Size of the protein-protein energy funnel in crowded environment

Association of proteins to a significant extent is determined by their geometric complementarity. Large-scale recognition factors, which directly relate to the funnel-like intermolecular energy landscape, provide important insights into the basic rules of protein recognition. Previously, we showed that simple energy functions and coarse-grained models reveal major characteristics of the energy landscape. As new computational approaches increasingly address structural modeling of a whole cell at the molecular level, it becomes important to account for the crowded environment inside the cell. The crowded environment drastically changes protein recognition properties, and thus significantly alters the underlying energy landscape. In this study, we addressed the effect of crowding on the protein binding funnel, focusing on the size of the funnel. As crowders occupy the funnel volume, they make it less accessible to the ligands. Thus, the funnel size, which can be defined by ligand occupancy, is generally reduced with the increase of the crowders concentration. This study quantifies this reduction for different concentration of crowders and correlates this dependence with the structural details of the interacting proteins. The results provide a better understanding of the rules of protein association in the crowded environment

Docking-based long timescale simulation of cell-size protein systems at atomic resolution

Computational methodologies are increasingly addressing modeling of the whole cell at the molecular level. Proteins and their interactions are the key component of cellular processes. Techniques for modeling protein interactions, thus far, have included protein docking and molecular simulation. The latter approaches account for the dynamics of the interactions but are relatively slow, if carried out at all-atom resolution, or are significantly coarse grained. Protein docking algorithms are far more efficient in sampling spatial coordinates. However, they do not account for the kinetics of the association (i.e., they do not involve the time coordinate). Our proof-of-concept study bridges the two modeling approaches, developing an approach that can reach unprecedented simulation timescales at all-atom resolution. The global intermolecular energy landscape of a large system of proteins was mapped by the pairwise fast Fourier transform docking and sampled in space and time by Monte Carlo simulations. The simulation protocol was parametrized on existing data and validated on a number of observations from experiments and molecular dynamics simulations. The simulation protocol performed consistently across very different systems of proteins at different protein concentrations. It recapitulated data on the previously observed protein diffusion rates and aggregation. The speed of calculation allows reaching second-long trajectories of protein systems that approach the size of the cells, at atomic resolution

Evidence Against Instanton Dominance of Topological Charge Fluctuations in QCD

The low-lying eigenmodes of the Dirac operator associated with typical gauge field configurations in QCD encode, among other low-energy properties, the physics behind the solution to the $U_A(1)$ problem (i.e. the origin of the $\eta'$ mass), the nature of spontaneous chiral symmetry breaking, and the physics of string-breaking, quark-antiquark pair production, and the OZI rule. Moreover, the space-time chiral structure of these eigenmodes reflects the space-time topological structure of the underlying gauge field. We present evidence from lattice QCD on the local chiral structure of low Dirac eigenmodes leading to the conclusion that topological charge fluctuations of the QCD vacuum are not instanton-dominated. The result supports Witten's arguments that topological charge is produced by confinement-related gauge fluctuations rather than instantons.Comment: 35 pages, 11 figure

Economic sustainability modeling provides decision support for assessing hybrid poplar-based biofuel development in California

Biofuels are expected to play a major role in meeting California's long-term energy needs, but many factors influence the commercial viability of the various feedstock and production technology options. We developed a spatially explicit analytic framework that integrates models of plant growth, crop adoption, feedstock location, transportation logistics, economic impact, biorefinery costs and biorefinery energy use and emissions. We used this framework to assess the economic potential of hybrid poplar as a feedstock for jet fuel production in Northern California. Results suggest that the region has sufficient suitable croplands (2.3 million acres) and nonarable lands (1.5 million acres) for poplar cultivation to produce as much as 2.26 billion gallons of jet fuel annually. However, there are major obstacles to such large-scale production, including, on nonarable lands, low poplar yields and broad spatial distribution and, on croplands, competition with existing crops. We estimated the production cost of jet fuel to be $4.40 to$5.40 per gallon for poplar biomass grown on nonarable lands and $3.60 to$4.50 per gallon for biomass grown on irrigated cropland; the current market price is $2.12 per gallon. Improved poplar yields, use of supplementary feedstocks at the biorefinery and economic supports such as carbon credits could help to overcome these barriers

Insulin Resistance and the IGF-I-Cortical Bone Relationship in Children Ages 9-13 Years

IGF-I is a pivotal hormone in pediatric musculoskeletal development. Although recent data suggest that the role of IGF-I in total body lean mass and total body bone mass accrual may be compromised in children with insulin resistance, cortical bone geometric outcomes have not been studied in this context. Therefore, we explored the influence of insulin resistance on the relationship between IGF-I and cortical bone in children. A secondary aim was to examine the influence of insulin resistance on the lean mass-dependent relationship between IGF-I and cortical bone. Children were otherwise healthy, early adolescent black and white boys and girls (ages 9 to 13 years) and were classified as having high (n = 147) or normal (n = 168) insulin resistance based on the homeostasis model assessment of insulin resistance (HOMA-IR). Cortical bone at the tibia diaphysis (66% site) and total body fat-free soft tissue mass (FFST) were measured by peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA), respectively. IGF-I, insulin, and glucose were measured in fasting sera and HOMA-IR was calculated. Children with high HOMA-IR had greater unadjusted IGF-I (p < 0.001). HOMA-IR was a negative predictor of cortical bone mineral content, cortical bone area (Ct.Ar), and polar strength strain index (pSSI; all p ≤ 0.01) after adjusting for race, sex, age, maturation, fat mass, and FFST. IGF-I was a positive predictor of most musculoskeletal endpoints (all p < 0.05) after adjusting for race, sex, age, and maturation. However, these relationships were moderated by HOMA-IR (pInteraction < 0.05). FFST positively correlated with most cortical bone outcomes (all p < 0.05). Path analyses demonstrated a positive relationship between IGF-I and Ct.Ar via FFST in the total cohort (βIndirect Effect = 0.321, p < 0.001). However, this relationship was moderated in the children with high (βIndirect Effect = 0.200, p < 0.001) versus normal (βIndirect Effect = 0.408, p < 0.001) HOMA-IR. These data implicate insulin resistance as a potential suppressor of IGF-I-dependent cortical bone development, though prospective studies are needed

Low-Energy Compton Scattering of Polarized Photons on Polarized Nucleons

The general structure of the cross section of $\gamma N$ scattering with polarized photon and/or nucleon in initial and/or final state is systematically described and exposed through invariant amplitudes. A low-energy expansion of the cross section up to and including terms of order $\omega^4$ is given which involves ten structure parameters of the nucleon (dipole, quadrupole, dispersion, and spin polarizabilities). Their physical meaning is discussed in detail. Using fixed-t dispersion relations, predictions for these parameters are obtained and compared with results of chiral perturbation theory. It is emphasized that Compton scattering experiments at large angles can fix the most uncertain of these structure parameters. Predictions for the cross section and double-polarization asymmetries are given and the convergence of the expansion is investigated. The feasibility of the experimental determination of some of the struture parameters is discussed.Comment: 41 pages of text, 9 figures; minor revisions prior to publication in Phys. Rev.

Inflammatory responses to acute exercise during pulmonary rehabilitation in patients with COPD

Objective Pulmonary rehabilitation is a cornerstone treatment in the management of chronic obstructive pulmonary disease (COPD). Acute bouts of exercise can lead to short bursts of inflammation in healthy individuals. However, it is unclear how COPD patients respond to acute bouts of exercise. This study assessed inflammatory responses to exercise in COPD patients at the start (phase 1) and end (phase 2) of pulmonary rehabilitation. Methods Blood samples were collected before and after an acute exercise bout at the start (phase 1, n = 40) and end (phase 2, n = 27) of pulmonary rehabilitation. The primary outcome was change in fibrinogen concentrations. Secondary outcomes were changes in CRP concentrations, total/differential leukocyte counts, markers of neutrophil activation (CD11b, CD62L and CD66b), and neutrophil subsets (mature, suppressive, immature, progenitor). Results Acute exercise (phase 1) did not induce significant changes in fibrinogen (p = 0.242) or CRP (p = 0.476). Total leukocyte count [mean difference (MD), 0.5 ± 1.1 (109 L−1); p = 0.004], neutrophil count [MD, 0.4 ± 0.8 (109 L−1); p < 0.001], and immature neutrophils (MD, 0.6 ± 0.8%; p < 0.001) increased post-exercise. Neutrophil activation markers, CD11b (p = 0.470), CD66b (p = 0.334), and CD62L (p = 0.352) were not significantly altered post-exercise. In comparison to the start of pulmonary rehabilitation (phase 2), acute exercise at the end of pulmonary rehabilitation led to a greater fibrinogen response (MD, 84 mg/dL (95% CI − 14, 182); p = 0.045). Conclusion An acute bout of exercise does not appear to induce significant alterations in the concentrations of inflammatory mediators but can increase white blood cell subsets post-exercise. A greater fibrinogen response to acute exercise is seen at the end of pulmonary rehabilitation when compared to the start. Further research is required to understand the clinical context of these acute inflammatory responses to exercise

Temporal and spectral multiplexing for EUV multibeam ptychography with a high harmonic light source

We demonstrate temporally multiplexed multibeam ptychography implemented for the first time in the EUV, by using a high harmonic based light source. This allows for simultaneous imaging of different sample areas, or of the same area at different times or incidence angles. Furthermore, we show that this technique is compatible with wavelength multiplexing for multibeam spectroscopic imaging, taking full advantage of the temporal and spectral characteristics of high harmonic light sources. This technique enables increased data throughput using a simple experimental implementation and with high photon efficiency. &nbsp;</p

Non-Linear Interactions between Consumers and Flow Determine the Probability of Plant Community Dominance on Maine Rocky Shores

Although consumers can strongly influence community recovery from disturbance, few studies have explored the effects of consumer identity and density and how they may vary across abiotic gradients. On rocky shores in Maine, recent experiments suggest that recovery of plant- or animal- dominated community states is governed by rates of water movement and consumer pressure. To further elucidate the mechanisms of consumer control, we examined the species-specific and density-dependent effects of rocky shore consumers (crabs and snails) on community recovery under both high (mussel dominated) and low flow (plant dominated) conditions. By partitioning the direct impacts of predators (crabs) and grazers (snails) on community recovery across a flow gradient, we found that grazers, but not predators, are likely the primary agent of consumer control and that their impact is highly non-linear. Manipulating snail densities revealed that herbivorous and bull-dozing snails (Littorina littorea) alone can control recovery of high and low flow communities. After ∼1.5 years of recovery, snail density explained a significant amount of the variation in macroalgal coverage at low flow sites and also mussel recovery at high flow sites. These density-dependent grazer effects were were both non-linear and flow-dependent, with low abundance thresholds needed to suppress plant community recovery, and much higher levels needed to control mussel bed development. Our study suggests that consumer density and identity are key in regulating both plant and animal community recovery and that physical conditions can determine the functional forms of these consumer effects

A Review of the Tools Used for Marine Monitoring in the UK: Combining Historic and Contemporary Methods with Modeling and Socioeconomics to Fulfill Legislative Needs and Scientific Ambitions

Marine environmental monitoring is undertaken to provide evidence that environmental management targets are being met. Moreover, monitoring also provides context to marine science and over the last century has allowed development of a critical scientific understanding of the marine environment and the impacts that humans are having on it. The seas around the UK are currently monitored by targeted, impact-driven, programmes (e.g., fishery or pollution based monitoring) often using traditional techniques, many of which have not changed significantly since the early 1900s. The advent of a new wave of automated technology, in combination with changing political and economic circumstances, means that there is currently a strong drive to move toward a more refined, efficient, and effective way of monitoring. We describe the policy and scientific rationale for monitoring our seas, alongside a comprehensive description of the types of equipment and methodology currently used and the technologies that are likely to be used in the future. We contextualize the way new technologies and methodologies may impact monitoring and discuss how whole ecosystems models can give an integrated, comprehensive approach to impact assessment. Furthermore, we discuss how an understanding of the value of each data point is crucial to assess the true costs and benefits to society of a marine monitoring programme