Polyfunctional Hiv-Specific Antibody Responses Are Associated with Spontaneous Hiv Control

Elite controllers (ECs) represent a unique model of a functional cure for HIV-1 infection as these individuals develop HIV-specific immunity able to persistently suppress viremia. Because accumulating evidence suggests that HIV controllers generate antibodies with enhanced capacity to drive antibody-dependent cellular cytotoxicity (ADCC) that may contribute to viral containment, we profiled an array of extra-neutralizing antibody effector functions across HIV-infected populations with varying degrees of viral control to define the characteristics of antibodies associated with spontaneous control. While neither the overall magnitude of antibody titer nor individual effector functions were increased in ECs, a more functionally coordinated innate immune–recruiting response was observed. Specifically, ECs demonstrated polyfunctional humoral immune responses able to coordinately recruit ADCC, other NK functions, monocyte and neutrophil phagocytosis, and complement. This functionally coordinated response was associated with qualitatively superior IgG3/IgG1 responses, whereas HIV-specific IgG2/IgG4 responses, prevalent among viremic subjects, were associated with poorer overall antibody activity. Rather than linking viral control to any single activity, this study highlights the critical nature of functionally coordinated antibodies in HIV control and associates this polyfunctionality with preferential induction of potent antibody subclasses, supporting coordinated antibody activity as a goal in strategies directed at an HIV-1 functional cure

Measuring the capability to raise revenue process and output dimensions and their application to the Zambia revenue authority

The worldwide diffusion of the good governance agenda and new public management has triggered a renewed focus on state capability and, more specifically, on the capability to raise revenue in developing countries. However, the analytical tools for a comprehensive understanding of the capability to raise revenue remain underdeveloped. This article aims at filling this gap and presents a model consisting of the three process dimensions ‘information collection and processing’, ‘merit orientation’ and ‘administrative accountability’. ‘Revenue performance’ constitutes the fourth capability dimension which assesses tax administration’s output. This model is applied to the case of the Zambia Revenue Authority. The dimensions prove to be valuable not only for assessing the how much but also the how of collecting taxes. They can be a useful tool for future comparative analyses of tax administrations’ capabilities in developing countries.Die weltweite Verbreitung der Good-Governance- und New-Public-Management-Konzepte hat zu einer zunehmenden Konzentration auf staatliche Leistungsfähigkeit und, im Besonderen, auf die Leistungsfähigkeit der Steuererhebung in Entwicklungsländern geführt. Allerdings bleiben die analytischen Werkzeuge für ein umfassendes Verständnis von Leistungsfähigkeit unterentwickelt. Dieser Artikel stellt hierfür ein Modell vor, das die drei Prozess-Dimensionen „Sammeln und Verarbeiten von Informationen“, „Leistungsorientierung der Mitarbeiter“ und „Verantwortlichkeit der Verwaltung“ beinhaltet. „Einnahmeperformanz“ ist die vierte Dimension und erfasst den Output der Steuerverwaltung. Das mehrdimensionale Modell wird für die Analyse der Leistungsfähigkeit der Steuerbehörde Zambias (Zambia Revenue Authority) genutzt. Es erweist sich nicht nur für die Untersuchung des Wieviel, sondern auch des Wie des Erhebens von Steuern als wertvoll. Die vier Dimensionen können in Zukunft zur umfassenden und vergleichenden Analyse der Leistungsfähigkeit verschiedener Steuerverwaltungen in Entwicklungsländern genutzt werden

Designing the climate observing system of the future

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Earth's Future 6 (2018): 80–102, doi:10.1002/2017EF000627.Climate observations are needed to address a large range of important societal issues including sea level rise, droughts, floods, extreme heat events, food security, and freshwater availability in the coming decades. Past, targeted investments in specific climate questions have resulted in tremendous improvements in issues important to human health, security, and infrastructure. However, the current climate observing system was not planned in a comprehensive, focused manner required to adequately address the full range of climate needs. A potential approach to planning the observing system of the future is presented in this article. First, this article proposes that priority be given to the most critical needs as identified within the World Climate Research Program as Grand Challenges. These currently include seven important topics: melting ice and global consequences; clouds, circulation and climate sensitivity; carbon feedbacks in the climate system; understanding and predicting weather and climate extremes; water for the food baskets of the world; regional sea-level change and coastal impacts; and near-term climate prediction. For each Grand Challenge, observations are needed for long-term monitoring, process studies and forecasting capabilities. Second, objective evaluations of proposed observing systems, including satellites, ground-based and in situ observations as well as potentially new, unidentified observational approaches, can quantify the ability to address these climate priorities. And third, investments in effective climate observations will be economically important as they will offer a magnified return on investment that justifies a far greater development of observations to serve society's needs

The modulating effect of education on semantic interference during healthy aging

Aging has traditionally been related to impairments in name retrieval. These impairments have usually been explained by a phonological transmission deficit hypothesis or by an inhibitory deficit hypothesis. This decline can, however, be modulated by the educational level of the sample. This study analyzed the possible role of these approaches in explaining both object and face naming impairments during aging. Older adults with low and high educational level and young adults with high educational level were asked to repeatedly name objects or famous people using the semantic-blocking paradigm. We compared naming when exemplars were presented in a semantically homogeneous or in a semantically heterogeneous context. Results revealed significantly slower rates of both face and object naming in the homogeneous context (i.e., semantic interference), with a stronger effect for face naming. Interestingly, the group of older adults with a lower educational level showed an increased semantic interference effect during face naming. These findings suggest the joint work of the two mechanisms proposed to explain age-related naming difficulties, i.e., the inhibitory deficit and the transmission deficit hypothesis. Therefore, the stronger vulnerability to semantic interference in the lower educated older adult sample would possibly point to a failure in the inhibitory mechanisms in charge of interference resolution, as proposed by the inhibitory deficit hypothesis. In addition, the fact that this interference effect was mainly restricted to face naming and not to object naming would be consistent with the increased age-related difficulties during proper name retrieval, as suggested by the transmission deficit hypothesis.This research was supported by grants PSI2013-46033-P to A.M., PSI2015-65502-C2-1-P to M.T.B., PCIN-2015-165-C02-01 to D.P., PSI2017-89324-C2-1-P to DP from the Spanish Ministry of Economy and Competitiveness (http://www.mineco.gob.es/)

The culture variable vis-à-vis anti-bribery law: a grey area in transnational corporate criminal liability

Cross-border transactions are generating corresponding globalisation of law enforcement efforts. Culture has significantly influenced the legal analysis of anti-bribery law. With the increase of transnational bribery, benefits from globalisation will be undermined unless an effective legal regime can mitigate the harm of bribery. It is perceived that corruption in China is more prevalent than in the West given its embedded place in Chinese culture. It is further alleged that Chinese multinational companies (MNCs) are taking advantage of an unlevel playing field, as they are not subject to stringently-enforced anti-bribery laws. This hypothesis creates a myriad of anti-bribery problems in terms of legislation and enforcement, which particularly manifest in China’s perceived cultural toleration of bribery. Cultural assumptions undermine the global anti-bribery regime and compromise potential collaborative anti-bribery efforts across jurisdictions in a rapidly globalizing world. The Chinese culture does not necessarily impede China’s criminalisation of paying bribes to foreign officials. It is argued that the cultural role should not be overestimated, otherwise the hazard of the ethnocentric engagement with the Chinese culture would affect the ability of foreign MNCs to integrate their global compliance programmes. Multinationals can only mitigate their exposure to criminal liability globally, provided that they comply robustly with anti-bribery laws of both home and host jurisdictions

Fate of Allochthonous Dissolved Organic Carbon in Lakes: A Quantitative Approach

Inputs of dissolved organic carbon (DOC) to lakes derived from the surrounding landscape can be stored, mineralized or passed to downstream ecosystems. The balance among these OC fates depends on a suite of physical, chemical, and biological processes within the lake, as well as the degree of recalcintrance of the allochthonous DOC load. The relative importance of these processes has not been well quantified due to the complex nature of lakes, as well as challenges in scaling DOC degradation experiments under controlled conditions to the whole lake scale. We used a coupled hydrodynamic-water quality model to simulate broad ranges in lake area and DOC, two characteristics important to processing allochthonous carbon through their influences on lake temperature, mixing depth and hydrology. We calibrated the model to four lakes from the North Temperate Lakes Long Term Ecological Research site, and simulated an additional 12 ‘hypothetical’ lakes to fill the gradients in lake size and DOC concentration. For each lake, we tested several mineralization rates (range: 0.001 d−1 to 0.010 d−1) representative of the range found in the literature. We found that mineralization rates at the ecosystem scale were roughly half the values from laboratory experiments, due to relatively cool water temperatures and other lake-specific factors that influence water temperature and hydrologic residence time. Results from simulations indicated that the fate of allochthonous DOC was controlled primarily by the mineralization rate and the hydrologic residence time. Lakes with residence times <1 year exported approximately 60% of the DOC, whereas lakes with residence times >6 years mineralized approximately 60% of the DOC. DOC fate in lakes can be determined with a few relatively easily measured factors, such as lake morphometry, residence time, and temperature, assuming we know the recalcitrance of the DOC

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD