Conversion of short fatigue cracks into a long crack

This paper presents a method for the statistical processing of results of initiation and propagation of short fatigue cracks. The distribution of the lengths of these cracks followed a Weibull distribution function. The value of the size parameter of this distribution grows with the number of cycles, but the value of the shape parameter declines as the number of cycles increases. A study of the modal value of fatigue crack lengths as a function of the number of cycles yielded a statistical criterion defining the conversion of the short fatigue crack initiation and propagation stage into the long fatigue crack propagation stage. One condition for this conversion is a zero magnitude of the first derivative of the modal value of fatigue crack lengths by the number of cycles. When the dependence of the Weibull distribution shape parameter and size parameter upon the number of cycles was inserted in this condition, solution of the resultant expression revealed the critical number of cycles that is necessary for the formation of a long fatigue crack

A critical role for donor-derived IL-22 in cutaneous chronic GVHD

Graft-versus-host disease (GVHD) is the major cause of nonrelapse morbidity and mortality after allogeneic stem cell transplantation (allo-SCT). Prevention and treatment of GVHD remain inadequate and commonly lead to end-organ dysfunction and opportunistic infection. The role of interleukin (IL)-17 and IL-22 in GVHD remains uncertain, due to an apparent lack of lineage fidelity and variable and contextually determined protective and pathogenic effects. We demonstrate that donor T cell-derived IL-22 significantly exacerbates cutaneous chronic GVHD and that IL-22 is produced by highly inflammatory donor CD4⁺ T cells posttransplantation. IL-22 and IL-17A derive from both independent and overlapping lineages, defined as T helper (Th)22 and IL-22⁺ Th17 cells. Donor Th22 and IL-22⁺ Th17 cells share a similar IL-6-dependent developmental pathway, and while Th22 cells arise independently of the IL-22⁺ Th17 lineage, IL-17 signaling to donor Th22 directly promotes their development in allo-SCT. Importantly, while both IL-22 and IL-17 mediate skin GVHD, Th17-induced chronic GVHD can be attenuated by IL-22 inhibition in preclinical systems. In the clinic, high levels of both IL-17A and IL-22 expression are present in the skin of patients with GVHD after allo-SCT. Together, these data demonstrate a key role for donor-derived IL-22 in patients with chronic skin GVHD and confirm parallel but symbiotic developmental pathways of Th22 and Th17 differentiation.Kate H. Gartlan, Hemamalini Bommiasamy, Katelyn Paz, Andrew N. Wilkinson, Mary Owen, Dawn K. Reichenbach, Tatjana Banovic, Kimberly Wehner, Faith Buchanan, Antiopi Varelias, Rachel D. Kuns, Karshing Chang, Yuri Fedoriw, Thomas Shea, James Coghill, Michael Zaiken, Maximilian W. Plank, Paul S. Foster, Andrew D. Clouston, Bruce R. Blazar, Jonathan S. Serody, Geoffrey R. Hil

Research on the detection of methane concentration using sensor with supporter catalyst filled element on constant temperature

Based on the basic principle of sensors with supporter filled element that measures the methane concentration, a method for designing Weston bridge by using the sensor and the reference element is proposed and the mathematical model of the automatic temperature control and the measurement of methane concentration is developed. The measurement results show that this design expands the measuring range, reduces burning-knot and vaporization of catalyst and extends the service life of the supporter catalyst filled element.link_to_subscribed_fulltex

Targeting PI3Kδ function for amelioration of murine chronic graft‐versus‐host disease

Chronic graft‐versus‐host disease (cGVHD) is a leading cause of morbidity and mortality following allotransplant. Activated donor effector T cells can differentiate into pathogenic T helper (Th)‐17 cells and germinal center (GC)–promoting T follicular helper (Tfh) cells, resulting in cGVHD. Phosphoinositide‐3‐kinase‐δ (PI3Kδ), a lipid kinase, is critical for activated T cell survival, proliferation, differentiation, and metabolism. We demonstrate PI3Kδ activity in donor T cells that become Tfh cells is required for cGVHD in a nonsclerodermatous multiorgan system disease model that includes bronchiolitis obliterans (BO), dependent upon GC B cells, Tfhs, and counterbalanced by T follicular regulatory cells, each requiring PI3Kδ signaling for function and survival. Although B cells rely on PI3Kδ pathway signaling and GC formation is disrupted resulting in a substantial decrease in Ig production, PI3Kδ kinase‐dead mutant donor bone marrow–derived GC B cells still supported BO cGVHD generation. A PI3Kδ‐specific inhibitor, compound GS‐649443, that has superior potency to idelalisib while maintaining selectivity, reduced cGVHD in mice with active disease. In a Th1‐dependent and Th17‐associated scleroderma model, GS‐649443 effectively treated mice with active cGVHD. These data provide a foundation for clinical trials of US Food and Drug Administration (FDA)–approved PI3Kδ inhibitors for cGVHD therapy in patients