Conformational Changes and Slow Dynamics through Microsecond Polarized Atomistic Molecular Simulation of an Integral Kv1.2 Ion Channel

Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins—not to mention numerous applications in drug design. Here, we present a full 1 µs atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120° rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation (∼35°) of the extracellular end of all S4 segments is present also in a reference 0.5 µs simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 310 helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4–lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5–1 µs). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs 1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). Interpretation: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury

Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. Methods: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. Findings: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. Interpretation: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing

On the choice of the best members of the Kim family and the improvement of its convergence

The best members of the Kim family, in terms of stability, are obtained by using complex dynamics. From this elements, parametric iterative methods with memory are designed. A dynamical analysis of the methods with memory is presented in order to obtain information about the stability of them. Numerical experiments are shown for confirming the theoretical results

CMMSE-2019 mean-based iterative methods for solving nonlinear chemistry problems

[EN] The third-order iterative method designed by Weerakoon and Fernando includes the arithmetic mean of two functional evaluations in its expression. Replacing this arithmetic mean with different means, other iterative methods have been proposed in the literature. The evolution of these methods in terms of order of convergence implies the inclusion of a weight function for each case, showing an optimal fourth-order convergence, in the sense of Kung-Traub's conjecture. The analysis of these new schemes is performed by means of complex dynamics. These methods are applied on the solution of the nonlinear Colebrook-White equation and the nonlinear system of the equilibrium conversion, both frequently used in Chemistry.This research was partially supported by PGC2018-095896-B-C22 (MCIU/AEI/FEDER/UE) and Generalitat Valenciana PROMETEO/2016/089.Chicharro, FI.; Cordero Barbero, A.; Martínez, TH.; Torregrosa Sánchez, JR. (2020). CMMSE-2019 mean-based iterative methods for solving nonlinear chemistry problems. Journal of Mathematical Chemistry. 58(3):555-572. https://doi.org/10.1007/s10910-019-01085-2S555572583O. Ababneh, New Newton’s method with third order convergence for solving nonlinear equations. World Acad. Sci. Eng. Technol. 61, 1071–1073 (2012)S. Amat, S. Busquier, Advances in iterative methods for nonlinear equations, chapter 5. SEMA SIMAI Springer Series. (Springer, Berlin, 2016), vol. 10, pp. 79–111R. Behl, Í. Sarría, R. González, Á.A. Magreñán, Highly efficient family of iterative methods for solving nonlinear models. J. Comput. Appl. Math. 346, 110–132 (2019)B. Campos, J. Canela, P. Vindel, Convergence regions for the Chebyshev-Halley family. Commun. Nonlinear Sci. Numer. Simul. 56, 508–525 (2018)F.I. Chicharro, A. Cordero, J.R. Torregrosa, Drawing dynamical and parameters planes of iterative families and methods. Sci. World J. 780513, 1–11 (2013)F.I. Chicharro, A. Cordero, J.R. Torregrosa, Dynamics of iterative families with memory based on weight functions procedure. J. Comput. Appl. Math. 354, 286–298 (2019)C.F. Colebrook, C.M. White, Experiments with fluid friction in roughened pipes. Proc. R. Soc. Lond. 161, 367–381 (1937)A. Constantinides, N. Mostoufi, Numerical Methods for Chemical Engineers with MATLAB Applications (Prentice-Hall, Englewood Cliffs, 1999)A. Cordero, J. Franceschi, J.R. Torregrosa, A.C. Zagati, A convex combination approach for mean-based variants of Newton’s method. Symmetry 11, 1062 (2019)A. Cordero, J.R. Torregrosa, Variants of Newton’s method using fifth order quadrature formulas. Appl. Math. Comput. 190, 686–698 (2007)H.T. Kung, J.F. Traub, Optimal order of one-point and multipoint iteration. J. Assoc. Comput. Math. 21, 643–651 (1974)T. Lukić, N. Ralević, Geometric mean Newton’s method for simple and multiple roots. Appl. Math. Lett. 21, 30–36 (2008)A. Özban, Some new variants of Newton’s method. Appl. Math. Lett. 17, 677–682 (2004)M. Petković, B. Neta, L. Petković, J. Dz̆unić, Multipoint Methods for Solving Nonlinear Equations (Academic Press, Cambridge, 2013)E. Shashi, Transmission Pipeline Calculations and Simulations Manual, Fluid Flow in Pipes (Elsevier, London, 2015), pp. 149–234M.K. Singh, A.K. Singh, A new-mean type variant of Newton’s method for simple and multiple roots. Int. J. Math. Trends Technol. 49, 174–177 (2017)K. Verma, On the centroidal mean Newton’s method for simple and multiple roots of nonlinear equations. Int. J. Comput. Sci. Math. 7, 126–143 (2016)S. Weerakoon, T.G.I. Fernando, A variant of Newton’s method with third-order convergence. Appl. Math. Lett. 13, 87–93 (2000)Z. Xiaojian, A class of Newton’s methods with third-order convergence. Appl. Math. Lett. 20, 1026–1030 (2007