A Plug-and-Play Platform for the Formation of Trifunctional Cysteine Bioconjugates that also Offers Control over Thiol Cleavability

Linkers that enable the site-selective synthesis of chemically modified proteins are of great interest to the field of chemical biology. Homogenous bioconjugates often show advantageous pharmacokinetic profiles and consequently increased efficacy in vivo. Cysteine residues have been exploited as a route to site-selectively modify proteins, and many successfully approved therapeutics make use of cysteine directed conjugation reagents. However, commonly used linkers, including maleimide–thiol conjugates, are not stable to the low concentrations of thiol present in blood. Furthermore, only a few cysteine-targeting reagents enable the site-selective attachment of multiple functionalities: a useful tool in the fields of theranostics and therapeutic blood half-life extension. Herein, we demonstrate the application of the pyridazinedione motif to enable site-selective attachment of three functionalities to a protein bearing a single cysteine residue. Extending upon previously documented dual modification work, here we demonstrate that by exploiting a bromide leaving group as an additional reactive point on the pyridazinedione scaffold, a thiol or aniline derivative can be added to a protein, post-conjugation. Thiol cleavability appraisal of the resultant C–S and C–N linked thio-bioconjugates demonstrated C–S functionalized linkers to be cleavable and C–N functionalized linkers to be noncleavable when incubated in an excess of glutathione. The plug-and-play trifunctional platform was exemplified by attaching clinically relevant motifs: biotin, fluorescein, a polyethylene glycol chain, and a model peptide. This platform provides a rare opportunity to combine up to three functionalities on a protein in a site-selective fashion. Furthermore, by selecting the use of a thiol or an amine for functionalization, we provide unique control over linker cleavability toward thiols, allowing this novel linker to be applied in a range of physiological environments

Emerging breast cancer epidemic: evidence from Africa

Cancer is an increasingly important public health problem in developing countries, including Africa [1]. As public and professional awareness of the cancer problem has grown, so has interest in the pattern of disease presentation, its epidemiology and treatment outcome. To date, however, there has been limited research about breast cancer in Africa. In the absence of systematic population-based cancer registration, most information has come from small clinical and pathology case series and the bias inherent in these types of studies has influenced current understanding of the pattern and characteristics of breast cancer in Africa. In this communication, we review the evidence for an emerging epidemic of breast cancer in Africa, its risk factors and likely future course. We conclude that, despite limited data, rising incidence of breast cancer is being driven by increasing life expectancy, improved control of infectious diseases, and changing lifestyle, diet, physical activity and obstetric practices. We also review current beliefs about hormone receptor subtypes of breast cancer in Africa and suggest that this is probably not systematically different from the pattern in other populations after adjusting for factors such as age and that the reported differences are related to poor tissue handling and laboratory processing practices

Conceptualizing pathways linking women's empowerment and prematurity in developing countries.

BackgroundGlobally, prematurity is the leading cause of death in children under the age of 5. Many efforts have focused on clinical approaches to improve the survival of premature babies. There is a need, however, to explore psychosocial, sociocultural, economic, and other factors as potential mechanisms to reduce the burden of prematurity. Women's empowerment may be a catalyst for moving the needle in this direction. The goal of this paper is to examine links between women's empowerment and prematurity in developing settings. We propose a conceptual model that shows pathways by which women's empowerment can affect prematurity and review and summarize the literature supporting the relationships we posit. We also suggest future directions for research on women's empowerment and prematurity.MethodsThe key words we used for empowerment in the search were "empowerment," "women's status," "autonomy," and "decision-making," and for prematurity we used "preterm," "premature," and "prematurity." We did not use date, language, and regional restrictions. The search was done in PubMed, Population Information Online (POPLINE), and Web of Science. We selected intervening factors-factors that could potentially mediate the relationship between empowerment and prematurity-based on reviews of the risk factors and interventions to address prematurity and the determinants of those factors.ResultsThere is limited evidence supporting a direct link between women's empowerment and prematurity. However, there is evidence linking several dimensions of empowerment to factors known to be associated with prematurity and outcomes for premature babies. Our review of the literature shows that women's empowerment may reduce prematurity by (1) preventing early marriage and promoting family planning, which will delay age at first pregnancy and increase interpregnancy intervals; (2) improving women's nutritional status; (3) reducing domestic violence and other stressors to improve psychological health; and (4) improving access to and receipt of recommended health services during pregnancy and delivery to help prevent prematurity and improve survival of premature babies.ConclusionsWomen's empowerment is an important distal factor that affects prematurity through several intervening factors. Improving women's empowerment will help prevent prematurity and improve survival of preterm babies. Research to empirically show the links between women's empowerment and prematurity is however needed

Magnetic resonance imaging of abnormal ventricular septal motion in heart diseases: a pictorial review

The purpose of this article is to illustrate the usefulness of MR imaging in the clinical evaluation of congenital and acquired cardiac diseases characterised by ventricular septal wall motion abnormality. Recognition of the features of abnormal ventricular septal motion in MR images is important to evaluate the haemodynamic status in patients with congenital and acquired heart diseases in routine clinical practice

A computer-based medical record system and personal digital assistants to assess and follow patients with respiratory tract infections visiting a rural Kenyan health centre

BACKGROUND: Clinical research can be facilitated by the use of informatics tools. We used an existing electronic medical record (EMR) system and personal data assistants (PDAs) to assess the characteristics and outcomes of patients with acute respiratory illnesses (ARIs) visiting a Kenyan rural health center. METHODS: We modified the existing EMR to include details on patients with ARIs. The EMR database was then used to identify patients with ARIs who were prospectively followed up by a research assistant who rode a bicycle to patients' homes and entered data into a PDA. RESULTS: A total of 2986 clinic visits for 2009 adult patients with respiratory infections were registered in the database between August 2002 and January 2005; 433 patients were selected for outcome assessments. These patients were followed up in the villages and assessed at 7 and 30 days later. Complete follow-up data were obtained on 381 patients (88%) and merged with data from the enrollment visit's electronic medical records and subsequent health center visits to assess duration of illness and complications. Symptoms improved at 7 and 30 days, but a substantial minority of patients had persistent symptoms. Eleven percent of patients sought additional care for their respiratory infection. CONCLUSION: EMRs and PDA are useful tools for performing prospective clinical research in resource constrained developing countries

Innovation and Access to Medicines for Neglected Populations: Could a Treaty Address a Broken Pharmaceutical R&D System?

As part of a cluster of articles leading up to the 2012 World Health Report and critically reflecting on the theme of “no health without research,” Suerie Moon and colleagues argue for a global health R&D treaty to improve innovation in new medicines and strengthening affordability, sustainable financing, efficiency in innovation, and equitable health-centered governance

Speciation and fate of trace metals in estuarine sediments under reduced and oxidized conditions, Seaplane Lagoon, Alameda Naval Air Station (USA)

We have identified important chemical reactions that control the fate of metal-contaminated estuarine sediments if they are left undisturbed (in situ) or if they are dredged. We combined information on the molecular bonding of metals in solids from X-ray absorption spectroscopy (XAS) with thermodynamic and kinetic driving forces obtained from dissolved metal concentrations to deduce the dominant reactions under reduced and oxidized conditions. We evaluated the in situ geochemistry of metals (cadmium, chromium, iron, lead, manganese and zinc) as a function of sediment depth (to 100 cm) from a 60 year record of contamination at the Alameda Naval Air Station, California. Results from XAS and thermodynamic modeling of porewaters show that cadmium and most of the zinc form stable sulfide phases, and that lead and chromium are associated with stable carbonate, phosphate, phyllosilicate, or oxide minerals. Therefore, there is minimal risk associated with the release of these trace metals from the deeper sediments contaminated prior to the Clean Water Act (1975) as long as reducing conditions are maintained. Increased concentrations of dissolved metals with depth were indicative of the formation of metal HS(- )complexes. The sediments also contain zinc, chromium, and manganese associated with detrital iron-rich phyllosilicates and/or oxides. These phases are recalcitrant at near-neutral pH and do not undergo reductive dissolution within the 60 year depositional history of sediments at this site. The fate of these metals during dredging was evaluated by comparing in situ geochemistry with that of sediments oxidized by seawater in laboratory experiments. Cadmium and zinc pose the greatest hazard from dredging because their sulfides were highly reactive in seawater. However, their dissolved concentrations under oxic conditions were limited eventually by sorption to or co-precipitation with an iron (oxy)hydroxide. About 50% of the reacted CdS and 80% of the reacted ZnS were bonded to an oxide-substrate at the end of the 90-day oxidation experiment. Lead and chromium pose a minimal hazard from dredging because they are bonded to relatively insoluble carbonate, phosphate, phyllosilicate, or oxide minerals that are stable in seawater. These results point out the specific chemical behavior of individual metals in estuarine sediments, and the need for direct confirmation of metal speciation in order to constrain predictive models that realistically assess the fate of metals in urban harbors and coastal sediments

Azimuthal anisotropy and correlations at large transverse momenta in p+pp+p and Au+Au collisions at sNN\sqrt{s_{_{NN}}}= 200 GeV

Results on high transverse momentum charged particle emission with respect to the reaction plane are presented for Au+Au collisions at $\sqrt{s_{_{NN}}}$= 200 GeV. Two- and four-particle correlations results are presented as well as a comparison of azimuthal correlations in Au+Au collisions to those in $p+p$ at the same energy. Elliptic anisotropy, $v_2$, is found to reach its maximum at $p_t \sim 3$ GeV/c, then decrease slowly and remain significant up to $p_t\approx 7$ -- 10 GeV/c. Stronger suppression is found in the back-to-back high-$p_t$ particle correlations for particles emitted out-of-plane compared to those emitted in-plane. The centrality dependence of $v_2$ at intermediate $p_t$ is compared to simple models based on jet quenching.Comment: 4 figures. Published version as PRL 93, 252301 (2004

Rapidity and Centrality Dependence of Proton and Anti-proton Production from Au+Au Collisions at sqrt(sNN) = 130GeV

We report on the rapidity and centrality dependence of proton and anti-proton transverse mass distributions from Au+Au collisions at sqrt(sNN) = 130GeV as measured by the STAR experiment at RHIC. Our results are from the rapidity and transverse momentum range of |y|<0.5 and 0.35 <p_t<1.00GeV/c. For both protons and anti-protons, transverse mass distributions become more convex from peripheral to central collisions demonstrating characteristics of collective expansion. The measured rapidity distributions and the mean transverse momenta versus rapidity are flat within |y|<0.5. Comparisons of our data with results from model calculations indicate that in order to obtain a consistent picture of the proton(anti-proton) yields and transverse mass distributions the possibility of pre-hadronic collective expansion may have to be taken into account.Comment: 4 pages, 3 figures, 1 table, submitted to PR