Stochastic effects are important in intrahost HIV evolution even when viral loads are high

Blood plasma viral loads and the time to progress to AIDS differ widely among untreated HIV-infected humans. Although people with certain HLA (HLA-I) alleles are more likely to control HIV infections without therapy, the majority of such untreated individuals exhibit high viral loads and progress to AIDS. Stochastic effects are considered unimportant for evolutionary dynamics in HIV-infected people when viral load is high or when selective forces strongly drive mutation. We describe a computational study of host–pathogen interaction demonstrating that stochastic effects can have a profound influence on disease dynamics, even in cases of high viral load and strong selective pressure. These stochastic effects are pronounced when the virus must traverse a fitness “barrier” in sequence space to escape the host’s cytotoxic T-lymphocyte (CTL) response, as often occurs when a fitness defect imposed by a CTL-driven mutation must be compensated for by other mutations. These “barrier-crossing” events are infrequent and stochastic, resulting in divergent disease outcomes in genetically identical individuals infected by the same viral strain. Our results reveal how genetic determinants of the CTL response control the probability with which an individual is able to control HIV infection indefinitely, and thus provide clues for vaccine design.     

Psychological defence and nuclear war

Society is influenced by the unconcious aspects of the minds of the member individuals. This paper describes a psychoanalytic approach to some aspects of the social processes that give rise to the attitudes in Western society towards nuclear war and the nuclear threat. It is concluded that there are profound hidden factors that work against changing the current views on war and nuclear war, and that some peace groups are inadvertently recruited into maintaining the status quo.     

Factors influencing short-term outcomes for older patients accessing emergency departments after a fall: The role of fall dynamics

BackgroundWhile the relevance of falls in raising the risk of fractures, hospitalization and disability in older age is well recognized, the factors influencing the onset of fractures and the need for ward admission after a fall have yet to be fully elucidated. We investigated which factors and fall dynamics were mainly associated with fall-related injuries and hospitalization among elderly persons accessing the Emergency Department (ED) following a fall.MethodsThe study involved 2144 older subjects who accessed the ED after a fall. Data on the fall´s nature and related injuries, ward admissions, history of falls, dementia, and medical therapies were examined for all patients. Considering dynamics, we distinguished accidental falls (due to interaction with environmental hazards while in motion) and falls from standing (secondary to syncope, lipothymia, drop attack, or vertigo).ResultsThe overall prevalence of fractures in our population did not differ significantly with advancing age, though hip fractures were more common in the oldest, and upper limb fractures in the youngest patients. Falls from standing were associated with polypharmacy and with higher ward admission rate despite a lower fractures´ prevalence than accidental falls. The chances of fall-related fractures were more than fourfold as high for accidental dynamics (OR = 4.05, 95%CI:3.10–5.29, p < 0.0001). Ward admission was associated with polypharmacy, dementia, anticoagulants´ use and fall-related fractures (OR = 6.84, 95%CI:5.45–8.58, p < 0.0001), while it correlated inversely with accidental fall dynamics.ConclusionsOutcomes of falls in older age depend not only on any fall-related injuries, but also on factors such as polypharmacy, cognitive status and fall dynamics.     

Reproduction, social behavior, and aging trajectories in honeybee workers

While a negative correlation between reproduction and life span is commonly observed, specialized reproductive individuals outlive their non-reproductive nestmates in all eusocial species, including the honeybee, Apis mellifera (L). The consequences of reproduction for individual life expectancy can be studied directly by comparing reproductive and non-reproductive workers. We quantified the life span consequences of reproduction in honeybee workers by removal of the queen to trigger worker reproduction. Furthermore, we observed the social behavior of large cohorts of workers under experimental and control conditions to test for associations with individual life expectancy. Worker life expectancy was moderately increased by queen removal. Queenless colonies contained a few long-lived workers, and oviposition behavior was associated with a strong reduction in mortality risk, indicating that a reproductive role confers a significant survival advantage. This finding is further substantiated by an association between brood care behavior and worker longevity that depends on the social environment. In contrast, other in-hive activities, such as fanning, trophallaxis, and allogrooming did not consistently affect worker life expectancy. The influence of foraging varied among replicates. An earlier age of transitioning from in-hive tasks to outside foraging was always associated with shorter life spans, in accordance with previous studies. In sum, our studies quantify how individual mortality is affected by particular social roles and colony environments and demonstrate interactions between the two. The exceptional, positive association between reproduction and longevity in honeybees extends to within-caste plasticity, which may be exploited for mechanistic studies.     

A possible therapeutic potential of quercetin through inhibition of μ-calpain in hypoxia induced neuronal injury:a molecular dynamics simulation study

The neuroprotective property of quercetin is well reported against hypoxia and ischemia in past studies.This property of quercetin lies in its antioxidant property with blood-brain barrier permeability and anti-inflammatory capabilities.μ-Calpain,a calcium ion activated intracellular cysteine protease causes serious cellular insult,leading to cell death in various pathological conditions including hypoxia and ischemic stroke.Hence,it may be considered as a potential drug target for the treatment of hypoxia induced neuronal injury.As the inhibitory property of μ-calpain is yet to be explored in details,hence,in the present study,we investigated the interaction of quercetin with μ-calpain through a molecular dynamics simulation study as a tool through clarifying the molecular mechanism of such inhibition and determining the probable sites and modes of quercetin interaction with the μ-calpain catalytic domain.In addition,we also investigated the structure-activity relationship of quercetin with μ-calpain.Affinity binding of quercetin with μ-calpain had a value of –28.73 k J/mol and a Ki value of 35.87 μM that may be a probable reason to lead to altered functioning of μ-calpain.Hence,quercetin was found to be an inhibitor of μ-calpain which might have a possible therapeutic role in hypoxic injury.     

Quaternary dynamics and plasticity underlie small heat shock protein chaperone function

Small Heat Shock Proteins (sHSPs) are a diverse family of molecular chaperones that prevent protein aggregation by binding clients destabilized during cellular stress. Here we probe the architecture and dynamics of complexes formed between an oligomeric sHSP and client by employing unique mass spectrometry strategies. We observe over 300 different stoichiometries of interaction, demonstrating that an ensemble of structures underlies the protection these chaperones confer to unfolding clients. This astonishing heterogeneity not only makes the system quite distinct in behavior to ATP-dependent chaperones, but also renders it intractable by conventional structural biology approaches. We find that thermally regulated quaternary dynamics of the sHSP establish and maintain the plasticity of the system. This extends the paradigm that intrinsic dynamics are crucial to protein function to include equilibrium fluctuations in quaternary structure, and suggests they are integral to the sHSPs’ role in the cellular protein homeostasis network.     

Multistart simulated annealing refinement of the crystal structure of the 70S ribosome

A macromolecular X-ray crystal structure is usually represented as a single static model with a single set of temperature factors representing a simple approximation of motion and disorder of the structure. Multiconformer representations of small proteins have been shown to better describe anisotropic motion and disorder and improve the quality of their electron density maps. Here, we apply multistart simulated annealing crystallographic refinement to a 70S ribosome-RF1 translation termination complex that was recently solved at 3.2 Å resolution. The analysis improves the interpretability of the electron density map of this 2.5-MDa ribonucleoprotein complex and provides insights into its structural dynamics. We also used multistart refinement and conventional Fourier difference maps to address a recent study in which cross-crystal averaging between two crystal forms of the 70S ribosome was used to evaluate reported differences between two ribosome crystal structures solved at 2.8 and 3.7 Å resolution. Our analysis suggests that results obtained from cross-crystal averaging are inherently biased toward the higher-resolution dataset.     

Dynamic structure of lipid-bound synaptobrevin suggests a nucleation-propagation mechanism for trans-SNARE complex formation

The synaptic vesicle protein synaptobrevin engages with syntaxin and SNAP-25 to form the SNARE complex, which drives membrane fusion in neuronal exocytosis. In the SNARE complex, the SNARE motif of synaptobrevin forms a 55-residue helix, but it has been assumed to be mostly unstructured in its prefusion form. NMR data for full-length synaptobrevin in dodecylphosphocholine micelles reveals two transient helical segments flanked by natively disordered regions and a third more stable helix. Transient helix I comprises the most N-terminal part of the SNARE motif, transient helix II extends the SNARE motif into the juxtamembrane region, and the more stable helix III is the transmembrane domain. These helices may have important consequences for SNARE complex folding and fusion: helix I likely forms a nucleation site, the C-terminal disordered SNARE motif may act as a folding arrest signal, and helix II likely couples SNARE complex folding and fusion.     

Experimental test of a predicted dynamics–structure–thermodynamics connection in molecularly complex glass-forming liquids

Understanding in a unified manner the generic and chemically specific aspects of activated dynamics in diverse glass-forming liquids over 14 or more decades in time is a grand challenge in condensed matter physics, physical chemistry, and materials science and engineering. Large families of conceptually distinct models have postulated a causal connection with qualitatively different “order parameters” including various measures of structure, free volume, thermodynamic properties, short or intermediate time dynamics, and mechanical properties. Construction of a predictive theory that covers both the noncooperative and cooperative activated relaxation regimes remains elusive. Here, we test using solely experimental data a recent microscopic dynamical theory prediction that although activated relaxation is a spatially coupled local–nonlocal event with barriers quantified by local pair structure, it can also be understood based on the dimensionless compressibility via an equilibrium statistical mechanics connection between thermodynamics and structure. This prediction is found to be consistent with observations on diverse fragile molecular liquids under isobaric and isochoric conditions and provides a different conceptual view of the global relaxation map. As a corollary, a theoretical basis is established for the structural relaxation time scale growing exponentially with inverse temperature to a high power, consistent with experiments in the deeply supercooled regime. A criterion for the irrelevance of collective elasticity effects is deduced and shown to be consistent with viscous flow in low-fragility inorganic network-forming melts. Finally, implications for relaxation in the equilibrated deep glass state are briefly considered.

An enormous number of seemingly orthogonal proposals exist for a fundamental connection between a (typically scalar) structural or excess (configurational) thermodynamic quantity and activated relaxation in supercooled liquids (1–12). High chemical complexity for fragile glass formers which exhibit strongly non-Arrhenius relaxation greatly complicates the formulation of predictive theories. A common generic view (1, 3, 8) is that the structural or alpha relaxation time (and viscosity, inverse diffusivity) evolves with cooling as shown in Fig. 1A. Different dynamical mechanisms in the high-, intermediate-, and low-temperature regimes are often envisioned: noncooperative Arrhenius (∼1 ps to 100 ps), critical power law (∼0.1 ns to 100 ns), and cooperative non-Arrhenius (∼0.1 μs to 100 s or beyond), respectively. Typically a causal connection is postulated between the logarithm of the alpha time (an effective barrier in thermal energy units) and a specific “order parameter”: 1) in the structural class (6, 7, 13–17), the intensity of the cage peak of the structure factor S(k), local aspect(s) of the radial distribution function g(r), or specific packing motifs; 2) in the thermodynamics class, various measures of free volume (18, 19), excess entropy (20), configurational entropy (21–25), internal energy and enthalpy (26), or with some arguing for an equilibrium phase transition at an inaccessibly low (high) temperature (density) (23, 27–29); 3) in the short time class, the high-frequency shear modulus (2, 30–32), Debye–Waller factor (33), or amplitude of special vibrational modes (33–35); and 4) in the intermediate time class, the concentration of dilute mobile excitations [e.g., strings (36, 37) or facilitating defects (38)]. Many of the proposed order parameters are hard or impossible to uniquely define and/or experimentally measure. The diverse models often claim to capture relaxation data over limited time windows typically based on fitting but usually fail at low and/or high enough temperature (5).Open in a separate windowFig. 1.Global relaxation map and theoretical picture and key predictions. (A) Three-regime relaxation map (curves) for the alpha time with Arrhenius and strongly non-Arrhenius behaviors separated by a crossover regime perhaps of a critical power law (6) form. The proposed two-regime scenario of ECNLE theory (39–42) is based solely on noncooperative and cooperative activated dynamics (slightly overlapping orange and green regions) with the inverse dimensionless compressibility (S0−1) as the relevant thermodynamic quantity. The approximately five to six decade range that simulations can probe is indicated. (B) Dynamic free energy for a metastable hard sphere (diameter σ) fluid (42) as a function of particle displacement at a high packing fraction of ϕ = 0.58. Relevant length and energy scales are indicated. (Inset) Schematic of the core physical idea for the alpha relaxation: hopping on the cage scale coupled with a collective elastic displacement of all particles outside the cage. (C) Main: local cage barrier as a function of inverse dimensionless compressibility for 0.44<ϕ <0.61 corresponding to a 16 decade increase of the alpha time (39, 41, 42). The metastable regime begins at ϕ ∼ 0.5 where the total barrier is ∼1.5 k_BT. (Inset) Total barrier as a function of S0−3 normalized by its ϕ = 0.5 value. The elastic barrier is 1 k_BT at ϕ ∼ 0.55. Packing fractions are given along the top x-axis.Here we present, using only experimental data, a test of a relationship between activated relaxation, local pair structure, and a specific thermodynamic property predicted by the Elastically Collective Nonlinear Langevin Equation (ECNLE) theory (39–41). The results provide support for the following: 1) the coupled local–nonlocal nature of relaxation deeply connected with collective elasticity, 2) the dimensionless amplitude of thermal density fluctuations, S₀, as the relevant (nonexcess) thermodynamic property, 3) a roadmap for organizing relaxation data in S₀, not in temperature, space, 4) irrelevance of collective elasticity as the origin for the crossover from fragile to strong glass formers, and 5) an explicit demonstration that a dynamics–thermodynamics correlation can be a noncausal consequence of the causal relation between local pair structure and S₀.