Identifying disease associations via genome-wide association studies

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies prove to be a powerful approach to identify the genetic basis of different human diseases. We studied the relationship between seven diseases characterized in a previous genome-wide association study by the Wellcome Trust Case Control Consortium. Instead of doing a horizontal association of SNPs to diseases, we did a vertical analysis of disease associations by comparing the genetic similarities of diseases. Our analysis was carried out at four levels – the nucleotide level (SNPs), the gene level, the protein level (through protein-protein interaction network), and the phenotype level.</p> <p>Results</p> <p>Our results show that Crohn's disease, rheumatoid arthritis, and type 1 diabetes share evidence of genetic associations at all levels of analysis, offering strong molecular support for the current grouping of the diseases. On the other hand, coronary artery disease, hypertension, and type 2 diabetes, despite being considered as a natural group with potential aetiological overlap, do not show any evidence of shared genetic basis at all levels.</p> <p>Conclusion</p> <p>Our study is a first attempt on mining of GWA data to examine genetic associations between different diseases. The positive result is apparently not a coincidence and hence demonstrates the promising use of our approach.</p

Studies on Dynamics of Suction Piles during Their Lowering Operations

Suction piles are used for anchoring the mooring lines at the seafloor. One of the challenges of their installing is the occurrence of the heave resonance of the pile-cable system and possibly the heave induced pitch resonance during the lowering process. When the heave and/or pitch frequency of the vessel which operates the lowering of the pile matches the heave natural frequency of the pile-cable system, the heave resonance may occur, resulting in large heave oscillations of the pile and thus significantly increasing loads on the lowering cable and lowering devices. Furthermore, the large heave may resonantly induce the pitch of a pile. To predict and possibly mitigate the heave/pitch resonance of the pile-cable system during the lowering process, it is crucial to under the mechanism of heave induced pitch resonance and estimate the added-mass and damping coefficients of the pile-cable system accurately. The model tests of the forced heave excitation of pile models were first conducted to investigate the added-mass coefficient for a pile model with different opening area ratios at its top cap at the Haynes Coastal Engineering Laboratory of Texas AandM University. In the model tests, it was observed that the resonant heave may occur if the heave excitation frequency matches the related heave natural frequency and the pitch resonance may be induced by the heave resonance. The results of the following theoretical analysis and numerical simulation of the heave excitation of the pile-cable system are found to be consistent with the related measurements, which is helpful to further understand the physics of lowering a pile-cable system. The results of this study may be used to determine the magnitudes of total heave added-mass and damping coefficient of a pile and the heave natural frequency of the pile-cable system based upon its main characteristics. The heave induced resonant pitch is found to occur when 1) the pitch natural frequency is roughly equal to one half of the heave natural frequency and 2) the heave excitation frequency is approximately equal to the heave natural frequency. If only one of the two conditions is satisfied, no significant pitch resonance will occur. These results may have important implications to the operation of lowering offshore equipment to the seafloor in deep water

The Role of Talin2 in Breast Cancer Tumorigenesis and Metastasis

Recent studies show that talin2 has a higher affinity to β-integrin tails and is indispensable for traction force generation and cell invasion. However, its roles in cell migration, cancer cell metastasis and tumorigenesis remain to be determined. Here, we used MDA-MB-231 human breast cancer cells as a model to define the roles of talin2 in cell migration, invasion, metastasis and tumorigenesis. We show here that talin2 knockdown (KD) inhibited cell migration and focal adhesion dynamics, a key step in cell migration, and that talin2 knockout (KO) inhibited cell invasion and traction force generation, the latter is crucial for cell invasion. Re-expression of talin2WT in talin2-KO cells restored traction force generation and cell invasion, but that of talin2S339C, a β-integrin-binding deficient mutant, did not. Moreover, talin2 KO (or KD) suppressed tumorigenesis and metastasis in mouse xenograft models. However, surprisingly, re-expression of talin2WT in talin2-KO cells did not rescue tumorigenesis. Thus, talin2 is required for breast cancer cell migration, invasion, metastasis and tumorigenesis, although exogenous expression of high levels of talin2 could inhibit tumorigenesis

Molecular characterization, structural analysis and determination of host range of a novel bacteriophage LSB-1

<p>Abstract</p> <p>Background</p> <p>Bacteriophages (phages) are widespread in the environment and play a crucial role in the evolution of their bacterial hosts and the emergence of new pathogens.</p> <p>Results</p> <p>LSB-1, a reference coliphage strain, was classified as a member of the Podoviridae family with a cystic form (50 ± 5 nm diameter) and short tail (60 ± 5 nm long). The double stranded DNA was about 30 kilobase pairs in length. We identified its host range and determined the gp17 sequences and protein structure using shotgun analysis and bioinformatics technology.</p> <p>Conclusions</p> <p>Coliphage LSB-1 possesses a tailspike protein with endosialidase activity which is probably responsible for its specific enteroinvasive <it>E.coli </it>host range within the laboratory.</p

Distinct interactions between fronto-parietal and default mode networks in impaired consciousness

Existing evidence suggests that the default-mode network (DMN) and fronto-pariatal network (FPN) play an important role in altered states of consciousness. However, the brain mechanisms underlying impaired consciousness and the specific network interactions involved are not well understood. We studied the topological properties of brain functional networks using resting-state functional MRI data acquired from 18 patients (11 vegetative state/unresponsive wakefulness syndrome, VS/UWS, and 7 minimally conscious state, MCS) and compared these properties with those of healthy controls. We identified that the topological properties in DMN and FPN are anti-correlated which comes, in part, from the contribution of interactions between dorsolateral prefrontal cortex of the FPN and precuneus of the DMN. Notably, altered nodal connectivity strength was distance-dependent, with most disruptions appearing in long-distance connections within the FPN but in short-distance connections within the DMN. A multivariate pattern-classification analysis revealed that combination of topological patterns between the FPN and DMN could predict conscious state more effectively than connectivity within either network. Taken together, our results imply distinct interactions between the FPN and DMN, which may mediate conscious state

p70S6K1 (S6K1)-Mediated Phosphorylation Regulates Phosphatidylinositol 4-Phosphate 5-Kinase Type I \u3cem\u3eγ\u3c/em\u3e Degradation and Cell Invasion

Phosphatidylinositol 4-phosphate 5-kinase type I γ (PIPKIγ90) ubiquitination and subsequent degradation regulate focal adhesion assembly, cell migration, and invasion. However, it is unknown how upstream signals control PIPKIγ90 ubiquitination or degradation. Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. Moreover, PIPKIγ90 phosphorylation is required for the development of focal adhesions and invadopodia, key machineries for cell migration and invasion. Surprisingly, substitution of Thr-553 and Ser-555 with Ala promoted PIPKIγ90 ubiquitination but enhanced the stability of PIPKIγ90, and depletion of S6K1 also enhanced the stability of PIPKIγ90, indicating that PIPKIγ90 ubiquitination alone is insufficient for its degradation. These data suggest that S6K1-mediated PIPKIγ90 phosphorylation regulates cell migration and invasion by controlling PIPKIγ90 degradation

CRISPR-Cas9 Mediated NOX4 Knockout Inhibits Cell Proliferation and Invasion in HeLa Cells

Increased expression of NOX4 protein is associated with cancer progression and metastasis but the role of NOX4 in cell proliferation and invasion is not fully understood. We generated NOX4 knockout HeLa cell lines using the CRISPR-Cas9 gene editing system to explore the cellular functions of NOX4. After transfection of CRISPR-Cas9 construct, we performed T7 endonuclease 1 assays and DNA sequencing to generate and identify insertion and deletion of the NOX4 locus. We confirmed the knockout of NOX4 by Western blotting. NOX4 knockout cell lines showed reduced cell proliferation with an increase of sub-G1 cell population and the decrease of S/G2/M population. Moreover, NOX4 deficiency resulted in a dramatic decrease in invadopodium formation and the invasive activity. In addition, NOX4 deficiency also caused a decrease in focal adhesions and cell migration in HeLa cells. These results suggest that NOX4 is required for both efficient proliferation and invasion of HeLa cells

Structure of catalytic domain of Matriptase in complex with Sunflower trypsin inhibitor-1

Seed storage proteins are both an important source of nutrition for humans and essential for seedling establishment. Interestingly, unusual napin-type 2S seed storage albumin precursors in sunflowers contain a sequence that is released as a macrocyclic peptide during post-translational processing. The mechanism by which such peptides emerge from linear precursor proteins has received increased attention; however, the structural characterization of intact precursor proteins has been limited. Here, we report the 3D NMR structure of the Helianthus annuus PawS1 (preproalbumin with sunflower trypsin inhibitor-1) and provide new insights into the processing of this remarkable dual-destiny protein. In seeds, PawS1 is matured by asparaginyl endopeptidases (AEPs) into the cyclic peptide SFTI-1 (sunflower trypsin inhibitor-1) and a heterodimeric 2S albumin. The structure of PawS1 revealed that SFTI-1 and the albumin are independently folded into well-defined domains separated by a flexible linker. PawS1 was cleaved in vitro with recombinant sunflower HaAEP1 and in situ using a sunflower seed extract in a way that resembled the expected in vivo cleavages. Recombinant HaAEP1 cleaved PawS1 at multiple positions, and in situ, its flexible linker was removed, yielding fully mature heterodimeric albumin. Liberation and cyclization of SFTI-1, however, was inefficient, suggesting that specific seed conditions or components may be required for in vivo biosynthesis of SFTI-1. In summary, this study has revealed the 3D structure of a macrocyclic precursor protein and provided important mechanistic insights into the maturation of sunflower proalbumins into an albumin and a macrocyclic peptide

The Influence of Neighbourhood Environment on Airbnb: a Geographically Weighed Regression Analysis

Sharing accommodation has emerged recently as a new business model in the accommodation sector. Due to the potential gentrification Airbnb might bring to an area, it is critical to understand the spatial patterns of sharing economy and its possible determinants. The neighbourhood environment has proven to be an important factor in the traditional hotel business, and whether it is the same for sharing accommodation is worth investigating. In this study, location data of 29,780 houses/apartments on Airbnb.com in London was collected. Using Ordinal Least Square and Geography Weighed Regression analysis, the spatial distribution features of Airbnb and its relationship with neighbourhood environment in London were explored. The results show that sharing accommodation is mainly located in the city centre and around tourist attractions. Neighbourhood elements such as Water, Vegetation Coverage, Art & Human Landscape, Travel & Transport, University, Nightlife Spot emerged as important factors influencing Airbnb. In addition, the distribution of Airbnb in London is spatially non-stationary, in some areas high Airbnb is associated with higher transportation accessibility, in other areas, high Airbnb is associated with more attractions or nightlife spots, suggesting that the role of different factors varies in different regions, proving Tobler’s first law of geography