Active role of the necrotic zone in desensitization of hypoxic macrophages and regulation of CSC-fate: A hypothesis

Fast-proliferating cancer cells in the hypoxic region face a shortage of oxygen and nutrients, undergo necrotic cell death, and release numerous signaling components. Hypoxia-induced chemo-attractants signal for macrophages/monocytes to clear debris and return the system to steady state. Accordingly, macrophages arrange into pre-necrotic positions, where they are continuously exposed to stress signals. It can thus be hypothesized that gradual alteration of gene expression in macrophages eventually turns offtheir phagocytic machinery. Uncleared cell corpses within the hypoxic region potentially provide a rich source of building blocks for anaerobic metabolism of cancer stem cells via macropinocytosis, and are conceivably implicated in tumor progression and invasion. © 2018 Mehrabi, Amini and Mehrabi

An environmental control box for serial crystallography enables multi-dimensional experiments

We present a new environmental enclosure for fixed-target, serial crystallography enabling full control of both the temperature and humidity. While maintaining the relative humidity to within a percent, this enclosure provides access to X-ray diffraction experiments in a wide temperature range from below 10 °C to above 80 °C. Coupled with the LAMA method, time-resolved serial crystallography experiments can now be carried out at truly physiological temperatures, providing fundamentally new insight into protein function. Using the hyperthermophile enzyme xylose isomerase, we demonstrate changes in the electron density as a function of increasing temperature and time. This method provides the necessary tools to successfully carry out multi-dimensional serial crystallography

Modeling Progressive Fibrosis with Pluripotent Stem Cells Identifies an Anti-fibrotic Small Molecule.

Progressive organ fibrosis accounts for one-third of all deaths worldwide, yet preclinical models that mimic the complex, progressive nature of the disease are lacking, and hence, there are no curative therapies. Progressive fibrosis across organs shares common cellular and molecular pathways involving chronic injury, inflammation, and aberrant repair resulting in deposition of extracellular matrix, organ remodeling, and ultimately organ failure. We describe the generation and characterization of an in vitro progressive fibrosis model that uses cell types derived from induced pluripotent stem cells. Our model produces endogenous activated transforming growth factor β (TGF-β) and contains activated fibroblastic aggregates that progressively increase in size and stiffness with activation of known fibrotic molecular and cellular changes. We used this model as a phenotypic drug discovery platform for modulators of fibrosis. We validated this platform by identifying a compound that promotes resolution of fibrosis in in vivo and ex vivo models of ocular and lung fibrosis

Assessment of some specific and nonspecific immune responses of beluga (Huso huso) following exposure to organophsphte diazinon

Nowadays, the offspring of sturgeon species in the Caspian Sea is under danger because of biological and non-biological impacts such as pollution and illegal catching as well as dams obstacles of fish migration to the upstream of the rivers for the spawning. One of the most practical way to protect and maintain the natural stocking of these valuable species in the sea is artificial propagation and releasing of the produced larvae into the sea and the entering rivers as Iran Fishery Organization is currently producing about 22 million larvae per year according to the forth national plan of the country. However, protecting these natural resources of these species from the toxic chemicals is a critical issue because of high level pollution of their natural environment. In this research work an attempt was made to evaluate the toxicity of diazinon and its effect on some specific and nonspecific immune parameters of these sturgeon species in particular great sturgeon in order to give some recommendations for improving of their natural environment. A number of 300 fish weighing 12±2 g from great sturgeon obtained from sturgeon farms in Golestan states were used. Fish were transported to the Caspian Sea institute of ecology and were kept in 2000 L tanks with well aeration. Fish were fed commercial feed containing Kilka meal. The water quality parameters consisting of NO2, NH3, pH, DO and hardness were 0.05) in the values of MCH, MCV and MCHC between these groups. Compare to control group (group A) the values of white blood cells and lymphocyte were significantly lower in the exposed fish to diazinon (groups of C, D, E, F, G and H) while, the level of neutrophile and eosinophil was higher than control one (P0.05).Furthermore, fish treated with diazinon showed a higher levels of asparate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) in the early stage of post-exposure, compare to control fishes, while the level of these enzymes was lower in this group for the rest of experiment. Also, fish treated with Antigen-diazinon showed generally lower and higher levels of total protein and glucose concentrations in blood plasma, respectively compared to fish untreated(control) (P0.05) in groups of B,F,G and H than group A up to 2 weeks post-treatment and then was lower for the rest of the experiment. The level of spleen lysozyme in groups of B,G and H was also, higher than group A for the first 2 weeks post-treatment and, then it reduced to below levels measured during the rest of experiment (P>0.05). Lysozyme level of sera samples were significantly higher (P<0.05) in groups of B, D, E, F, G and H than group A in the one week post-treatment. There was significant difference in the lysozyme contents of tissues of liver, spleen and serum between groups of A and E,F,G,H(P<0.05). Mean spontaneous CL response in groups of diazinon bath were significantly lower than group A throughout the experiment (P<0.05). Maximum peak was found in group D one day post-exposure, while the minimum peak was found in group E throughout the experiment. The antibody titration in groups of treated with diazinon bath generally lower than control group (P<0.05).but the antibody titer in group B that treated with Antigen without diazinon bath was higher than the other groups. The histopathological effects of diazinon on the liver, kidney, spleen, gills, nostril and barbels of gain sturgeon examined under light and electron microscope, showed that diazinon caused severe damage to the cell structure such as congestion of blood vessels, hemorrhage, cellular infiltration, pyknosis of cells nuclei, vacuolar degeneration and general necrosis in the tissues of kidney, spleen and liver. There were also degenerative changes of interstitial tissue, detachment of tubular basement membrane in kidney. In the gills, hyperplasia and fusion of secondary lamellae, separation and sloughing of epithelium from the underlying basement membrane were also observed In conclusion, diazinon at toxic and sub lethal concentrations is able to seriously affect the sturgeon immunity resulting in suppression of fish immune system and making fish susceptible to both non-infectious and infectious diseases

The HARE chip for efficient time-resolved serial synchrotron crystallography

Serial synchrotron crystallography (SSX) is an emerging technique for static and time-resolved protein structure determination. Using specifically patterned silicon chips for sample delivery, the `hit-and-return' (HARE) protocol allows for efficient time-resolved data collection. The specific pattern of the crystal wells in the HARE chip provides direct access to many discrete time points. HARE chips allow for optical excitation as well as on-chip mixing for reaction initiation, making a large number of protein systems amenable to time-resolved studies. Loading of protein microcrystals onto the HARE chip is streamlined by a novel vacuum loading platform that allows fine-tuning of suction strength while maintaining a humid environment to prevent crystal dehydration. To enable the widespread use of time-resolved serial synchrotron crystallography (TR-SSX), detailed technical descriptions of a set of accessories that facilitate TR-SSX workflows are provided