BEHIND THE IRON CURTAIN: DEXRAS1 MEDIATES GLUTAMATEN-MDA INDUCED NEURONAL IRON UPTAKE

Iron is an enigmatic molecule – a divalent metal absolutely required for life, but toxic in excess. Because of this dual nature, iron trafficking within the cell is tightly regulated, with little free iron available in the cytosol. Iron entry into the cell is mediated through two distinct pathways, both of which utilize the Divalent Metal Transporter (DMT1), a twelve-transmembrane protein which is the only known iron importer in the cell. Dexras1 is a small G-protein regulated by glucocorticoids and neuronal nitric oxide synthase (nNOS). Using yeast-two-hybrid analysis, we have discovered that Dexras1 interacts with DMT1 via an adaptor protein, the Peripheral Benzodiazepine Receptor Associated Protein (PAP7). We have identified a novel signaling cascade in neurons whereby stimulation of glutamate-NMDA receptors activates nNOS, leading to Snitrosylation of Dexras1, which by its interaction with PAP7 and DMT1, physiologically induces iron uptake. We have also investigated whether misregulation of this pathway participates in NMDA-mediated neuronal excitoxicity

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Integrated genetic and pharmacologic interrogation of rare cancers

Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets. Integrating these three complementary and orthogonal methods, we identify CDK4 and XPO1 as potential therapeutic targets in this cancer, which has no known alterations in these genes. These observations establish an approach that integrates new patient-derived models, functional genomics and chemical screens to facilitate the discovery of targets in rare cancers

Concise Total Synthesis of (+)-Luteoalbusins A and B

The first total synthesis of (+)-luteoalbusins A and B is described. Highly regio- and diastereoselective chemical transformations in our syntheses include a Friedel–Crafts C3-indole addition to a cyclotryptophan-derived diketopiperazine, a late-stage diketopiperazine dihydroxylation, and a C11-sulfidation sequence, in addition to congener-specific polysulfane synthesis and cyclization to the corresponding epipolythiodiketopiperazine. We also report the cytoxicity of both alkaloids, and closely related derivatives, against A549, HeLa, HCT116, and MCF7 human cancer cell lines.National Institute of General Medical Sciences (U.S.) (GM089732

Perceived Neighborhood Environment and Its Association with Health Screening and Exercise Participation amongst Low-Income Public Rental Flat Residents in Singapore

10.3390/ijerph16081384INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH16

NAMPT Is the Cellular Target of STF-31-Like Small-Molecule Probes

The small-molecule probes STF-31 and its analogue compound 146 were discovered while searching for compounds that kill VHL-deficient renal cell carcinoma cell lines selectively and have been reported to act via direct inhibition of the glucose transporter GLUT1. We profiled the sensitivity of 679 cancer cell lines to STF-31 and found that the pattern of response is tightly correlated with sensitivity to three different inhibitors of nicotinamide phosphoribosyltransferase (NAMPT). We also performed whole-exome next-generation sequencing of compound 146-resistant HCT116 clones and identified a recurrent NAMPT-H191R mutation. Ectopic expression of NAMPT-H191R conferred resistance to both STF-31 and compound 146 in cell lines. We further demonstrated that both STF-31 and compound 146 inhibit the enzymatic activity of NAMPT in a biochemical assay in vitro. Together, our cancer-cell profiling and genomic approaches identify NAMPT inhibition as a critical mechanism by which STF-31-like compounds inhibit cancer cells

Comprehensive synthesis of various functionalized graphene nanoribbons

The contemporary semiconductor industry is experiencing problems with the miniaturization and efficiency of silicon-based components. After its first successful isolation in 2004, graphene has been widely researched due to the potential of surpassing silicon as the ubiquitous semiconductor material. The unprecedented electric conduction properties combined with possibilities of controlling the graphene fragment edges with atomic precision make it a true nano-scale building material that might revolutionize the whole logic circuit and semiconductor industries. Graphene is the carbon allotrope of single atomic layer of carbon atoms arranged into a hexagonally symmetrical honeycomb structure. Due to the confinement into a singular layer and the ultimate symmetry of the lattice, graphene exhibits highly unusually hybridized energy bands, which are the source of its coveted electromagnetic and mechanical properties. These properties can be tuned in a versatile manner by patterning graphene in nanometer scale. Especially the symmetric and well-defined graphene nanoribbons (GNRs) are of high interest, and their production has been under increasing research. The aim of this thesis was to assess various methods capable of producing nano-scale functionalized graphene structures. The most advanced contemporary method for this is the surfaceassisted self-assembly (SASA) of intelligently designed precursor molecules on transition metal surfaces. Five batches of different target molecules were synthesized in order to be used as precursor materials for GNR formation through the SASA approach. The synthesis details of these molecules have been presented in the experimental section of this work. The SASA approach is currently the only synthesis method capable of providing atomic scale control over the graphene domain edges. Other graphene synthesis methods include exfoliation from graphite, unzipping carbon nanotubes and epitaxial film synthesis from simple hydrocarbon gasses. The quality of graphene is highly affected by the synthesis transition metal catalyst, and the properties exhibited by graphene domains are directly influenced by the substrate. It is therefore of high importance to be aware of the properties and interactions of various substrate materials. Decoupling the graphene fragments from unfit surfaces and applying them on optimal substrates is a necessary step of the synthesis. Hexagonal boron nitride (hBN) is currently the best known substrate for graphene-based devices. While the exceptional nature of graphene has already been demonstrated by producing highly effective experimental devices, the challenges associated with scale-up and mass-production of well-defined graphene structures remain currently unsolved.Nykyaikaisessa puolijohdeteollisuudessa pii-peräisten komponenttien tehostukseen ja miniatyrisointiin liittyviä ongelmia on yritetty ratkaista etsimällä vaihtoehtoisia komponenttimateriaaleja. Grafeenia on tutkittu runsaasti vuoden 2004 jälkeen, jolloin ensimmäinen onnistunut yksikerroksisen grafeenin eristystapa esitettiin. Grafeenin erityislaatuiset sähkönjohtokykyyn liittyvät ominaisuudet yhdistettynä grafeenisaarekkeiden mahdolliseen atomitason reunakontrolliin tekevät siitä potentiaalisesti mullistavan nano-mittakaavan logiikkapiiri- ja puolijohdemateriaalin. Grafeeni on hiilen allotrooppi, jossa hiiliatomit järjestäytyvät yksikerroksiseksi, säännölliseksi, kuusikulmaiseksi hilaksi. Korkeasta symmetriasta ja yhden atomin paksuudesta johtuen grafeenin energiatasot ovat hybridisoituneet hyvin epätavallisen muotoisesti, mistä johtuen mm. sen sähkönjohtokyky on ilmiömäinen. Näiden energiatasojen (ja siten sähkömagneettisien ominaisuuksien) järjestäytymiseen voidaan vaikuttaa monipuolisesti leikkaamalla grafeenia nanometrien mittakaavassa. Erityisesti symmetristen ja atomitasolla kontrolloitujen grafeeninauhojen (GNR) onnistunut ja laajamittainen synteesi on suuresti kiinnostava ja tutkittu aihe. Tämän työn tarkoituksena oli perehtyä mahdollisiin keinoihin valmistaa nanometrien mittaisia, funktionalisoituja grafeenirakenteita. Edistynein nykyaikainen menetelmä tähän tarkoitukseen on ennalta suunniteltujen lähtöaineiden hallittu ja katalysoitu terminen hajottaminen ja yhdistyminen laadukkailla siirtymämetallipinnoilla (SASA). Tähän tarkoitukseen valmistettiin viisi eri tuotemolekyylierää, joiden synteesireitit on esitelty työn tutkimusosassa. Grafeenirakenteiden reunojen atomitason kontrolli ei ole toistaiseksi mahdollista muilla menetelmillä, joilla on puolestaan muita etuja käytännön grafeenikomponenttien valmistusta ajatellen. Näitä menetelmiä ovat mm. grafeenin mekaaninen kuoriminen grafiitista, nanoputkien kemiallinen aukaiseminen, sekä epitaksiaalisten grafeenifilmien valmistus yksinkertaisista hiilivedyistä. Koska grafeenin laatu ja havaittavat ominaisuudet riippuvat suuresti synteesissä käytetystä siirtymämetallista sekä pinnasta, jonka päälle se on sittemmin asetettu, on pintamateriaalien aiheuttamien interaktioiden tunteminen tärkeää. Synteesivaiheessa katalyyttisten ominaisuuksiensa takia käytetyt siirtymämetallit eivät sovellu alustoiksi mahdollisille grafeenikomponenteille. Tästä syystä grafeenin siirtomahdollisuudet tulee ottaa synteesissä huomioon. Heksagonaalinen boorinitridi (hBN) on tähän mennessä paras tunnettu pintamateriaali grafeenille. Tähän mennessä on jo näytetty toteen grafeenin erinomaisuus kokeellisten komponenttien muodossa, mutta massatuotantoon ja funktionalisoitujen grafeenirakenteiden ongelmattomaan synteesiin liittyvät haasteet ovat vielä toistaiseksi ratkaisematta