Structure and reactivity of Trypanosoma brucei pteridine reductase: inhibition by the archetypal antifolate methotrexate

The protozoan Trypanosoma brucei has a functional pteridine reductase (TbPTR1), an NADPH-dependent short-chain reductase that participates in the salvage of pterins, which are essential for parasite growth. PTR1 displays broad-spectrum activity with pterins and folates, provides a metabolic bypass for inhibition of the trypanosomatid dihydrofolate reductase and therefore compromises the use of antifolates for treatment of trypanosomiasis. Catalytic properties of recombinant TbPTR1 and inhibition by the archetypal antifolate methotrexate have been characterized and the crystal structure of the ternary complex with cofactor NADP(+) and the inhibitor determined at 2.2 Å resolution. This enzyme shares 50% amino acid sequence identity with Leishmania major PTR1 (LmPTR1) and comparisons show that the architecture of the cofactor binding site, and the catalytic centre are highly conserved, as are most interactions with the inhibitor. However, specific amino acid differences, in particular the placement of Trp221 at the side of the active site, and adjustment of the β6-α6 loop and α6 helix at one side of the substrate-binding cleft significantly reduce the size of the substrate binding site of TbPTR1 and alter the chemical properties compared with LmPTR1. A reactive Cys168, within the active site cleft, in conjunction with the C-terminus carboxyl group and His267 of a partner subunit forms a triad similar to the catalytic component of cysteine proteases. TbPTR1 therefore offers novel structural features to exploit in the search for inhibitors of therapeutic value against African trypanosomiasis

Primary stroke prevention worldwide : translating evidence into action

Funding Information: The stroke services survey reported in this publication was partly supported by World Stroke Organization and Auckland University of Technology. VLF was partly supported by the grants received from the Health Research Council of New Zealand. MOO was supported by the US National Institutes of Health (SIREN U54 HG007479) under the H3Africa initiative and SIBS Genomics (R01NS107900, R01NS107900-02S1, R01NS115944-01, 3U24HG009780-03S5, and 1R01NS114045-01), Sub-Saharan Africa Conference on Stroke Conference (1R13NS115395-01A1), and Training Africans to Lead and Execute Neurological Trials & Studies (D43TW012030). AGT was supported by the Australian National Health and Medical Research Council. SLG was supported by a National Heart Foundation of Australia Future Leader Fellowship and an Australian National Health and Medical Research Council synergy grant. We thank Anita Arsovska (University Clinic of Neurology, Skopje, North Macedonia), Manoj Bohara (HAMS Hospital, Kathmandu, Nepal), Denis ?erimagi? (Poliklinika Glavi?, Dubrovnik, Croatia), Manuel Correia (Hospital de Santo Ant?nio, Porto, Portugal), Daissy Liliana Mora Cuervo (Hospital Moinhos de Vento, Porto Alegre, Brazil), Anna Cz?onkowska (Institute of Psychiatry and Neurology, Warsaw, Poland), Gloria Ekeng (Stroke Care International, Dartford, UK), Jo?o Sargento-Freitas (Centro Hospitalar e Universit?rio de Coimbra, Coimbra, Portugal), Yuriy Flomin (MC Universal Clinic Oberig, Kyiv, Ukraine), Mehari Gebreyohanns (UT Southwestern Medical Centre, Dallas, TX, USA), Ivete Pillo Gon?alves (Hospital S?o Jos? do Avai, Itaperuna, Brazil), Claiborne Johnston (Dell Medical School, University of Texas, Austin, TX, USA), Kristaps Jurj?ns (P Stradins Clinical University Hospital, Riga, Latvia), Rizwan Kalani (University of Washington, Seattle, WA, USA), Grzegorz Kozera (Medical University of Gda?sk, Gda?sk, Poland), Kursad Kutluk (Dokuz Eylul University, ?zmir, Turkey), Branko Malojcic (University Hospital Centre Zagreb, Zagreb, Croatia), Micha? Maluchnik (Ministry of Health, Warsaw, Poland), Evija Migl?ne (P Stradins Clinical University Hospital, Riga, Latvia), Cassandra Ocampo (University of Botswana, Princess Marina Hospital, Botswana), Louise Shaw (Royal United Hospitals Bath NHS Foundation Trust, Bath, UK), Lekhjung Thapa (Upendra Devkota Memorial-National Institute of Neurological and Allied Sciences, Kathmandu, Nepal), Bogdan Wojtyniak (National Institute of Public Health, Warsaw, Poland), Jie Yang (First Affiliated Hospital of Chengdu Medical College, Chengdu, China), and Tomasz Zdrojewski (Medical University of Gda?sk, Gda?sk, Poland) for their comments on early draft of the manuscript. The views expressed in this article are solely the responsibility of the authors and they do not necessarily reflect the views, decisions, or policies of the institution with which they are affiliated. We thank WSO for funding. The funder had no role in the design, data collection, analysis and interpretation of the study results, writing of the report, or the decision to submit the study results for publication. Funding Information: The stroke services survey reported in this publication was partly supported by World Stroke Organization and Auckland University of Technology. VLF was partly supported by the grants received from the Health Research Council of New Zealand. MOO was supported by the US National Institutes of Health (SIREN U54 HG007479) under the H3Africa initiative and SIBS Genomics (R01NS107900, R01NS107900-02S1, R01NS115944-01, 3U24HG009780-03S5, and 1R01NS114045-01), Sub-Saharan Africa Conference on Stroke Conference (1R13NS115395-01A1), and Training Africans to Lead and Execute Neurological Trials & Studies (D43TW012030). AGT was supported by the Australian National Health and Medical Research Council. SLG was supported by a National Heart Foundation of Australia Future Leader Fellowship and an Australian National Health and Medical Research Council synergy grant. We thank Anita Arsovska (University Clinic of Neurology, Skopje, North Macedonia), Manoj Bohara (HAMS Hospital, Kathmandu, Nepal), Denis Čerimagić (Poliklinika Glavić, Dubrovnik, Croatia), Manuel Correia (Hospital de Santo António, Porto, Portugal), Daissy Liliana Mora Cuervo (Hospital Moinhos de Vento, Porto Alegre, Brazil), Anna Członkowska (Institute of Psychiatry and Neurology, Warsaw, Poland), Gloria Ekeng (Stroke Care International, Dartford, UK), João Sargento-Freitas (Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal), Yuriy Flomin (MC Universal Clinic Oberig, Kyiv, Ukraine), Mehari Gebreyohanns (UT Southwestern Medical Centre, Dallas, TX, USA), Ivete Pillo Gonçalves (Hospital São José do Avai, Itaperuna, Brazil), Claiborne Johnston (Dell Medical School, University of Texas, Austin, TX, USA), Kristaps Jurjāns (P Stradins Clinical University Hospital, Riga, Latvia), Rizwan Kalani (University of Washington, Seattle, WA, USA), Grzegorz Kozera (Medical University of Gdańsk, Gdańsk, Poland), Kursad Kutluk (Dokuz Eylul University, İzmir, Turkey), Branko Malojcic (University Hospital Centre Zagreb, Zagreb, Croatia), Michał Maluchnik (Ministry of Health, Warsaw, Poland), Evija Miglāne (P Stradins Clinical University Hospital, Riga, Latvia), Cassandra Ocampo (University of Botswana, Princess Marina Hospital, Botswana), Louise Shaw (Royal United Hospitals Bath NHS Foundation Trust, Bath, UK), Lekhjung Thapa (Upendra Devkota Memorial-National Institute of Neurological and Allied Sciences, Kathmandu, Nepal), Bogdan Wojtyniak (National Institute of Public Health, Warsaw, Poland), Jie Yang (First Affiliated Hospital of Chengdu Medical College, Chengdu, China), and Tomasz Zdrojewski (Medical University of Gdańsk, Gdańsk, Poland) for their comments on early draft of the manuscript. The views expressed in this article are solely the responsibility of the authors and they do not necessarily reflect the views, decisions, or policies of the institution with which they are affiliated. We thank WSO for funding. The funder had no role in the design, data collection, analysis and interpretation of the study results, writing of the report, or the decision to submit the study results for publication. Funding Information: VLF declares that the PreventS web app and Stroke Riskometer app are owned and copyrighted by Auckland University of Technology; has received grants from the Brain Research New Zealand Centre of Research Excellence (16/STH/36), Australian National Health and Medical Research Council (NHMRC; APP1182071), and World Stroke Organization (WSO); is an executive committee member of WSO, honorary medical director of Stroke Central New Zealand, and CEO of New Zealand Stroke Education charitable Trust. AGT declares funding from NHMRC (GNT1042600, GNT1122455, GNT1171966, GNT1143155, and GNT1182017), Stroke Foundation Australia (SG1807), and Heart Foundation Australia (VG102282); and board membership of the Stroke Foundation (Australia). SLG is funded by the National Health Foundation of Australia (Future Leader Fellowship 102061) and NHMRC (GNT1182071, GNT1143155, and GNT1128373). RM is supported by the Implementation Research Network in Stroke Care Quality of the European Cooperation in Science and Technology (project CA18118) and by the IRIS-TEPUS project from the inter-excellence inter-cost programme of the Ministry of Education, Youth and Sports of the Czech Republic (project LTC20051). BN declares receiving fees for data management committee work for SOCRATES and THALES trials for AstraZeneca and fees for data management committee work for NAVIGATE-ESUS trial from Bayer. All other authors declare no competing interests. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseStroke is the second leading cause of death and the third leading cause of disability worldwide and its burden is increasing rapidly in low-income and middle-income countries, many of which are unable to face the challenges it imposes. In this Health Policy paper on primary stroke prevention, we provide an overview of the current situation regarding primary prevention services, estimate the cost of stroke and stroke prevention, and identify deficiencies in existing guidelines and gaps in primary prevention. We also offer a set of pragmatic solutions for implementation of primary stroke prevention, with an emphasis on the role of governments and population-wide strategies, including task-shifting and sharing and health system re-engineering. Implementation of primary stroke prevention involves patients, health professionals, funders, policy makers, implementation partners, and the entire population along the life course.publishersversionPeer reviewe

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.</p

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol�which is a marker of cardiovascular risk�changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95 credible interval 3.7 million�4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world. © 2020, The Author(s), under exclusive licence to Springer Nature Limited

A century of trends in adult human height

Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5-22.7) and 16.5 cm (13.3-19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8-144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3�6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55 of the global rise in mean BMI from 1985 to 2017�and more than 80 in some low- and middle-income regions�was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing�and in some countries reversal�of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories. © 2019, The Author(s)