Dynamics analysis of cavitation disintegration of microparticles during nanopowder preparation in a new Water Jet Mill (WJM) device

A physical analysis of cavitation-based implosive breakage of solid particles focusing on practical application during fine particle disintegration in a liquid suspension is submitted in the present paper. The physical source of the cavitation dynamics phenomena involved is an extreme velocity gradient induced by an ultrahigh-energy liquid jet mixing together with a slow liquid suspension of milled particles. Extreme tensile stresses occurring at velocity gradients over 1000 ms−1mm−1 at the operating temperature of 65 °C generates high-intensity pure vapor cavitation in the degassed water dispersion with extreme values of impact pressure in the final of bubble implosions on particle surfaces. Preparation of silicon nanoparticles with median diameter approximately 148 nm using a newly developed “Water Jet Mill” (WJM) device is demonstrated in the present article as an example of application of the aforementioned disintegration method as well as of theoretical analysis of this method. The disintegration method is characterized by a high potential for milling of submicron particles with high efficiency.Web of Science22564363

CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4(+) T lymphocytes

Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific blockade of Rac1 activation through binding of azathioprine-generated 6-thioguanine triphosphate (6-Thio-GTP) to Rac1 instead of GTP. The activation of Rac1 target genes such as mitogen-activated protein kinase kinase (MEK), NF-κB, and bcl-x(L) was suppressed by azathioprine, leading to a mitochondrial pathway of apoptosis. Azathioprine thus converts a costimulatory signal into an apoptotic signal by modulating Rac1 activity. These findings explain the immunosuppressive effects of azathioprine and suggest that 6-Thio-GTP derivates may be useful as potent immunosuppressive agents in autoimmune diseases and organ transplantation

A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function

Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990CT, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival