The refined 2.3 Å crystal structure of human leukocyte elastase in a complex with a valine chloromethyl ketone inhibitor

AbstractThe stoichiometric complex formed between human leukocyte elastase and a synthetic MeO-Suc-Ala-Ala-Pro-Val chloromethyl ketone inhibitor was co-crystallized and its X-ray structure determined, using Patterson search methods. Its structure has been crystallographically refined to a final R value of 0.145 (8.0 and 2.3 Å). The enzyme structure is very similar to that recently observed in a complex formed with the ovomucoid third domain from turkey [(1986) EMBO J. 5,2453–2458]. The rms deviation of all α-carbon atoms is 0.32 Å. The peptidic inhibitor is bound in a similar overall conformation as the ovomucoid binding segment. Covalent bonds are formed between Val-P1 of the inhibitor and His-57 NE2 and Ser-195 OG of the enzyme. The carbonyl carbon is tetrahedrally deformed to a hemiketal. The valine side chain is arranged in the S1 pocket in the g− conformation

The International Mountain Conference, Innsbruck, Austria, September 2019 (IMC2019): A Synthesis with Recommendations for Research

This paper presents a synthesis of the outcomes of sessions and recommendations for future research in mountain areas from the International Mountain Conference (IMC), held in Innsbruck, Austria, in September 2019. The thematic sections of the paper consider: first, the paleosciences, particularly archaeology; second, (bio)physical systems—the climate system, the cryo- and hydrosphere, and the biosphere—and their relationships with human systems; third, natural hazards and risks; and fourth, demographic and sociocultural trends, globalization (energy and transport networks, tourism, food supplies), policymaking, development, and research. Each section includes key literature relating to its theme, together with recommendations from the respective sessions. The paper concludes with a discussion and conclusions on the process of producing the synthesis, and its value for preparation and synthesis strategies for future conferences

Rising slopes-Bibliometrics of mountain research 1900-2019

Mountain areas provide essential resources for a significant proportion of the Earth's population. This study presents the development of mountain research between 1900 and 2019 based on peer-reviewed articles in English listed in Web of Science TM (WOS). We analyzed the number of publications over time, journals and scientific categories, frequent topics, and geographical distributions based on 40 mountain ranges and authors' countries as well as institutional contributions. From 1900-2019, 195k +/- 10% mountain research papers were published; over 50% from 2010-2019. While papers were published in more than 1000 different journals, indicating a wide range of disciplines engaged in mountain research, 94% of the papers were assigned to "Science & Technology", only <5% to "Social Sciences" and "Arts & Humanities". The most papers were written by researchers in the USA, followed by China. The number of papers per area or capita showed high variability across the investigated mountain ranges. Thus, geographically and disciplinarily more balanced research activities and better accessibility of knowledge about mountain regions are recommended

PUFA-induced metabolic enteritis as a fuel for Crohn's disease

BACKGROUND & AIMS: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human IBD remains elusive. Here, we aimed at delineating how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, impacts gut inflammation and disease course. We hypothesized that the unfolded protein response and anti-oxidative activity of Glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs. METHODS: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in two mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box-binding protein 1 (Xbp1) or Gpx4. We translated findings to human CD epithelial organoids and correlated PUFA intake, estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in two independent CD cohorts. RESULTS: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1-/-IEC and in Gpx4+/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor IRE1α by toll-like receptor 2 (TLR2) sensing of oxygen specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients. CONCLUSION: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy