Methodological assessment of 2b-RAD genotyping technique for population structure inferences in yellowfin tuna (Thunnus albacares).

Global population genetic structure of yellowfin tuna (Thunnus albacares) is still poorly understood despite its relevance for the tuna fishery industry. Low levels of genetic differentiation among oceans speak in favour of the existence of a single panmictic population worldwide of this highly migratory fish. However, recent studies indicated genetic structuring at a much smaller geographic scales than previously considered, pointing out that YFT population genetic structure has not been properly assessed so far. In this study, we demonstrated for the first time, the utility of 2b-RAD genotyping technique for investigating population genetic diversity and differentiation in high gene-flow species. Running de novo pipeline in Stacks, a total of 6772 high-quality genome-wide SNPs were identified across Atlantic, Indian and Pacific population samples representing all major distribution areas. Preliminary analyses showed shallow but significant population structure among oceans (FST=0.0273; P-value<0.01). Discriminant Analysis of Principal Components endorsed the presence of genetically discrete yellowfin tuna populations among three oceanic pools. Although such evidence needs to be corroborated by increasing sample size, these results showed the efficiency of this genotyping technique in assessing genetic divergence in a marine fish with high dispersal potential.

Crystal structures of PRK1 in complex with the clinical compounds lestaurtinib and tofacitinib reveal ligand induced conformational changes.

Protein kinase C related kinase 1 (PRK1) is a component of Rho-GTPase, androgen receptor, histone demethylase and histone deacetylase signaling pathways implicated in prostate and ovarian cancer. Herein we describe the crystal structure of PRK1 in apo form, and also in complex with a panel of literature inhibitors including the clinical candidates lestaurtinib and tofacitinib, as well as the staurosporine analog Ro-31-8220. PRK1 is a member of the AGC-kinase class, and as such exhibits the characteristic regulatory sequence at the C-terminus of the catalytic domain--the 'C-tail'. The C-tail fully encircles the catalytic domain placing a phenylalanine in the ATP-binding site. Our inhibitor structures include examples of molecules which both interact with, and displace the C-tail from the active site. This information may assist in the design of inhibitors targeting both PRK and other members of the AGC kinase family.

Aminopurine based JNK inhibitors for the prevention of ischemia reperfusion injury.

In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury.

Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor.

In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.

Accuracy of ultrasound-guided and palpation-guided knee injections by an experienced and less-experienced injector using a superolateral approach: a cadaveric study.

OBJECTIVES: To evaluate the accuracy of ultrasound (US)-guided and palpation-guided knee injections by an experienced and a less-experienced clinician with use of a superolateral approach. DESIGN: Single-blinded, prospective study. SETTING: Academic institution procedural skills laboratory. PARTICIPANTS: Twenty cadaveric knee specimens without trauma, surgery, or major deformity. INTERVENTION: US-guided and palpation-guided knee injections of colored liquid latex were performed in each specimen by an experienced and a less-experienced clinician with use of a superolateral approach. The order of injections was randomized. The specimens were subsequently dissected by a blinded investigator and assessed for accuracy. MAIN OUTCOMES: Accuracy was divided into 3 categories: (1) accurate (all of the injectate was within the joint), (2) partially accurate (some of the injectate was within the joint and some was within the periarticular tissues), and (3) inaccurate (none of the injectate was within the joint). The accuracy rates were calculated for each clinician and guidance method. RESULTS: US-guided knee injections that used a superolateral approach were 100% accurate for both clinicians. Palpation-guided knee injections that used a superolateral approach were significantly influenced by experience, with the less-experienced investigator demonstrating an accuracy rate of 55% (95% confidence interval = 34%-74%) and the more experienced investigator demonstrating an accuracy rate of 100% (95% confidence interval = 81%-100%). CONCLUSIONS: US-guided knee injections that use a superolateral approach are very accurate in a cadaveric model, whereas the accuracy of palpation-guided knee injections that use the same approach is variable and appears to be significantly influenced by clinician experience. These findings suggest that US guidance should be considered when one performs knee injections with a superolateral approach that require a high degree of accuracy.