Formation of electron beam fields with 3D printed filters

In this research the electron beam traverse profiles beam before and after the application of the developed filter element was calculated and experimentally obtained. The article presents the calculated parameters of the unit form and geometrical dimension, forming the determined electron beam profile, and the physical configuration of the filter produced by 3D print method. The electron beam field distributions before and after filtration obtained with the help of GAFCHROMIC EBT2 radiographic films are illustrated. The calculation method of the filter actual density determination is presented. In the paper the comparison results of the electron beam experimental and calculated profiles are shown

Development of the method for the electron beam spatial distribution determination in the transverse plane

The article presents the device destined for flux density distribution of electrons in the beam cross section without consumables, with a resolution of about 1 mm and slightly dependent on the electron energy. The possibility of the cross section reconstruction of the electron flux density distribution by the inverse Radon transformation is shown. The results of mathematical reconstruction are illustrated and upon which the projections optimum quantity are specified. In the paper the experimental set up developed based on proposed method is introduced. The results of the experimental tests of the scanning device functionability are presented

Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice

Lung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease. Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, is known to mediate the development of lung injury and emphysema. Here, we discovered the endolysosomal cation channel mucolipin 3 (TRPML3) as a regulator of MMP-12 reuptake from broncho-alveolar fluid, driving in two independently generated Trpml3-/- mouse models enlarged lung injury, which is further exacerbated after elastase or tobacco smoke treatment. Mechanistically, using a Trpml3IRES-Cre/eR26-τGFP reporter mouse model, transcriptomics, and endolysosomal patch-clamp experiments, we show that in the lung TRPML3 is almost exclusively expressed in alveolar macrophages, where its loss leads to defects in early endosomal trafficking and endocytosis of MMP-12. Our findings suggest that TRPML3 represents a key regulator of MMP-12 clearance by alveolar macrophages and may serve as therapeutic target for emphysema and chronic obstructive pulmonary disease

Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue!

Lysosomal storage diseases (LSDs) resulting from inherited gene mutations constitute a family of disorders that disturb lysosomal degradative function leading to abnormal storage of macromolecular substrates. In most LSDs, central nervous system (CNS) involvement is common and leads to the progressive appearance of neurodegeneration and early death. A growing amount of evidence suggests that ion channels in the endolysosomal system play a crucial role in the pathology of neurodegenerative LSDs. One of the main basic mechanisms through which the endolysosomal ion channels regulate the function of the endolysosomal system is Ca2+ release, which is thought to be essential for intracellular compartment fusion, fission, trafficking and lysosomal exocytosis. The intracellular TRPML (transient receptor potential mucolipin) and TPC (two-pore channel) ion channel families constitute the main essential Ca2+-permeable channels expressed on endolysosomal membranes, and they are considered potential drug targets for the prevention and treatment of LSDs. Although TRPML1 activation has shown rescue effects on LSD phenotypes, its activity is pH dependent, and it is blocked by sphingomyelin accumulation, which is characteristic of some LSDs. In contrast, TPC2 activation is pH-independent and not blocked by sphingomyelin, potentially representing an advantage over TRPML1. Here, we discuss the rescue of cellular phenotypes associated with LSDs such as cholesterol and lactosylceramide (LacCer) accumulation or ultrastructural changes seen by electron microscopy, mediated by the small molecule agonist of TPC2, TPC2-A1-P, which promotes lysosomal exocytosis and autophagy. In summary, new data suggest that TPC2 is a promising target for the treatment of different types of LSDs such as MLIV, NPC1, and Batten disease, both in vitro and in vivo

PI(3,5)P2 and NAADP: Team players or lone warriors?-New insights into TPC activation modes

NAADP (nicotinic acid adenine dinucleotide phosphate) is a second messenger, releasing Ca2+ from acidic calcium stores such as endosomes and lysosomes. PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate) is a phospho-inositide, residing on endolysosomal membranes and likewise releasing Ca2+ from endosomes and lysosomes. Both compounds have been shown to activate endolysosomal two-pore channels (TPCs) in mammalian cells. However, their effects on ion permeability as demonstrated specifically for TPC2 differ. While PI(3,5)P2 elicits predominantly Na+-selective currents, NAADP increases the Ca2+ permeability of the channel. What happens when both compounds are applied simultaneously was unclear until recentl