Eukaryotic cells respond to low-oxygen concentrations by upregulating hypoxic nuclear genes (hypoxic signaling). Although it has been shown previously that the mitochondrial respiratory chain is ...required for hypoxic signaling, its underlying role in this process has been unclear. Here, we find that yeast and rat liver mitochondria produce nitric oxide (NO) at dissolved oxygen concentrations below 20 μM. This NO production is nitrite (NO
2
−) dependent, requires an electron donor, and is carried out by cytochrome
c oxidase in a pH-dependent fashion. Mitochondrial NO production in yeast is influenced by the YHb flavohemoglobin NO oxidoreductase, stimulates expression of the hypoxic nuclear gene
CYC7, and is accompanied by an increase in protein tyrosine nitration. These findings demonstrate an alternative role for the mitochondrial respiratory chain under hypoxic or anoxic conditions and suggest that mitochondrially produced NO is involved in hypoxic signaling, possibly via a pathway that involves protein tyrosine nitration.
Quantum biology is the study of quantum effects on biochemical mechanisms and biological function. We show that the biological production of reactive oxygen species (ROS) in live cells can be ...influenced by coherent electron spin dynamics, providing a new example of quantum biology in cellular regulation. ROS partitioning appears to be mediated during the activation of molecular oxygen (O
) by reduced flavoenzymes, forming spin-correlated radical pairs (RPs). We find that oscillating magnetic fields at Zeeman resonance alter relative yields of cellular superoxide (O
) and hydrogen peroxide (H
O
) ROS products, indicating coherent singlet-triplet mixing at the point of ROS formation. Furthermore, the orientation-dependence of magnetic stimulation, which leads to specific changes in ROS levels, increases either mitochondrial respiration and glycolysis rates. Our results reveal quantum effects in live cell cultures that bridge atomic and cellular levels by connecting ROS partitioning to cellular bioenergetics.
Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, suggesting that ROS might be involved in the development of these cells. ...However, recent studies suggest that inducing an excess of ROS in cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumors frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially modulate the development of these cells by controlling their ROS production. Low levels of ROS are also important for the development and survival of normal cells. In this manuscript, we present data on the influence of the suppression of the Earth's magnetic field (low level magnetic fields or LLF) which magnitudes range from 0.2 µT to 2 µT on the modulation of hydrogen peroxide (H(2)O(2)) in human fibrosarcoma cancer cell line HT1080, pancreatic AsPC-1 cancer cell line, and bovine pulmonary artery endothelial cells (PAEC) exposed to geomagnetic field (control; 45 µT-60 µT). Reduction of the Earth's magnetic field suppressed H(2)O(2) production in cancer cells and PAEC. The addition of catalase and superoxide dismutase (SOD) mimetic MnTBAP inhibited the magnetic field effect. Modulating ROS production by magnetic fields may open new venues of biomedical research and therapeutic strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This paper compares the pozzolanic activity of metakaolin (MK) obtained by thermal treatment at 700
°C for 1
h and amorphous kaolin obtained by mechanochemical treatment in a Herzog oscillating mill ...for 15–120
min. The starting materials used included two raw kaolins and an industrial (washed) kaolin. The production of the amorphous materials was followed by their thermal analysis (DTA, TGA), X-ray diffraction (XRD), Fourier transform infrared spectrometry (FTIR), particle size distribution (PSD) and transmission electron microscopy (TEM). The pozzolanic activity of the amorphous kaolins was assessed in accordance with ASTM C 311. Based on the results, both types of treatment allow reactive pozzolans to be obtained from kaolinite clays. The pozzolan obtained by mechanochemical treatment of raw kaolin with high quartz content was found to perform especially well. In sample KV2, with a minor amount of kaolinite, it was possible to obtain an active pozzolan by mechanical treatment but not by thermal treatment. The pozzolanic index and the mechanical resistances obtained by grinding were similar to the thermal treatment. The outcome of the mechanochemical process depends on the type of kaolin used and its and mineralogical composition, and also on its grinding time.
Repetitive control has proven to be an efficient control technique in power factor correction by active filtering.
Unfortunately, this technique shows a dramatic performance decay when the network ...frequency is not exactly known or
it varies with time. In order to overcome the varying/uncertain frequency problem, a robust high-order repetitive control
strategy can be used; however, most internal models obtained by these approaches are unstable. Although this fact does not
compromise the closed-loop stability, practical problems can arise during the implementation. This study proposes and studies
a stable second-order odd-harmonic repetitive control system, presents a stability analysis of high-order internal models and
describes the performance degradation of the standard repetitive control in terms of the active filter (AF) application. In
this way, an experimental validation has been carried out implementing the proposed internal model in a shunt AF current
controller. As a result, this high-order controller allows dealing with the grid frequency variations without using adaptive
schemes.
Targeted resequencing has become the most used and cost-effective approach for identifying causative mutations of Mendelian diseases both for diagnostics and research purposes. Due to very rapid ...technological progress, NGS laboratories are expanding their capabilities to address the increasing number of analyses. Several open source tools are available to build a generic variant calling pipeline, but a tool able to simultaneously execute multiple analyses, organize, and categorize the samples is still missing.
Here we describe VarGenius, a Linux based command line software able to execute customizable pipelines for the analysis of multiple targeted resequencing data using parallel computing. VarGenius provides a database to store the output of the analysis (calling quality statistics, variant annotations, internal allelic variant frequencies) and sample information (personal data, genotypes, phenotypes). VarGenius can also perform the "joint analysis" of hundreds of samples with a single command, drastically reducing the time for the configuration and execution of the analysis. VarGenius executes the standard pipeline of the Genome Analysis Tool-Kit (GATK) best practices (GBP) for germinal variant calling, annotates the variants using Annovar, and generates a user-friendly output displaying the results through a web page. VarGenius has been tested on a parallel computing cluster with 52 machines with 120GB of RAM each. Under this configuration, a 50 M whole exome sequencing (WES) analysis for a family was executed in about 7 h (trio or quartet); a joint analysis of 30 WES in about 24 h and the parallel analysis of 34 single samples from a 1 M panel in about 2 h.
We developed VarGenius, a "master" tool that faces the increasing demand of heterogeneous NGS analyses and allows maximum flexibility for downstream analyses. It paves the way to a different kind of analysis, centered on cohorts rather than on singleton. Patient and variant information are stored into the database and any output file can be accessed programmatically. VarGenius can be used for routine analyses by biomedical researchers with basic Linux skills providing additional flexibility for computational biologists to develop their own algorithms for the comparison and analysis of data. The software is freely available at: https://github.com/frankMusacchia/VarGenius.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Primary hyperoxaluria type 1 (PH1) is an inborn error of liver metabolism due to deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT), which catalyzes conversion of ...glyoxylate into glycine. AGT deficiency results in overproduction of oxalate that ultimately leads to end-stage renal disease and death. Organ transplantation as either preemptive liver transplantation or combined liver/kidney transplantation is the only available therapy to prevent disease progression. Gene therapy is an attractive option to provide an alternative treatment for PH1. Toward this goal, we investigated helper-dependent adenoviral (HDAd) vectors for liver-directed gene therapy of PH1. Compared with saline controls, AGT-deficient mice injected with an HDAd encoding the AGT under the control of a liver-specific promoter showed a significant reduction of hyperoxaluria and less increase of urinary oxalate following challenge with ethylene glycol, a precursor of glyoxylate. These studies may thus pave the way to clinical application of HDAd for PH1 gene therapy.
Ischemia-reperfusion injury in free flaps is associated with tissue damage and is one of the main factors causing flap failure in reconstructive microsurgery. The aim of this study is to assess ...whether any ischemia-reperfusion injury takes place during a microsurgical flap reconstruction as seen through the levels of malondialdehyde (MDA) and superoxide dismutase, biomarkers of oxidative stress, and to analyze the effect of lidocaine in this process.
Twenty-four patients operated for immediate breast reconstruction using the Deep Inferior Epigastric Perforator free flap technique were divided into two groups: one group was treated with a lidocaine intravenous perfusion and the other group with a saline perfusion. MDA and superoxide dismutase (SOD) levels were measured at several points before, during, and after surgery.
There was an increase in MDA levels in both groups, but the lidocaine group experienced a decrease during reperfusion. On the other hand, we observed a rise in SOD levels in both groups, but a decrease during reperfusion in the placebo group. However, these differences between groups were not statistically significant.
The decreased SOD activity and increased MDA content in our research prove a redox imbalance and high reactive oxygen species levels in flaps, indicating that tissues experience ischemia-reperfusion injury during microsurgical reconstruction. Lidocaine may have a protective effect in free flap surgery, but our results were not statistically significant, so further studies will be required.
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