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Suicide is defined as the action of harming oneself with the intention of dying. It is estimated that worldwide one suicide occurs every 40 seconds, making it a major health problem. Studies in families have suggested that suicide has a genetic component, around the world studies have been carried out in search of genetic variants associated with suicidal behavior, these variants could be useful as potential biomarkers to identify people at risk of suicide. In this area in Mexico, some studies of variants in genes related to neurotransmission and other important pathways have been carried out and a possible association of variants located in genes has been suggested: SLC6A4, SAT-1, TPH-2, ANKK1, GSHR, SCARA50, RGS10, STK33, COMT, and FKBP5. This systematic review shows the genetic studies on the Mexican population. This article contributes by compiling the existing information on genetic variants and genes associated with suicidal behavior, said variants in the future could be used as potential biomarkers to identify people at risk of suicide.

Background The reduction of low-density lipoprotein cholesterol (LDLc) levels is Key for improving the prognosis of patiens with acute coronary syndrome (ACS). Purpose To estimate the clinical characteristics and treatments of patients with a first episode of ACS in real world in a large database in Spain. Methods An observational and retrospective study was carried out based on electronic medical records of primary care centers and hospitals including 969.587 spanish patients aged >18 years.From these, we selected the ones with a first episode of ACS between 01/07/2016 and 30/06/2018, with a follow-up period of 18 months. Patients were divided according to the intensity of their lipid-lowering treatments: low, moderate, high (high intensity statin/moderate plus ezetimibe), very high (high intensity statin plus ezetimibe) and extreme (IPCSK added) and those on treatment with lipid-lowering drugs other than statins. The incidence of new cardiovascular events, the reduction of LDLc levels, the persistence rates at 9 and 18 months, and the mortality rates were estimated. The concomitant treatments prescribed at the start of the study were registered. Results A first episode of ACS was detected in 7,150 patients (mean age: 70 years [SD: 9.6]; males: 62.2%). The intensity of their lipid-lowering treatments: low [n=172 (2.4%)], moderate [n=370 (5.2%)], high [n=3,751 (52.5%)], very high [n=2,457 (34.4%)], extreme [n=67 (0.9%)])and non-statins lipid-lowering treatments (n=333 [4.7%]). Patients with lipid-lowering treatments other than statins had the highest incidence rate of cardiovascular events (33.0%), followed by those on treatment with low intensity treatments (32.0%): acute myocardial infarction and angina were the most frequent cardiovascular events. The deepest reductions of LDLc levels at 18 months were reported in patients with extreme intensity and very-high intensity treatments (−60.5 mg/dL [42.9%] and −31.6 mg/dL [24.3%], respectively). The persistence rates at 9 and 18 months were higher in patients with extreme intensity and very high intensity lipid-lowering treatments. The highest mortality rate was observed in patients with lipid-lowering treatments other than statins (12.6%), with the median time to death being 221 days (P25–P75: 116–327). The lowest mortality rate was registered in patients with extreme intensity lipid-lowering treatments, who showed a median time to death of 405 days (P25–P75: 396–0).Overall, referral to Cardiac Rehabilitation in ACS is less than 20% in Spain. Conclusion Patients with ACS who received lipid-lowering treatments other than statins and low intensity treatments had the highest incidence of cardiovascular events and mortality rates.The reduction of LDLc levels increased with the intensity of the lipid-lowering treatments, which may lead to a reduced risk of cardiovascular events and death. More referral to Cardiac Rehabilitation could also improve these results Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): SANOFI

We present heavy ion and proton data on AlGaN high-voltage HEMTs showing single event burnout (SEB), total ionizing dose, and displacement damage responses. These are the first such data for materials of this type. Two different designs of the epitaxial structure were tested for SEB. The default layout design showed burnout voltages that decreased rapidly with increasing LET, falling to about 25% of nominal breakdown voltage for ions with LET of about 34 MeV $\cdot $ cm2/mg for both structures. Samples of the device structure with lower AlN content were tested with varying gate–drain spacing and revealed an improved robustness to heavy ions, resulting in burnout voltages that did not decrease up to at least 33.9 MeV $\cdot $ cm2/mg. Failure analysis showed that there was consistently a point, location random, where gate and drain had been shorted. Oscilloscope traces of terminal voltages and currents during burnout events lend support to the hypothesis that burnout events begin with a heavy ion strike in the vulnerable region between gate and drain. This subsequently initiates a cascade of events resulting in damage that is largely manifested elsewhere in the device. This hypothesis also suggests a path for greatly improving the susceptibility to SEB as development of this technology goes forward. Testing with 2.5-MeV protons showed only minor changes in device characteristics.

Chronic liver inflammation may lead to hepatic cirrhosis, limiting its regenerative capacity. The clinical standard of care is transplantation, although stem cell therapy may be an alternative option. The study aim was to induce endogenous hematopoietic stem cells (HSCs) with granulocyte colony stimulating factor (G-CSF) and/or intravenous administration of adipose tissue-derived mesenchymal stem cells (MSCs) to decrease hepatic fibrosis in an experimental model.A liver fibrosis model was developed with female Wistar rats via multiple intraperitoneal doses of carbon tetrachloride. Three rats were selected to confirm cirrhosis, and the rest were set into experimental groups to evaluate single and combined therapies of G-CSF-stimulated HSC mobilization and intravenous MSC administration.Treatment with MSCs and G-CSF significantly improved alanine amino transferase levels, while treatment with G-CSF, MSCs, and G-CSF+MSCs decreased aspartate amino transferase levels. Hepatocyte growth factor (HGF) and interleukin 10 levels increased with MSC treatment. Transforming growth factor β levels were lower with MSC treatment. Interleukin 1β and tumor necrosis factor alpha levels decreased in all treated groups. Histopathology showed that MSCs and G-CSF reduced liver fibrosis from F4 to F2.MSC treatment improves liver function, decreases hepatic fibrosis, and plays an anti-inflammatory role; it promotes HGF levels and increased proliferating cell nuclear antigen when followed by MSC treatment mobilization using G-CSF. When these therapies were combined, however, fibrosis improvement was less evident.

Brn-3a and Brn-3b are transcription factors expressed mainly in somatosensory neurons during embryonic stage; but they are absent in adulthood. Both share the same DNA binding site with an antagonist effect. Brn-3a expression has been reported 300 fold increased in Cervical Intraepithelial Neoplasia grade 3 (CIN3) compared with normal cervix tissue; some studies suggest that Brn-3a may increase the expression of HPV onco-proteins E6 and E7 by interaction with the promoter region of some high risk HPV genotypes. In this study, we analyzed the expression of Brn-3a and Brn-3b in laryngeal tissue biopsies from patients with Recurrent Respiratory Papillomatosis (RRP) and in volunteers´ health tissue. HPV was detected in all RRP samples and only HPV-6 and HPV-11 were detected in the samples of RRP. Brn-3a was expressed in 87% of the samples and Brn-3b in 45% coexpressed with Brn-3a. Brn-3a is expressed in laryngeal papillomas of patients with RRP diagnostic; but not in normal laryngeal tissue. The most of the samples expresses Brn-3a and only half weakly expresses Brn-3b; which suggests that the antagonist role of Brn-3b over Brn-3a is absent in this process.

In this study, we present low-energy proton single-event upset (SEU) data on a 65 nm SOI SRAM whose substrate has been completely removed. Since the protons only had to penetrate a very thin buried oxide layer, these measurements were affected by far less energy loss, energy straggle, flux attrition, and angular scattering than previous datasets. The minimization of these common sources of experimental interference allows more direct interpretation of the data and deeper insight into SEU mechanisms. The results show a strong angular dependence, demonstrate that energy straggle, flux attrition, and angular scattering affect the measured SEU cross sections, and prove that proton direct ionization is the dominant mechanism for low-energy proton-induced SEUs in these circuits.

This conference presents the recipients of the Outstanding Conference Paper Award from the 2015 IEEE Nuclear and Space Radiation Effects Conference.

Low- and high-energy proton experimental data and error rate predictions are presented for many bulk Si and SOI circuits from the 20-90 nm technology nodes to quantify how much low-energy protons (LEPs) can contribute to the total on-orbit single-event upset (SEU) rate. Every effort was made to predict LEP error rates that are conservatively high; even secondary protons generated in the spacecraft shielding have been included in the analysis. Across all the environments and circuits investigated, and when operating within 10% of the nominal operating voltage, LEPs were found to increase the total SEU rate to up to 4.3 times as high as it would have been in the absence of LEPs. Therefore, the best approach to account for LEP effects may be to calculate the total error rate from high-energy protons and heavy ions, and then multiply it by a safety margin of 5. If that error rate can be tolerated then our findings suggest that it is justified to waive LEP tests in certain situations. Trends were observed in the LEP angular responses of the circuits tested. As a result, grazing angles were the worst case for the SOI circuits, whereas the worst-case angle was at or nearmore » normal incidence for the bulk circuits.« less

The recipients of the 2014 NSREC Outstanding Conference Paper Award are Nathaniel A. Dodds, James R. Schwank, Marty R. Shaneyfelt, Paul E. Dodd, Barney L. Doyle, Michael Trinczek, Ewart W. Blackmore, Kenneth P. Rodbell, Michael S. Gordon, Robert A. Reed, Jonathan A. Pellish, Kenneth A. LaBel, Paul W. Marshall, Scot E. Swanson, Gyorgy Vizkelethy, Stuart Van Deusen, Frederick W. Sexton, and M. John Martinez, for their paper entitled "Hardness Assurance for Proton Direct Ionization-Induced SEEs Using a High-Energy Proton Beam." For older CMOS technologies, protons could only cause single-event effects (SEEs) through nuclear interactions. Numerous recent studies on 90 nm and newer CMOS technologies have shown that protons can also cause SEEs through direct ionization. Furthermore, this paper develops and demonstrates an accurate and practical method for predicting the error rate caused by proton direct ionization (PDI).

The low-energy proton energy spectra of all shielded space environments have the same shape. This shape is easily reproduced in the laboratory by degrading a high-energy proton beam, producing a high-fidelity test environment. We use this test environment to dramatically simplify rate prediction for proton direct ionization effects, allowing the work to be done at high-energy proton facilities, on encapsulated parts, without knowledge of the IC design, and with little or no computer simulations required. Proton direct ionization (PDI) is predicted to significantly contribute to the total error rate under the conditions investigated. Scaling effects are discussed using data from 65-nm, 45-nm, and 32-nm SOI SRAMs. These data also show that grazing-angle protons will dominate the PDI-induced error rate due to their higher effective LET, so PDI hardness assurance methods must account for angular effects to be conservative. As a result, we show that this angular dependence can be exploited to quickly assess whether an IC is susceptible to PDI.

Refolding of the acid-unfolded precursor to mitochondrial aspartate aminotransferase (pmAAT) is inhibited when cytosolic Hsc70 is included in the refolding reaction (Artigues, A., Iriarte, A., and Martinez-Carrion, M. (1997) J. Biol. Chem. 272, 16852-16861). At low molar excess of Hsc70 pmAAT is recovered in insoluble aggregates containing equal amounts of Hsc70. However, in the presence of a large excess of Hsc70, refolding of pmAAT is still arrested, but the enzyme remains in solution. Similar behavior was observed with two other cytosolic chaperones, bovine Hsp90 and yeast Ydj1. Coimmunoprecipitation of pmAAT using Hsc70 antibodies confirmed the formation of soluble Hsc70-pmAAT complexes at high concentrations of the chaperone. Data from analytical centrifugation, sedimentation in glycerol gradients, and partial purification of the soluble complexes indicate that multiple Hsc70 molecules bind per pmAAT polypeptide chain. The absence of catalytic activity together with the protease susceptibility of pmAAT bound to Hsc70, Hsp90, or Ydj1 suggest that these chaperones bind and maintain pmAAT in a partially unfolded state, analogous to the import-competent conformation of the protein synthesized in cell-free extracts. Remarkably, the purified pmAAT bound to Hsc70 or Ydj1, but not to Hsp90, is imported by isolated mitochondria in a reticulocyte lysate-dependent manner. Thus, both Hsc70 and Ydj1 can trap an import-competent folding intermediate of pmAAT, but productive binding and import into mitochondria require the collaboration of additional cytosolic factors from the lysate.

The possible contribution of the mature portion of a mitochondrial precursor protein to its interaction with membrane lipids is unclear. To address this issue, we examined the interaction of the precursor to mitochondrial aspartate aminotransferase (pmAAT) and of a synthetic peptide corresponding to the 29-residue presequence peptide (mAAT-pp) with anionic phospholipid vesicles. The affinity of mAAT-pp and pmAAT for anionic vesicles is nearly identical. Results obtained by analyzing the effect of mAAT-pp or full-length pmAAT on either the permeability or microviscosity of the phospholipid vesicles are consistent with only a shallow insertion of the presequence peptide in the bilayer. Analysis of the quenching of Trp-17 fluorescence by brominated phospholipids reveals that this presequence residue inserts to a depth of approximately 9 A from the center of the bilayer. Furthermore, in membrane-bound pmAAT or mAAT-pp, both Arg-8 and Arg-28 are accessible to the solvent. These results suggest that the presequence segment lies close to the surface of the membrane and that the mature portion of the precursor protein has little effect on the affinity or mode of binding of the presequence to model membranes. In the presence of vesicles, mAAT-pp adopts considerable α-helical structure. Hydrolysis by trypsin after Arg-8 results in the dissociation of the remaining 21-residue C-terminal peptide fragment from the membrane bilayer, suggesting that the N-terminal portion of the presequence is essential for membrane binding. Based on these results, we propose that the presequence peptide may contain dual recognition elements for both the lipid and import receptor components of the mitochondrial membrane.

At 30 degrees C, the precursor to mitochondrial aspartate aminotransferase (pmAspAT) cannot fold after synthesis in rabbit reticulocyte lysate (RRL), a model for studying intracellular protein folding. However, it folds rapidly once imported into mitochondria. Guanidinium chloride denatured pmAspAT likewise cannot refold at 30 degrees C in a defined in vitro system. However, it refolds rapidly and in good yield in the presence of the intramitochondrial chaperone homologues GroEL and GroES. In this report, we demonstrate that GroEL and GroES can also facilitate the folding of nascent pmAspAT in reticulocyte lysate under conditions where it otherwise would not. When added alone, GroEL arrests the slow folding of nascent pmAspAT and inhibits import into mitochondria. These effects are significantly reversed by adding GroES. These observations suggest that added GroEL participates in an equilibrium with endogenous chaperones in the cytosol which inhibit folding and promote import competence. Native gel electrophoresis suggests that nascent pmAspAT exists in RRL as a heterogeneous population of partially folded species, some of which bind to added GroEL more readily than others. The GroEL-trapped species appear to be among the productive pmAspAT folding intermediates formed in RRL or they at least appear to equilibrate with these intermediates, since they become import competent after GroES-stimulated release from GroEL.

Cytosolic Hsc70 discriminates between the homologous mitochondrial and cytosolic isozymes of aspartate aminotransferase, binding exclusively the mitochondrial form. By screening a library of synthetic peptides spanning the sequence of the mitochondrial enzyme, we have identified binding sites in this polypeptide that interact with Hsc70. These potential binding sites are scattered over the entire sequence and map to secondary structure elements, particularly the a-helix, that are partly exposed on the surface of the native protein. Several peptides corresponding to analogous positions in the cytosolic enzyme sequence do not bind to Hsc70. Phylogenetic analyses suggest that Hsc70 binding sequences have diverged as a consequence of biochemical specialization ensuring differential interaction of each isozyme with the cellular machinery in charge of protein folding and translocation.