Increased systemic oxidative stress is common in schizophrenia (SZ) patients. NADPH-oxidase 4 (NOX4) is the cell oxidoreductase, catalyzing the hydrogen peroxide formation. Presumably, NOX4 is the ...main oxidative stress factor in a number of diseases such as cardiovascular diseases and cancer. We hypothesized that NOX4 may be involved in the oxidative stress development caused by the disease in the schizophrenic patients' peripheral blood lymphocytes (PBL).
The SZ group included 100 patients (68 men and 32 women aged 28 ± 11 years). The control group included 60 volunteers (35 men and 25 women aged 25 ± 12 years). Flow cytometry analysis (FCA) was used for DNA damage markers (8-oxodG, ɣH2AX), pro- and antiapoptotic proteins (BAX1 and BCL2) and the master-regulator of anti-oxidant response NRF2 detection in the lymphocytes of the untreated SZ patients (N = 100) and the healthy control (HC, N = 60). FCA and RT-qPCR were used for NOX4 and RNANOX4 detection in the lymphocytes. RT-qPCR was used for mtDNA quantitation in peripheral blood mononuclear cells. Cell-free DNA concentration was determined in blood plasma fluorimetrically.
8-oxodG, NOX4, and BCL2 levels in the PBL in the SZ group were higher than those in the HC group (p < 0.001). ɣH2AX protein level was increased in the subgroup with high 8-oxodG (p<0.02) levels and decreased in the subgroup with low 8-oxodG (p <0.0001) levels. A positive correlation was found between 8-oxodG, ɣH2AX and BAX1 levels in the SZ group (p <10-6). NOX4 level in lymphocytes did not depend on the DNA damage markers values and BAX1 and BCL2 proteins levels. In 15% of PBL of the HC group a small cellular subfraction was found (5-12% of the total lymphocyte pool) with high DNA damage level and elevated BAX1 protein level. The number of such cells was maximal in PBL samples with low NOX4 protein levels.
Significant NOX4 gene expression was found a in SZ patients' lymphocytes, but the corresponding protein is probably not a cause of the DNA damage.
The roughness of pore surfaces in shale reservoirs can affect the fluid flow, which makes it necessary to be characterized. Fractal dimension, a key component in fractal geometry, can be used to ...describe the surface irregularities. In this paper, we evaluated and compared the fractal dimensions of several shale samples with three major fractal models based on nitrogen adsorption isotherms. The results showed that Frenkel-Halsey-Hill (FHH), Neimark, and Wang-Li models all can be applied for fractal dimension characterization of shale samples. From theoretical thermodynamics, these three models should be considered identical based on the FHH equation. However, the experimental data obtained from these samples showed that the fractal dimensions that are derived from the Neimark model and Wang-Li model are the same while a discrepancy was observed with the results from the FHH model. The difference in the fractal dimensions in the experimental data among these three models was attributed to the micropore structures. It was found that as the micropore surface area or the micropore volume increases in the samples, the difference in the fractal dimensions would increase as well. If the number of micropores present in the samples is limited, all three models can become suitable for fractal dimension calculation in shale samples, otherwise, the Neimark or Wang-Li model is preferred.
Chronic kidney disease (CKD) is a non-specific type of kidney disease that causes a gradual decline in kidney function (from months to years). CKD is a significant risk factor for death, ...cardiovascular disease, and end-stage renal disease. CKDs of different origins may have the same clinical and laboratory manifestations but different progression rates, which requires early diagnosis to determine. This review focuses on protein/peptide biomarkers of the leading causes of CKD: diabetic nephropathy, IgA nephropathy, lupus nephritis, focal segmental glomerulosclerosis, and membranous nephropathy. Mass spectrometry (MS) approaches provided the most information about urinary peptide and protein contents in different nephropathies. New analytical approaches allow urinary proteomic-peptide profiles to be used as early non-invasive diagnostic tools for specific morphological forms of kidney disease and may become a safe alternative to renal biopsy. MS studies of the key pathogenetic mechanisms of renal disease progression may also contribute to developing new approaches for targeted therapy.
This review covers the results of the application of mass spectrometric (MS) techniques to study the diversity of beta-amyloid (Aβ) peptides in human samples. Since Aβ is an important hallmark of ...Alzheimer's disease (AD), which is a socially significant neurodegenerative disorder of the elderly worldwide, analysis of its endogenous variations is of particular importance for elucidating the pathogenesis of AD, predicting increased risks of the disease onset, and developing effective therapy. MS approaches have no alternative for the study of complex samples, including a wide variety of Aβ proteoforms, differing in length and modifications. Approaches based on matrix-assisted laser desorption/ionization time-of-flight and liquid chromatography with electrospray ionization tandem MS are most common in Aβ studies. However, Aβ forms with isomerized and/or racemized Asp and Ser residues require the use of special methods for separation and extra sensitive and selective methods for detection. Overall, this review summarizes current knowledge of Aβ species found in human brain, cerebrospinal fluid, and blood plasma; focuses on application of different MS approaches for Aβ studies; and considers the potential of MS techniques for further studies of Aβ-peptides.
In light of the high prevalence of nonalcoholic fatty liver disease and obesity, treatment options for nonalcoholic steatohepatitis are of particular interest. The purpose of the study is to assess ...the efficacy of L-carnitine and its effects on the functional state of the liver, as well as on lipid and carbohydrate metabolism in patients with nonalcoholic steatohepatitis and concomitant obesity.
People in the control group followed a hypocaloric diet and received 1 tablet of simvastatin 20 mg once a day and 2 capsules of essential phospholipids 600 mg three times a day for 90 days. People in the experimental group followed a hypocaloric diet and received 1 tablet of simvastatin 20 mg once a day and L-carnitine 10 mL orally two times a day for 90 days.
L-carnitine normalized the blood lipid profile of subjects, as demonstrated by a significant decrease in the blood levels of total cholesterol, triglycerides, low-density lipoproteins, atherogenic index, and insulin resistance. The use of L-carnitine in patients with nonalcoholic steatohepatitis and concomitant obesity contributes to the steady reduction of the main clinical and biochemical symptoms of nonalcoholic steatohepatitis.
L-carnitine produces positive effects on the blood lipid profile and carbohydrate metabolism.
Early recognition of the risk of Alzheimer’s disease (AD) onset is a global challenge that requires the development of reliable and affordable screening methods for wide-scale application. Proteomic ...studies of blood plasma are of particular relevance; however, the currently proposed differentiating markers are poorly consistent. The targeted quantitative multiple reaction monitoring (MRM) assay of the reported candidate biomarkers (CBs) can contribute to the creation of a consistent marker panel. An MRM-MS analysis of 149 nondepleted EDTA–plasma samples (MHRC, Russia) of patients with AD (n = 47), mild cognitive impairment (MCI, n = 36), vascular dementia (n = 8), frontotemporal dementia (n = 15), and an elderly control group (n = 43) was performed using the BAK 125 kit (MRM Proteomics Inc., Canada). Statistical analysis revealed a significant decrease in the levels of afamin, apolipoprotein E, biotinidase, and serum paraoxonase/arylesterase 1 associated with AD. Different training algorithms for machine learning were performed to identify the protein panels and build corresponding classifiers for the AD prognosis. Machine learning revealed 31 proteins that are important for AD differentiation and mostly include reported earlier CBs. The best-performing classifiers reached 80% accuracy, 79.4% sensitivity and 83.6% specificity and were able to assess the risk of developing AD over the next 3 years for patients with MCI. Overall, this study demonstrates the high potential of the MRM approach combined with machine learning to confirm the significance of previously identified CBs and to propose consistent protein marker panels.
Coagulation factor XII (fXII) is important for arterial thrombosis, but its physiological activation mechanisms are unclear. In this study, we elucidated the role of platelets and platelet-derived ...material in fXII activation. FXII activation was only observed upon potent platelet stimulation (with thrombin, collagen-related peptide, or calcium ionophore, but not ADP) accompanied by phosphatidylserine exposure and was localised to the platelet surface. Platelets from three patients with grey platelet syndrome did not activate fXII, which suggests that platelet-associated fXII-activating material might be released from α-granules. FXII was preferentially bound by phosphotidylserine-positive platelets and annexin V abrogated platelet-dependent fXII activation; however, artificial phosphotidylserine/phosphatidylcholine microvesicles did not support fXII activation under the conditions herein. Confocal microscopy using DAPI as a poly-phosphate marker did not reveal poly-phosphates associated with an activated platelet surface. Experimental data for fXII activation indicates an auto-inhibition mechanism (ki/ka = 180 molecules/platelet). Unlike surface-associated fXII activation, platelet secretion inhibited activated fXII (fXIIa), particularly due to a released C1-inhibitor. Platelet surface-associated fXIIa formation triggered contact pathway-dependent clotting in recalcified plasma. Computer modelling suggests that fXIIa inactivation was greatly decreased in thrombi under high blood flow due to inhibitor washout. Combined, the surface-associated fXII activation and its inhibition in solution herein may be regarded as a flow-sensitive regulator that can shift the balance between surface-associated clotting and plasma-dependent inhibition, which may explain the role of fXII at high shear and why fXII is important for thrombosis but negligible in haemostasis.
•First absolute age constraints for seismic stratigraphy from IODP Expedition 381.•Rapid spatiotemporal variations in fault network activity in the Corinth Rift.•Acceleration of fault slip rates when ...rift border fault system links.•Border fault system is kinematically coherent with slip rates >7 mm/yr.•Seismic deficit in the central and western rift equal to a Mw ∼6.5 earthquake.
As a young (<5 Myr old) active rift with high resolution spatial and temporal constraints, the Corinth Rift is a natural laboratory for testing models of rift and fault network development in the early stages of continental rifting. New analyses of the rift fault network in the offshore syn-rift sequence are combined with ocean drilling borehole data from IODP Expedition 381. The expedition drilled and sampled syn-rift sediments from the last few Myr and provides the first absolute age framework for the offshore rift, allowing determination of robust fault slip rates and temporal patterns in fault network activity.
Spatial variations in activity and rates throughout the rift fault network, for four time intervals over the past ∼2 Myr, illustrate changes in strain distribution and highlight three dominant processes controlling the development of the fault network: 1) progressive strain localisation and transfer of strain from major S-dipping to major N-dipping faults from ∼2 Ma – 130 ka; 2) linkage of a southern border fault system and subsequent acceleration of fault slip rates on major N-dipping faults at ∼335 ka; 3) increased rift margin flexure and subsequent deformation since ∼130 ka, a response to rapid subsidence in the hanging wall of an established crustal scale border fault system.
Since ∼130 ka the rift fault network has experienced a two-fold increase in average cumulative slip rates, with the highest slip rates (>7 mm/yr) occurring on major segments of the border fault system in the central rift. A comparison of seismic moment rates from historical earthquakes (last 320 years) is consistent with the geological timescale of fault slip rates (highest rates in the western and central rift), but not with the distribution of very recent activity (from 50-year earthquake records). As a result, a moment deficit is present along the central rift, which could be accommodated by a large (Mw 6.5) earthquake, potentially even rupturing multiple linked fault segments.
The details of rift fault network activity from this study reveal how quickly strain can migrate and become localised during early continental rifting, and how rapidly fault slip accelerates in response to the establishment of major rift border fault systems. Identifying the nature and timescales of these important rift processes furthers our models of early rift evolution and has implications for assessing seismic hazard in regions of active continental rifting.
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