Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genome-wide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate (ADP) induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (p-value=1.67e-33). After correction for CYP2C19*2 no other SNP reached genome-wide significance. GWAS for a combined clinical endpoint of cardiovascular death, myocardial infarction, or stroke (5.0% event rate) or a combined endpoint of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA and CTRAC1 showed genome-wide significance (lowest p-values 1.07e-09, 4.53e-08 and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.Previously, our lab developed high molecular weight (MW) tense (T) quaternary state glutaraldehyde polymerized bovine hemoglobins (PolybHbs) that exhibited reduced vasoactivity in several small animal models. In this study, we prepared PolybHb in the T and relaxed (R) quaternary state with ultrahigh MW (>500 kDa) with varying cross-link densities, and investigated the effect of MW on key biophysical properties (i.e., O2 affinity, cooperativity (Hill) coefficient, hydrodynamic diameter, polydispersity, polymer composition, viscosity, gaseous ligand-binding kinetics, auto-oxidation, and haptoglobin [Hp]-binding kinetics). To further optimize current PolybHb synthesis and purification protocols, we performed a comprehensive meta-data analysis to evaluate correlations between procedural parameters (i.e., cross-linkerbovine hemoglobin (bHb) molar ratio, gas-liquid exchange time, temperature during sodium dithionite addition, and number of diafiltration cycles) and the biophysical properties of both T- and R-state PolybHbs. Our results showed that, the duration of the fast-step auto-oxidation phase of R-state PolybHb increased with decreasing glutaraldehydebHb molar ratio. Additionally, T-state PolybHbs exhibited significantly higher bimolecular rate constants for binding to Hp and unimolecular O2 offloading rate constants compared to R-state PolybHbs. The methemoglobin (metHb) level in the final product was insensitive to the molar ratio of glutaraldehyde to bHb for all PolybHbs. During tangential flow filtration processing of the final product, 14 diafiltration cycles was found to yield the lowest metHb level.Human adenoviruses (HAdVs) cause widespread acute and persistent infections. Infections are usually mild and controlled by humoral and cell-based immunity. Reactivation of persistently infected immune cells can lead to a life-threatening disease in immunocompromised individuals, especially children and transplant recipients. To date, no effective therapy or vaccine against HAdV disease is available to the public. HAdV-C2 and C5 are the best-studied of more than 100 HAdV types. They persist in infected cells and release their progeny by host cell lysis to neighbouring cells and fluids, a process facilitated by the adenovirus death protein (ADP). ADP consists of about 100 amino acids and harbours a single membrane-spanning domain. It undergoes post-translational processing in endoplasmic reticulum and Golgi compartments, before localizing to the inner nuclear membrane. Here, we discuss the current knowledge on how ADP induces membrane rupture. Membrane rupture is essential for both progression of disease and efficacy of therapeutic viruses in clinical applications, in particular oncolytic therapy.Background and purpose There is an urgent but unmet need for mitigating radiation-induced intestinal toxicity while radio sensitising tumours for abdominal radiotherapy. We aimed to investigate the effects of metformin on radiation-induced intestinal toxicity and radiosensitivity of colorectal tumours. Experimental approach Acute and chronic histological injuries of the intestine from mice were used to assess radioprotection, and IEC-6 cell line was used to investigate the mechanisms in vitro. The fractionated abdominal radiation model of HCT116 and HT29 tumour grafts was used to determine the effects on colorectal cancer. Key results Metformin alleviated radiation-induced acute and chronic intestinal toxicity by optimising mitophagy which was AMPK-dependent. In addition, our data indicated that metformin increased the radiosensitivity of colorectal tumours with P53 mutation both in vitro and in vivo. Conclusion and implications Metformin may be a radiotherapy adjuvant agent for colorectal cancers especially those carrying P53 mutation. EPZ011989 Our findings provide a new strategy for further precise clinical trials for metformin on radiotherapy.This article comments on Tsogtbaatar E, Cocuron J-C, Alonso AP. 2020. Non-conventional pathways enable pennycress (Thlaspi arvense L.) embryos to achieve high biosynthetic efficiency. Journal of Experimental Botany 71, 3037–3051.Objective Chronic inflammatory back pain (IBP) is frequently reported in axial SpA (axSpA) but also in the general population. We evaluated a recently proposed two-step referral system for early recognition of axSpA in primary care and compare it with other combinations of symptoms and SpA-related items. Methods Consecutive chronic back pain patients ≤45 years of age answered a questionnaire and were seen by a primary care physician who decided whether HLA-B27 needed to be determined. They were then referred to a rheumatologist who made the diagnosis. Generally sticking to the two-step system with HLA-B27 as an additional option, combinations with a sensitivity ≥90% and a likelihood ratio >4 were compared. Results A total of 326 patients were included, 46 of whom were diagnosed with axSpA (14.1%). The sensitivity of the strategy was 87%, the specificity was 56.8% and the positive and negative predictive values were 24.8% and 96.4%, respectively. A 'good response to NSAIDs', 'morning stiffness >30 min' and 'elevated C-reactive protein' performed best, with a sensitivity of 91%, specificity of 67%, positive predictive value of 31% and negative predictive value of 98%.