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The 3-D structure of human lactoferrin was first solved in atomic detail in 1987. Since that time, a variety of proven and postulated activities have been added to the original annotation of lactoferrin as an iron-binding protein. Structural studies have also expanded to include iron-bound and iron-free (apo) forms, mutants, and the lactoferrins of different species. In this review, we take the current information on both structure and function and show that the 3-D structure provides a useful framework for understanding some activities and also points to productive research directions that could help elucidate other reported functions. Some functions relate to iron binding where the role of lactoferrin is to scavenge and retain iron across a wide pH range. We specifically focus on functions that depend on the surface structure of the molecule, identifying features that may determine the many other protective properties of this multifunctional protein. [ABSTRACT FROM AUTHOR]

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Mycobacterium tuberculosis ( Mtb), the causative agent of TB, remains a serious world health problem owing to limitations of the available drugs and the emergence of resistant strains. In this context, key biosynthetic enzymes from Mtb are attractive targets for the development of new therapeutic drugs. Here, the 1.5 Å resolution crystal structure of Mtb phosphoserine aminotransferase (MtbPSAT) in complex with its cofactor, pyridoxal 5′-phosphate (PLP), is reported. MtbPSAT is an essential enzyme in the biosynthesis of serine and in pathways of one-carbon metabolism. The structure shows that although the Mtb enzyme differs substantially in sequence from other PSAT enzymes, its fold is conserved and its PLP-binding site is virtually identical. Structural comparisons suggest that this site remains unchanged throughout the catalytic cycle. On the other hand, PSAT enzymes are obligate dimers in which the two active sites are located in the dimer interface and distinct differences in the MtbPSAT dimer are noted. These impact on the substrate-binding region and access channel and suggest options for the development of selective inhibitors. [ABSTRACT FROM AUTHOR]

Background: The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues of rilpivirine are described in the patent literature, but detailed analyses of their antiviral activities have not been published. This work addresses the ability of several of these analogues to inhibit the replication of wild-type (WT) and drug-resistant HIV-1. Results: We used a combination of structure activity relationships and X-ray crystallography to examine NNRTIs that are structurally related to rilpivirine to determine their ability to inhibit WT RT and several clinically relevant RT mutants. Several analogues showed broad activity with only modest losses of potency when challenged with drug-resistant viruses. Structural analyses (crystallography or modeling) of several analogues whose potencies were reduced by RT mutations provide insight into why these compounds were less effective. Conclusions: Subtle variations between compounds can lead to profound differences in their activities and resistance profiles. Compounds with larger substitutions replacing the pyrimidine and benzonitrile groups of rilpivirine, which reorient pocket residues, tend to lose more activity against the mutants we tested. These results provide a deeper understanding of how rilpivirine and related compounds interact with the NNRTI binding pocket and should facilitate development of novel inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Two new marine-derived sesquiterpene benzoquinones which we designate as neopetrosiquinones A (1) and B (2), have been isolated from a deep-water sponge of the family Petrosiidae. The structures were elucidated on the basis of their spectroscopic data. Compounds 1 and 2 inhibit the in vitro proliferation of the DLD-1 human colorectal adenocarcinoma cell line with IC50 values of 3.7 and 9.8μM, respectively, and the PANC-1 human pancreatic carcinoma cell line with IC50 values of 6.1 and 13.8μM, respectively. Neopetrosiquinone A (1) also inhibited the in vitro proliferation of the AsPC-1 human pancreatic carcinoma cell line with an IC50 value of 6.1μM. The compounds are structurally related to alisiaquinone A, cyclozonarone, and xestoquinone. [Copyright &y& Elsevier]

A key focus of concern in relation to the future shape of the nursing workforce internationally and nationally has been the perceived high attrition rate of graduates. This concern has been accompanied by a plethora of literature on graduate transition to practice. Many of the studies have been carried out from the perspective of the employing organisation and look at graduates turnover intent and retention strategies within the first year of practice. In recent years New Zealand has responded with some success to these concerns by introducing graduate programmes covering the first twelve months of practice. There are fewer published studies that have used local, regional or national populations of nursing graduates to explore actual turnover for periods longer than the first twelve months transition. This paper reviews these latter studies and shows that the most likely reasons for mobility, both within nursing or out of the profession, have been found to be related to the work environment and family responsibilities. Although some graduates leave the nursing profession early in their career, many more have made an employment move within nursing, and younger mobile graduates in particular are interested in career promotion. These findings suggest that ongoing innovation in roles and skills within the professional work context is required to ensure longer term retention of graduates. As New Zealand is now collecting graduate nursing workforce data these international findings have implications which should be considered in the development of New Zealand nursing workforce strategy. Encouraging graduate stability depends on a graduate workforce strategy which takes a perspective longer than twelve months. [ABSTRACT FROM AUTHOR]

Summary: The main objective of this study was to identify the best predictors for student achievements (Undergraduate Grade Point Average (UGPA)) in their first year in an undergraduate nursing programme. Data were acquired from the Tracking Project database which is held by the Faculty of Medical and Health Sciences at the University of Auckland. The data (n =134) included information on student demographics, final year secondary school achievements (National Certificate of Educational Achievement Grade Point Average (NCEAGPA) & NCEA Credits), university admission ranking scores, and achievements in first year in the undergraduate nursing programme (UGPA). Linear regression models were used to identify the best predictors for first year students'' UGPA in the nursing programme. The regression models suggest that the best predictor for the first year GPA is the NCEAGPA (beta=.488; R2(for the entire model)=.53), followed by the admission ranking scores (beta=.308; R2 =.40). Based on these findings, it is suggested that a Dual Admission Model (DAM) be utilised whereby students could be admitted either by the current university admission criteria or by an alternative model, which is purely based on the predictability of achievement within the nursing programme. Application of the DAM to other institutions/countries was discussed. [Copyright &y& Elsevier]

Nuclear protein import in eukaryotic cells is mediated by karyopherin proteins, which bind to specific nuclear localization signals on substrate proteins and transport them across the nuclear envelope and into the nucleus. Replication protein A (RPA) is a nuclear protein comprised of three subunits (termed Rfa1, Rfa2, and Rfa3 in Saccharomyces cerevisiae) that binds single-stranded DNA and is essential for DNA replication, recombination, and repair. RPA associates with two different karyopherins in yeast, Kap95, and Msn5/Kap142. However, it is unclear which of these karyopherins is responsible for RPA nuclear import. We have generated GFP fusion proteins with each of the RPA subunits and demonstrate that these Rfa-GFP chimeras are functional in yeast cells. The intracellular localization of the RPA proteins in live cells is similar in wild-type and msn5Δ deletion strains but becomes primarily cytoplasmic in cells lacking functional Kap95. Truncating the C-terminus of any of the RPA subunits results in mislocalization of the proteins to the cytoplasm and a loss of protein-protein interactions between the subunits. Our data indicate that Kap95 is likely the primary karyopherin responsible for RPA nuclear import in yeast and that the C-terminal regions of Rfa1, Rfa2, and Rfa3 are essential for efficient nucleocytoplasmic transport of each RPA subunit. [ABSTRACT FROM AUTHOR]

To report time from the onset of symptoms to hospital presentation in Australian and New Zealand patients with subsequently confirmed acute coronary syndrome, and to identify factors associated with prehospital delay time in these patients. Patients with coronary artery disease enrolled in a randomized clinical trial testing an intervention to reduce delay in responding to acute coronary syndrome symptoms had been followed for 24 months. In cases of admission to the ED for possible acute coronary syndrome, medical records were reviewed to determine the diagnosis, prehospital delay time, mode of transport to the hospital and aspirin use before admission. Clinical and demographic data were taken from the trial database. Patients ( n= 140) had an average (SD) age of 67.3 (11.5) years; 36% were female. Two-thirds of patients went to hospital by ambulance and 89.3% had a final diagnosis of unstable angina. The median time from onset of symptoms to arrival at the ED was 2 h and 25 min (interquartile range 1:25-4:59); 12.1% arrived ≤ 1 h and 66% within 4 h. Multiple linear regression analysis showed that use of ambulance (Beta = 0.247, P= 0.012) and younger age (Beta = 0.198, P= 0.043) were independent predictors of shorter delay times. The time from the onset of symptoms to hospital presentation was too long for maximal benefit from treatment in most patients. Further efforts are needed to reduce treatment-seeking delay in response to symptoms of acute coronary syndrome. [ABSTRACT FROM AUTHOR]

Mycothiol ligase (Mshc) is a key enzyme in the biosynthesis of mycothiol, a small molecular weight thiol that is unique to actinomycetes and whose primary role is to maintain intracellular redox balance and remove toxins. MshC catalyzes the adenosine triphosphate (ATP)-dependent condensation of cysteine and glucosamine-inositol (GI) to produce cysteine-glucosamine-inositol (CGI). MshC is essential to mycobacterium tuberculosis and therefore represents an attractive target for chemotherapeutic intervention. a screening protocol was developed to identify MshC inhibitors based on quantification of residual ATP using a coupled luminescent assay. the protocol was used to screen a library of 3100 compounds in a 384-well plate format (Z' ≥ 0.65). Fifteen hits (0.48%) were identified from the screen, and 2 hits were confirmed in a secondary assay that measures production of CGI. the structures of both hits contain N-substituted quinolinium moieties, and the more potent of the 2—namely, dequalinium chloride—inhibits MshC with an IC50 value of 24 ± 1 μM. Further studies showed dequalinium to be an ATP-competitive inhibitor of MshC, to bind MshC with a KD of 0.22 μM, and to inhibit the growth of M. tuberculosis under aerobic and anaerobic conditions with minimum inhibitory and anaerobic bactericidal concentrations of 1.2 and 0.3 μg/mL, respectively. the screening protocol described is robust and has enabled the identification of new MshC inhibitors. [ABSTRACT FROM AUTHOR]