RESUMEN

AIMS: Talipes equinovarus (clubfoot) is a congenital lower foot deformity that results from a neuromuscular deficiency, but the precise etiology remains elusive. Vitamin D is important for fetal neuromuscular development. In this study, we investigated the association between dietary vitamin D intake during pregnancy and incidence of clubfoot in neonates, since such a question has thus far been overlooked. METHODS: We conducted a secondary analysis of data collected in the United States, between 2007 and 2011 for a case-control study of children born with clubfoot. Participating mothers were interviewed by telephone about dietary and other health and life-style indicators. Exposure to vitamin D was recorded as the average daily intake of dietary vitamin D over a period of 6 months before pregnancy began. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. RESULTS: The dataset included 2667 study participants, of which 663 were cases. Logistic regression showed no significant association between dietary vitamin D or log10 (Vitamin D) intake during pregnancy and incidence of clubfoot in neonates (OR = 1.00, CI = 1.00-1.00, OR = 1.51, CI = 0.83-2.82, respectively). No interaction in the regression model was found between vitamin D and other predictor variables. Results were not confounded by supplement intake of vitamin D during pregnancy. CONCLUSIONS: Results show no evidence of an association between dietary vitamin D intake and incidence of clubfoot in neonates. The lack of association is not confounded by consumption of vitamin D supplements during pregnancy.

Asunto(s)

RESUMEN

BACKGROUND: Our ability to self-care can play a crucial role in the prevention, management and rehabilitation of diverse conditions, including chronic non-communicable diseases. Various tools have been developed to support the measurement of self-care capabilities of healthy individuals, those experiencing everyday self-limiting conditions, or one or more multiple long-term conditions. We sought to characterise the various non-mono-disease specific self-care measurement tools for adults as such a review was lacking. OBJECTIVE: The aim of the review was to identify and characterise the various non-mono-disease specific self-care measurement tools for adults. Secondary objectives were to characterise these tools in terms of their content, structure and psychometric properties. DESIGN: Scoping review with content assessment. METHODS: The search was conducted in Embase, PubMed, PsycINFO and CINAHL databases using a variety of MeSH terms and keywords covering 1 January 1950 to 30 November 2022. Inclusion criteria included tools assessing health literacy, capability and/or performance of general health self-care practices and targeting adults. We excluded tools targeting self-care in the context of disease management only or indicated to a specific medical setting or theme. We used the Seven Pillars of Self-Care framework to inform the qualitative content assessment of each tool. RESULTS: We screened 26,304 reports to identify 38 relevant tools which were described in 42 primary reference studies. Descriptive analysis highlighted a temporal shift in the overall emphasis from rehabilitation-focused to prevention-focused tools. The intended method of administration also transitioned from observe-and-interview style methods to the utilisation of self-reporting tools. Only five tools incorporated questions relevant to the seven pillars of self-care. CONCLUSIONS: Various tools exist to measure individual self-care capability, but few consider assessing capability against all seven pillars of self-care. There is a need to develop a comprehensive, validated tool and easily accessible tool to measure individual self-care capability including the assessment of a wide range of self-care practices. Such a tool could be used to inform targeted health and social care interventions.

Asunto(s)

RESUMEN

DNA polymerase ß is a member of the X-family of DNA polymerases, playing a critical role in the base excision repair (BER) pathway in mammalian cells by implementing the nucleotide gap-filling step. In vitro phosphorylation of DNA polymerase ß with PKC on S44 causes loss in the enzyme's DNA polymerase activity but not single-strand DNA binding. Although these studies have shown that single-stranded DNA binding is not affected by phosphorylation, the structural basis behind the mechanism underlying phosphorylation-induced activity loss remains poorly understood. Previous modeling studies suggested phosphorylation of S44 was sufficient to induce structural changes that impact the enzyme's polymerase function. However, the S44 phosphorylated-enzyme/DNA complex has not been modeled so far. To address this knowledge gap, we conducted atomistic molecular dynamics simulations of pol ß complexed with gapped DNA. Our simulations, which used explicit solvent and lasted for microseconds, revealed that phosphorylation at the S44 site, in the presence of Mg ions, induced significant conformational changes in the enzyme. Specifically, these changes led to the transformation of the enzyme from a closed to an open structure. Additionally, our simulations identified phosphorylation-induced allosteric coupling between the inter-domain region, suggesting the existence of a putative allosteric site. Taken together, our results provide a mechanistic understanding of the conformational transition observed due to phosphorylation in DNA polymerase ß interactions with gapped DNA. Our simulations shed light on the mechanisms of phosphorylation-induced activity loss in DNA polymerase ß and reveal potential targets for the development of novel therapeutics aimed at mitigating the effects of this post-translational modification.

Asunto(s)

RESUMEN

DNA polymerase ß (pol ß) is a member of the X- family of DNA polymerases that catalyze the distributive addition of nucleoside triphosphates during base excision DNA repair. Previous studies showed that the enzyme was phosphorylated in vitro with PKC at two serines (44 and 55), causing loss of DNA polymerase activity but not DNA binding. In this work, we have investigated the phosphorylation-induced conformational changes in DNA polymerase ß in the presence of Mg ions. We report a comprehensive atomic resolution study of wild type and phosphorylated DNA polymerase using molecular dynamics (MD) simulations. The results are examined via novel methods of internal dynamics and energetics analysis to reveal the underlying mechanism of conformational transitions observed in DNA pol ß. The results show drastic conformational changes in the structure of DNA polymerase ß due to S44 phosphorylation. Phosphorylation-induced conformational changes transform the enzyme from a closed to an open structure. The dynamic cross-correlation shows that phosphorylation enhances the correlated motions between the different domains. Centrality network analysis reveals that the S44 phosphorylation causes structural rearrangements and modulates the information pathway between the Lyase domain and base pair binding domain. Further analysis of our simulations reveals that a critical hydrogen bond (between S44 and E335) disruption and the formation of three additional salt bridges are potential drivers of these conformational changes. In addition, we found that two of these additional salt bridges form in the presence of Mg ions on the active sites of the enzyme. These results agree with our previous study of DNA pol ß S44 phosphorylation without Mg ions which predicted the deactivation of DNA pol ß. However, the phase space of structural transitions induced by S44 phosphorylation is much richer in the presence of Mg ions.

RESUMEN

DNA polymerase ß is a 39 kDa enzyme that is a major component of Base Excision Repair in human cells. The enzyme comprises two major domains, a 31 kDa domain responsible for the polymerase activity and an 8 kDa domain, which bind ssDNA and has a deoxyribose phosphate (dRP) lyase activity. DNA polymerase ß was shown to be phosphorylated in vitro with protein kinase C (PKC) at serines 44 and 55 (S44 and S55), resulting in loss of its polymerase enzymic activity, but not its ability to bind ssDNA. In this study, we investigate the potential phosphorylation-induced structural changes for DNA polymerase ß using molecular dynamics simulations. The simulations show drastic conformational changes of the polymerase structure as a result of S44 phosphorylation. Phosphorylation-induced conformational changes transform the closed (active) enzyme structure into an open one. Further analysis of the results points to a key hydrogen bond and newly formed salt bridges as potential drivers of these structural fluctuations. The changes observed with S55/44 and S55 phosphorylation were less dramatic and the integrity of the H-bond was not compromised. Thus the phosphorylation of S44 is the major contributor to structural fluctuations that lead to loss of enzymatic activity.

Asunto(s)

RESUMEN

DNA polymerase ß is a 39kDa enzyme that is a major component of Base Excision Repair in human cells. The enzyme comprises two major domains, a 31kDa domain responsible for the polymerase activity and an 8kDa domain, which bind ssDNA and has a deoxyribose phosphate (dRP) lyase activity. DNA polymerase ß was shown to be phosphorylated in vitro with protein kinase C (PKC) at serines 44 and 55 (S44 and S55), resulting in loss of its polymerase enzymic activity, but not its ability to bind ssDNA. In this study, we investigate the potential phosphorylation-induced structural changes for DNA polymerase ß using molecular dynamics. The simulations show drastic conformational changes of the polymerase structure as a result of S44 phosphorylation. Phosphorylation-induced conformational changes transform the closed (active) enzyme structure into an open one. Further analysis of the results points to a key hydrogen bond and newly formed salt bridges as potential drivers of these structural fluctuations. The changes observed with S44/55 and S55 phosphorylation were less dramatic than S44 and the integrity of the H-bond was not compromised. Thus the phosphorylation of S44 is likely the major contributor to structural fluctuations that lead to loss of enzymatic activity.

Asunto(s)

RESUMEN

Transformed cells progress to cancer because they are not eliminated by apoptosis. In this brief minireview I propose, based on published data, that the cell possesses a 'last check point' (LCP) apoptotic step in the form of assembly of nitrotyrosinated alpha-tubulin onto microtubules. This leads to microtubule dysfunction and ultimately apoptosis. I also propose that cells that escape this LCP apoptotic step develop into cancer. Phosphorylation of tubulin tyrosine ligase (TTL) is postulated to cause escape from LCP apoptosis. Phosphorylation also ensures that cancer cells survive a hostile milieu (e.g. chemotherapy).

Asunto(s)

RESUMEN

Mammalian DNA polymerase beta(beta-pol) is a single polypeptide chain enzyme of 39kDa. beta-pol has enzymatic activities appropriate for roles in base excision repair and other DNA metabolism events involving gap-filling DNA synthesis. Many crystal structures of beta-pol complexed with dNTP and DNA substrates have been solved, and mouse fibroblast cell lines deleted in the beta-pol gene have been examined. These approaches have enhanced our understanding of structural and functional aspects of beta-pol's role in protecting genomic DNA.

Asunto(s)