Exploration of the relationship between topology and designability of conformations.
Ontology highlight
ABSTRACT: Protein structures are evolutionarily more conserved than sequences, and sequences with very low sequence identity frequently share the same fold. This leads to the concept of protein designability. Some folds are more designable and lots of sequences can assume that fold. Elucidating the relationship between protein sequence and the three-dimensional (3D) structure that the sequence folds into is an important problem in computational structural biology. Lattice models have been utilized in numerous studies to model protein folds and predict the designability of certain folds. In this study, all possible compact conformations within a set of two-dimensional and 3D lattice spaces are explored. Complementary interaction graphs are then generated for each conformation and are described using a set of graph features. The full HP sequence space for each lattice model is generated and contact energies are calculated by threading each sequence onto all the possible conformations. Unique conformation giving minimum energy is identified for each sequence and the number of sequences folding to each conformation (designability) is obtained. Machine learning algorithms are used to predict the designability of each conformation. We find that the highly designable structures can be distinguished from other non-designable conformations based on certain graphical geometric features of the interactions. This finding confirms the fact that the topology of a conformation is an important determinant of the extent of its designability and suggests that the interactions themselves are important for determining the designability.
Project description:Understanding protein structure and dynamics is essential for understanding their function. This is a challenging task due to the high complexity of the conformational landscapes of proteins and their rugged energy levels. In particular, it is important to detect highly populated regions which could correspond to intermediate structures or local minima.We present a hierarchical clustering and algebraic topology based method that detects regions of interest in protein conformational space. The method is based on several techniques. We use coarse grained protein conformational search, efficient robust dimensionality reduction and topological analysis via persistent homology as the main tools. We use two dimensionality reduction methods as well, robust Principal Component Analysis (PCA) and Isomap, to generate a reduced representation of the data while preserving most of the variance in the data.Our hierarchical clustering method was able to produce compact, well separated clusters for all the tested examples.
Project description:Most of what we know about gene transcription comes from the view of cells as molecular machines: focusing on the role of molecular modifications to the proteins carrying out transcriptional reactions at a loci-by-loci basis. This view ignores a critical reality: biological reactions do not happen in an empty space, but in a highly complex, interrelated, and dense nanoenvironment that profoundly influences chemical interactions. We explored the relationship between the physical nanoenvironment of chromatin and gene transcription in vitro. We analytically show that changes in the fractal dimension, D, of chromatin correspond to simultaneous increases in chromatin accessibility and compaction heterogeneity. Using these predictions, we demonstrate experimentally that nanoscopic changes to chromatin D within thirty minutes correlate with concomitant enhancement and suppression of transcription. Further, we show that the increased heterogeneity of physical structure of chromatin due to increase in fractal dimension correlates with increased heterogeneity of gene networks. These findings indicate that the higher order folding of chromatin topology may act as a molecular-pathway independent code regulating global patterns of gene expression. Since physical organization of chromatin is frequently altered in oncogenesis, this work provides evidence pairing molecular function to physical structure for processes frequently altered during tumorigenesis.
Project description:Diffusion-weighted imaging (DWI) Alberta Stroke Program Early CT Score (ASPECTS), a surrogate of infarct volume, predicts outcome in anterior large vessel occlusion strokes. We aim to determine whether topological information captured by DWI ASPECTS contributes additional prognostic value.Adults with intracranial internal carotid artery, M1 or M2 middle carotid artery occlusions who underwent endovascular therapy were included. The primary outcome measure was poor clinical outcome (3-month modified Rankin Scale score, 3-6). Prognostic value of the 10 DWI ASPECTS regions in predicting poor outcome was determined by multivariable logistic regression, controlling for final infarct volume, age, and laterality.Two hundred and thirteen patients (mean age, 66.1±14.5 years; median National Institutes of Health Stroke Scale, 15) were included. Inter-rater reliability was good for DWI ASPECTS (deep regions, ?=0.72; cortical regions, ?=0.63). All DWI ASPECTS regions with the exception of the putamen were significant predictors (P<0.05) of poor outcome in univariate analyses. Statistical collinearity among ASPECTS regions was not observed. Using penalized multivariable logistic regression, only M4 (odds ratio, 2.82; 95% confidence interval, 1.39-5.76) and M6 (odds ratio, 2.45; 95% confidence interval, 1.15-5.3) involvement were associated with poor outcome. M6 involvement independently predicted poor outcome in right hemispheric strokes (odds ratio, 5.8; 95% confidence interval, 1.9-20.3), whereas M4 (odds ratio, 4.3; 95% confidence interval, 1.3-15.0) involvement predicted poor outcome in left hemispheric strokes adjusting for infarct volume. Topologic information modestly improved the predictive ability of a prognostic score that incorporates age, infarct volume, and hemorrhagic transformation.Involvement of the right parieto-occipital (M6) and left superior frontal (M4) regions affect clinical outcome in anterior large vessel occlusions over and above the effect of infarct volume and should be considered during prognostication.
Project description:The relationship between biological network architectures and evolution is unclear. Within the phylum nematoda olfaction represents a critical survival tool. For nematodes, olfaction contributes to multiple processes including the finding of food, hosts, and reproductive partners, making developmental decisions, and evading predators. Here we examine a dynamic nematode odor genetic network to investigate how divergence, diversity, and contribution are shaped by network topology. Our findings describe connectivity frameworks and characteristics that correlate with molecular evolution and contribution across the olfactory network. Our data helps guide the development of a robust evolutionary description of the nematode odor network that may eventually aid in the prediction of interactive and functional qualities of novel nodes.
Project description:The network topology in disordered materials is an important structural descriptor for understanding the nature of disorder that is usually hidden in pairwise correlations. Here, we compare the covalent network topology of liquid and solidified silicon (Si) with that of silica (SiO2) on the basis of the analyses of the ring size and cavity distributions and tetrahedral order. We discover that the ring size distributions in amorphous (a)-Si are narrower and the cavity volume ratio is smaller than those in a-SiO2, which is a signature of poor amorphous-forming ability in a-Si. Moreover, a significant difference is found between the liquid topology of Si and that of SiO2. These topological features, which are reflected in diffraction patterns, explain why silica is an amorphous former, whereas it is impossible to prepare bulk a-Si. We conclude that the tetrahedral corner-sharing network of AX2, in which A is a fourfold cation and X is a twofold anion, as indicated by the first sharp diffraction peak, is an important motif for the amorphous-forming ability that can rule out a-Si as an amorphous former. This concept is consistent with the fact that an elemental material cannot form a bulk amorphous phase using melt quenching technique.
Project description:Methicillin resistant Staphylococcus aureus (MRSA) has become a major health concern which has brought about an urgent need for new therapeutic agents. As the S. aureus Sortase A (SrtA) enzyme contributes to the adherence of the bacteria to the host cells, inhibition thereof by small molecules could be employed as potential antivirulence agents, also towards resistant strains. Albeit several virtual docking SrtA campaigns have been reported, no strongly inhibitatory non-covalent binders have as yet emerged therefrom. In order to better understand the binding modes of small molecules, and the effect of different receptor structures employed in the screening, we herein report on an exploratory study employing 10 known binders and 500 decoys on 100 SrtA structures generated from regular or steered molecular dynamics simulations on four different SrtA crystal/NMR structures. The results suggest a correlation between the protein structural flexibility and the virtual screening performance, and confirm the noted immobilization of the β6/β7 loop upon substrate binding. The NMR structures reported appear to perform slightly better than the Xray-crystal structures, but the binding modes fluctuate tremendously, and it might be suspected that the catalytic site is not necessarily the preferred site of binding for some of the reported active compounds.
Project description:ObjectiveTo determine the household food insecurity (HFI) prevalence in Canadians with diabetes and its relationship with diabetes management, self-care practices, and health status.Research design and methodsWe analyzed data from Canadians with diabetes aged >or=12 years (n = 6,237) from cycle 3.1 of the Canadian Community Health Survey, a population-based cross-sectional survey conducted in 2005. The HFI prevalence in Canadians with diabetes was compared with that in those without diabetes. The relationships between HFI and management services, self-care practices, and health status were examined for Ontarians with diabetes (n = 2,523).ResultsHFI was more prevalent among individuals with diabetes (9.3% [8.2-10.4]) than among those without diabetes (6.8% [6.5-7.0]) and was not associated with diabetes management services but was associated with physical inactivity (odds ratio 1.54 [95% CI 1.10-2.17]), lower fruit and vegetable consumption (0.52 [0.33-0.81]), current smoking (1.71 [1.09-2.69]), unmet health care needs (2.71 [1.74-4.23]), having been an overnight patient (2.08 [1.43-3.04]), having a mood disorder (2.18 [1.54-3.08]), having effects from a stroke (2.39 [1.32-4.32]), lower satisfaction with life (0.28 [0.18-0.43]), self-rated general (0.37 [0.21-0.66]) and mental (0.17 [0.10-0.29]) health, and higher self-perceived stress (2.04 [1.30-3.20]). The odds of HFI were higher for an individual in whom diabetes was diagnosed at age <40 years (3.08 [1.96-4.84]).ConclusionsHFI prevalence is higher among Canadians with diabetes and is associated with an increased likelihood of unhealthy behaviors, psychological distress, and poorer physical health.
Project description:Hyperphosphatemia is a risk factor associated with mortality in patients on maintenance hemodialysis. Gut absorption of phosphate is the major source. Recent studies indicated that the intestinal flora of uremic patients changed a lot compared with the healthy population, and phosphorus is an essential element of bacterial survival and reproduction. The purpose of this study was to explore the role of intestinal microbiota in phosphorus metabolism. A prospective self-control study was performed from October 2015 to January 2016. Microbial DNA was isolated from the stools of 20 healthy controls and 21 maintenance hemodialysis patients. Fourteen out of the 21 patients were treated with lanthanum carbonate for 12 weeks. Thus, stools were also collected before and after the treatment. The bacterial composition was analyzed based on 16S ribosomal RNA pyrosequencing. Bioinformatics tools, including sequence alignment, abundance profiling, and taxonomic diversity, were used in microbiome data analyses. Correlations between genera and the serum phosphorus were detected with Pearson's correlation. For visualization of the internal interactions and further measurement of the microbial community, SparCC was used to calculate the Spearman correlation coefficient with the corresponding P value between each two genera. Thirteen genera closely correlated with serum phosphorus and the correlation coefficient was above 0.4 (P < 0.05). We also found that 58 bacterial operational taxonomic units (OTUs) were significantly different and more decreased OTUs were identified and seven genera (P < 0.05) were obviously reduced after using the phosphate binder. Meanwhile, the microbial richness and diversity presented downward trend in hemodialysis patients compared with healthy controls and more downward trend after phosphorus reduction. The co-occurrence network of genera revealed that the network complexity of hemodialysis patients was significantly higher than that of controls, whereas treatment with lanthanum carbonate reduced the network complexity. Gut flora related to phosphorus metabolism in hemodialysis patients, and improving intestinal microbiota may regulate the absorption of phosphate in the intestine. The use of phosphate binder lanthanum carbonate leads to a tendency of decreasing microbial diversity and lower network complexity.
Project description:Firms should deploy exploration and exploitation to foster organizational adaptation. Previous research on exploration and exploitation lacked a focus on disruption implications in different contexts. This study aims to empirically test a moderation model including disruption events, exploration, exploitation, and organizational adaptation and enable a deeper understanding of organizational learning and innovation theory to yield competitive advantage and sustainability of innovative firms. Our results reveal that exploration is more effective during outside disruption events. The results do not support the concept that exploitation is more effective during inside disruptions. Disruptions also moderate the combined effect of exploration and exploitation. Although they are generally complementary in facilitating organizational adaptation, a singular focus on either exploration or exploitation is as effective as is combining exploration and exploitation during inside and outside disruption events. The results of an event study using seven Chinese international firms, including Alibaba, Meituan, Dianping, Baidu, Beibei, TP-link, and Maxio, provided 132 completed and usable questionnaires that supported our hypotheses. Our study contributes to a better understanding of disruption, exploration, exploitation, and related performance implications.
Project description:Background and aimsExperiencing a traumatic event may lead to Posttraumatic Stress Disorder (PTSD), including symptoms such as flashbacks and hyperarousal. Individuals suffering from PTSD are at increased risk of cardiovascular disease (CVD), but it is unclear why. This study assesses shared genetic liability and potential causal pathways between PTSD and CVD.MethodsWe leveraged summary-level data of genome-wide association studies (PTSD: N= 1,222,882; atrial fibrillation (AF): N=482,409; coronary artery disease (CAD): N=1,165,690; hypertension: N=458,554; heart failure (HF): N=977,323). First, we estimated genetic correlations and utilized genomic structural equation modeling to identify a common genetic factor for PTSD and CVD. Next, we assessed biological, behavioural, and psychosocial factors as potential mediators. Finally, we employed multivariable Mendelian randomization to examine causal pathways between PTSD and CVD, incorporating the same potential mediators.ResultsSignificant genetic correlations were found between PTSD and CAD, HT, and HF (rg =0.21-0.32, p≤ 3.08 · 10-16), but not between PTSD and AF. Insomnia, smoking, alcohol dependence, waist-to-hip ratio, and inflammation (IL6, C-reactive protein) partly mediated these associations. Mendelian randomization indicated that PTSD causally increases CAD (IVW OR=1.53, 95% CIs=1.19-1.96, p=0.001), HF (OR=1.44, CIs=1.08-1.92, p=0.012), and to a lesser degree hypertension (OR=1.25, CIs=1.05-1.49, p=0.012). While insomnia, smoking, alcohol, and inflammation were important mediators, independent causal effects also remained.ConclusionsIn addition to shared genetic liability between PTSD and CVD, we present strong evidence for causal effects of PTSD on CVD. Crucially, we implicate specific lifestyle and biological mediators (insomnia, substance use, inflammation) which has important implications for interventions to prevent CVD in PTSD patients.