Allostery in Its Many Disguises: From Theory to Applications.

Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts

Health behaviors and their relationship with disease control in people attending genetic clinics with a family history of breast or colorectal cancer

The current work aimed to assess health behaviors, perceived risk and control over breast/colorectal cancer risk and views on lifestyle advice amongst attendees at cancer family history clinics. Participants attending the East of Scotland Genetics Service were invited to complete a questionnaire (demographic data, weight and height, health behaviors and psycho-social measures of risk and perceived control) and to participate in an in-depth interview. The questionnaire was completed by 237 (49%) of attendees, ranging from 18 to 77years (mean age 46 (±10) years). Reported smoking rates (11%) were modest, most (54%) had a BMI>25kg/m2, 55% had low levels of physical activity, 58% reported inappropriate alcohol intakes and 90% had fiber intakes indicative of a low plant diet. Regression analysis indicated that belief in health professional control was associated with higher, and belief in fatalism with poorer health behavior. Qualitative findings highlighted doubts about the link between lifestyle and cancer, and few were familiar with the current evidence. Whilst lifestyle advice was considered interesting in general there was little appetite for non-tailored guidance. In conclusion, current health behaviors are incongruent with cancer risk reduction guidance amongst patients who have actively sought advice on disease risk. There are some indications that lifestyle advice would be welcomed but endorsement requires a sensitive and flexible approach, and the acceptability of lifestyle interventions remains to be explored

Invasion Genetics of the Western Flower Thrips in China: Evidence for Genetic Bottleneck, Hybridization and Bridgehead Effect

The western flower thrips, Frankliniella occidentalis (Pergande), is an invasive species and the most economically important pest within the insect order Thysanoptera. F. occidentalis, which is endemic to North America, was initially detected in Kunming in southwestern China in 2000 and since then it has rapidly invaded several other localities in China where it has greatly damaged greenhouse vegetables and ornamental crops. Controlling this invasive pest in China requires an understanding of its genetic makeup and migration patterns. Using the mitochondrial COI gene and 10 microsatellites, eight of which were newly isolated and are highly polymorphic, we investigated the genetic structure and the routes of range expansion of 14 F. occidentalis populations in China. Both the mitochondrial and microsatellite data revealed that the genetic diversity of F. occidentalis of the Chinese populations is lower than that in its native range. Two previously reported cryptic species (or ecotypes) were found in the study. The divergence in the mitochondrial COI of two Chinese cryptic species (or ecotypes) was about 3.3% but they cannot be distinguished by nuclear markers. Hybridization might produce such substantial mitochondrial-nuclear discordance. Furthermore, we found low genetic differentiation (global FST = 0.043, P<0.001) among all the populations and strong evidence for gene flow, especially from the three southwestern populations (Baoshan, Dali and Kunming) to the other Chinese populations. The directional gene flow was further supported by the higher genetic diversity of these three southwestern populations. Thus, quarantine and management of F. occidentalis should focus on preventing it from spreading from the putative source populations to other parts of China

Identification of multiple integrin β1 homologs in zebrafish (Danio rerio)

BACKGROUND: Integrins comprise a large family of α,β heterodimeric, transmembrane cell adhesion receptors that mediate diverse essential biological functions. Higher vertebrates possess a single β1 gene, and the β1 subunit associates with a large number of α subunits to form the major class of extracellular matrix (ECM) receptors. Despite the fact that the zebrafish (Danio rerio) is a rapidly emerging model organism of choice for developmental biology and for models of human disease, little is currently known about β1 integrin sequences and functions in this organism. RESULTS: Using RT-PCR, complete coding sequences of zebrafish β1 paralogs were obtained from zebrafish embryos or adult tissues. The results show that zebrafish possess two β1 paralogs (β1–1 and β1–2) that have a high degree of identity to other vertebrate β1 subunits. In addition, a third, more divergent, β1 paralog is present (β1–3), which may have altered ligand-binding properties. Zebrafish also have other divergent β1-like transcripts, which are C-terminally truncated forms lacking the transmembrane and cytoplasmic domains. Together with β1–3 these truncated forms comprise a novel group of β1 paralogs, all of which have a mutation in the ADMIDAS cation-binding site. Phylogenetic and genomic analyses indicate that the duplication that gave rise to β1–1 and β1–2 occurred after the divergence of the tetrapod and fish lineages, while a subsequent duplication of the ancestor of β1–2 may have given rise to β1–3 and an ancestral truncated paralog. A very recent tandem duplication of the truncated β1 paralogs appears to have taken place. The different zebrafish β1 paralogs have varied patterns of temporal expression during development. β1–1 and β1–2 are ubiquitously expressed in adult tissues, whereas the other β1 paralogs generally show more restricted patterns of expression. CONCLUSION: Zebrafish have a large set of integrin β1 paralogs. β1–1 and β1–2 may share the roles of the solitary β1 subunit found in other vertebrates, whereas β1–3 and the truncated β1 paralogs may have acquired novel functions

Gene-Gene and Gene-Environmental Interactions of Childhood Asthma: A Multifactor Dimension Reduction Approach

Background: The importance of gene-gene and gene-environment interactions on asthma is well documented in literature, but a systematic analysis on the interaction between various genetic and environmental factors is still lacking. Methodology/Principal Findings: We conducted a population-based, case-control study comprised of seventh-grade children from 14 Taiwanese communities. A total of 235 asthmatic cases and 1,310 non-asthmatic controls were selected for DNA collection and genotyping. We examined the gene-gene and gene-environment interactions between 17 singlenucleotide polymorphisms in antioxidative, inflammatory and obesity-related genes, and childhood asthma. Environmental exposures and disease status were obtained from parental questionnaires. The model-free and non-parametrical multifactor dimensionality reduction (MDR) method was used for the analysis. A three-way gene-gene interaction was elucidated between the gene coding glutathione S-transferase P (GSTP1), the gene coding interleukin-4 receptor alpha chain (IL4Ra) and the gene coding insulin induced gene 2 (INSIG2) on the risk of lifetime asthma. The testing-balanced accuracy on asthma was 57.83 % with a cross-validation consistency of 10 out of 10. The interaction of preterm birth and indoor dampness had the highest training-balanced accuracy at 59.09%. Indoor dampness also interacted with many genes, including IL13, beta-2 adrenergic receptor (ADRB2), signal transducer and activator of transcription 6 (STAT6). We also used likelihood ratio tests for interaction and chi-square tests to validate our results and all tests showed statistical significance

Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD

Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD