4,299 research outputs found

    Yes, size does matter (for cycling safety)! Comparing behavioral and safety outcomes in S, M, L, and XL cities from 18 countries

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    Although most actions aimed at promoting the use of active transport means have been conducted in ‚Äėlarge‚Äô cities, recent studies suggest that their cycling dynamics could hinder the efforts put into infrastructural, modal share, and cycling culture improvements. Aim: The present study aimed to assess the role of city sizes on riding behavioral and crash-related cycling outcomes in an extensive sample of urban bicycle users. Methods: For this purpose, a full sample of 5705 cyclists from &gt;300 cities in 18 countries responded to the Cycling Behavior Questionnaire (CBQ), one of the most widely used behavioral questionnaires to assess risky and positive riding behaviors. Following objective criteria, data were grouped according to small cities (S; population of 50,000 or fewer), medium cities (M; population between 50,000 and 200,000), large cities (L; population between 200,000 and one million), and megacities (XL; population larger than one million). Results: Descriptive analyses endorsed the associations between city size, cycling behavioral patterns, and mid-term self-reported crash outcomes. Also, it was observed a significant effect of the city size on cyclists' traffic violations and errors (all p &lt;.001). However, no significant effects of the city size on positive behaviors were found. Also, it stands out that cyclists from megacities self-reported significantly more violations and errors than any of the other groups. Further, the outcomes of this study suggest that city sizes account for cycling safety outcomes through statistical associations, differences, and confirmatory predictive relationships through the mediation of risky cycling behavioral patterns. Conclusion: The results of the present study highlight the need for authorities to promote road safety education and awareness plans aimed at cyclists in larger cities. Furthermore, path analysis suggests that ‚Äúsize does matter‚ÄĚ, and it statistically accounts for cycling crashes, but only through the mediation of riders' risky behaviors.</p

    Scalar-tensor theory with EGB term from Einstein Chern-Simons gravity

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    It is shown that the compactification a la Randall Sundrum of the so called, five dimensional Einstein Chern Simons action gravity leads to an action for a four dimensional scalar tensor gravity that includes a Gauss Bonnet term, which belongs to a particular case of the action of the Horndeski theory. The five dimensional action includes new gravitational degrees of freedom that were introduced requiring that the action be invariant under symmetries greater than the usual Poincare or (A)dS symmetries, namely the so called generalized Poincare algebras B5.Comment: To be published in Nucl. Phys.

    Author Correction: The power of genetic diversity in genome-wide association studies of lipids

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    Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors

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    Abstract Background Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process. Methods We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens. Results We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR‚ÄČ=‚ÄČ1.57 [1.06‚ÄČ‚ąí‚ÄČ2.33]; p‚ÄČ=‚ÄČ0.023) and overall (HR‚ÄČ=‚ÄČ2.65 [1.31‚ÄČ‚ąí‚ÄČ5.37], p‚ÄČ=‚ÄČ0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC‚ÄČ=‚ÄČ0.77, p‚ÄČ<‚ÄČ0.01). Conclusion Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer

    Additional file 12 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

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    Additional file 12: Table S8. PheWAS UKB-MVP meta-analysis results for each lipid PGS

    Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models

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    The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.Therapeutic cell differentiatio

    Histone H3 serine-57 is a CHK1 substrate whose phosphorylation affects DNA repair

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    Abstract Histone post-translational modifications promote a chromatin environment that controls transcription, DNA replication and repair, but surprisingly few phosphorylations have been documented. We report the discovery of histone H3 serine-57 phosphorylation (H3S57ph) and show that it is implicated in different DNA repair pathways from fungi to vertebrates. We identified CHK1 as a major human H3S57 kinase, and disrupting or constitutively mimicking H3S57ph had opposing effects on rate of recovery from replication stress, 53BP1 chromatin binding, and dependency on RAD52. In fission yeast, mutation of all H3 alleles to S57A abrogated DNA repair by both non-homologous end-joining and homologous recombination, while cells with phospho-mimicking S57D alleles were partly compromised for both repair pathways, presented aberrant Rad52 foci and were strongly sensitised to replication stress. Mechanistically, H3S57ph loosens DNA-histone contacts, increasing nucleosome mobility, and interacts with H3K56. Our results suggest that dynamic phosphorylation of H3S57 is required for DNA repair and recovery from replication stress, opening avenues for investigating the role of this modification in other DNA-related processes
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