Studies towards the total synthesis of Tagetitoxin

Tagetitoxin is a phytotoxin which was isolated in 1981 from the plant pathogenic bacterium, Pseudomonas syringae pv. tagetis. It is an inhibitor of chloroplast and bacterial RNA polymerases, but more importantly, it is the only known natural product which is a selective inhibitor of eukaryotic RNA polymerase III. Synthesis of this compound would therefore be useful for biologists studying transcription. The proposed structure of tagetitoxin is highly functionalised and consists of two bridged heterocyclic rings, however the absolute configuration is not known and other ambiguities remain. Recently, the validity of this structure has been challenged and has provided further motivation for its synthesis. Our initial route to form the tagetitoxin core involved a carbene-mediated ring expansion strategy which had been successfully tested on monocyclic substrates. We planned to form the ring expansion precursor, a 1,3-oxathiolane, from the corresponding tert-butyl ß-hydroxysulfide using a novel reaction developed in our group. Methodology work was carried out on simpler substrates in order to investigate the scope of this reaction. It was found that this reaction worked well on substrates containing a range of functional groups and moderate to good yields were obtained in general. Although this provided a basis for the final stages of the synthesis, many difficulties were encountered during during the initial stages which led to an alternative strategy being adopted. During other work in the group, the first synthesis of the bicyclic tagetitoxin core was achieved via the cyclisation of a thiol onto an electrophilic ketoester. This strategy was thus employed in approaches to an analogue of the natural product, decarboxytagetitoxin, and tagetitoxin itself. Starting from a carbohydrate precursorm and advanced intermediate for the synthesis of decarboxytagetitoxin was prepared, although time constraints prevented completion of the synthesis. Difficulties in forming a diol intermediate through Payne rearrangement meant that only limited progress was made towards the synthesis of tagetitoxin

Evaluation of Patient Radiation Doses in Skull Radiography

Purpose: Exposures to medical ionizing radiations elevate the risk of stochastic effects such as cancer in exposed individuals. It is of utmost importance to monitor the radiation doses delivered to patients and their optimization to reduce the associated radiation risks without limiting the diagnostic information. Methods: Entrance surface air kerma (ESAK) in a total of 64 adult patients in diagnostic digital Xray examinations were calculated and effective doses were estimated as per International Atomic Energy Agency (IAEA). Results: Median ESAK (mGy) and associated effective doses obtained were skull PA (0.45mGy, 0.005mSv) and skull Lat (0.25mGy, 0.003mSv). Results were compared with UK diagnostic reference levels and studies in India.Conclusion: The comparison revealed that the calculated ESAK and effective dose values wereless than the published literature. ESAK values reported in this study could further contribute toestablishing LDRLs

Factors influencing pharmacists and pharmaceutical scientists’ membership in professional organisations: an international survey

Background: Professional organisations exist as international or national organisations, with each country establishing at least one national professional association. There remains a knowledge gap about factors that influence professional organisational involvement of pharmacists and pharmaceutical scientists. This study aims to explore the motivators and barriers of pharmacy professionals holding organisation membership from a global perspective. Methods: An online questionnaire was developed and disseminated between May and July 2021. The survey was open to all pharmacists and pharmaceutical scientists. The survey consisted of four sections; demographic information, questions about professional organisations, about the International Pharmaceutical Federation (FIP) and its impact on the members. Data were analysed descriptively. Results: A total of 1033 complete survey responses were received and included in the analysis. Of all respondents, 761 (73.7%) respondents were current members of a professional organisation and 272 (26.3%) were not members of any professional organisation. Overall, findings demonstrated networking, education, training and professional development opportunities as the main interests and anticipated activities, while the lack of clarity or need to join organisation, time, and financial constraints as the main barriers of pharmacy professionals holding membership. The majority of FIP members are satisfied with current FIP activities, and anticipate further networking opportunities, educational resources and grants made available to members. Conclusions: Understanding the perceptions and needs, as well as factors that influence engagement of pharmacists and pharmaceutical scientists is the key to enhancing membership. Professional organisations are highly encouraged to strengthen and target activities according to the identified motivators and barriers

Severe childhood malaria syndromes defined by plasma proteome profiles

BACKGROUND Cerebral malaria (CM) and severe malarial anemia (SMA) are the most serious life-threatening clinical syndromes of Plasmodium falciparum infection in childhood. Therefore it is important to understand the pathology underlying the development of CM and SMA, as opposed to uncomplicated malaria (UM). Different host responses to infection are likely to be reflected in plasma proteome-patterns that associate with clinical status and therefore provide indicators of the pathogenesis of these syndromes. METHODS AND FINDINGS Plasma and comprehensive clinical data for discovery and validation cohorts were obtained as part of a prospective case-control study of severe childhood malaria at the main tertiary hospital of the city of Ibadan, an urban and densely populated holoendemic malaria area in Nigeria. A total of 946 children participated in this study. Plasma was subjected to high-throughput proteomic profiling. Statistical pattern-recognition methods were used to find proteome-patterns that defined disease groups. Plasma proteome-patterns accurately distinguished children with CM and with SMA from those with UM, and from healthy or severely ill malaria-negative children. CONCLUSIONS We report that an accurate definition of the major childhood malaria syndromes can be achieved using plasma proteome-patterns. Our proteomic data can be exploited to understand the pathogenesis of the different childhood severe malaria syndromes

Weak, Strong and Dynamic Controllability of Access-Controlled Workflows Under Conditional Uncertainty

A workflow (WF) is a formal description of a business process in which single atomic work units (tasks), organized in a partial order, are assigned to processing entities (agents) in order to achieve some business goal(s). A workflow management system must coordinate the execution of tasks and WF instances. Usually, the assignment of tasks to agents is accomplished by external constraints not represented in a WF. An access-controlled workflow (ACWF) extends a classical WF by explicitly representing agent availability for each task and authorization constraint. Authorization constraints model which users are authorized for which tasks depending on \u201cwho did what\u201d. Recent research has addressed temporal controllability of WFs under conditional and temporal uncertainty. However, controllability analysis for ACWFs under conditional uncertainty has never been addressed before. In this paper, we define weak, strong and dynamic controllability of ACWFs under conditional uncertainty, we present algorithmic approaches to address each of these types of controllability, and we synthesize execution strategies that specify which user has been (or will be) assigned to which task

Chemical and biomechanical characterization of hyperhomocysteinemic bone disease in an animal model

BACKGROUND: Classical homocystinuria is an autosomal recessive disorder caused by cystathionine β-synthase (CBS) deficiency and characterized by distinctive alterations of bone growth and skeletal development. Skeletal changes include a reduction in bone density, making it a potentially attractive model for the study of idiopathic osteoporosis. METHODS: To investigate this aspect of hyperhomocysteinemia, we supplemented developing chicks (n = 8) with 0.6% dl-homocysteine (hCySH) for the first 8 weeks of life in comparison to controls (n = 10), and studied biochemical, biomechanical and morphologic effects of this nutritional intervention. RESULTS: hCySH-fed animals grew faster and had longer tibiae at the end of the study. Plasma levels of hCySH, methionine, cystathionine, and inorganic sulfate were higher, but calcium, phosphate, and other indices of osteoblast metabolism were not different. Radiographs of the lower limbs showed generalized osteopenia and accelerated epiphyseal ossification with distinct metaphyseal and suprametaphyseal lucencies similar to those found in human homocystinurics. Although biomechanical testing of the tibiae, including maximal load to failure and bone stiffness, indicated stronger bone, strength was proportional to the increased length and cortical thickness in the hCySH-supplemented group. Bone ash weights and IR-spectroscopy of cortical bone showed no difference in mineral content, but there were higher Ca(2+)/PO(4)(3- )and lower Ca(2+)/CO(3)(2- )molar ratios than in controls. Mineral crystallization was unchanged. CONCLUSION: In this chick model, hyperhomocysteinemia causes greater radial and longitudinal bone growth, despite normal indices of bone formation. Although there is also evidence for an abnormal matrix and altered bone composition, our finding of normal biomechanical bone strength, once corrected for altered morphometry, suggests that any increase in the risk of long bone fracture in human hyperhomocysteinemic disease is small. We also conclude that the hCySH-supplemented chick is a promising model for study of the connective tissue abnormalities associated with homocystinuria and an important alternative model to the CBS knock-out mouse

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Replication of Putative Susceptibility Loci from Genome-Wide Association Studies Associated with Coronary Atherosclerosis in Chinese Han Population

BACKGROUND: Coronary atherosclerosis, the main cause of cardiovascular disease, is a progressive disease. Recent Genome Wide Association Studies (GWASs) discovered several novel loci associated with coronary artery disease (CAD) or its main complication myocardial infarction (MI). In this study, we investigated the associations between previously reported CAD- and MI-associated variants and coronary atherosclerosis in Chinese Han population. METHODOLOGY/PRINCIPAL FINDINGS: We performed a case-control association study with 2,335 coronary atherosclerosis patients and 1,078 controls undergoing coronary angiography of Chinese Han from China. Fourteen single nucleotide polymorphisms (SNPs), located at 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21.3, 10q11.21 and 15q22.33, were genotyped in our sample collection. Six SNPs at 9p21 were associated with coronary atherosclerosis susceptibility (P(trend)<0.05) and rs10757274 showed the most significant association (P = 2.38×10(-08), OR = 1.34). These associations remained significant after adjustment for multiple comparisons. Rs17465637 at 1q41 (P(trend) = 6.83×10(-03), OR = 0.86) also showed significant association with coronary atherosclerosis, but the association was not significant after multiple comparisons. Additionally, rs501120 (P = 8.36×10(-03), OR = 0.80) at 10q11.21 was associated with coronary atherosclerosis in females, but did not show association in males and all participants. Variants at 1p13.3, 2q36.3, 6q25.1 and 15q22.33 showed no associations with coronary atherosclerosis and main cardiovascular risk factors in our data. CONCLUSIONS/SIGNIFICANCE: Our findings indicated variants at 9p21 were significantly associated with coronary atherosclerosis in Han Chinese. Variants at 1q41 showed suggestive evidence of association and variants at 10q11.21 showed suggestive evidence of association in females, which warrant further study in a larger sample