The amino acid antiporter system Xc
is important for the synthesis of glutathione (GSH) that functions to prevent lipid peroxidation and protect cells from nonapoptotic, iron-dependent death (i.e., ...ferroptosis). While the activity of system Xc
often positively correlates with the expression level of its light chain encoded by SLC7A11, inhibition of system Xc
activity by small molecules (e.g., erastin) causes a decrease in the intracellular GSH level, leading to ferroptotic cell death. How system Xc
is regulated during ferroptosis remains largely unknown. Here we report that activating transcription factor 3 (ATF3), a common stress sensor, can promote ferroptosis induced by erastin. ATF3 suppressed system Xc
, depleted intracellular GSH, and thereby promoted lipid peroxidation induced by erastin. ATF3 achieved this activity through binding to the SLC7A11 promoter and repressing SLC7A11 expression in a p53-independent manner. These findings thus add ATF3 to a short list of proteins that can regulate system Xc
and promote ferroptosis repressed by this antiporter.
Background Neuroimaging studies have shown that major depressive disorder (MDD) is accompanied by structural and functional abnormalities in specific brain regions and connections; yet, little is ...known about alterations of the topological organization of whole-brain networks in MDD patients. Methods Thirty drug-naive, first-episode MDD patients and 63 healthy control subjects underwent a resting-state functional magnetic resonance imaging scan. The whole-brain functional networks were constructed by thresholding partial correlation matrices of 90 brain regions, and their topological properties (e.g., small-world, efficiency, and nodal centrality) were analyzed using graph theory-based approaches. Nonparametric permutation tests were further used for group comparisons of topological metrics. Results Both the MDD and control groups showed small-world architecture in brain functional networks, suggesting a balance between functional segregation and integration. However, compared with control subjects, the MDD patients showed altered quantitative values in the global properties, characterized by lower path length and higher global efficiency, implying a shift toward randomization in their brain networks. The MDD patients exhibited increased nodal centralities, predominately in the caudate nucleus and default-mode regions, including the hippocampus, inferior parietal, medial frontal, and parietal regions, and reduced nodal centralities in the occipital, frontal (orbital part), and temporal regions. The altered nodal centralities in the left hippocampus and the left caudate nucleus were correlated with disease duration and severity. Conclusions These results suggest that depressive disorder is associated with disruptions in the topological organization of functional brain networks and that this disruption may contribute to disturbances in mood and cognition in MDD patients.
The ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase 1 (CHK1) pathway plays an essential role in suppressing replication stress from DNA damage and oncogene activation.
Preclinical ...studies have shown that cancer cells with defective DNA repair mechanisms or cell cycle checkpoints may be particularly sensitive to ATR inhibitors. Preclinical and clinical data from early-phase trials on three ATR inhibitors (M6620, AZD6738, and BAY1895344), either as monotherapy or in combination, were reviewed.
Data from ATR inhibitor-based combinational trials might lead to future expansion of this therapy to homologous recombination repair pathway-proficient cancers and potentially serve as a rescue therapy for patients who have progressed through poly ADP-ribose polymerase inhibitors.
Adding different materials to soil can improve its engineering properties, but traditional materials such as cement, lime, fly ash, etc., have caused pollution to the environment. Recently, ...biopolymers have shown many advantages, such as economy and environmental protection, which make them applicable to geotechnical engineering. This study summarizes the effects of biopolymers on soil’s engineering properties and the main directions of current research. Firstly, the advantages and disadvantages of a variety of widely used biopolymer materials and their effects on the specific engineering characteristics of soil (i.e., water retention characteristics, strength characteristics, permeability characteristics, microstructure) are introduced, as well as the source, viscosity, pH, and cost of these biopolymers. Then, based on the theory of unsaturated soil, the current research progress on the water retention characteristics of improved soil is summarized. The key factors affecting the strength of biopolymer-treated soil are introduced. Due to the actual environmental conditions, such as rainfall, the permeability and durability of biopolymer-treated soil are also worthy of attention. In summary, it is necessary to study the variation laws of the engineering properties of biopolymer-treated soil in the full suction range, and to predict such laws reasonably. The relevant results are conducive to the safer and more scientific application of biopolymers in geotechnical engineering practice.
Many civil engineering projects are related to hydro-mechanical behavior of unsaturated expansive soils over a wide suction range, which was investigated by imposing suctions on an expansive soil ...using the axis-translation technique and the vapor equilibrium technique with saturated salt solution in this paper. Water retention test results on compacted expansive soil show that void ratio keeps decreasing along with increasing the suction in an entire suction range (from 0 to about 1000 MPa), and the soil–water retention curves in terms of gravimetric water content versus suction relation are independent of the dry density or void ratio when the suction is higher than 250 kPa. Therefore, the mechanical tests on an unsaturated expansive soil with constant water content can be considered as that at constant suction when suction is higher than 250 kPa. The stress–strain behavior at different constant suctions in the entire suction range measured from triaxial shear tests under a constant net confining stress shows that the strength and stress–strain curve of specimens with higher suction are higher than those with lower suction and the higher the suction, the more dilative the specimens. The strain softening appears when the suction is higher than a specific value and the appearance of strain softening is related to the sliding surface. The tested compacted expansive soil with extremely high suctions (i.e., 38.0 and 368 MPa) shows distinct peak strength, strain-softening and dilative behavior.
DNA repair, in particular, DNA double-strand break (DSB) repair, is essential for the survival of both normal and cancer cells. An elaborate repair mechanism has been developed in cells to ...efficiently repair the damaged DNA. The pathways predominately involved in DSB repair are homologous recombination and classic nonhomologous end-joining, although the alternative NHEJ pathway, a third DSB repair pathway, could also be important in certain contexts. The protein of BRCA1 encoded by the tumor suppressor gene BRCA1 regulates all DSB repair pathways. Given that DSBs represent the most biologically significant lesions induced by ionizing radiation and that impaired DSB repair leads to radiation sensitivity, it has been expected that cancer patients with BRCA1 mutations should benefit from radiation therapy. However, the clinical data have been conflicting and inconclusive. We provide an overview about the current status of the data regarding BRCA1 deficiency and radiation therapy sensitivity in both experimental models and clinical investigations. In addition, we discuss a strategy to potentiate the effects of radiation therapy by poly(ADP-ribose) polymerase inhibitors, the pharmacologic drugs being investigated as monotherapy for the treatment of patients with BRCA1/2 mutations.
Gaomiaozi (GMZ) bentonite produced in Inner Mongolia has been chosen as a matrix material of buffer/backfill materials in the deep geological disposal to isolate the high level radioactive waste in ...China. Swelling characteristics of GMZ bentonite and bentonite–sand mixtures inundated with distilled water were studied by experimental methods. The test result shows that the relation between the void ratio and the swelling pressure of compacted GMZ bentonite–sand mixtures at full saturation is independent of the initial conditions such as the initial dry density and initial water content, and dependent on bentonite/sand ratio. An empirical equation is proposed to predict the swelling deformation and swelling pressure of the mixtures with different densities and bentonite/sand ratios. Finally, the swelling capacities of GMZ, Kunigel-V1 and MX-80 bentonites are compared.
•Void ratio vs swelling pressure at saturation is independent of initial condition.•Mt void ratio vs swelling pressure is independent of bentonite/sand ratios.•Mt void ratio vs swelling pressure at saturation is dependent on type of Mt.•A method is proposed to predict the swelling characteristics of the mixtures.
Recently, deep learning technologies have rapidly expanded into medical image analysis, including both disease detection and classification. As far as we know, migraine is a disabling and common ...neurological disorder, typically characterized by unilateral, throbbing and pulsating headaches. Unfortunately, a large number of migraineurs do not receive the accurate diagnosis when using traditional diagnostic criteria based on the guidelines of the International Headache Society. As such, there is substantial interest in developing automated methods to assist in the diagnosis of migraine.
To the best of our knowledge, no studies have evaluated the potential of deep learning technologies in assisting with the classification of migraine patients. Here, we used deep learning methods in combination with three functional measures (the amplitude of low-frequency fluctuations, regional homogeneity and regional functional correlation strength) based on rs-fMRI data to distinguish not only between migraineurs and healthy controls, but also between the two subtypes of migraine. We employed 21 migraine patients without aura, 15 migraineurs with aura, and 28 healthy controls.
Compared with the traditional support vector machine classifier, which has an accuracy of 83.67%, our Inception module-based convolutional neural network approach showed a significant improvement in classification output (over 86.18%). Our data also indicate that the Inception module-based CNN performs better than the AlexNet-based CNN (Inception module-based CNN reached an accuracy of 99.25%). Finally, we also found that regional functional correlation strength (RFCS) could be regarded as the optimum input out of the three indices (ALFF, ReHo, RFCS).
Overall, our study shows that combining the three functional measures of rs-fMRI with deep learning classification is a powerful method to distinguish between migraineurs and healthy individuals. Our data also highlight that deep learning-based frameworks could be used to develop more complicated models or systems to aid in clinical decision making in the future.
In sustaining arch locked-segment-type slopes, natural soil arches play a key anti-sliding role in the slope's evolution. In this study, a self-developed model test device was used to simulate the ...whole process of deformation evolution of sustaining arch locked-segment-type slopes, and the formation of natural sustaining arch and its locking control effect on slope stability were studied. The test results show that the continuous formation and progressive destruction of the sustaining arch were observed. The sustaining arch formed in the second time has the best locking effect, and the anti-sliding force reaches its stress peak point. However, the slope is not in a critically unstable state, instead, the stress is continuously adjusted to form a larger range of soil arch to resist the slope thrust. Consequently, the slope destabilizes until the ultimate shear strength of arch foots is exceeded, at which point the critical arch height of the arch is reached. The critical arch height mechanical model for slope stability analysis was developed based on the soil arching effect and limit equilibrium theory. The applicability of the model was demonstrated by the physical test and Xintan slope data, which can provide some guidance for early warning of landslides.
Abstract
The well-known ion migration in mixed halide perovskites has been intensely investigated within the area under uniform light illumination. Here, the authors demonstrate that the anion ...segregation in these materials is a nonlocal effect of which the ion redistribution may occur at a macroscopic or mesoscopic scale beyond.
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