Molecular Targets for 17α-Ethynyl-5-Androstene-3β,7β,17β-Triol, an Anti-Inflammatory Agent Derived from the Human Metabolome

HE3286, 17α-ethynyl-5-androstene-3β, 7β, 17β-triol, is a novel synthetic compound related to the endogenous sterol 5-androstene-3β, 7β, 17β-triol (β-AET), a metabolite of the abundant adrenal steroid dehydroepiandrosterone (DHEA). HE3286 has shown efficacy in clinical studies in impaired glucose tolerance and type 2 diabetes, and in vivo models of types 1 and 2 diabetes, autoimmunity, and inflammation. Proteomic analysis of solid-phase HE3286-bound bead affinity experiments, using extracts from RAW 264.7 mouse macrophage cells, identified 26 binding partners. Network analysis revealed associations of these HE3286 target proteins with nodes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for type 2 diabetes, insulin, adipokine, and adipocyte signaling. Binding partners included low density lipoprotein receptor-related protein (Lrp1), an endocytic receptor; mitogen activated protein kinases 1 and 3 (Mapk1, Mapk3), protein kinases involved in inflammation signaling pathways; ribosomal protein S6 kinase alpha-3 (Rsp6ka3), an intracellular regulatory protein; sirtuin-2 (Sirt2); and 17β-hydroxysteroid dehydrogenase 1 (Hsd17β4), a sterol metabolizing enzyme

Gene Expression Analysis in the Thalamus and Cerebrum of Horses Experimentally Infected with West Nile Virus

Gene expression associated with West Nile virus (WNV) infection was profiled in the central nervous system of horses. Pyrosequencing and library annotation was performed on pooled RNA from the CNS and lymphoid tissues on horses experimentally infected with WNV (vaccinated and naïve) and non-exposed controls. These sequences were used to create a custom microarray enriched for neurological and immunological sequences to quantitate gene expression in the thalamus and cerebrum of three experimentally infected groups of horses (naïve/WNV exposed, vaccinated/WNV exposed, and normal)

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action

Carnivore Translocations and Conservation: Insights from Population Models and Field Data for Fishers (Martes pennanti)

Translocations are frequently used to restore extirpated carnivore populations. Understanding the factors that influence translocation success is important because carnivore translocations can be time consuming, expensive, and controversial. Using population viability software, we modeled reintroductions of the fisher, a candidate for endangered or threatened status in the Pacific states of the US. Our model predicts that the most important factor influencing successful re-establishment of a fisher population is the number of adult females reintroduced (provided some males are also released). Data from 38 translocations of fishers in North America, including 30 reintroductions, 5 augmentations and 3 introductions, show that the number of females released was, indeed, a good predictor of success but that the number of males released, geographic region and proximity of the source population to the release site were also important predictors. The contradiction between model and data regarding males may relate to the assumption in the model that all males are equally good breeders. We hypothesize that many males may need to be released to insure a sufficient number of good breeders are included, probably large males. Seventy-seven percent of reintroductions with known outcomes (success or failure) succeeded; all 5 augmentations succeeded; but none of the 3 introductions succeeded. Reintroductions were instrumental in reestablishing fisher populations within their historical range and expanding the range from its most-contracted state (43% of the historical range) to its current state (68% of the historical range). To increase the likelihood of translocation success, we recommend that managers: 1) release as many fishers as possible, 2) release more females than males (55–60% females) when possible, 3) release as many adults as possible, especially large males, 4) release fishers from a nearby source population, 5) conduct a formal feasibility assessment, and 6) develop a comprehensive implementation plan that includes an active monitoring program

Evaluation of the professional worth of scientific papers, their citation responding and the publication authority

Ve většině případů má paradigma "zveřejnit nebo zlikvidovat" nevyhnutelné důsledky pro kvalitu publikovaného výzkumu, protože vědecké výsledky jsou hodnoceny kvantitativně a nikoliv kvalitou. Tlak na vícenásobné publikování má za následek vytvoření takzvaných žurnálů predátorů, které působí bez požadovaného navrácení vrstevníků. Kromě toho citační záznamy dokumentů neodrážejí řádnou vědeckou kvalitu, která zvyšuje pouhé množství. Růst sofistikovaných "push-and-button" zařízení umožňuje snadnější přípravu publikací a usnadňuje data připravená k publikování. Články lze tedy sestavit pouhým kombinováním různých měření, obvykle bez představy o čem to všechno je a za jakým účelem to může sloužit. Navíc jakákoli hluboce zakořeněná teorie, která je v rozporu s běžnými popravami, není vítána, protože přerůstá beznadějnou často dlouhou praxi. Zatímco počet publikací je jednoznačně kvantitativním kritériem, hodně naděje bylo kladeno na citaci, která slíbila, že bude sloužit jako přiměřené měřítko skutečné vědecké hodnoty, tj. Kvality vědecké práce. Faktor dopadu souvisí s právem van't Hoffova koeficientu aktivity. Zejména je zkoumán případ ruské publikační politiky a politiky JTAC. JTAC je osvícen tím, že poskytuje základnu pro nové oblasti vědy o tepelných materiálech, které by měly být uznány jako dosud chybějící dopad.For the most part, the “publish or perish” paradigm has inevitable implications on the quality of research published because the scientific results are evaluated by quantity and not by quality. The pressure for multiple publication results in creation of so-called predators journals acting without the required peer reviving. Moreover, the citation records of papers do not reflect duly their scientific quality enhancing mere quantity. The growth of sophisticated “push-andbutton” apparatuses allows easier preparation of publications while facilitating ready-to-publish data. Articles can thus be compiled by mere combination of different measurements usually without idea what it all is about and to what purpose this may serve. Moreover, any deep-rooted theory which is contravening mainstream executions is not welcome because is breaking the effortless often long-established practice. While the number of publications is clearly a quantitative criterion, much hopes has been placed on citation, which promised to serve well as an adequate measure of the genuine scientific value, i.e., of quality of the scientific work. The impact factor is related to the van’t Hoff law of activity coefficient. The case of Russian publication policy and that of JTAC are particularly examined. JTAC is enlightened by providing basis for new fields of thermal material science which should be recognized as a yet missing impact

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action