Off-Pathway Assembly: A Broad-Spectrum Mechanism of Action for Drugs That Undermine Controlled HIV-1 Viral Capsid Formation.

The early and late stages of human immunodeficiency virus (HIV) replication are orchestrated by the capsid (CA) protein, which self-assembles into a conical protein shell during viral maturation. Small molecule drugs known as capsid inhibitors (CIs) impede the highly regulated activity of CA. Intriguingly, a few CIs, such as PF-3450074 (PF74) and GS-CA1, exhibit effects at multiple stages of the viral lifecycle at effective concentrations in the pM to nM regimes, while the majority of CIs target a single stage of the viral lifecycle and are effective at nM to μM concentrations.

Entropic forces drive clustering and spatial localization of influenza A M2 during viral budding.

The influenza A matrix 2 (M2) transmembrane protein facilitates virion release from the infected host cell. In particular, M2 plays a role in the induction of membrane curvature and/or in the scission process whereby the envelope is cut upon virion release. Here we show using coarse-grained computer simulations that various M2 assembly geometries emerge due to an entropic driving force, resulting in compact clusters or linearly extended aggregates as a direct consequence of the lateral membrane stresses.

Immature HIV-1 lattice assembly dynamics are regulated by scaffolding from nucleic acid and the plasma membrane.

The packaging and budding of Gag polyprotein and viral RNA is a critical step in the HIV-1 life cycle. High-resolution structures of the Gag polyprotein have revealed that the capsid (CA) and spacer peptide 1 (SP1) domains contain important interfaces for Gag self-assembly. However, the molecular details of the multimerization process, especially in the presence of RNA and the cell membrane, have remained unclear.

Links between soil microbial communities and plant traits in a species-rich grassland under long-term climate change.

Climate change can influence soil microorganisms directly by altering their growth and activity but also indirectly via effects on the vegetation, which modifies the availability of resources. Direct impacts of climate change on soil microorganisms can occur rapidly, whereas indirect effects mediated by shifts in plant community composition are not immediately apparent and likely to increase over time. We used molecular fingerprinting of bacterial and fungal communities in the soil to investigate the effects of 17 years of temperature and rainfall manipulations in a species-rich grassland near Buxton, UK.

Coarse-grained simulation reveals key features of HIV-1 capsid self-assembly.

The maturation of HIV-1 viral particles is essential for viral infectivity. During maturation, many copies of the capsid protein (CA) self-assemble into a capsid shell to enclose the viral RNA. The mechanistic details of the initiation and early stages of capsid assembly remain to be delineated.

'Keeping going': chronic joint pain in older people who describe their health as good.

It is common for people with chronic conditions to report their health as good, although models of healthy ageing do not account for this. The concept of successful ageing focuses on overcoming problems, in contrast to the concept of resilience, which can acknowledge vulnerability. Osteoarthritis (OA) is the main cause of joint pain in older people, but research in this area has tended to focus on OA as an illness.

Highly Scalable and Memory Efficient Ultra-Coarse-Grained Molecular Dynamics Simulations.

The use of coarse-grained (CG) models can significantly increase the time and length scales accessible to computational molecular dynamics (MD) simulations. To address very large-scale phenomena, however, requires a careful consideration of memory requirements and parallel MD load balancing in order to make efficient use of current supercomputers. In this work, a CG-MD code is introduced which is specifically designed for very large, highly parallel simulations of systems with markedly non-uniform particle distributions, such as those found in highly CG models having an implicit solvent.

Exploring the relationship between multi-morbidity, resilience and social connectedness across the lifecourse.

Multi-morbidity is receiving considerable attention in public policy, health and social care. From the perspective of the individual, multi-morbidity is a more complex experience than solely having a clinical diagnosis. In this article, we will argue that understanding multi-morbidity can be facilitated by considering the relationship between adversity (in this case multi-morbidity), resilience and social connectedness within a life course framework.

Developing a model osteoarthritis consultation: a Delphi consensus exercise.

Background: Osteoarthritis (OA) is a common condition managed in general practice, but often not in line with published guidance. The ideal consultation for a patient presenting with possible OA is not known. The aim of the study was to develop the content of a model OA consultation for the assessment and treatment of older adults presenting in general practice with peripheral joint problems.

Defining the content of an opportunistic osteoarthritis consultation with primary health care professionals: a Delphi consensus study.

Objective: To define the core content for an opportunistic consultation between a health care professional (HCP) and a patient with osteoarthritis (OA) in primary care.

Methods: An ideas generation round and a 2-round Delphi postal consensus study allowed participants to rank the importance of tasks for an opportunistic consultation. The study was conducted with a lay group (n = 18) and 3 groups of HCPs (n = 30 for general practitioners, n = 19 for practice nurses, and n = 37 for allied health professionals).

Early stages of the HIV-1 capsid protein lattice formation.

The early stages in the formation of the HIV-1 capsid (CA) protein lattice are investigated. The underlying coarse-grained (CG) model is parameterized directly from experimental data and examined under various native contact interaction strengths, CA dimer interfacial configurations, and local surface curvatures. The mechanism of early contiguous mature-style CA p6 lattice formation is explored, and a trimer-of-dimers structure is found to be crucial for CA lattice production.

Troubling stoicism: Sociocultural influences and applications to health and illness behaviour.

In light of the ambiguity of meanings attributed to the concept of stoicism we critically explore its use as a label to explain and describe health and illness behaviour, juxtaposing the often negative portrayals of contemporary stoicism against its classical and philosophical origins. By reflecting critically on the term 'stoicism', its application and dimensionality, we show how the term has evolved from classical to contemporary times in relation to changing context, and explore different understandings of the term across medical and health literature. We attend to sociocultural factors that are seen to influence the conceptualization of stoicism such as generational influences, gender and geographies.

Comment on "Productivity is a poor predictor of plant species richness".

Adler et al. (Reports, 23 September 2011, p. 1750) reported "weak and variable" relationships between productivity and species richness and dispute the "humped-back" model (HBM) of plant diversity.

Developing written information on osteoarthritis for patients: facilitating user involvement by exposure to qualitative research.

Introduction: In developing a guidebook on osteoarthritis (OA), we collaborated with people who have chronic joint pain (users). But to advise, users need to be aware of and sensitive about their own state of knowledge and educationalists argue that adults sometimes lack such awareness. This paper will report on our experience of providing users with findings from qualitative research to increase awareness of their level of knowledge.

Fine-scale community and genetic structure are tightly linked in species-rich grasslands.

Recent evidence indicates that grassland community structure and species diversity are influenced by genetic variation within species. We review what is known regarding the impact of intraspecific diversity on grassland community structure, using an ancient limestone pasture as a focal example. Two genotype-dependent effects appear to modify community structure in this system.

Underdeveloped embryos and germination in Aristolochia galeata seeds.

Aristolochiaceae have been described as having seeds with underdeveloped embryos and morphological or morphophysiological dormancy. Aristolochia galeata is a native climber found in the Cerrado biome, associated with road and gallery forest edges. The aims of this study were to investigate: embryo growth rate, morphology and seed germination parameters under different treatments.

Effects of Discrete Charge Clustering in Simulations of Charged Interfaces.

A system of counterions between charged surfaces is investigated, with the surfaces represented by uniform charged planes and three different arrangements of discrete surface charges - an equispaced grid and two different clustered arrangements. The behaviors of a series of systems with identical net surface charge density are examined, with particular emphasis placed on the long ranged corrections via the method of "charged slabs" and the effects of the simulation cell size. Marked differences are observed in counterion distributions and the osmotic pressure dependent on the particular representation of the charged surfaces; the uniformly charged surfaces and equispaced grids of discrete charge behave in a broadly similar manner, but the clustered systems display a pronounced decrease in osmotic pressure as the simulation size is increased.

Community and ecosystem effects of intraspecific genetic diversity in grassland microcosms of varying species diversity.

Studies of whether plant community structure and ecosystem properties depend on the genetic diversity of component populations have been largely restricted to species monocultures and have involved levels of genetic differentiation that do not necessarily correspond to that exhibited by neighboring mature individuals in the field. We established experimental communities of varying intraspecific genetic diversity, using genotypes of eight species propagated from clonal material of individuals derived from a small (100-m2) limestone grassland community, and tested whether genetic diversity (one, four, and eight genotypes per species) influenced community composition and annual aboveground productivity across communities of one, four, and eight species. Eight-species communities were represented by common grass, sedge, and forb species, and four- and one-species communities were represented by four graminoids and the dominant grass Festuca ovina, respectively.

Perceptions of joint pain and feeling well in older people who reported being healthy: a qualitative study.

Background: Older people often view osteoarthritis as a part of normal ageing and see themselves as healthy despite painful joints. Professionals have mixed views about this. One concern is that seeing osteoarthritis as a result of 'wear and tear' leads to restricting exercise in order to avoid further wear.

Decreased osmotic pressure via interfacial charge clustering.

Behaviors of a model interfacial system featuring the clustering of discrete, mobile wall charges and a counterion solution are investigated. The results demonstrate that even very small localized charge clusters produce significant effects for the osmotic pressure, effects that are not adequately represented in common colloidal models. We observe a pronounced decrease in osmotic pressure where a certain level of clustering is attained, with potentially significant implications for theories of colloidal stability and biochemical processes at microscopic length scales.

Genetic variation in plant morphology contributes to the species-level structure of grassland communities.

It is becoming apparent that genetic diversity can influence the species diversity and structure of ecological communities. Here, we investigated the intraspecific trait variation responsible for this relationship. We grew 10 genotypes of the sedge Carex caryophyllea, as monocultures, under standardized conditions and measured traits related to morphology, growth, and life history.

Interaction between charged surfaces mediated by rodlike counterions: the influence of discrete charge distribution in the solution and on the surfaces.

The interaction between two charged surfaces, with discrete or uniform charge distributions, embedded in a solution of rodlike counterions has been studied. Monte Carlo simulations and density functional theory have been applied to study the concentration profiles of counterions and the force between the charged surfaces. We show that for low surface charge densities the repulsive force between like-charged surfaces is observed regardless of the rod length.

Quantitative visualization of passive transport across bilayer lipid membranes.

The ability to predict and interpret membrane permeation coefficients is of critical importance, particularly because passive transport is crucial for the effective delivery of many pharmaceutical agents to intracellular targets. We present a method for the quantitative measurement of the permeation coefficients of protonophores by using laser confocal scanning microscopy coupled to microelectrochemistry, which is amenable to precise modeling with the finite element method. The technique delivers well defined and high mass transport rates and allows rapid visualization of the entire pH distribution on both the cis and trans side of model bilayer lipid membranes (BLMs).