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. We present coarse-grained simulations of capsid assembly under various conditions, considering not only capsid lattice self-assembly but also the potential disassembly of capsid upon delivery to the cytoplasm of a target cell. The effects of CA concentration, molecular crowding, and the conformational variability of CA are described, with results indicating that capsid nucleation and growth is a multi-stage process requiring well-defined metastable intermediates. Generation of the mature capsid lattice is sensitive to local conditions, with relatively subtle changes in CA concentration and molecular crowding influencing self-assembly and the ensemble of structural morphologies

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. We present coarse-grained simulations of capsid assembly under various conditions, considering not only capsid lattice self-assembly but also the potential disassembly of capsid upon delivery to the cytoplasm of a target cell. The effects of CA concentration, molecular crowding, and the conformational variability of CA are described, with results indicating that capsid nucleation and growth is a multi-stage process requiring well-defined metastable intermediates. Generation of the mature capsid lattice is sensitive to local conditions, with relatively subtle changes in CA concentration and molecular crowding influencing self-assembly and the ensemble of structural morphologies

Sex Ratio at Birth and Mortality Rates Are Negatively Related in Humans

Evolutionary theory posits that resource availability and parental investment ability could signal offspring sex selection, in order to maximize reproductive returns. Non-human studies have provided evidence for this phenomenon, and maternal condition around the time of conception has been identified as most important factor that influence offspring sex selection. However, studies on humans have reported inconsistent results, mostly due to use of disparate measures as indicators of maternal condition. In the present study, the cross-cultural differences in human natal sex ratio were analyzed with respect to indirect measures of condition namely, life expectancy and mortality rate. Multiple regression modeling suggested that mortality rates have distinct predictive power independent of cross-cultural differences in fertility, wealth and latitude that were earlier shown to predict sex ratio at birth. These findings suggest that sex ratio variation in humans may relate to differences in parental and environmental conditions

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

An Asymptotic Analysis of Differential Electrical Mobility Classifiers

An asymptotic analysis of balanced flow operations of differential mobility analyzers (DMAs) and a new class of instruments that includes opposed migration aerosol classifiers (OMACs) and inclined grid mobility analyzers (IGMAs) provides new insights into the similarities and differences between the devices. The characteristic scalings of different instruments found from minimal models are shown to relate the resolving powers, dynamic ranges, and efficiencies of most such devices. The resolving powers of all of the instruments in the nondiffusive regime of high voltage classifications, R_(nd), is determined by the ratio of the flow rate of the separation gas (sheath or crossflow) to that of the aerosol. At lowvoltage,when diffusion degrades the classification, the OMAC and the IGMA share an R_(nd) factor advantage in dynamic range of mobilities over the DMA, although the OMAC also suffers greater losses because diffusion immediately deposits particles onto its porous electrodes. On the basis of this analysis, a single master operating diagram is proposed for DMAs, OMACs, and IGMAs. Analysis of this operating diagram and its consequences for the design of differential electrical mobility classifiers suggests that OMACs and IGMAs also have advantages over DMAs in design flexibility and miniaturization. Most importantly, OMACs and IGMAs may outperform DMAs for the currently difficult classification of particles with diameters less than 10 nm. On the other hand, DMAs are more amenable to voltage scanning-mode operation to enable accelerated size distribution measurements, whereas it is most convenient to operate OMACs and IGMAs in voltage stepping-mode operation

The Theory of Ultra-Coarse-Graining. 3. Coarse-Grained Sites with Rapid Local Equilibrium of Internal States

When viewed through a coarse-grained lens, important molecular and biophysical systems can appear to undergo discrete, switch-like state changes in addition to more continuous configurational motions. One of our recent papers described a theory for bottom-up coarse-graining of the equilibrium statistics of models with such behavior, called ultra-coarse-grained (UCG) models, and a follow up paper described an implementation when the states of the coarse-grained sites or “beads” change rarely. However, not all systems with this discrete behavior fall under that special limit. This article develops the general UCG theory for the opposite limit, that is, where the internal states of the CG particles or beads adjust rapidly so as to always remain effectively at quasi-equilibrium no matter what the positions of the coarse-grained particles. This rapid local equilibrium allows ultra-coarse-graining to mix standard coarse-grained force fields by using local order parameters to control the degree of mixing, which adds an environmental dependence and many-body effects to the coarse-grained model while requiring minimal new coding. This article first presents the definition of such UCG force fields as well as their fitting procedures from atomistic-scale data, and then it presents three examples of UCG simulations with an approach that we call UCG with rapid local equilibrium (UCG-RLE). We then present an application of UCG-RLE using the full bottom-up methodology to coarse-grain and simulate cooperative hydrophobic association of neopentane in methanol solvent. UCG-RLE force matching does a superior job of matching solute–solute correlation functions and solute cluster size distributions compared to the more standard force-matched models not having coarse-grained sites with discrete internal states