Rickets: Twists and turns in the Gordian knot.
Ontology highlight
ABSTRACT:
SUBMITTER: Garg MK
PROVIDER: S-EPMC3659873 | biostudies-literature | 2013 Jan
REPOSITORIES: biostudies-literature
Publications
Rickets: Twists and turns in the Gordian knot.
Indian journal of endocrinology and metabolism 20130101 1
Similar Datasets
Project description:Protein-protein interactions involve hotspots as small as 4 sequential amino acids. Corresponding tetrapeptides have no structure in water. Here we report linking side chains of amino acids X and Z to form 24 cyclic tetrapeptides, cyclo-[XAAZ]-NH2, and stabilise 14-18 membered rings that mimic different kinds of non-regular secondary structures found in protein hotspots. 2D NMR spectra allowed determination of 3D structures for 14 cyclic tetrapeptides in water. Five formed two (i, i + 3) hydrogen bonds and a beta/gamma (6, 7) or beta (9, 19, 20) turn; eight formed one (i, i + 4) hydrogen bond and twisted into a non-helical (13, 18, 21, 22, 24) or helical (5, 17, 23) alpha turn; one was less structured (15). A beta or gamma turn was favoured for Z = Dab, Orn or Glu due to a χ1 gauche (+) rotamer, while an alpha turn was favoured for Z = Dap (but not X = Dap) due to a gauche (-) rotamer. Surprisingly, an unstructured peptide ARLARLARL could be twisted into a helix when either a helical or non-helical alpha turn (5, 13, 17, 18, 21-24) with Z = Dap was attached to the N-terminus. These structural models provide insights into stability for different turns and twists corresponding to non-regular folds in protein hotspots.
| S-EPMC7020788 | biostudies-literature
Project description: Not available
| S-EPMC3107275 | biostudies-literature
Project description: Not available
| S-EPMC7462407 | biostudies-literature
Project description:The networks of blood and lymphatic vessels and of the extracellular matrix and their cellular and structural components, that are collectively termed the tumor microenvironment, are frequently co-opted and shaped by cancer cells to survive, invade, and form distant metastasis. With an enviable capacity to adapt to continually changing environments, cancer represents the epitome of functional chaos, a stark contrast to the hierarchical and organized differentiation processes that dictate the development and life of biological organisms. The consequences of changing landscapes such as hypoxia and acidic extracellular pH in and around tumors create a cascade of changes in multiple pathways and networks that become apparent only several years later as recurrence and metastasis. These molecular and phenotypic changes, several of which are mediated by COX-2, approach the complexities of a "Gordian Knot." We review evidence from our studies and from literature suggesting that cyclooxygenase-2 (COX-2) biology presents a nodal point in cancer biology and an "Achilles heel" of COX-2-dependent tumors.
| S-EPMC3619664 | biostudies-literature
Project description:Hyperuricemia is defined as serum uric acid level of more than 7 mg/dL and blood levels of uric acid are causally associated with gout, as implicated by evidence from randomized clinical trials using urate lowering therapies. Uric acid as a cardiovascular risk factor often accompanies metabolic syndrome, hypertension, diabetes, dyslipidemia, chronic renal disease, and obesity. Despite the association of hyperuricemia with cardiovascular risk factors, it has remained controversial as to whether uric acid is an independent predictor of cardiovascular disease. To settle this issue, and in the absence of large randomized controlled trials, Mendelian randomization analysis in which the exposure is defined based on the presence or absence of a specific allele that influences a risk factor of interest have tried to shed light on this.
| S-EPMC5179380 | biostudies-literature
Project description:This study examines whether there are age-related differences in the experience of life events across adulthood. We hypothesized that older adults would report life events that are less anticipated, less normative, less controllable, less positive, and more strenuous than younger adults due to increasing developmental losses and decreasing gains. We investigated how age (linear, quadratic, and cubic) relates to life-event characteristics by comparing different events and analyzing the same events across individuals, to distinguish between the effects observed across life events and those that emerge after accounting for the specific life event in question. Additionally, we hypothesized that older adults would cope better with less favorable events due to their life experience and emotion regulation skills. Analyses of 6,688 participants (18-90 years) showed that while older adults reported less favorable life events, they coped better with the same events than younger adults. The results underscore the importance of distinguishing between age and life event effects. They also show that life-event characteristics are consistently linked to well-being throughout adulthood.
| S-EPMC11743415 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is the most frequent genetic disorder resulting in increased low-density lipoprotein cholesterol (LDL-C) levels from childhood, leading to premature atherosclerotic cardiovascular disease (ASCVD) if left untreated. FH diagnosis is based on clinical criteria and/or genetic testing and its prevalence is estimated as being up to 1:300,000−400,000 for the homozygous and ~1:200−300 for the heterozygous form. Apart from its late diagnosis, FH is also undertreated, despite the available lipid-lowering therapies. In addition, elevated lipoprotein(a) (Lp(a)) (>50 mg/dL; 120 nmol/L), mostly genetically determined, has been identified as an important cardiovascular risk factor with prevalence rate of ~20% in the general population. Novel Lp(a)-lowering therapies have been recently developed and their cardiovascular efficacy is currently investigated. Although a considerable proportion of FH patients is also diagnosed with high Lp(a) levels, there is a debate whether these two entities are associated. Nevertheless, Lp(a), particularly among patients with FH, has been established as a significant cardiovascular risk factor. In this narrative review, we present up-to-date evidence on the pathophysiology, diagnosis, and treatment of both FH and elevated Lp(a) with a special focus on their association and joint effect on ASCVD risk.
| S-EPMC9693181 | biostudies-literature
Project description:INTRODUCTION:Junior residents routinely prescribe medications for hospitalised patients with only arms-length supervision, which compromises patient safety. A cardinal example is insulin prescribing, which is commonplace, routinely delegated to very junior doctors, difficult, potentially very dangerous, and getting no better. Our aim was to operationalise the concept of 'readiness to prescribe' by validating an instrument to quality-improve residents' workplace prescribing education. METHODS:Guided by theories of behaviour change, implementation, and error, and by empirical evidence, we developed and refined a mixed-methods 24-item evaluation instrument, and analysed numerical responses from Foundation Trainees (junior residents) in Northern Ireland, UK using principal axis factoring, and conducted a framework analysis of participants' free-text responses. RESULTS:255 trainees participated, 54% women and 46% men, 80% of whom were in the second foundation year. The analysis converged on a 4-factor solution explaining 57% of the variance. Participants rated their capability to prescribe higher (79%) than their capability to learn to prescribe (69%; p<0.001) and rated the support to their prescribing education lower still (43%; p<0.001). The findings were similar in men and women, first and second year trainees, and in different hospitals. Free text responses described an unreflective type of learning from experience in which participants tended to 'get by' when faced with complex problems. DISCUSSION:Operationalising readiness to prescribe as a duality, comprising residents' capability and the fitness of their educational environments, demonstrated room for improvement in both. We offer the instrument to help clinical educators improve the two in tandem.
| S-EPMC6980548 | biostudies-literature
Project description:If any proof were needed of DNA's versatile roles and use, it is certainly provided by the numerous depositions of new three-dimensional (3D) structures to the coordinate databanks (PDB, NDB) over the last two years. Quadruplex motifs involving G-repeats, adducted sequences and oligo-2'-deoxynucleotides (ODNs) with bound ligands are particularly well represented. In addition, structures of chemically modified DNAs (CNAs) and artificial analogs are yielding insight into stability, pairing properties, and dynamics, including those of the native nucleic acids. Besides being of significance for establishing diagnostic tools and in the analysis of protein-DNA interactions, chemical modification in conjunction with investigations of the structural consequences may yield novel nucleic acid-based therapeutics. DNA's predictable and highly specific pairing behavior makes it the material of choice for constructing 3D-nanostructures of defined architecture. Recently the first examples of DNA nanoparticle and self-assembled 3D-crystals were reported. Although the structures discussed in this review are all based either on X-ray crystallography or solution NMR, small angle X-ray scattering (SAXS), and cryoEM are proving to be useful approaches for the characterization of nanoscale DNA architecture.
| S-EPMC2911523 | biostudies-literature
Project description:The complexity of cancer requires a comprehensive approach to understand its diverse manifestations and underlying mechanisms. Initially outlined by Hanahan and Weinberg in 2000 and updated in 2010, the hallmarks of cancer provide a conceptual basis for understanding inherent variability in cancer biology. Recent expansions have further elucidated additional hallmarks, including phenotypic plasticity and senescent cells. The International Agency for Research on Cancer (IARC) has identified the key characteristics of carcinogens (KCCs) to evaluate their carcinogenic potential. We analyzed chemicals of concern for environmental exposure that interact with specific receptors to induce genomic instability, epigenetic alterations, immune suppression, and receptor-mediated effects, thereby contributing to chronic inflammation. Despite their varying degrees of carcinogenicity, these chemicals have similar KCC profiles. Our analysis highlights the pivotal role of receptor binding in activating most other KCCs, underscoring their significance in cancer initiation. Although KCCs are associated with early molecular or cellular events, they do not encompass processes directly linked to full cellular malignancy. Thus, there is a need to integrate clear endpoints that anchor KCCs to the acquisition of a complete malignant phenotype into chemical testing. From the perspective of toxicology and cancer research, an all-encompassing strategy that incorporates both existing and novel KCCs and cancer hallmarks is essential to enable the targeted identification of prevalent carcinogens and facilitate zone-specific prevention strategies. To achieve this goal, collaboration between the KCC and cancer hallmarks communities becomes essential.
| S-EPMC11491790 | biostudies-literature