Novel therapeutic strategies targeting HIV integrase

Integration of the viral genome into host cell chromatin is a pivotal and unique step in the replication cycle of retroviruses, including HIV. Inhibiting HIV replication by specifically blocking the viral integrase enzyme that mediates this step is an obvious and attractive therapeutic strategy. After concerted efforts, the first viable integrase inhibitors were developed in the early 2000s, ultimately leading to the clinical licensure of the first integrase strand transfer inhibitor, raltegravir. Similarly structured compounds and derivative second generation integrase strand transfer inhibitors, such as elvitegravir and dolutegravir, are now in various stages of clinical development. Furthermore, other mechanisms aimed at the inhibition of viral integration are being explored in numerous preclinical studies, which include inhibition of 3' processing and chromatin targeting. The development of new clinically useful compounds will be aided by the characterization of the retroviral intasome crystal structure. This review considers the history of the clinical development of HIV integrase inhibitors, the development of antiviral drug resistance and the need for new antiviral compounds

The influence of care home managers on the implementation of a complex intervention: Findings from the process evaluation of a randomised controlled trial of Dementia Care Mapping

Background: Many people with dementia live in care homes, where staff can struggle to meet their complex needs. Successful practice improvement interventions in these settings require strong managerial support, but little is known about how managers can support implementation in practice, or what factors support or hinder care home managers in providing this support. Using Dementia Care Mapping™ (DCM) as an example, this study explored how care home managers can support the implementation of complex interventions, and identified factors affecting their ability to provide this support. Methods: We undertook interviews with 48 staff members (managers and intervention leads) from care homes participating in the intervention arm of the DCM EPIC trial of DCM implementation. Results: Managerial support played a key role in facilitating the implementation of a complex intervention in care home settings. Managers could provide practical and financial support in many forms. However, managerial support and leadership approaches towards implementation were highly variable in practice, and implementation was easily de-stabilised by management changes or competing managerial priorities. How well managers understood, valued and engaged with the intervention, alongside the leadership style they adopted to support implementation, were key influences on implementation success. Conclusions: For care home managers to effectively support interventions they must fully understand the proposed intervention and its potential value. This is especially important during times of managerial or practice changes, when managers lack the skills required to effectively support implementation, or when the intervention is complex. It may be unfeasible to successfully implement new interventions during times of managerial or practice instability

Topographic heterogeneity explains patterns of vegetation response to climate change (1972–2008) across a mountain landscape, Niwot Ridge, Colorado

The distributions of biomes worldwide are predicted to shift as vegetation tracks climate change. Ecologists often use coarse-scale climate models to predict these shifts along broad elevational and latitudinal gradients, but these assessments could fail to capture important dynamics by ignoring fine-scale heterogeneity. We ask how the elevational ranges of vegetation types have changed in a mountainous landscape, and investigate the influence of fine-scale topographic, snowpack, and soil properties on vegetation change. We manually classified vegetation from high-resolution repeat aerial photographs from 1972 and 2008 at Niwot Ridge, Colorado, USA, and generally found that trees and shrubs colonized tundra, while tundra colonized barren soils. Only shrubs expanded their elevational range. Several fine-scale topographic, soil and snow characteristics, including elevation, slope, solar radiation, soil bulk density, and interannual snowpack variability, modulated where plant establishment occurred. Each vegetation type had a unique suite of variables best predicting its establishment in new areas. We suggest that fine-scale heterogeneity may strongly control how plants in mountainous regions respond to climate change, and different vegetation types may be sensitive to different aspects of this heterogeneity. An improved understanding of the factors controlling vegetation change gives us a broader understanding of ecosystem response to climate change, nitrogen deposition, and release from grazing

Detritus, trophic dynamics and biodiversity

Traditional approaches to the study of food webs emphasize the transfer of local primary productivity in the form of living plant organic matter across trophic levels. However, dead organic matter, or detritus, a common feature of most ecosystems plays a frequently overlooked role as a dynamic heterogeneous resource and habitat for many species. We develop an integrative framework for understanding the impact of detritus that emphasizes the ontogeny and heterogeneity of detritus and the various ways that explicit inclusion of detrital dynamics alters generalizations about the structure and functioning of food webs. Through its influences on food web composition and dynamics, detritus often increases system stability and persistence, having substantial effects on trophic structure and biodiversity. Inclusion of detrital heterogeneity in models of food web dynamics is an essential new direction for ecological research