The α(1,3)fucosyltransferases FucT-IV and FucT-VII Exert Collaborative Control over Selectin-Dependent Leukocyte Recruitment and Lymphocyte Homing

AbstractE-, P-, and L-selectin counterreceptor activities, leukocyte trafficking, and lymphocyte homing are controlled prominently but incompletely by α(1,3)fucosyltransferase FucT-VII-dependent fucosylation. Molecular determinants for FucT-VII-independent leukocyte trafficking are not defined, and evidence for contributions by or requirements for other FucTs in leukocyte recruitment is contradictory and incomplete. We show here that inflammation-dependent leukocyte recruitment retained in FucT-VII deficiency is extinguished in FucT-IV−/−/FucT-VII−/− mice. Double deficiency yields an extreme leukocytosis characterized by decreased neutrophil turnover and increased neutrophil production. FucT-IV also contributes to HEV-born L-selectin ligands, since lymphocyte homing retained in FucT-VII−/− mice is revoked in FucT-IV−/−/FucT-VII−/− mice. These observations reveal essential FucT-IV-dependent contributions to E-, P-, and L-selectin ligand synthesis and to the control of leukocyte recruitment and lymphocyte homing

A Phase I, Randomized, Double‐Blind, Placebo‐Controlled, Single‐Dose and Multiple‐Rising‐Dose Study of the BTK Inhibitor TAK‐020 in Healthy Subjects

Bruton’s tyrosine kinase (BTK) is a target for treatment of hematologic malignancies and autoimmune diseases. TAK‐020 is a highly selective covalent BTK inhibitor that inhibits both B cell receptor and fragment crystallizable receptor signaling. We assessed the safety/tolerability and pharmacokinetics/pharmacodynamics (PDs) of TAK‐020 in healthy subjects. Each cohort of the single‐rising dose (n = 72; 9 cohorts) and the multiple‐rising dose (n = 48; 6 cohorts) portions of the study comprised six TAK‐020‐treated and two placebo‐treated, subjects aged 18–55 years (inclusive). The PD effects were assessed by measuring BTK occupancy and the inhibition of fragment crystallizable epsilon receptor 1 (FcεRI)‐mediated activation of basophils. Overall, treatment‐emergent adverse events (TEAEs) were similar to placebo; there were no serious TEAEs or no TEAEs leading to discontinuation. TAK‐020 was rapidly absorbed (median time to maximum plasma concentration (Tmax) 45–60 minutes) with a half‐life of ~ 3–9 hours at doses ≥ 2.5 mg. TAK‐020 exposure was generally dose proportional for single doses ≤ 70 mg and after multiple doses of ≤ 60 mg once daily. Target occupancy was dose dependent, with doses ≥ 2.5 mg yielding maximum and sustained occupancy > 70% for > 96 hours. Single doses ≥ 4.4 mg reduced FcεRI‐mediated activation of basophils by > 80% and comparable inhibition was observed with daily dosing ≥3.75 mg for 9 days. Inhibition persisted for 24–72 hours postdose and the duration generally increased with dose. TAK‐020 was generally well‐tolerated in healthy subjects after single and multiple doses and demonstrated target engagement and pathway modulation. The PD effects outlasted drug exposures, as expected for covalent inhibition of BTK

Problems of operation of electric pumping sectional type units on kimberlite mines of ALROSA and the ways of their solution

Актуальность. Российская Федерация является одним из мировых лидеров по добыче алмазов. В настоящее время преобладающая часть (порядка 95 %) всех российских алмазов добывается на рудных (кимберлитовых) и россыпных месторождениях, расположенных на территории Якутии. Практика показывает, что подземная разработка кимберлитовых месторождений на территории Западной Якутии сопряжена с обильным поступлением шахтной воды в горные выработки. Без применения достаточного количества насосного оборудования проникающие в горные выработки шахтные воды делают процесс добычи алмазосодержащих руд более сложным и в первую очередь небезопасным для рабочего персонала. В настоящее время с целью борьбы с шахтными водопритоками на кимберлитовых рудниках используются электронасосные агрегаты секционного типа. Так как шахтный водоотлив является неотъемлемым технологическим процессом при добыче алмазосодержащего сырья, повышение надежности относящегося к нему оборудования является актуальной научно-практической задачей. Объекты: электронасосные агрегаты секционного типа кимберлитовых рудников «Мир», «Удачный», «Интернациональный» и «Айхал». Цель: изучение влияния различных производственных факторов, главным образом гидрогеологических условий, на показатели долговечности насосного оборудования водоотливных хозяйств кимберлитовых рудников АК «АЛРОСА». Методы. Для достижения поставленной цели использовался комплексный подход, включающий: анализ физико-химического состава шахтных вод, анализ значительного практического материала по работе насосного оборудования, а также ранее опубликованных работ по тематике исследования, натурные исследования электронасосных агрегатов секционного типа кимберлитовых рудников АК «АЛРОСА». Результаты. По результатам проведенных научных исследований были предложены рекомендации по повышению надежности насосного оборудования водоотливных установок кимберлитовых рудников, находящихся в ведении компании «АЛРОСА».The relevance. Russian Federation is one of the world's leaders in diamond industry. Today, the predominant part (about 95 %) of all Russian diamonds is mined on ore (kimberlite) and alluvial deposits, which are located on the territory of Yakutia. Practice shows that underground mining of kimberlite fields in Western Yakutia is associated with the abundant water flow to mine workings. Without application of sufficient number of pumping equipment, water penetrating to mine workings makes diamond extraction more difficult and un+ safe for people. Today, for dealing with mine water inflows the electric pump sectional type unit are used on kimberlite mines. As mine drainage is an essential process in diamond extraction, improving the reliability of the related equipment is the relavant scientific and practical task. Objects: electric pumping sectional type units of kimberlite mines «Mir», «Udachny», «Internatsionalny» and «Aykhal». The main aim of the research is to study the influence of different production factors, mainly hydrogeological conditions, on durability of pumping equipment of kimberlite mines drainage systems of «ALROSA» JSC. Methods. To achieve this aim the author has used a comprehensive approach including: analysis of the physico-chemical composition of mine waters, analysis of significant practical material by these pumping equipment work and previously published articles on the subject of research, experimental researches of kimberlite mines electric pump units of «ALROSA» JSC. Results. According to the results of the researches, the author proposed the recommendations for improving reliability of a pumping equipment of kimberlite mines drainage units, which are administered by «ALROSA» JSC