisms associated with trait anxiety

Physiology-based regularization of the electrocardiographic inverse problem

The inverse problem of electrocardiography aims at noninvasively reconstructing electrical activity of the heart from recorded body-surface electrocardiograms. A crucial step is regularization, which deals with ill-posedness of the problem by imposing constraints on the possible solutions. We developed a regularization method that includes electrophysiological input. Body-surface potentials are recorded and a computed tomography scan is performed to obtain the torso-heart geometry. Propagating waveforms originating from several positions at the heart are simulated and used to generate a set of basis vectors representing spatial distributions of potentials on the heart surface. The real heart-surface potentials are then reconstructed from the recorded body-surface potentials by finding a sparse representation in terms of this basis. This method, which we named 'physiology-based regularization' (PBR), was compared to traditional Tikhonov regularization and validated using in vivo recordings in dogs. PBR recovered details of heart-surface electrograms that were lost with traditional regularization, attained higher correlation coefficients and led to improved estimation of recovery times. The best results were obtained by including approximate knowledge about the beat origin in the PBR basis

Selective inhibition of T suppressor-cell function by a monosaccharide

Interactions between regulatory T lymphocytes and other cells are assumed to occur at the level of the cell surface. T cells which suppress the generation of specifically effector cells have been described as having antigenic, idiotypic, allotypic and I-region specificity1−4. Other T suppressor cells generated by in vitro cultivation with or without mitogenic stimulation5,6 have suppressive activity for T and B cells but no specificity can be assigned to them. These T suppressor cells (Ts) inhibit various lymphoid functions—this either reflects their polyclonal origin or indicates that the structures recognized by the Ts receptors must be common for many cell types. Carbohydrates on cell membrane-inserted glycoproteins or glycolipids might function as specific ligands for recognition by cellular receptors or soluble factors. Almost all cell-surface proteins of mammalian cells are glycosylated. There is evidence for lectin-like carbohydrate binding proteins not only in plants7 but also in toxins8, viruses9, prokaryotic cells10 and even mammalian cells, including T cells11. A functional role for these lectin-like proteins has been described for slime moulds and suggested for the selective association of embryonic cells12,13. We report here that addition of a monosaccharide can counteract the effect of T suppressor cells during the generation of alloreactive cytotoxic T cells (CTLs) in vitro

A Bound on the Superpotential

We prove a general bound on the superpotential in theories with broken supersymmetry and broken R-symmetry, 2|W|< f_a F, where f_a and F are the R-axion and Goldstino decay constants, respectively. The bound holds for weakly coupled as well as strongly coupled theories, thereby providing an exact result in theories with broken supersymmetry. We briefly discuss several possible applications.Comment: 20 page

Structural similarity assessment for drug sensitivity prediction in cancer

<p>Abstract</p> <p>Background</p> <p>The ability to predict drug sensitivity in cancer is one of the exciting promises of pharmacogenomic research. Several groups have demonstrated the ability to predict drug sensitivity by integrating chemo-sensitivity data and associated gene expression measurements from large anti-cancer drug screens such as NCI-60. The general approach is based on comparing gene expression measurements from sensitive and resistant cancer cell lines and deriving drug sensitivity profiles consisting of lists of genes whose expression is predictive of response to a drug. Importantly, it has been shown that such profiles are generic and can be applied to cancer cell lines that are not part of the anti-cancer screen. However, one limitation is that the profiles can not be generated for untested drugs (i.e., drugs that are not part of an anti-cancer drug screen). In this work, we propose using an existing drug sensitivity profile for drug A as a substitute for an untested drug B given high structural similarities between drugs A and B.</p> <p>Results</p> <p>We first show that structural similarity between pairs of compounds in the NCI-60 dataset highly correlates with the similarity between their activities across the cancer cell lines. This result shows that structurally similar drugs can be expected to have a similar effect on cancer cell lines. We next set out to test our hypothesis that we can use existing drug sensitivity profiles as substitute profiles for untested drugs. In a cross-validation experiment, we found that the use of substitute profiles is possible without a significant loss of prediction accuracy if the substitute profile was generated from a compound with high structural similarity to the untested compound.</p> <p>Conclusion</p> <p>Anti-cancer drug screens are a valuable resource for generating omics-based drug sensitivity profiles. We show that it is possible to extend the usefulness of existing screens to untested drugs by deriving substitute sensitivity profiles from structurally similar drugs part of the screen.</p

Lymphatic Filariasis Control in Tanzania: Effect of Six Rounds of Mass Drug Administration with Ivermectin and Albendazole on Infection and Transmission.

Control of lymphatic filariasis (LF) in most countries of sub-Saharan Africa is based on annual mass drug administration (MDA) with a combination of ivermectin and albendazole, in order to interrupt transmission. We present findings from a detailed study on the effect of six rounds of MDA with this drug combination as implemented by the National Lymphatic Filariasis Elimination Programme (NLFEP) in a highly endemic rural area of north-eastern Tanzania.\ud The effect of treatment on transmission and human infection was monitored in a community- and a school-based study during an 8-year period (one pre-intervention and 7 post-intervention years) from 2003 to 2011. Before intervention, 24.5% of the community population had microfilariae (mf) in the blood, 53.3% had circulating filarial antigens (CFA) and 78.9% had specific antibodies to the recombinant filarial antigen Bm14. One year after the sixth MDA, these values had decreased considerably to 2.7%, 19.6% and 27.5%, respectively. During the same period, the CFA prevalence among new intakes of Standard 1 pupils in 10 primary schools decreased from 25.2% to 5.6%. In line with this, transmission by the three vectors (Anopheles gambiae, An. funestus and Culex quinquefasciatus) as determined by dissection declined sharply (overall vector infectivity rate by 99.3% and mean monthly transmission potential by 99.2% between pre-intervention and fifth post-intervention period). A major shift in vector species composition, from predominantly anopheline to almost exclusively culicine was observed over the years. This may be largely unrelated to the MDAs but may have important implications for the epidemiology of LF in the area. Six MDAs caused considerable decrease in all the measured indices for transmission and human infection. In spite of this, indices were still relatively high in the late period of the study, and it may take a long time to reach the recommended cut-off levels for interruption of transmission unless extra efforts are made. These should include increased engagement of the target population in the control activities, to ensure higher treatment coverage. It is expected that the recent initiative to distribute insecticide impregnated bed nets to every household in the area will also contribute towards reaching the goal of successful LF elimination

Developing a Simplified Consent Form for Biobanking

BACKGROUND: Consent forms have lengthened over time and become harder for participants to understand. We sought to demonstrate the feasibility of creating a simplified consent form for biobanking that comprises the minimum information necessary to meet ethical and regulatory requirements. We then gathered preliminary data concerning its content from hypothetical biobank participants. METHODOLOGY/PRINCIPAL FINDINGS: We followed basic principles of plain-language writing and incorporated into a 2-page form (not including the signature page) those elements of information required by federal regulations and recommended by best practice guidelines for biobanking. We then recruited diabetes patients from community-based practices and randomized half (n = 56) to read the 2-page form, first on paper and then a second time on a tablet computer. Participants were encouraged to use "More information" buttons on the electronic version whenever they had questions or desired further information. These buttons led to a series of "Frequently Asked Questions" (FAQs) that contained additional detailed information. Participants were asked to identify specific sentences in the FAQs they thought would be important if they were considering taking part in a biorepository. On average, participants identified 7 FAQ sentences as important (mean 6.6, SD 14.7, range: 0-71). No one sentence was highlighted by a majority of participants; further, 34 (60.7%) participants did not highlight any FAQ sentences. CONCLUSIONS: Our preliminary findings suggest that our 2-page form contains the information that most prospective participants identify as important. Combining simplified forms with supplemental material for those participants who desire more information could help minimize consent form length and complexity, allowing the most substantively material information to be better highlighted and enabling potential participants to read the form and ask questions more effectively