Solution Structures of a DNA Dodecamer Duplex with and without a Cisplatin 1,2-d(GG) Intrastrand Cross-Link: Comparison with the Same DNA Duplex Containing an Oxaliplatin 1,2-d(GG) Intrastrand Cross-Link † , ‡

Proteins that discriminate between cisplatin–DNA adducts and oxaliplatin–DNA adducts are thought to be responsible for the differences in tumor range, toxicity, and mutagenicity of these two important chemotherapeutic agents. However, the structural basis for differential protein recognition of these adducts has not been determined and could be important for the design of more effective platinum anticancer agents. We have determined high-resolution NMR structures for cisplatin–GG and undamaged DNA dodecamers in the AGGC sequence context and have compared these structures with the oxaliplatin–GG structure in the same sequence context determined previously in our laboratory. This structural study allows the first direct comparison of cisplatin–GG DNA and oxaliplatin–GG DNA solution structures referenced to undamaged DNA in the same sequence context. Non-hydrogen atom rmsds of 0.81 and 1.21 were determined for the 15 lowest-energy structures for cisplatin–GG DNA and undamaged DNA, respectively, indicating good structural convergence. The theoretical NOESY spectra obtained by back-calculation from the final average structures showed excellent agreement with the experimental data, indicating that the final structures are consistent with the NMR data. Several significant conformational differences were observed between the cisplatin–GG adduct and the oxaliplatin–GG adduct, including buckle at the 5′ G6•C19 base pair, opening at the 3′ G7•C18 base pair, twist at the A5G6•T20C19 base pair step, slide, twist, and roll at the G6G7•C19C18 base pair step, slide at the G7C8•C18G17 base pair step, G6G7 dihedral angle, and overall bend angle. We hypothesize that these conformational differences may be related to the ability of various DNA repair proteins, DNA binding proteins, and DNA polymerases to discriminate between cisplatin–GG and oxaliplatin–GG adducts

Carbohydrate-derived iminium salt organocatalysts for the asymmetric epoxidation of alkenes

A new family of carbohydrate-based dihydroisoquinolinium salts has been prepared and tested for potential as asymmetric catalysts for the epoxidation of unfunctionalized alkene substrates, providing up to 57% ee in the product epoxides

Immunogenicity of a Promiscuous T Cell Epitope Peptide Based Conjugate Vaccine against Benzo[a]pyrene: Redirecting Antibodies to the Hapten

The prototype polycyclic aromatic hydrocarbon benzo[a]pyrene (B[a]P) is an environmental pollutant and food contaminant of epidemiological importance. To protect against adverse effects of this ubiquitous carcinogen, we developed an immunoprophylactic strategy based on a B[a]P-protein conjugate vaccine to induce B[a]P specific antibodies (Grova et al., Vaccine. 2009;27:4142–51). Here, we investigated in mice the efficacy of B[a]P-peptide conjugates based on promiscuous T cell epitopes (TCE) into further improve this approach. We showed that B[a]P-peptide conjugates induced very different levels of hapten-specific antibodies with variable functional efficacy, depending on the carrier. In some cases peptide carriers induced a more efficient antibody response against B[a]P than tetanus toxoid as a protein carrier, with the capacity to sequester more B[a]P in the blood. Reducing the carrier size to a single TCE can dramatically shift the antibody bias from the carrier to the B[a]P. Conjugates based on the TCE FIGITEL induced the best anti-hapten response and no antibodies against the carrier peptide. Some peptide conjugates increased the selectivity of the antibodies for the activated metabolite 7,8-diol-B[a]P and B[a]P by one or two orders of magnitude. The antibody efficacy was also demonstrated in their ability to sequester B[a]P in the blood and modulate its faecal excretion (15–56%). We further showed that pre-existing immunity to the carrier from which the TCE was derived did not reduce the immunogenicity of the peptide conjugate. In conclusion, we showed that a vaccination against B[a]P using promiscuous TCEs of tetanus toxin as carriers is feasible even in case of a pre-existing immunity to the toxoid and that some TCE epitopes dramatically redirect the antibody response to the hapten. Further studies to demonstrate a long-term protection of an immunoprophylactic immunisation against B[a]P are warranted

Queueing Theory an Index Factor for Production Inventory Control in Automotive Industry—A Review

In this paper, various approaches to inventory control within the automotive industry were reviewed using queueing theory. Different models used in past literature were stated and the model considered to be most effective in this review is dock management modeling. This model was used to analyze inventory control and how effectively automotive industries can minimize inventory by getting the component needed in the assembly line just in time, this helps to reduce additional costs for warehouse maintenance and capital tied down in form of excess inventory. Analytical and simulation models are the mathematical models that are considered in this review as they are used in several papers by different authors

Essentially biased: why people are fatalistic about genes

We propose that people are genetic essentialists—that is, they tend to think of genetic attributions as being immutable, of a specific etiology, natural, and dividing people into homogenous and discrete groups. Although there are rare conditions where genes operate in these kinds of deterministic ways, people overgeneralize from these to the far more common conditions where genes are not at all deterministic. These essentialist biases are associated with some harmful outcomes such as racism, sexism, pessimism in the face of illnesses, political polarization, and support for eugenics, while at the same time they are linked with increased tolerance and sympathy for gay rights, mental illness, and less severe judgments of responsibility for crime. We will also discuss how these essentialist biases connect with the burgeoning direct-to-consumer genomics industry and various kinds of genetic engineering. Overall, these biases appear rather resistant to efforts to reduce them, although genetics literacy predicts weaker essentialist tendencies

Improving the assessment and management of obesity in UK children and adolescents: the PROMISE research programme including a RCT

BackgroundFive linked studies were undertaken to inform identified evidence gaps in the childhood obesity pathway.Objectives(1) To scope the impact of the National Child Measurement Programme (NCMP) (study A). (2) To develop a brief evidence-based electronic assessment and management tool (study B). (3) To develop evidence-based algorithms for identifying the risk of obesity comorbidities (study B). (4) To conduct an efficacy trial of the Healthy Eating and Lifestyle Programme (HELP) (study C). (5) To improve the prescribing of anti-obesity drugs in UK adolescents (study D). (6) To investigate the safety, outcomes and predictors of outcome of adolescent bariatric surgery in the UK (study E).MethodsFive substudies – (1) a parental survey before and after feedback from the National Childhood Measurement Programme, (2) risk algorithm development and piloting of a new primary care management tool, (3) a randomised controlled trial of the Healthy Eating and Lifestyle Programme, (4) quantitative and qualitative studies of anti-obesity drug treatment in adolescents and (5) a prospective clinical audit and cost-effectiveness evaluation of adolescent bariatric surgery in one centre.ResultsStudy A – before the National Childhood Measurement Programme feedback, three-quarters of parents of overweight and obese children did not recognise their child to be overweight. Eighty-seven per cent of parents found the National Childhood Measurement Programme feedback to be helpful. Feedback had positive effects on parental knowledge, perceptions and intentions. Study B – risk estimation models for cardiovascular and psychosocial comorbidities of obesity require further development. An online consultation tool for primary care practitioners is acceptable and feasible. Study C – the Healthy Eating and Lifestyle Programme, when delivered in the community by graduate mental health workers, showed no significant effect on body mass index at 6 months (primary outcome) when compared with enhanced usual care. Study D – anti-obesity drugs appear efficacious in meta-analysis, and their use has expanded rapidly in the last decade. However, the majority of prescriptions are rapidly discontinued after 1–3 months of treatment. Few young people described positive experiences of anti-obesity drugs. Prescribing was rarely compliant with the National Institute for Health and Care Excellence guidance. Study E – bariatric surgery appears safe, effective and highly cost-effective in adolescents in the NHS.Future work and limitationsWork is needed to evaluate behaviour and body mass index change in the National Childhood Measurement Programme more accurately and improve primary care professionals’ understanding of the National Childhood Measurement Programme feedback, update and further evaluate the Computer-Assisted Treatment of CHildren (CATCH) tool, investigate delivery of weight management interventions to young people from deprived backgrounds and those with significant psychological distress and obtain longer-term data on anti-obesity drug use and bariatric surgery outcomes in adolescence.Trial registrationCurrent Controlled Trials ISRCTN99840111.FundingThis project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full inProgramme Grants for Applied Research; Vol. 8, No. 3. See the NIHR Journals Library website for further project information.</jats:sec