UHSP Collections (University of Health Sciences and Pharmacy)
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Genetic Code Evolution Investigated through the Synthesis and Characterisation of Proteins from Reduced-Alphabet Libraries
No full textThe universal genetic code of 20 amino acids is the product of evolution. It is believed that earlier versions of the code had fewer residues. Many theories for the order in which amino acids were integrated into the code have been proposed, considering factors ranging from prebiotic chemistry to codon capture. Several meta-analyses combined these theories to yield a feasible consensus chronology of the genetic code\u27s evolution, but there is a dearth of experimental data to test the hypothesised order. We used combinatorial chemistry to synthesise libraries of random polypeptides that were based on different subsets of the 20 standard amino acids, thus representing different stages of a plausible history of the alphabet. Four libraries were comprised of the five, nine, and 16 most ancient amino acids, and all 20 extant residues for a direct side-by-side comparison. We characterised numerous variants from each library for their solubility and propensity to form secondary, tertiary or quaternary structures. Proteins from the two most ancient libraries were more likely to be soluble than those from the extant library. Several individual protein variants exhibited inducible protein folding and other traits typical of intrinsically disordered proteins. From these libraries, we can infer how primordial protein structure and function might have evolved with the genetic code
Plasma irisin is increased following 12 weeks of Nordic walking and associates with glucose homoeostasis in overweight/obese men with impaired glucose regulation
No full textIrisin is a myokine that is thought to be secreted in response to exercise that may help to prevent obesity and maintain normal glucose metabolism. In this study we investigated the associations between irisin and glucose homeostasis in middle-aged, overweight and obese men (n = 144) with impaired glucose regulation, and the impact of exercise training on these relationships. The participants underwent 12 weeks of resistance or aerobic (Nordic walking) exercise training three times per week, 60 minutes per session. Venous blood (n = 105) and skeletal muscle samples (n = 45) were obtained at baseline and post-intervention. Compared to controls, Nordic walking, but not resistance training, increased irisin levels in plasma (9.6 ± 4.2%, P= 0.014; 8.7 ± 4.9%, P= 0.087; respectively) compared to controls. When considering all subjects, baseline irisin correlated positively with atherogenic index of plasma (r= 0.244, P= 0.013) and 2-hour insulin levels (r = 0.214, P= 0.028), and negatively with age (r = −0.262, P= 0.007), adiponectin (r = −0.240, P= 0.014) and McAuley index (r = −0.259, P= 0.008). Training-induced FNDC5 mRNA changes were negatively correlated with HbA1c (r= −0.527, P= 0.030) in the resistance training group and with chemerin in the Nordic walking group (r = −0.615, P = 0.033). In conclusion, 12-weeks of Nordic walking was more effective than resistance training in elevating plasma irisin, in middle-aged men with impaired glucose tolerance. Thus, the change in irisin in response to exercise training varied by the type of exercise but showed limited association with improvements in glucose homeostasis
Pharmacokinetic Models for Active Learning of Differential Equations
No full textWe present adaptable activities for models of drug movement in the human body–pharmacokinetics–that motivate the learning of ordinary differential equations with an interdisciplinary topic. Specifically, we model aspirin, caffeine, and digoxin. We discuss the pedagogy of guiding students to understand, develop, and analyze models, progressing in complexity to a system of differential equations. We investigate the effects of parameter values that distinguish various health levels, and dosing that may have toxic effects. Our assignments include modeling in a student-centered, active, and increasingly inquiry-oriented setting through which the mathematics and biology inform and reinforce each other. We include supplemental information regarding inquiry methods, student learning outcomes, a student’s commentary about our activities, and support through mathematical communities such as POGIL and SIMIODE
Doctors as moral pioneers: Negotiated boundaries of assisted conception in Colombia
No full textNew biotechnologies such as assisted conception are socially embedded artefacts that raise context-specific ethical, moral and social anxieties. In contexts where the regulations of these profitable developments are limited or ambiguous, and competition between private facilities is high, individual doctors become morally and socially responsible for determining the parameters of administering such therapies. Ethnographic research at two private fertility centres in Colombia reveals that doctors do not determine boundaries based on monetary gain but rather personal morals, social norms and professional obligations. Medical professionals hold diverse perceptions of assisted conception, and often struggle to make decisions regarding who should access such therapies, who are ideal gamete donors and the fate of extra embryos. The complexity of these perceptions applied in a context of limited regulation and the competition of private medicine impacts the praxis of assisted conception. As doctors determine the boundaries of their practice they not only create variation between clinical practices, but also make moral decisions regarding who should be parents, how families should be formed and the significance of embryos. Thus, in navigating their everyday practices, doctors also shape the social world
Development of novel liver X receptor modulators based on a 1,2,4-triazole scaffold
No full textLiver X Receptor (LXR) agonists have been reported as a potential treatment for atherosclerosis, Alzheimer\u27s disease and hepatitis C virus (HCV) infection. We have designed and synthesized a series of potent compounds based on a 1,2,4-triazole scaffold as novel LXR modulators. In cell-based cotransfection assays these compounds generally functioned as LXR agonists and we observed compounds with selectivity towards LXRα (7-fold) and LXRβ (7-fold) in terms of potency. Assessment of the effects of selected compounds on LXR target gene expression in HepG2 cells revealed that compounds 6a-b and 8a-b behaved as inverse agonists on FASN expression even though they were agonists in the LXRα and LXRβ cotransfection assays. Interestingly, these compounds had no effect on the expression of SREBP-1c confirming a unique LXR modulator pharmacology. Molecular docking studies and evaluation of ADME properties in-silico show that active compounds possess favorable binding modes and ADME profiles. Thus, these compounds may be useful for in vivo characterization of LXR modulators with unique profiles and determination of their potential clinical utility
Doubled lifespan and patient-like pathologies in progeria mice fed high-fat diet
No full textHutchinson-Gilford Progeria Syndrome (HGPS) is a devastating premature aging disease. Mouse models have been instrumental for understanding HGPS mechanisms and for testing therapies, which to date have had only marginal benefits in mice and patients. Barriers to developing effective therapies include the unknown etiology of progeria mice early death, seemingly unrelated to the reported atherosclerosis contributing to HGPS patient mortality, and mice not recapitulating the severity of human disease. Here, we show that progeria mice die from starvation and cachexia. Switching progeria mice approaching death from regular diet to high-fat diet (HFD) rescues early lethality and ameliorates morbidity. Critically, feeding the mice only HFD delays aging and nearly doubles lifespan, which is the greatest lifespan extension recorded in progeria mice. The extended lifespan allows for progeria mice to develop degenerative aging pathologies of a severity that emulates the human disease. We propose that starvation and cachexia greatly influence progeria phenotypes and that nutritional/nutraceutical strategies might help modulate disease progression. Importantly, progeria mice on HFD provide a more clinically relevant animal model to study mechanisms of HGPS pathology and to test therapies
Health informatics competencies for pharmacists in training
No full textObjective. To gather feedback from focus groups regarding health informatics competencies that should be taught in a Doctor of Pharmacy (PharmD) curricula and to revise the competencies based on this feedback. Methods. The pharmacy informatics task force of the American Association of Colleges of Pharmacy (AACP) used 11 sources to create a list of pharmacy informatics competencies. Subsequently, faculty feedback about the competency list was obtained via two synchronous online focus groups in August 2015. The list was then revised based on the feedback. Results. Eight people (a department chair, six faculty members and a graduate student) participated in the focus groups (six were from private and two were from public institutions). Participants felt the list had too many competencies to be covered in a timely manner and some indicated that basic computer and Internet competencies should be considered pre-requisites. Participants also recommended that competencies be split by proposed curricular placement (eg, prerequisite, required, elective, didactic, experiential) for each objective. The competency list was revised in response to focus group feedback. Conclusion. The proposed curriculum aligns with the new Accreditation Council for Pharmacy Education (ACPE) standards requiring that professional pharmacy curricula cover multiple aspects of health informatics. The proposed competencies list can serve as a reference to assist in the development of the curriculum and ensure compliance with the new standards
Comparison of Adverse Drug Reactions between Patients Treated with Ceftaroline or Ceftriaxone: A Single-Center, Matched Cohort Study
No full textLittle information is available on the relative tolerability of ceftaroline versus other cephalosporins in clinical practice. We sought to compare adverse drug reactions (ADRs) associated with ceftaroline with those associated with ceftriaxone in hospitalized patients. Materials and Methods: This was a retrospective, single-center matched cohort (according to age, indication, and duration) study of patients treated with ceftaroline or ceftriaxone at the VA St Louis Health Care System between 29 October 2010 and 28 March 2017, to compare rates of ADRs between the agents. Patients included received ≥2 doses of either medication to treat osteomyelitis, acute bacterial skin and skin structure infection, blood stream infection, pneumonia, infective endocarditis, septic arthritis, prosthetic joint infection, or empyema. The primary and secondary outcomes were the composite of any ADR during therapy and any ADR leading to premature discontinuation of therapy. The ADRs evaluated included rash, neutropenia, acute kidney injury, eosinophilia, thrombocytopenia, transaminitis, and hyperbilirubinemia. Results: After matching, 50 patients per group were included and analyzed. An ADR occurred in 20% (10 of 50) of patients treated with ceftriaxone and 16% (8 of 50) of those treated with ceftaroline (P =. 60). Two percent (1 of 50) of those treated with ceftriaxone and 16% (8 of 50) treated with ceftaroline had therapy discontinued owing to an ADR (P =. 03). The most common ADR was eosinophilia (3 of 50) in the ceftriaxone group and rash (5 of 50) in the ceftaroline group. Ceftaroline therapy was identified as an independent risk factor for an ADR requiring premature discontinuation (odds ratio, 10.2; 95% confidence interval, 1.19-87.8; P =. 03). Conclusions: Although there was no difference in the rates of ADRs between patients in the ceftriaxone and ceftaroline groups, significantly more ceftaroline-treated patients required premature discontinuation
Migraine overview and summary of current and emerging treatment options
No full textMigraine is a leading cause of disability worldwide. Approximately 15% of Americans experience migraines. Most people who have migraines feel that people who do not have them often underestimate their condition. Migraines affect people\u27s quality of life and ability to participate in work, family, and social events. A new class of medication, calcitonin gene-related peptide (CGRP) antagonists, has been approved for migraine prevention in adults. The newly approved CGRP antagonists are erenumab, fremanezumab, and galcanezumab, while eptinezumab looks to 2020 for approval. Lasmiditan, ubrogepant, and rimegepant are currently emerging acute migraine therapies that may be added to the arsenal of current migraine management