On optimization of heterogeneous materials for enhanced resistance to bulk fracture

We propose a novel approach to optimize the design of heterogeneous materials, with the goal of enhancing their effective fracture toughness under mode-I loading. The method employs a Gaussian processes-based Bayesian optimization framework to determine the optimal shapes and locations of stiff elliptical inclusions within a periodic microstructure in two dimensions. To model crack propagation, the phase-field fracture method with an efficient interior-point monolithic solver and adaptive mesh refinement, is used. To account for the high sensitivity of fracture properties to initial crack location with respect to heterogeneities, we consider multiple cases of initial crack and optimize the material for the worst-case scenario. We also impose a minimum clearance constraint between the inclusions to ensure design feasibility. Numerical experiments demonstrate that the method significantly improves the fracture toughness of the material compared to the homogeneous case

Cj0683 Is a Competence Protein Essential for Efficient Initialization of DNA Uptake in Campylobacter jejuni

C. jejuni is an important food-borne pathogen displaying high genetic diversity, substantially based on natural transformation. The mechanism of DNA uptake from the environment depends on a type II secretion/type IV pilus system, whose components are partially known. Here, we quantified DNA uptake in C. jejuni at the single cell level and observed median transport capacities of approximately 30 kb per uptake location. The process appeared to be limited by the initialization of DNA uptake, was finite, and, finalized within 30 min of contact to DNA. Mutants lacking either the outer membrane pore PilQ or the inner membrane channel ComEC were deficient in natural transformation. The periplasmic DNA binding protein ComE was negligible for DNA uptake, which is in contrast to its proposed function. Intriguingly, a mutant lacking the unique periplasmic protein Cj0683 displayed rare but fully functional DNA uptake events. We conclude that Cj0683 was essential for the efficient initialization of DNA uptake, consistent with the putative function as a competence pilus protein. Unravelling features important in natural transformation might lead to target identification, reducing the adaptive potential of pathogens

Educating the Next Generation of Pharmacogenomics Experts: Global Educational Needs and Concepts

Personalised Therapeutic

Curcumin Mitigates Immune-Induced Epithelial Barrier Dysfunction by Campylobacter jejuni

Campylobacter jejuni (C. jejuni) is the most common cause of foodborne gastroenteritis worldwide. The bacteria induce diarrhea and inflammation by invading the intestinal epithelium. Curcumin is a natural polyphenol from turmeric rhizome of Curcuma longa, a medical plant, and is commonly used in curry powder. The aim of this study was the investigation of the protective effects of curcumin against immune-induced epithelial barrier dysfunction in C. jejuni infection. The indirect C. jejuni-induced barrier defects and its protection by curcumin were analyzed in co-cultures with HT-29/B6-GR/MR epithelial cells together with differentiated THP-1 immune cells. Electrophysiological measurements revealed a reduction in transepithelial electrical resistance (TER) in infected co-cultures. An increase in fluorescein (332 Da) permeability in co-cultures as well as in the germ-free IL-10-/- mouse model after C. jejuni infection was shown. Curcumin treatment attenuated the C. jejuni-induced increase in fluorescein permeability in both models. Moreover, apoptosis induction, tight junction redistribution, and an increased inflammatory response-represented by TNF-α, IL-1β, and IL-6 secretion-was observed in co-cultures after infection and reversed by curcumin. In conclusion, curcumin protects against indirect C. jejuni-triggered immune-induced barrier defects and might be a therapeutic and protective agent in patients

Individualized versus Standardized Risk Assessment in Patients at High Risk for Adverse Drug Reactions (The IDrug Randomized Controlled Trial)–Never Change a Running System?

The aim of this study was to compare effects of an individualized with a standardized risk assessment for adverse drug reactions to improve drug treatment with antithrombotic drugs in older adults. A randomized controlled trial was conducted in general practitioner (GP) offices. Patients aged 60 years and older, multi-morbid, taking antithrombotic drugs and at least one additional drug continuously were randomized to individualized and standardized risk assessment groups. Patients were followed up for nine months. A composite endpoint defined as at least one bleeding, thromboembolic event or death reported via a trigger list was used. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. In total, N = 340 patients were enrolled from 43 GP offices. Patients in the individualized risk assessment group met the composite endpoint more often than in the standardized group (OR 1.63 [95%CI 1.02–2.63]) with multiple adjustments. The OR was higher in patients on phenprocoumon treatment (OR 1.99 [95%CI 1.05–3.76]), and not significant on DOAC treatment (OR 1.52 [95%CI 0.63–3.69]). Pharmacogenenetic variants of CYP2C9, 2C19 and VKORC1 were not observed to be associated with the composite endpoint. The results of this study may indicate that the time point for implementing individualized risk assessments is of importance

The FKBP5 polymorphism rs1360780 influences the effect of an algorithm-based antidepressant treatment and is associated with remission in patients with major depression

Objective: The FKBP5-gene influences the HPA-system by modulating the sensitivity of the glucocorticoid receptor (GR). The polymorphism rs1360780 has been associated with response in studies with heterogeneous antidepressant treatment. In contrast, several antidepressant studies with standardized antidepressant treatment could not detect this effect. We therefore compared patients with standardized vs naturalistic antidepressant treatment to (a) investigate a possible interaction between FKBP5-genotype and treatment mode and (b) replicate the effect of the FKBP5-genotype on antidepressant treatment outcome. Methods: A total of 298 major depressive disorder (MDD) inpatients from the multicentred German project and the Zurich Algorithm Project were genotyped for their FKBP5 status. Patients were treated as usual (n=127) or according to a standardized algorithm (n=171). Main outcome criteria was remission (Hamilton Depression Rating Scale-21<10). Results: We detected an interaction of treatment as usual (TAU) treatment and C-allele with the worst outcome for patients combining those two factors (HR=0.46;p=0.000). Even though C-allele patients did better when treated in the structured, stepwise treatment algorithm (SSTR) group, we still could confirm the influence of the FKBP5-genotype in the whole sample (HR=0.52;p=0.01). Conclusions: This is the first study to show an interaction between a genetic polymorphism and treatment mode. Patients with the C-allele of the rs1360780 polymorphism seem to benefit from a standardized antidepressant treatment

Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update

CYP2D6 and CYP2C19 polymorphisms affect the exposure, efficacy and safety of tricyclic antidepressants (TCAs), with some drugs being affected by CYP2D6 only (e.g., nortriptyline and desipramine) and others by both polymorphic enzymes (e.g., amitriptyline, clomipramine, doxepin, imipramine, and trimipramine). Evidence is presented for CYP2D6 and CYP2C19 genotype-directed dosing of TCAs. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. CYP2D6 and CYP2C19 polymorphisms can influence the metabolism of SSRIs, thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide dosing recommendations for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotype (updates at www.pharmgkb.org)

Variation in the plasma membrane monoamine transporter (PMAT) (encoded by SLC29A4) and organic cation transporter 1 (OCT1) (encoded by SLC22A1) and gastrointestinal intolerance to metformin in type 2 diabetes:An IMI direct study

OBJECTIVE Gastrointestinal adverse effects occur in 20–30% of patients with metformin-treated type 2 diabetes, leading to premature discontinuation in 5–10% of the cases. Gastrointestinal intolerance may reflect localized high concentrations of metformin in the gut. We hypothesized that reduced transport of metformin via the plasma membrane monoamine transporter (PMAT) and organic cation transporter 1 (OCT1) could increase the risk of severe gastrointestinal adverse effects. RESEARCH DESIGN AND METHODS The study included 286 severe metformin-intolerant and 1,128 metformin-tolerant individuals from the IMI DIRECT (Innovative Medicines Initiative: DIabetes REsearCh on patient straTification) consortium. We assessed the association of patient characteristics, concomitant medication, and the burden of mutations in the SLC29A4 and SLC22A1 genes on odds of intolerance. RESULTS Women (P < 0.001) and older people (P < 0.001) were more likely to develop metformin intolerance. Concomitant use of transporter-inhibiting drugs increased the odds of intolerance (odds ratio [OR] 1.72, P < 0.001). In an adjusted logistic regression model, the G allele at rs3889348 (SLC29A4) was associated with gastrointestinal intolerance (OR 1.34, P = 0.005). rs3889348 is the top cis-expression quantitative trait locus for SLC29A4 in gut tissue where carriers of the G allele had reduced expression. Homozygous carriers of the G allele treated with transporter-inhibiting drugs had more than three times higher odds of intolerance compared with carriers of no G allele and not treated with inhibiting drugs (OR 3.23, P < 0.001). Use of a genetic risk score derived from rs3889348 and SLC22A1 variants found that the odds of intolerance were more than twice as high in individuals who carry three or more risk alleles compared with those carrying none (OR 2.15, P = 0.01). CONCLUSIONS These results suggest that intestinal metformin transporters and concomitant medications play an important role in the gastrointestinal adverse effects of metformin

Transformative Materials to Create 3D Functional Human Tissue Models In Vitro in a Reproducible Manner

Recreating human tissues and organs in the petri dish to establish models as tools in biomedical sciences has gained momentum. These models can provide insight into mechanisms of human physiology, disease onset, and progression, and improve drug target validation, as well as the development of new medical therapeutics. Transformative materials play an important role in this evolution, as they can be programmed to direct cell behavior and fate by controlling the activity of bioactive molecules and material properties. Using nature as an inspiration, scientists are creating materials that incorporate specific biological processes observed during human organogenesis and tissue regeneration. This article presents the reader with state-of-the-art developments in the field of in vitro tissue engineering and the challenges related to the design, production, and translation of these transformative materials. Advances regarding (stem) cell sources, expansion, and differentiation, and how novel responsive materials, automated and large-scale fabrication processes, culture conditions, in situ monitoring systems, and computer simulations are required to create functional human tissue models that are relevant and efficient for drug discovery, are described. This paper illustrates how these different technologies need to converge to generate in vitro life-like human tissue models that provide a platform to answer health-based scientific questions.</p