Hairpin structures formed by alpha satellite DNA of human centromeres are cleaved by human topoisomerase IIα

Although centromere function has been conserved through evolution, apparently no interspecies consensus DNA sequence exists. Instead, centromere DNA may be interconnected through the formation of certain DNA structures creating topological binding sites for centromeric proteins. DNA topoisomerase II is a protein, which is located at centromeres, and enzymatic topoisomerase II activity correlates with centromere activity in human cells. It is therefore possible that topoisomerase II recognizes and interacts with the alpha satellite DNA of human centromeres through an interaction with potential DNA structures formed solely at active centromeres. In the present study, human topoisomerase IIα-mediated cleavage at centromeric DNA sequences was examined in vitro. The investigation has revealed that the enzyme recognizes and cleaves a specific hairpin structure formed by alpha satellite DNA. The topoisomerase introduces a single-stranded break at the hairpin loop in a reaction, where DNA ligation is partly uncoupled from the cleavage reaction. A mutational analysis has revealed, which features of the hairpin are required for topoisomerease IIα-mediated cleavage. Based on this a model is discussed, where topoisomerase II interacts with two hairpins as a mediator of centromere cohesion

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

Optimal probabilistic reliability-oriented planning of islanded microgrids considering hydrogen-based storage systems, hydrogen vehicles, and electric vehicles under various climatic conditions

Much attention has been paid to the deployment of Hydrogen storage systems (HSSs) and Hydrogen vehicles (HVs) in the modernized energy system. However, a research gap exists in the literature about optimal probabilistic planning of microgrids (MGs) equipped with HSS, considering the uncertainties of renewable energy resources and electric vehicle (EV) and HV owners’ behaviors. The main purpose of this research is to fill such a gap by developing a new probabilistic optimization problem to determine the capacity of Hydrogen-based MGs’ sub-systems. Another contribution is to consider the reliability constraints and loss of energy cost (LOEC) in the MGs’ total net present cost (TNPC). The Monte Carlo simulation (MCS) and Flower Pollination Algorithm (FPA) are used to model stochastic behaviors and solve the proposed probabilistic optimization problem. This paper studies different actual climates of Iran based on historical data, while various coordinated/uncoordinated charging modes of EVs and HVs are examined. Test results infer that a significant inaccuracy (more than 4.66% depends on the climate conditions and vehicle scenarios) occurs due to neglecting the uncertainties. The sensitivity analyses imply that the reliability constraints, LOEC, and their interactions might affect the MGs’ optimal design

Hairpins in a DNA site for topoisomerase II studied by 1H- and 31P-NMR.

1H- and 31P-NMR and UV-absorption studies were carried out with the oligonucleotide strands d(AGCT-TATC-ATC-GATAAGCT) (-ATC-) and d(AGCTTATC-GAT-GATAAGCT) (-GAT-) contained in the strongest and salt resistant cleavage site for topoisomerase II in pBR322 DNA. We found that the two oligonucleotides were stabilized under a hairpin structure characterized by a eight base pair stem and a three base loop at low DNA and salt concentrations. In such experimental conditions, only the -GAT- oligonucleotide displayed a partial homoduplex structure in slow equilibrium with its folded structure. Temperature dependencies of imino protons showed that the partial homoduplex of -GAT- melted at a lower temperature than the hairpin structure. It was suggested that the appearance of the partial homoduplex in -GAT- is related to the formation of two stabilizing (G.T) mismatched base pairs in the central loop of this structure. Finally, it was inferred from the dispersion of chemical shifts in the 31P-NMR spectra that the distortions affecting the backbone of the hairpin loop are larger in the case of -ATC- compared with -GAT-. At the same time NOEs proved that the base stacking was stronger within the loop of the -ATC- hairpin

Magnetocaloric properties of metallic nanostructures

A compilation of magnetocaloric properties of metallic nanostructures with Curie temperature (TC) between 260 and 340 K has been tabulated. The tabulated data show that nanostructure plays an important role in enhancing the magnetocaloric properties of a material, namely by reducing the peak of magnetic entropy, but broadening of the magnetocaloric effect curve with an average of 10 K sliding window for Curie temperature. A second table lists all bulk metallic and intermetallic materials, in which there is no nanostructural data, with an entropy change of at least 20 J/kg K and a Curie temperature between 260 and 340 K. We propose that further experiments should be made on the nanostructured form of these materials

Magnetocaloric properties of metallic nanostructures

Abstract: A compilation of magnetocaloric properties of metallic nanostructures with Curie temperature (T C ) between 260 and 340 K has been tabulated. The tabulated data show that nanostructure plays an important role in enhancing the magnetocaloric properties of a material, namely by reducing the peak of magnetic entropy, but broadening of the magnetocaloric effect curve with an average of 10 K sliding window for Curie temperature. A second table lists all bulk metallic and intermetallic materials, in which there is no nanostructural data, with an entropy change of at least 20 J/kg K and a Curie temperature between 260 and 340 K. We propose that further experiments should be made on the nanostructured form of these materials

Correlational Approach to Predict the Enthalpy of Mixing for Chloride Melt Systems

A methodology to estimate the heat of mixing (Delta H-mix) for salt liquids in unexplored AkCl-AnCl(x)/LnCl(x) (Ak = alkali, An = actinide, Ln = lanthanide) systems is developed. It improves upon previous empirical approaches by eliminating the need for arbitrarily choosing the required composition at maximum short-range ordering, the minimum Delta H-mix prior to performing the estimation, which avoids the intrinsic ambiguity of that approach. This semiempirical method has computationally reproduced the behavior of NaCl-UCl3 and KCl-UCl3 systems, providing Delta H-mix values that agree well with the reported measurements within a propagated two standard deviations (2 sigma). The capability of the approach is demonstrated in its application to the entirety of the AkCl-UCl3 and AkCl-PuCl3 systems, the results from which have facilitated the accurate thermodynamic modeling of these and other AkCl-AnCl(3)/LnCl(3) systems. The resultant assessed Gibbs energy functions and models have been incorporated in the Molten Salt Thermal Properties Database-Thermochemical (MSTDB-TC).National Nuclear Security Administration of the U.S. Department of Energy [89233218NCA000001]The authors acknowledge support from the MSTDB-TC development effort under the Nuclear Energy Advanced Modeling and Simulation Program administered by Los Alamos National Laboratory, which is operated by Triad National Security, LLC, for the National Nuclear Security Administration of the U.S. Department of Energy under contract number 89233218NCA000001