Investigations of 2-Thiazoline-2-thiol as a Ligand: Synthesis and X-ray Structures of [Mn\u3csub\u3e2\u3c/sub\u3e(CO)\u3csub\u3e7\u3c/sub\u3e(\u3cem\u3eμ\u3c/em\u3e-NS\u3csub\u3e2\u3c/sub\u3eC\u3csub\u3e3\u3c/sub\u3eH\u3csub\u3e4\u3c/sub\u3e)\u3csub\u3e2\u3c/sub\u3e] and [Mn(CO)\u3csub\u3e3\u3c/sub\u3e(PPh\u3csub\u3e3\u3c/sub\u3e)(\u3cem\u3eκ\u3c/em\u3e\u3csup\u3e2\u3c/sup\u3e-NS\u3csub\u3e2\u3c/sub\u3eC\u3csub\u3e3\u3c/sub\u3eH\u3csub\u3e4\u3c/sub\u3e)]

Treatment of Mn2(CO)10 with 2-thiazoline-2-thiol in the presence of Me3NO at room temperature afforded the dimanganese complexes [Mn2(CO)7(μ-NS2C3H4)2] (1) and [Mn2(CO)6(μ-NS2C3H4)2] (2) in 51 and 34% yields, respectively. Compound 1 was quantitatively converted into 2 when reacted with one equiv of Me3NO. Reaction of 1 with triphenylphosphine at room temperature furnished the mononuclear complex [Mn(CO)3(PPh3)(κ 2-NS2C3H4)] (3) in 66% yield. All three new complexes have been characterized by elemental analyzes and spectroscopic data together with single crystal X-ray diffraction studies for 1 and 3. Compound 1 crystallizes in the orthorhombic space group Pbca with a = 12.4147(2), b = 16.2416(3), c = 19.0841(4) Å, β = 90°, Z = 8 and V = 3848.01(12) Å3 and 3 crystallizes in the monoclinic space group P 21/n with a = 10.41730(10), b = 14.7710(2), c = 14.9209(2) Å, β = 91.1760(10)°, Z = 4 and V = 2295.45(5) Å3

A method to extract slip system dependent information for crystal plasticity models

A tool to implement a length scale dependency to classical crystal plasticity simulations is presented. Classical crystal plasticity models do not include a size effect; therefore, the size of the grain does not influence the simulated deformation. Classical crystal plasticity advancements have been through the inclusion of stress or strain gradient based constitutive models to improve the simulation of length scale dependent deformation. However, this tool presents an alternative to implementing a length scale, where the influence of slip pile-up in the form of dislocations at grain boundaries as a potential to explaining the Hall-Petch effect in materials. This is achieved by calculating the slip distance in adjacent grains for each slip system, by assuming the total slip length spans the grain in the slip direction. These calculations can occur in two ways. The first is the analysis occurs at the start of the simulation, therefore, only occurs once. If this approach is used, the computational cost of this tool is minute. However, if the simulations consider large deformations, during which it is expected that the grains are going to undergo large rotations, then it would be advantageous to the have the tool recalculate the information during the analysis. Consequently, the computational cost would depend on the resolution of the modelled geometry, the number of grains, and the number of slip systems. The tool also provides a capability to develop constitutive models based on complex grain boundary features which can be implemented in classical crystal plasticity models and gradient based crystal plasticity models. The described calculation process is implemented through a Fortran subroutine, which has been designed to be easily used in crystal plasticity simulations. The presented tool also includes Python code designed to link with microstructures built using DREAM.3D to extract the required input data to the Fortran subroutine. The proposed tool is not limited to classical crystal plasticity formulations, instead the data extracted and outputted from the Fortran subroutine can be used to serve alternative purposes in both stress and strain gradient crystal plasticity models. The proposed tool can be modified to extract additional data to that presented. The slip distance in the adjacent grain, the distance from the grain boundary of the current calculation point, and the interaction between slip systems between grains can be used in any crystal plasticity constitutive models

Triggering of Suicidal Erythrocyte Death by Psammaplin A

Background/Aims: Psammaplin A, a natural product isolated from marine sponges, triggers apoptosis of tumor cells and is thus considered for the treatment of malignancy. In analogy to apoptosis of nucleated tumor cells, erythrocytes may enter eryptosis, a suicidal death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms stimulating eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress and ceramide. The present study explored, whether Psammaplin A induces eryptosis and to possibly shed some light on the underlying mechanisms. Methods: Phosphatidylserine exposing erythrocytes were identified utilizing annexin-V-binding, cell volume was estimated from forward scatter, [Ca2+]i determined utilizing Fluo3-fluorescence, the abundance of reactive oxygen species (ROS) quantified with DCFDA dependent fluorescence, and ceramide abundance at the erythrocyte surface detected with specific antibodies. Results: A 48 hours exposure of human erythrocytes to Psammaplin A (2-8 \u3bcg/ml) significantly decreased forward scatter and significantly increased the percentage of annexin-V-binding cells. Psammaplin A significantly increased Fluo3-fluorescence, the effect of Psammaplin A on annexin-V-binding and forward scatter was, however, not significantly blunted by removal of extracellular Ca2+. Psammaplin A significantly increased DCFDA fluorescence and ceramide abundance. Conclusions: Psammaplin A triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect paralleled by increase of [Ca2+]i, induction of oxidative stress and enhanced appearance of ceramide

Stimulation of Suicidal Erythrocyte Death by Ceritinib-Treatment of Human Erythrocytes

Background/Aims: The anaplastic lymphoma kinase (ALK) inhibitor ceritinib is utilized for the treatment of ALK positive non-small cell lung carcinoma. Side effects of the drug include decrease of blood hemoglobin concentration. Possible causes of anemia include stimulation of suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling of eryptosis includes increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, staurosporine sensitive protein kinase C, SB203580 sensitive p38 kinase, D4476 sensitive casein kinase 1, and zVAD sensitive caspases. The present study explored, whether ceritinib induces eryptosis and, if so, to shed light on the cellular mechanisms involved. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Results: A 48 hours exposure of human erythrocytes to ceritinib (1 \ub5g/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter, significantly increased Fluo3-fluorescence, but did not significantly modify DCFDA fluorescence or ceramide abundance. The effect of ceritinib on annexin-V-binding was significantly blunted but not abolished by removal of extracellular Ca2+, by the kinase inhibitors staurosporine (1 \ub5M), SB203580 (2 \ub5M) and D4476 (10 \ub5M), as well as by caspase inhibitor zVAD (10 \ub5M). Conclusions: Ceritinib triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca2+ entry, as well as activation of kinases and Caspases

Stimulating effect of elvitegravir on suicidal erythrocyte death

Background/Aims: The antiviral drug Elvitegravir is used for the treatment of Human Immunodeficiency Virus (HIV) infections. The present study explored whether the drug is able to trigger eryptosis, the suicidal death of erythrocytes. Eryptosis is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, activated p38 kinase and activated caspases. The present study explored, whether Elvitegravir induces eryptosis and, if so, to shed light on the mechanisms involved. Methods: Phosphatidylserine abundance at the erythrocyte surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, abundance of reactive oxygen species (ROS) from DCFDA dependent fluorescence, and ceramide abundance at the erythrocyte surface utilizing specific antibodies. Results: A 48 hours exposure of human erythrocytes to Elvitegravir ( 65 1.5 \u3bcg/ml) significantly increased the percentage of annexin-V-binding cells, and significantly decreased forward scatter. Elvitegravir (2.5 \u3bcg/ml) significantly increased Fluo3-fluorescence, but did not significantly modify DCFDA fluorescence or ceramide abundance. The effect of Elvitegravir on annexin-V-binding was significantly blunted by removal of extracellular Ca2+, but not in the presence of p38 kinase inhibitor SB203580 (2 \u3bcM) or in the presence of pancaspase inhibitor zVAD (10 \u3bcM). Conclusions: Elvitegravir triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part due to entry of extracellular Ca2+

Multi-run concrete autoencoder to identify prognostic lncRNAs for 12 cancers

Background: Long non-coding RNA plays a vital role in changing the expression profiles of various target genes that lead to cancer development. Thus, identifying prognostic lncRNAs related to different cancers might help in developing cancer therapy. Method: To discover the critical lncRNAs that can identify the origin of different cancers, we propose the use of the state-of-the-art deep learning algorithm concrete autoencoder (CAE) in an unsupervised setting, which efficiently identifies a subset of the most informative features. However, CAE does not identify reproducible features in different runs due to its stochastic nature. We thus propose a multi-run CAE (mrCAE) to identify a stable set of features to address this issue. The assumption is that a feature appearing in multiple runs carries more meaningful information about the data under consideration. The genome-wide lncRNA expression profiles of 12 different types of cancers, with a total of 4768 samples available in The Cancer Genome Atlas (TCGA), were analyzed to discover the key lncRNAs. The lncRNAs identified by multiple runs of CAE were added to a final list of key lncRNAs that are capable of identifying 12 different cancers. Results: Our results showed that mrCAE performs better in feature selection than single-run CAE, standard autoencoder (AE), and other state-of-the-art feature selection techniques. This study revealed a set of top-ranking 128 lncRNAs that could identify the origin of 12 different cancers with an accuracy of 95%. Survival analysis showed that 76 of 128 lncRNAs have the prognostic capability to differentiate high-and low-risk groups of patients with different cancers. Conclusion: The proposed mrCAE, which selects actual features, outperformed the AE even though it selects the latent or pseudo-features. By selecting actual features instead of pseudo-features, mrCAE can be valuable for precision medicine. The identified prognostic lncRNAs can be further studied to develop therapies for different cancers

Correlation of serum aspartate aminotransferase level to platelet count ratio index with non-alcoholic fatty liver disease activity score

In case of non-alcoholic fatty liver disease, the ratio of serum aspartate  aminotransferase (AST) level to platelet count index has been proposed as a non-invasive and readily available tool for the assessment of non-alcoholic steatohepatitis. The study was conducted on 50  non-alcoholic fatty liver disease patient (25  non-alcoholic steatohepatitis and 25 simple steatosis). The mean (± SD) serum AST level in the non-alcoholic steatohepatitis group  was 55.2 ± 30.1 IU/L whereas in simple steatosis group it was 33.6 ± 20.0 IU/L. The mean platelet count in the non-alcoholic steatohepatitis group was 303.1 ± 68.7 x 109 /L whereas in the simple steatosis group it was 327.8 ± 66.8 x 109/L. The mean AST platelet ratio index (APRI) score in non-alcoholic steatohepatitis group was 0.5 ± 0.3 and in the simple steatosis group it was 0.3 ± 0.2. In conclusion, the APRI  was  significantly higher in the non-alcoholic steatohepatitis group than the simple steatosis group

Stimulating effect of terfenadine on erythrocyte cell membrane scrambling

Background/Aims: The antihistaminic drug Terfenadine may trigger apoptosis of tumor cells, an effect unrelated to its effect on histamine receptors. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal death of erythrocytes characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling triggering eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, and ceramide. The present study explored, whether Terfenadine is capable to trigger eryptosis. Methods: Flow cytometry was employed to estimate phosphatidylserine abundance at the erythrocyte surface from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, abundance of reactive oxygen species (ROS) from 2\u2032,7\u2032-dichlorodihydrofluorescein (DCF) diacetate dependent fluorescence, and ceramide abundance at the human erythrocyte surface utilizing specific antibodies. Hemolysis was quantified from haemoglobin concentration in the supernatant. Results: A 48 hours exposure of human erythrocytes to Terfenadine ( 65 5 \u3bcM) significantly increased the percentage of annexin-V-binding cells and triggered hemolysis without significantly modifying the average forward scatter. Terfenadine (7.5 \u3bcM) significantly increased Fluo3-fluorescence, but did not significantly modify DCF fluorescence or ceramide abundance. The effect of Terfenadine on annexin-V-binding was significantly blunted but not abolished by removal of extracellular Ca2+. Exposure of human erythrocytes to Ca2+ ionophore ionomycin (1 \u3bcM, 15 min) triggered annexin-V-binding, an effect augmented by Terfenadine pretreatment (10 \u3bcM, 48 hours). Conclusions: Terfenadine triggers phospholipid scrambling of the human erythrocyte cell membrane, an effect in part due to entry of extracellular Ca2+ and in part due to sensitizing human erythrocyte cell membrane scrambling to Ca2+