An investigation into pharmaceutically relevant mutagenicity data and the influence on Ames predictive potential

Mutagenicity presents a challenging problem in modeling despite the addition of modern prediction methods and easier access to data. Previous studies have focused mainly on treatment of all mutagenic compound classes, while some have focused on a very small sets of alerting compounds such as aromatic amines with quantitative mutagenicity data. Data currently available at Novartis provide a large, unique set of mutagenicity data originating from one laboratory, providing compounds connected to the discovery and production of medicinal compounds rather than compounds associated with agricultural, environmental and foodstuff concern. We were especially interested in predicting the The performance of commonly used descriptors and methods performed quite poorly for the set of aromatic amines, while using the reaction energy to produce a reactive intermediate provides a prediction accuracy of at least 70% across multiple data sets. Whereas many papers have represented the study of aromatic amines and Ames results as a platform for study of prediction methods with good performance, we show that the set is quite difficult. The performance of methods in our hands will be compared with previously compiled datasets and reported models

Increased overwinter mortalities of white-tailed deer (Odocoileus virginianus) fawns during a drought year

Mortality rates of white-tailed deer (Odocoileus virginianus (Zimmerman, 1780)) fawns have been quantified throughout North America. Few studies, however, have assessed cause-specific mortality of fawns after the first 3 months of life or during a severe weather event. During 2010-2014, we captured and radiotracked 93 fawns in southern and central Illinois and recorded 18 mortality events. In order of importance, survival rates were affected by days since capture, year of drought, age at capture, week post-capture (1/0 indicator), and region. Estimated overwinter (fall through spring) survival rate (± SE) of fawns in both regions during 2010-14 was 0.83 ± 0.04. However, estimated overwinter survival rates were depressed during 2012-13, following the severe drought of 2012 (0.63 ± 0.11 or 0.66 ± 0.11 depending on model). Main causes of mortality were capture-related and predation, though some dead deer also showed signs of hemorrhagic disease. We suspect that the extreme drought of 2012 created favorable conditions for fall-spring mortality of fawns, due to elevated disease transmission and lower forage quality and quantity for deer. In addition, drought may have contributed to predation by reducing abundance of alternative prey. Our results suggest that severe weather conditions during summer can substantially impact overwinter fawn survival

Cardiac Safety Implications of hNav1.5 Blockade and a Framework for Pre-Clinical Evaluation

The human cardiac sodium channel (hNav1.5, encoded by the SCN5A gene) is critical for action potential generation and propagation in the heart. Drug-induced sodium channel inhibition decreases the rate of cardiomyocyte depolarization and consequently conduction velocity and can have serious implications for cardiac safety. Genetic mutations in hNav1.5 have also been linked to a number of cardiac diseases. Therefore, off-target hNav1.5 inhibition may be considered a risk marker for a drug candidate. Given the potential safety implications for patients and the costs of late stage drug development, detection, and mitigation of hNav1.5 liabilities early in drug discovery and development becomes important. In this review, we describe a pre-clinical strategy to identify hNav1.5 liabilities that incorporates in vitro, in vivo, and in silico techniques and the application of this information in the integrated risk assessment at different stages of drug discovery and development

Extension of thermonuclear functions through the pathway model including Maxwell-Boltzmann and Tsallis distributions

The Maxwell-Boltzmannian approach to nuclear reaction rate theory is extended to cover Tsallis statistics (Tsallis, 1988) and more general cases of distribution functions. An analytical study of respective thermonuclear functions is being conducted with the help of statistical techniques. The pathway model, recently introduced by Mathai (2005), is utilized for thermonuclear functions and closed-form representations are obtained in terms of H-functions and G-functions. Maxwell-Boltzmannian thermonuclear functions become particular cases of the extended thermonuclear functions. A brief review on the development of the theory of analytic representations of nuclear reaction rates is given.Comment: 16 pages, LaTe

Why place matters: imaginative geography and international student mobility

This paper develops and extends the recent work on international student mobility by expanding beyond the traditional push–pull factors of migration to show that students are influenced by more than the economic in their decision of where to study. It uses original data collected through interviews and focus groups with 38 higher education international students at three UK universities located in Aberdeen, Belfast and Nottingham to show that when students choose to study overseas they are influenced by diverse perceptions of place that they have constructed over long periods of time. These imaginative geographies are the direct result of exposure to a range of different media, as well as stories relayed to them from members of their social networks. This paper demonstrates that students studying in Scotland and Northern Ireland appear to have highly developed imaginative geographies in relation to their chosen study sites. By contrast, international students studying in England tended to have little conception of their chosen place of study. In this case the powerful imaginative geographies that had been instilled within them focused on London, overshadowing their understanding of their chosen study site

Trypanosoma cruzi Gene Expression in Response to Gamma Radiation

Trypanosoma cruzi is an organism highly resistant to ionizing radiation. Following a dose of 500 Gy of gamma radiation, the fragmented genomic DNA is gradually reconstructed and the pattern of chromosomal bands is restored in less than 48 hours. Cell growth arrests after irradiation but, while DNA is completely fragmented, RNA maintains its integrity. In this work we compared the transcriptional profiles of irradiated and non-irradiated epimastigotes at different time points after irradiation using microarray. In total, 273 genes were differentially expressed; from these, 160 were up-regulated and 113 down-regulated. We found that genes with predicted functions are the most prevalent in the down-regulated gene category. Translation and protein metabolic processes, as well as generation of precursor of metabolites and energy pathways were affected. In contrast, the up-regulated category was mainly composed of obsolete sequences (which included some genes of the kinetoplast DNA), genes coding for hypothetical proteins, and Retrotransposon Hot Spot genes. Finally, the tyrosyl-DNA phosphodiesterase 1, a gene involved in double-strand DNA break repair process, was up-regulated. Our study demonstrated the peculiar response to ionizing radiation, raising questions about how this organism changes its gene expression to manage such a harmful stress

PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL).

B cells provide immunity to extracellular pathogens by secreting a diverse repertoire of antibodies with high affinity and specificity for exposed antigens. The B cell receptor (BCR) is a transmembrane antibody, which facilitates the clonal selection of B cells producing secreted antibodies of the same specificity. The diverse antibody repertoire is generated by V(D)J recombination of heavy and light chain genes, whereas affinity maturation is mediated by activation-induced cytidine deaminase (AID)-mediated mutagenesis. These processes, which are essential for the generation of adaptive humoral immunity, also render B cells susceptible to chromosomal rearrangements and point mutations that in some cases lead to cancer. In this chapter, we will review the central role of PI3K s in mediating signals from the B cell receptor that not only facilitate the development of functional B cell repertoire, but also support the growth and survival of neoplastic B cells, focusing on chronic lymphocytic leukemia (CLL) B cells. Perhaps because of the central role played by PI3K in BCR signaling, B cell leukemia and lymphomas are the first diseases for which a PI3K inhibitor has been approved for clinical use

Interventions for drug-using offenders with co-occurring mental health problems

Background This review represents one from a family of three reviews focusing on interventions for drug‐using offenders. Many people under the care of the criminal justice system have co‐occurring mental health problems and drug misuse problems; it is important to identify the most effective treatments for this vulnerable population. Objectives To assess the effectiveness of interventions for drug‐using offenders with co‐occurring mental health problems in reducing criminal activity or drug use, or both. This review addresses the following questions. • Does any treatment for drug‐using offenders with co‐occurring mental health problems reduce drug use? • Does any treatment for drug‐using offenders with co‐occurring mental health problems reduce criminal activity? • Does the treatment setting (court, community, prison/secure establishment) affect intervention outcome(s)? • Does the type of treatment affect treatment outcome(s)? Search methods We searched 12 databases up to February 2019 and checked the reference lists of included studies. We contacted experts in the field for further information. Selection criteria We included randomised controlled trials designed to prevent relapse of drug use and/or criminal activity among drug‐using offenders with co‐occurring mental health problems. Data collection and analysis We used standard methodological procedures as expected by Cochrane . Main results We included 13 studies with a total of 2606 participants. Interventions were delivered in prison (eight studies; 61%), in court (two studies; 15%), in the community (two studies; 15%), or at a medium secure hospital (one study; 8%). Main sources of bias were unclear risk of selection bias and high risk of detection bias. Four studies compared a therapeutic community intervention versus (1) treatment as usual (two studies; 266 participants), providing moderate‐certainty evidence that participants who received the intervention were less likely to be involved in subsequent criminal activity (risk ratio (RR) 0.67, 95% confidence interval (CI) 0.53 to 0.84) or returned to prison (RR 0.40, 95% CI 0.24 to 0.67); (2) a cognitive‐behavioural therapy (one study; 314 participants), reporting no significant reduction in self‐reported drug use (RR 0.78, 95% CI 0.46 to 1.32), re‐arrest for any type of crime (RR 0.69, 95% CI 0.44 to 1.09), criminal activity (RR 0.74, 95% CI 0.52 to 1.05), or drug‐related crime (RR 0.87, 95% CI 0.56 to 1.36), yielding low‐certainty evidence; and (3) a waiting list control (one study; 478 participants), showing a significant reduction in return to prison for those people engaging in the therapeutic community (RR 0.60, 95% CI 0.46 to 0.79), providing moderate‐certainty evidence. One study (235 participants) compared a mental health treatment court with an assertive case management model versus treatment as usual, showing no significant reduction at 12 months' follow‐up on an Addictive Severity Index (ASI) self‐report of drug use (mean difference (MD) 0.00, 95% CI ‐0.03 to 0.03), conviction for a new crime (RR 1.05, 95% CI 0.90 to 1.22), or re‐incarceration to jail (RR 0.79, 95% CI 0.62 to 1.01), providing low‐certainty evidence. Four studies compared motivational interviewing/mindfulness and cognitive skills with relaxation therapy (one study), a waiting list control (one study), or treatment as usual (two studies). In comparison to relaxation training, one study reported narrative information on marijuana use at three‐month follow‐up assessment. Researchers reported a main effect < .007 with participants in the motivational interviewing group, showing fewer problems than participants in the relaxation training group, with moderate‐certainty evidence. In comparison to a waiting list control, one study reported no significant reduction in self‐reported drug use based on the ASI (MD ‐0.04, 95% CI ‐0.37 to 0.29) and on abstinence from drug use (RR 2.89, 95% CI 0.73 to 11.43), presenting low‐certainty evidence at six months (31 participants). In comparison to treatment as usual, two studies (with 40 participants) found no significant reduction in frequency of marijuana use at three months post release (MD ‐1.05, 95% CI ‐2.39 to 0.29) nor time to first arrest (MD 0.87, 95% CI ‐0.12 to 1.86), along with a small reduction in frequency of re‐arrest (MD ‐0.66, 95% CI ‐1.31 to ‐0.01) up to 36 months, yielding low‐certainty evidence; the other study with 80 participants found no significant reduction in positive drug screens at 12 months (MD ‐0.7, 95% CI ‐3.5 to 2.1), providing very low‐certainty evidence. Two studies reported on the use of multi‐systemic therapy involving juveniles and families versus treatment as usual and adolescent substance abuse therapy. In comparing treatment as usual, researchers found no significant reduction up to seven months in drug dependence on the Drug Use Disorders Identification Test (DUDIT) score (MD ‐0.22, 95% CI ‐2.51 to 2.07) nor in arrests (RR 0.97, 95% CI 0.70 to 1.36), providing low‐certainty evidence (156 participants). In comparison to an adolescent substance abuse therapy, one study (112 participants) found significant reduction in re‐arrests up to 24 months (MD 0.24, 95% CI 0.76 to 0.28), based on low‐certainty evidence. One study (38 participants) reported on the use of interpersonal psychotherapy in comparison to a psychoeducational intervention. Investigators found no significant reduction in self‐reported drug use at three months (RR 0.67, 95% CI 0.30 to 1.50), providing very low‐certainty evidence. The final study (29 participants) compared legal defence service and wrap‐around social work services versus legal defence service only and found no significant reductions in the number of new offences committed at 12 months (RR 0.64, 95% CI 0.07 to 6.01), yielding very low‐certainty evidence. Authors' conclusions Therapeutic community interventions and mental health treatment courts may help people to reduce subsequent drug use and/or criminal activity. For other interventions such as interpersonal psychotherapy, multi‐systemic therapy, legal defence wrap‐around services, and motivational interviewing, the evidence is more uncertain. Studies showed a high degree of variation, warranting a degree of caution in interpreting the magnitude of effect and the direction of benefit for treatment outcomes

The Biochemistry, Ultrastructure, and Subunit Assembly Mechanism of AMPA Receptors

The AMPA-type ionotropic glutamate receptors (AMPA-Rs) are tetrameric ligand-gated ion channels that play crucial roles in synaptic transmission and plasticity. Our knowledge about the ultrastructure and subunit assembly mechanisms of intact AMPA-Rs was very limited. However, the new studies using single particle EM and X-ray crystallography are revealing important insights. For example, the tetrameric crystal structure of the GluA2cryst construct provided the atomic view of the intact receptor. In addition, the single particle EM structures of the subunit assembly intermediates revealed the conformational requirement for the dimer-to-tetramer transition during the maturation of AMPA-Rs. These new data in the field provide new models and interpretations. In the brain, the native AMPA-R complexes contain auxiliary subunits that influence subunit assembly, gating, and trafficking of the AMPA-Rs. Understanding the mechanisms of the auxiliary subunits will become increasingly important to precisely describe the function of AMPA-Rs in the brain. The AMPA-R proteomics studies continuously reveal a previously unexpected degree of molecular heterogeneity of the complex. Because the AMPA-Rs are important drug targets for treating various neurological and psychiatric diseases, it is likely that these new native complexes will require detailed mechanistic analysis in the future. The current ultrastructural data on the receptors and the receptor-expressing stable cell lines that were developed during the course of these studies are useful resources for high throughput drug screening and further drug designing. Moreover, we are getting closer to understanding the precise mechanisms of AMPA-R-mediated synaptic plasticity