Adaptive approximate Bayesian computation for complex models

Approximate Bayesian computation (ABC) is a family of computational techniques in Bayesian statistics. These techniques allow to fi t a model to data without relying on the computation of the model likelihood. They instead require to simulate a large number of times the model to be fi tted. A number of re finements to the original rejection-based ABC scheme have been proposed, including the sequential improvement of posterior distributions. This technique allows to de- crease the number of model simulations required, but it still presents several shortcomings which are particu- larly problematic for costly to simulate complex models. We here provide a new algorithm to perform adaptive approximate Bayesian computation, which is shown to perform better on both a toy example and a complex social model.Comment: 14 pages, 5 figure

Global health learning outcomes for pharmacy students in the UK

Context : The pharmacy world is a highly globalised environment. Pharmacy graduates must therefore be adequately prepared. The question for educators is, how best to prepare our students. We propose that integrating global health learning outcomes within the core curriculum would ensure that all students – irrespective of their personal interest and intended work sector - are engaged with global issues. / Description: Internal discussions were held with representatives from all disciplines within University College London (UCL) School of Pharmacy and existing curriculum documents were reviewed. A draft set of learning outcomes was proposed and then revised following consultation with representatives from the United Kingdom (UK) pharmacy profession and others with an interest in global health. / Evaluation: Analysis of the consultation data led to the derivation of a revised set of global health learning outcomes for pharmacy. / Future plan: Embedding and assessing global health learning outcomes within the UCL School of Pharmacy’s undergraduate curriculum is now our focus

A critical evaluation of automatic atom mapping algorithms and tools

The identification of the atoms which change their position in chemical reactions is an important knowledge within the field of Metabolic Engineering. This can lead to new advances at different levels from the reconstruction of metabolic networks to the classification of chemical reactions, through the identification of the atomic changes inside a reaction. The Atom Mapping approach was initially developed in the 1960s, but recently suffered important advances, being used in diverse biological and biotechnological studies. The main methodologies used for atom mapping are the Maximum Common Substructure and the Linear Optimization methods, which both require computational know-how and powerful resources to run the underlying tools. In this work, we assessed a number of previously implemented atom mapping frameworks, and built a framework able of managing the different data inputs and outputs, as well as the mapping process provided by each of these third-party tools. We evaluated the admissibility of the calculated atom maps from different algorithms, also assessing if with different approaches we were capable of returning equivalent atom maps for the same chemical reaction.ERDF -European Regional Development Fund(UID/BIO/04469/2013)info:eu-repo/semantics/publishedVersio

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

Transcription factor NRF2 is an important regulator of oxidative stress. It is involved in cancer progression, and has abnormal constitutive expression in acute myeloid leukaemia (AML). Posttranscriptional regulation by microRNAs (miRNAs) can affect the malignant phenotype of AML cells. In this study, we identified and characterised NRF2-regulated miRNAs in AML. An miRNA array identified miRNA expression level changes in response to NRF2 knockdown in AML cells. Further analysis of miRNAs concomitantly regulated by knockdown of the NRF2 inhibitor KEAP1 revealed the major candidate NRF2-mediated miRNAs in AML. We identified miR-125B to be upregulated and miR-29B to be downregulated by NRF2 in AML. Subsequent bioinformatic analysis identified putative NRF2 binding sites upstream of the miR-125B1 coding region and downstream of the mir-29B1 coding region. Chromatin immunoprecipitation analyses showed that NRF2 binds to these antioxidant response elements (AREs) located in the 5′ untranslated regions of miR-125B and miR-29B. Finally, primary AML samples transfected with anti-miR-125B antagomiR or miR-29B mimic showed increased cell death responsiveness either alone or co-treated with standard AML chemotherapy. In summary, we find that NRF2 regulation of miR-125B and miR-29B acts to promote leukaemic cell survival, and their manipulation enhances AML responsiveness towards cytotoxic chemotherapeutics

A structural MRI study of excoriation (skin-picking) disorder and its relationship to clinical severity

Excoriation (skin-picking) disorder (SPD) shares symptomology with other obsessive-compulsive and related disorders. Few studies, however, have examined the neurological profile of patients with SPD. This study examined differences in cortical thickness and basal ganglia structural volumes between 20 individuals with SPD and 16 healthy controls using magnetic resonance imaging (MRI). There were no significant differences in demographic variables (age, gender, education and race) between groups. All subjects completed a structural MRI scan and completed a battery of clinical assessments focusing on SPD symptom severity, depression and anxiety symptoms, and quality of life. No statistically significant differences in basal ganglia (caudate, putamen, and nucleus accumbens) structural volumes were found between groups. In individuals with SPD, increasing impulsiveness correlated positively with increased cortical thickness in the left insula, and skin picking severity correlated negatively with cortical thickness in the left supramarginal gyrus and a region encompassing the right inferior parietal, right temporal and right supramarginal gyrus. This study suggests similarities and differences exist in symptomology between SPD and the other obsessive-compulsive and related disorders. Additional neuroimaging research is needed to better delineate the underlying neurobiology of SPD.Mr. Michael Harries, Ms. Sarah Redden and Mr. Austin Blum report no conflicts of interest. Dr. Samuel Chamberlain consults for Cambridge Cognition and Shire. He also receives funding from the Wellcome Trust Clinical Fellowship (110049/Z/15/Z). Dr. Brian Odlaug has received research funding from the TLC Foundation for Body Focused Repetitive Behaviors and has received royalties from Oxford University Press and Johns Hopkins Press. He has consulted for and is currently employed by H. Lundbeck A/S. His contribution to this project concluded prior to his employment with H. Lundbeck A/S. Dr. Jon Grant currently has research grants from the National Center for Responsible Gaming, Brainsway, the American Foundation for Suicide Prevention, the TLC Foundation for Body Focused Repetitive Behaviors, Forest Takeda and Psyadon Pharmaceuticals. He receives yearly compensation from Springer Publishing for acting as Editor-in-Chief of the Journal of Gambling Studies and has received royalties from Oxford University Press, Johns Hopkins Press, American Psychiatric Publishing, Inc., Norton Press, and McGraw Hill

Gambling disorder and suicide: An overview of the associated co-morbidity and clinical characteristics

Context: A high prevalence of suicide and attempted suicide in relation to gambling disorder is in increasing evidence in current scientific data. The objective of this review was to explore if there was a primary correlation between psychiatric co-morbidities and gambling and/or a secondary correlation with suicide acts. Evidence Acquisition: We performed a critical analysis of the most recent papers in the scientific literature in this regard and report on the most significant findings. Results: A direct relationship between gambling and suicidality was highlighted in a number of European, American, and Asian countries. However, it was not clear whether or not gambling increased the risk of suicidal behavior. Twogeneral trends were noted. The first was that gamblers with extreme gambling behavior incurred economic losses and debts to such an extent that suicidal acts appeared to be the only solution. The second was that suicidal acts by gamblers were precipitated by interpersonal and/or working challenges, in conjunction with personality traits of impulsivity and psychiatric co-morbidities. Conclusions: A combination of impulsivity, certain psychiatric disorders, and social factors may explain the frequent occurrence of suicidal behavior in gamblers

Phosphoenolpyruvate carboxylase dentified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism

Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in thePlasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery

The use of a P. falciparum specific coiled-coil domain to construct a self-assembling protein nanoparticle vaccine to prevent malaria.

The parasitic disease malaria remains a major global public health concern and no truly effective vaccine exists. One approach to the development of a malaria vaccine is to target the asexual blood stage that results in clinical symptoms. Most attempts have failed. New antigens such as P27A and P27 have emerged as potential new vaccine candidates. Multiple studies have demonstrated that antigens are more immunogenic and are better correlated with protection when presented on particulate delivery systems. One such particulate delivery system is the self-assembling protein nanoparticle (SAPN) that relies on coiled-coil domains of proteins to form stable nanoparticles. In the past we have used de novo designed amino acid domains to drive the formation of the coiled-coil scaffolds which present the antigenic epitopes on the particle surface. Here we use naturally occurring domains found in the tex1 protein to form the coiled-coil scaffolding of the nanoparticle. Thus, by engineering P27A and a new extended form of the coiled-coil domain P27 onto the N and C terminus of the SAPN protein monomer we have developed a particulate delivery system that effectively displays both antigens on a single particle that uses malaria tex1 sequences to form the nanoparticle scaffold. These particles are immunogenic in a murine model and induce immune responses similar to the ones observed in seropositive individuals in malaria endemic regions. We demonstrate that our P27/P27A-SAPNs induce an immune response akin to the one in seropositive individuals in Burkina Faso. Since P27 is highly conserved among different Plasmodium species, these novel SAPNs may even provide cross-protection between Plasmodium falciparum and Plasmodium vivax the two major human malaria pathogens. As the SAPNs are also easy to manufacture and store they can be delivered to the population in need without complication thus providing a low cost malaria vaccine

Predictors of early sexual initiation among a nationally representative sample of Nigerian adolescents

<p>Abstract</p> <p>Background</p> <p>Early sexual debut among adolescents is associated with considerable negative heath and development outcomes. An understanding of the determinants or predictors of the timing of sexual debut is important for effective intervention, but very few studies to date have addressed this issue in the Nigerian context. The aim of the present study is to examine predictors of adolescent sexual initiation among a nationally representative sample of adolescents in Nigeria.</p> <p>Methods</p> <p>Interviewer-collected data of 2,070 never-married adolescents aged 15–19 years were analysed to determine association between age of sexual debut and demographic, psychosocial and community factors. Using Cox proportional hazards regression multivariate analysis was carried out with two different models – one with and the other without psychosocial factors. Hazard ratio (HR) and 95% confidence interval (CI) were calculated separately for males and females.</p> <p>Results</p> <p>A fifth of respondents (18% males; 22% females) were sexually experienced. In the South 24.3% males and 28.7% females had initiated sex compared to 12.1% of males and 13.1% females in the North (p < 0.001). In the first model, only region was significantly associated with adolescent sexual initiation among both males and females; however, educational attainment and age were also significant among males. In the second (psychosocial) model factors associated with adolescent sexual debut for both genders included more positive attitudes regarding condom efficacy (males: HR = 1.28, 95% CI = 1.07–1.53; females: HR = 1.24, 95% CI = 1.05–1.46) and more positive attitudes to family planning use (males: HR = 1.19, 95% CI = 1.09–1.31; females: HR = 1.18, 95% CI = 1.07–1.30). A greater perception of condom access (HR = 1.42, 95% CI = 1.14–1.76) and alcohol use (HR = 1.90, 95% CI = 1.38–2.62) among males and positive gender-related attitudes (HR = 1.13, 95% CI = 1.04–1.23) among females were also associated with increased likelihood of adolescent sexual initiation. Conversely, personal attitudes in favour of delayed sexual debut were associated with lower sexual debut among both males (males: HR = 0.36, 95% CI = 0.25–0.52) and females (HR = 0.38, 95% CI = 0.25–0.57). Higher level of religiosity was associated with lower sexual debut rates only among females (HR = 0.59, 95% CI = 0.37–0.94).</p> <p>Conclusion</p> <p>Given the increased risk for a number of sexually transmitted health problems, understanding the factors that are associated with premarital sexual debut will assist programmes in developing more effective risk prevention interventions.</p