Mapping the topography of a protein energy landscape

Protein energy landscapes are highly complex, yet the vast majority of states within them tend to be invisible to experimentalists. Here, using site-directed mutagenesis and exploiting the simplicity of tandem-repeat protein structures, we delineate a network of these states and the routes between them. We show that our target, gankyrin, a 226-residue 7-ankyrin-repeat protein, can access two alternative (un)folding pathways. We resolve intermediates as well as transition states, constituting a comprehensive series of snapshots that map early and late stages of the two pathways and show both to be polarized such that the repeat array progressively unravels from one end of the molecule or the other. Strikingly, we find that the protein folds via one pathway but unfolds via a different one. The origins of this behavior can be rationalized using the numerical results of a simple statistical mechanics model that allows us to visualize the equilibrium behavior as well as single-molecule folding/unfolding trajectories, thereby filling in the gaps that are not accessible to direct experimental observation. Our study highlights the complexity of repeat-protein folding arising from their symmetrical structures; at the same time, however, this structural simplicity enables us to dissect the complexity and thereby map the precise topography of the energy landscape in full breadth and remarkable detail. That we can recapitulate the key features of the folding mechanism by computational analysis of the native structure alone will help toward the ultimate goal of designed amino-acid sequences with made-to-measure folding mechanisms—the Holy Grail of protein folding

Influence of gestational age at initiation of antihypertensive therapy: secondary analysis of CHIPS trial data (control of hypertension in pregnancy study)

For hypertensive women in CHIPS (Control of Hypertension in Pregnancy Study), we assessed whether the maternal benefits of tight control could be achieved, while minimizing any potentially negative effect on fetal growth, by delaying initiation of antihypertensive therapy until later in pregnancy. For the 981 women with nonsevere, chronic or gestational hypertension randomized to less-tight (target diastolic blood pressure, 100 mm Hg), or tight (target, 85 mm Hg) control, we used mixed-effects logistic regression to examine whether the effect of less-tight (versus tight) control on major outcomes was dependent on gestational age at randomization, adjusting for baseline factors as in the primary analysis and including an interaction term between gestational age at randomization and treatment allocation. Gestational age was considered categorically (quartiles) and continuously (linear or quadratic form), and the optimal functional form selected to provide the best fit to the data based on the Akaike information criterion. Randomization before (but not after) 24 weeks to less-tight (versus tight) control was associated with fewer babies with birth weight 48 hours (Pinteraction=0.354). For the mother, less-tight (versus tight) control was associated with more severe hypertension at all gestational ages but particularly so before 28 weeks (Pinteraction=0.076). In women with nonsevere, chronic, or gestational hypertension, there seems to be no gestational age at which less-tight (versus tight) control is the preferred management strategy to optimize maternal or perinatal outcomes

Four steps for the Earth: mainstreaming the post-2020 global biodiversity framework

The upcoming Convention on Biological Diversity (CBD) meeting, and adoption of the new Global Biodiversity Framework, represent an opportunity to transform humanity's relationship with nature. Restoring nature while meeting human needs requires a bold vision, including mainstreaming biodiversity conservation in society. We present a framework that could support this: the Mitigation and Conservation Hierarchy. This places the Mitigation Hierarchy for mitigating and compensating the biodiversity impacts of developments (1, avoid; 2, minimize; 3, restore; and 4, offset, toward a target such as "no net loss" of biodiversity) within a broader framing encompassing all conservation actions. We illustrate its application by national governments, sub-national levels (specifically the city of London, a fishery, and Indigenous groups), companies, and individuals. The Mitigation and Conservation Hierarchy supports the choice of actions to conserve and restore nature, and evaluation of the effectiveness of those actions, across sectors and scales. It can guide actions toward a sustainable future for people and nature, supporting the CBD's vision

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Soluble forms of tau are toxic in Alzheimer's disease

Accumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer Disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer’s disease and other tauopathies

Mejoramiento de leguminosas forrajeras, especialmente para su adaptacion a suelos acidos infertiles

Se discuten varios conceptos relativos al mejoramiento de leguminosas forrajeras y a su adaptacion a suelos acidos de baja fertilidad. Se observa que es raro que un ecotipo nativo selecionado ofrezca todas las caracteristicas requeridas para praderas de pastoreo. Los objetivos del mejoramiento deben ser muy especificos, lo cual se logra con una estrecha colaboracion entre los introduccionistas de plantas, agronomos especialistas en leguminosas y cientificos en la utilizacion de pasturas. Una caracteristica vital es la facil nodulacion con Rhizobium eficaces, lo cual requiere la colaboracion de los microbiologos de suelos. Otras caracteristicas tratadas son la persistencia, en condiciones de sobre-pastoreo periodico y, tal vez de mal manejo. Se indica que es posible obtener amplia adaptabilidad mediante el cruzamiento de ecotipos provenientes de condiciones edaficas y climaticas radicalmente diferentes. Se senala que las tecnicas de mejoramiento involucran recursos considerables y se describe un metodo rapido de desarrollo de nuevas lineas mejoradas. Se describe a grandes rasgos el trabajo realizado en el CIAT con Stylosanthes capitata, Centrosema pubescens y Leucaena leucocephala, el cual se fortalece con conteos cromosomaticos y trabajo citologico apropiado. (CIAT

Opening Address:The role of legumes in pastures.

Keywords: animal production; fertilizer requirements; legumes; nitrogen fixation; nodulation; pastures; role; southern afric