Protective Effects of Pyruvic Acid Salt Against Lithium Toxicity andOxidative Damage in Human Blood Mononuclear Cells

Purpose: Aim of present work was to study cytoprotective properties of lithium pyruvate, as a prospective pharmacological agent. Pyruvate has a lot of potential benefits due to positive influence on cell metabolism. Lithium is “gold-standard” mood-stabilizer. Combination of both may lead advantages. Methods: Lithium pyruvate was tested as cytoprotector on human blood mononuclears under induced oxidative stress. Cells were obtained from healthy donors and patients with alcoholism. The detection of cell viability, apoptosis and determination of oxidative stress level were conducted by flow cytometry. Results: Lithium pyruvate showed excellent cytoprotective properties in normal and oxidation conditions. This effect was independent from cell donor health status. It was shown on cells from healthy donors and alcoholics patients. Conclusion: Obtained results allow considering lithium pyruvate as potential normothymic agents (mood stabilizer) with excellent cytoprotective properties

Protective Effects of Pyruvic Acid Salt Against Lithium Toxicity andOxidative Damage in Human Blood Mononuclear Cells

Purpose: Aim of present work was to study cytoprotective properties of lithium pyruvate, as a prospective pharmacological agent. Pyruvate has a lot of potential benefits due to positive influence on cell metabolism. Lithium is “gold-standard” mood-stabilizer. Combination of both may lead advantages. Methods: Lithium pyruvate was tested as cytoprotector on human blood mononuclears under induced oxidative stress. Cells were obtained from healthy donors and patients with alcoholism. The detection of cell viability, apoptosis and determination of oxidative stress level were conducted by flow cytometry. Results: Lithium pyruvate showed excellent cytoprotective properties in normal and oxidation conditions. This effect was independent from cell donor health status. It was shown on cells from healthy donors and alcoholics patients. Conclusion: Obtained results allow considering lithium pyruvate as potential normothymic agents (mood stabilizer) with excellent cytoprotective properties

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Exploring, Refining, and Validating the Paradynamics QM/MM Sampling

The performance of the paradynamics (PD) reference potential approach in QM/MM calculations is examined. It is also clarified that, in contrast to some possible misunderstandings, this approach provides a rigorous strategy for QM/MM free energy calculations. In particular, the PD approach provides a gradual and controlled way of improving the evaluation of the free energy perturbation associated with moving from the EVB reference potential to the target QM/MM surface. This is achieved by moving from the linear response approximation to the full free energy perturbation approach in evaluating the free energy changes. We also present a systematic way of improving the reference potential by using Gaussian-based correction potentials along a reaction coordinate. In parallel, we review other recent adaptations of the reference potential approach, emphasizing and demonstrating the advantage of using the EVB potential as a reference potential, relative to semiempirical QM/MM molecular orbital potentials. We also compare the PD results to those obtained by direct calculations of the potentials of the mean force (PMF). Additionally, we propose a way of accelerating the PMF calculations by using Gaussian-based negative potentials along the reaction coordinate (which are also used in the PD refinement). Finally, we discuss performance of the PD and the metadynamics approaches in ab initio QM/MM calculations and emphasize the advantage of using the PD approach

Molecular Origin of Mechanical Sensitivity of the Reaction Rate in Anthracene Cyclophane Isomerization Reveals Structural Motifs for Rational Design of Mechanophores

The observed pressure sensitivity of the isomerization reaction rate of bis-anthracene cyclophane photoisomer has attracted significant attention in the rational design of mechanically sensitive materials. However, the molecular origin of this sensitivity remains unclear. We developed an ab initio molecular model to quantify the effect of pressure on the reaction rate and to elucidate its molecular origin. Pressure-induced deformations and changes along the reaction free-energy surfaces are estimated from ab initio molecular dynamics trajectories. Our model predicts a barrier reduction of ∼2 kcal/mol at 0.9 GPa (in agreement with experiment). The barrier reduction is linear in the low-pressure regime (up to 2 GPa) but has a nonlinear dependence at higher pressures. We find that pressure alters the reaction path and that the mechanical sensitivity of the reaction rate is caused by an uneven distribution of the free-energy increase along the reaction surface. The uneven distribution primarily results from destabilization of the reactant, which has a lower mechanical rigidity along a particular deformation mode (flattening of anthracene rings as they are pushed toward each other in the cyclophane framework). Exploiting similar structural motifs to maximize rigidity differences along the reaction coordinate represents a promising rational design strategy

Quantifying the Risks of Asparagine Deamidation and Aspartate Isomerization in Biopharmaceuticals by Computing Reaction Free-Energy Surfaces

Early identification of asparagine deamidation and aspartate isomerization degradation sites can facilitate the successful development of biopharmaceuticals. Several knowledge-based models have been proposed to assess these degradation risks. In this study, we propose a physics-based approach to identify the degradation sites on the basis of the free-energy barriers along the prechemical conformational step and the chemical reaction pathway. These contributions are estimated from classical and quantum mechanics/molecular mechanics molecular dynamics simulations. The computed barriers are compared to those for reference reactions in water within GNG and GDG sequence motifs in peptides (which demonstrate the highest degradation rates). Two major factors decreasing the degradation rates relative to the reference reactions are steric hindrance toward accessing reactive conformations and replacement of water by less polar side chains in the solvation shell of transition states. Among the potential degradation sites in the complementarity-determining region of trastuzumab and between two DK sites in glial cell-derived neurotropic factor, this method identified N³⁰T, N⁵⁵G, D¹⁰²G, and D⁹⁵K, respectively, in agreement with experiments. This approach can be incorporated in early computational screening of chemical degradation sites in biopharmaceuticals

Quantifying the Mechanism of Phosphate Monoester Hydrolysis in Aqueous Solution by Evaluating the Relevant Ab Initio QM/MM Free-Energy Surfaces

Understanding the nature of the free-energy surfaces for phosphate hydrolysis is a prerequisite for understanding the corresponding key chemical reactions in biology. Here, the challenge has been to move to careful ab initio QM/MM (QM­(ai)/MM) free-energy calculations, where obtaining converging results is very demanding and computationally expensive. This work describes such calculations, focusing on the free-energy surface for the hydrolysis of phosphate monoesters, paying special attention to the comparison between the one water (1W) and two water (2W) paths for the proton-transfer (PT) step. This issue has been explored before by energy minimization with implicit solvent models and by nonsystematic QM/MM energy minimization, as well as by nonsystematic free-energy mapping. However, no study has provided the needed reliable 2D (3D) surfaces that are necessary for reaching concrete conclusions. Here we report a systematic evaluation of the 2D (3D) free-energy maps for several relevant systems, comparing the results of QM­(ai)/MM and QM­(ai)/implicit solvent surfaces, and provide an advanced description of the relevant energetics. It is found that the 1W path for the hydrolysis of the methyl diphosphate (MDP) trianion is 6–9 kcal/mol higher than that the 2W path. This difference becomes slightly larger in the presence of the Mg²⁺ ion because this ion reduces the p<i>K</i>_a of the conjugated acid form of the phosphate oxygen that accepts the proton. Interestingly, the BLYP approach (which has been used extensively in some studies) gives a much smaller difference between the 1W and 2W activation barriers. At any rate, it is worth pointing out that the 2W transition state for the PT is not much higher that the common plateau that serves as the starting point of both the 1W and 2W PT paths. Thus, the calculated catalytic effects of proteins based on the 2W PT mechanistic model are not expected to be different from the catalytic effects predicted using the 1W PT mechanistic model, which was calibrated on the observed barrier in solution and in which the TS charge distribution was similar to the that of the plateau (as was done in all of our previous EVB studies)

The mitochondria-targeted antioxidants and remote kidney preconditioning ameliorate brain damage through kidney-to-brain cross-talk.

BACKGROUND: Many ischemia-induced neurological pathologies including stroke are associated with high oxidative stress. Mitochondria-targeted antioxidants could rescue the ischemic organ by providing specific delivery of antioxidant molecules to the mitochondrion, which potentially suffers from oxidative stress more than non-mitochondrial cellular compartments. Besides direct antioxidative activity, these compounds are believed to activate numerous protective pathways. Endogenous anti-ischemic defense may involve the very powerful neuroprotective agent erythropoietin, which is mainly produced by the kidney in a redox-dependent manner, indicating an important role of the kidney in regulation of brain ischemic damage. The goal of this study is to track the relations between the kidney and the brain in terms of the amplification of defense mechanisms during SkQR1 treatment and remote renal preconditioning and provide evidence that the kidney can generate signals inducing a tolerance to oxidative stress-associated brain pathologies. METHODOLOGY/PRINCIPAL FINDINGS: We used the cationic plastoquinone derivative, SkQR1, as a mitochondria-targeted antioxidant to alleviate the deleterious consequences of stroke. A single injection of SkQR1 before cerebral ischemia in a dose-dependent manner reduces infarction and improves functional recovery. Concomitantly, an increase in the levels of erythropoietin in urine and phosphorylated glycogen synthase kinase-3β (GSK-3β) in the brain was detected 24 h after SkQR1 injection. However, protective effects of SkQR1 were not observed in rats with bilateral nephrectomy and in those treated with the nephrotoxic antibiotic gentamicin, indicating the protective role of humoral factor(s) which are released from functional kidneys. Renal preconditioning also induced brain protection in rats accompanied by an increased erythropoietin level in urine and kidney tissue and P-GSK-3β in brain. Co-cultivation of SkQR1-treated kidney cells with cortical neurons resulted in enchanced phosphorylation of GSK-3β in neuronal cells. CONCLUSION: The results indicate that renal preconditioning and SkQR1-induced brain protection may be mediated through the release of EPO from the kidney

Macrophage Phenotype in Combination with Tumor Microbiome Composition Predicts RCC Patients’ Survival: A Pilot Study

The identification of new prognostic markers of renal cell carcinoma (RCC) is an urgent problem in oncourology. To investigate the potential prognostic significance of tumor microbiome and stromal inflammatory markers, we studied a cohort of 66 patients with RCC (23 clear cell RCC, 19 papillary RCC and 24 chromophobe RCC). The microbiome was analyzed in tumor and normal tissue by 16S rRNA amplicon sequencing. Characterization of the tumor stroma was performed using immunohistochemistry. A significant difference in alpha diversity was demonstrated between normal kidney tissue and all types of RCC. Further, we demonstrated that the bacterial burden was higher in adjacent normal tissue than in a tumor. For the first time, we demonstrated a significant correlation between bacterial burden and the content of PU.1+ macrophages and CD66b+ neutrophils in kidney tumors. Tumors with high content of PU.1+ cells and CD66b+ cells in the stroma were characterized by a lower bacterial burden. In the tumors with high bacterial burden, the number of PU.1+ cells and CD66b+ was associated with a poor prognosis. The identified associations indicate the great prognostic potential of a combined tumor microbiome and stromal cell analysis

Pressure-Induced Neutral-to-Ionic Transition in an Amorphous Organic Material

Pressure-Induced Neutral-to-Ionic Transition in an Amorphous Organic Materia