Exploring High Dimensional Free Energy Landscapes: Temperature Accelerated Sliced Sampling

Biased sampling of collective variables is widely used to accelerate rare events in molecular simulations and to explore free energy surfaces. However, computational efficiency of these methods decreases with increasing number of collective variables, which severely limits the predictive power of the enhanced sampling approaches. Here we propose a method called Temperature Accelerated Sliced Sampling (TASS) that combines temperature accelerated molecular dynamics with umbrella sampling and metadynamics to sample the collective variable space in an efficient manner. The presented method can sample a large number of collective variables and is advantageous for controlled exploration of broad and unbound free energy basins. TASS is also shown to achieve quick free energy convergence and is practically usable with ab initio molecular dynamics techniques

Sampling Free Energy Surfaces as Slices by Combining Umbrella Sampling and Metadynamics

Metadynamics (MTD) is a very powerful technique to sample high-dimensional free energy landscapes, and due to its self-guiding property, the method has been successful in studying complex reactions and conformational changes. MTD sampling is based on filling the free energy basins by biasing potentials and thus for cases with flat, broad and unbound free energy wells, the computational time to sample them becomes very large. To alleviate this problem, we combine the standard Umbrella Sampling (US) technique with MTD to sample orthogonal collective variables (CVs) in a simultaneous way. Within this scheme, we construct the equilibrium distribution of CVs from biased distributions obtained from independent MTD simulations with umbrella potentials. Reweighting is carried out by a procedure that combines US reweighting and Tiwary-Parrinello MTD reweighting within the Weighted Histogram Analysis Method (WHAM). The approach is ideal for a controlled sampling of a CV in a MTD simulation, making it computationally efficient in sampling flat, broad and unbound free energy surfaces. This technique also allows for a distributed sampling of a high-dimensional free energy surface, further increasing the computational efficiency in sampling. We demonstrate the application of this technique in sampling high-dimensional surface for various chemical reactions using ab initio and QM/MM hybrid molecular dynamics simulations. Further, in order to carry out MTD bias reweighting for computing forward reaction barriers in ab initio or QM/MM simulations, we propose a computationally affordable approach that does not require recrossing trajectories

Mechanism and kinetics of Aztreonam hydrolysis catalyzed by class-C β-lactamase : a temperature-accelerated sliced sampling study

Enhanced sampling of large number of collective variables (CVs) is inevitable in molecular dynamics (MD) simulations of complex chemical processes such as enzymatic reactions. Because of the computational overhead of hybrid quantum mechanical/molecular mechanical (QM/MM)-based MD simulations, especially together with density functional theory, predictions of reaction mechanism, and estimation of free-energy barriers have to be carried out within few tens of picoseconds. We show here that the recently developed temperature-accelerated sliced sampling method allows one to sample large number of CVs, thereby enabling us to obtain rapid convergence in free-energy estimates in QM/MM MD simulation of enzymatic reactions. Moreover, the method is shown to be efficient in exploring flat and broad free-energy basins that commonly occur in enzymatic reactions. We demonstrate this by studying deacylation and reverse acylation reactions of aztreonam drug catalyzed by a class-C β lactamase (CBL) bacterial enzyme. Mechanistic details and nature of kinetics of aztreonam hydrolysis by CBL are elaborated here. The results of this study point to characteristics of the aztreonam drug that are responsible for its slow hydrolysis

Synthesis and Crystallization Studies of Thermo-plastic Polyster/Titania Nanocomposites

The present work reports the non-isothermal crystallization kinetics of PET-TiO2 nanocomposites. The average particle size of TiO2 nanoparticles, prepared by chemical route, has been calculated 32 nm using Debay-Scherrer’s formula in XRD peaks. PET-TiO2 nanocomposites have been synthesized using solution casting method. The investigation of non-isothermal crystallization behavior has been conducted by means of Differential Scanning Calorimeter (DSC). The crystallization temperature shift to lower temperature for both PET pristine and PET-TiO2 nanocomposites due to decrease in mobility of chain segments and heterogeneous nucleation. Also, the inclusion of TiO2 nanoparticles may accelerate nucleation rate in nanocomposites that causes the crystallization time and absolute crystallinity fraction. The thermal conductivity of inorganic filler TiO2 nanoparticles may affect the crystallization temperature

Mechanism of Mg 2+ -accompanied product release in sugar nucleotidyltransferases

The nucleotidyl transfer reaction, catalyzed by sugar nucleotidyltransferases (SNTs), is assisted by two active site Mg 2+ ions. While studying this reaction using X-ray crystallography, we captured snapshots of the pyrophosphate (product) as it exits along a pocket. Surprisingly, one of the active site Mg 2+ ions remains coordinated to the exiting pyrophosphate. This hints at the participation of Mg 2+ in the process of product release, besides its role in catalyzing nucleotidyl transfer. These observations are further supported by enhanced sampling molecular dynamics simulations. Free energy computations suggest that the product release is likely to be rate limiting in SNTs, and the origin of the high free energy barrier for product release could be traced back to the “slow” conformational change of an Arg residue at the exit end of the pocket. These results establish a dual role for Mg 2+, and propose a general mechanism of product release during the nucleotidyl transfer by SNTs

Mass deworming to improve developmental health and wellbeing of children in low-income and middle-income countries: a systematic review and network meta-analysis

Background Soil-transmitted helminthiasis and schistosomiasis, considered among the neglected tropical diseases by WHO, aff ect more than a third of the world’s population, with varying intensity of infection. We aimed to evaluate the eff ects of mass deworming for soil-transmitted helminths (with or without deworming for schistosomiasis or cointerventions) on growth, educational achievement, cognition, school attendance, quality of life, and adverse eff ects in children in endemic helminth areas. Methods We searched 11 databases up to Jan 14, 2016, websites and trial registers, contacted authors, and reviewed reference lists. We included studies published in any language of children aged 6 months to 16 years, with mass deworming for soil-transmitted helminths or schistosomiasis (alone or in combination with other interventions) for 4 months or longer, that reported the primary outcomes of interest. We included randomised and quasi-randomised trials, controlled before–after studies, interrupted time series, and quasi-experimental studies. We screened in duplicate, then extracted data and appraised risk of bias in duplicate with a pre-tested form. We conducted randomeff ects meta-analysis and Bayesian network meta-analysis. Findings We included 52 studies of duration 5 years or less with 1 108 541 children, and four long-term studies 8–10 years after mass deworming programmes with more than 160 000 children. Overall risk of bias was moderate. Mass deworming for soil-transmitted helminths compared with controls led to little to no improvement in weight over a period of about 12 months (0·99 kg, 95% credible interval [CrI] −0·09 to 0·28; moderate certainty evidence) or height (0·07 cm, 95% CrI −0·10 to 0·24; moderate certainty evidence), little to no diff erence in proportion stunted (eight fewer per 1000 children, 95% CrI −48 to 32; high certainty evidence), cognition measured by short-term attention (−0·23 points on a 100 point scale, 95% CI −0·56 to 0·14; high certainty evidence), school attendance (1% higher, 95% CI −1 to 3; high certainty evidence), or mortality (one fewer per 1000 children, 95% CI −3 to 1; high certainty evidence). We found no data on quality of life and little evidence of adverse eff ects. Mass deworming for schistosomiasis might slightly increase weight (0·41 kg, 95% CrI −0·20 to 0·91) and has little to no eff ect on height (low certainty evidence) and cognition (moderate certainty evidence). Our analyses do not suggest indirect benefi ts for untreated children from being exposed to treated children in the community. We are uncertain about eff ects on long-term economic productivity (hours worked), cognition, literacy, and school enrolment owing to very low certainty evidence. Results were consistent across sensitivity and subgroup analyses by age, worm prevalence, baseline nutritional status, infection status, impact on worms, infection intensity, types of worms (ascaris, hookworm, or trichuris), risk of bias, cluster versus individual trials, compliance, and attrition. Interpretation Mass deworming for soil-transmitted helminths with or without deworming for schistosomiasis had little eff ect. For schistosomiasis, mass deworming might be eff ective for weight but is probably ineff ective for height, cognition, and attendance. Future research should assess which subset of children do benefi t from mass deworming, if any, using individual participant data meta-analysis

Mass deworming to improve developmental health and wellbeing of children in low-income and middle-income countries: a systematic review and network meta-analysis.

BACKGROUND: Soil-transmitted helminthiasis and schistosomiasis, considered among the neglected tropical diseases by WHO, affect more than a third of the world's population, with varying intensity of infection. We aimed to evaluate the effects of mass deworming for soil-transmitted helminths (with or without deworming for schistosomiasis or co-interventions) on growth, educational achievement, cognition, school attendance, quality of life, and adverse effects in children in endemic helminth areas. METHODS: We searched 11 databases up to Jan 14, 2016, websites and trial registers, contacted authors, and reviewed reference lists. We included studies published in any language of children aged 6 months to 16 years, with mass deworming for soil-transmitted helminths or schistosomiasis (alone or in combination with other interventions) for 4 months or longer, that reported the primary outcomes of interest. We included randomised and quasi-randomised trials, controlled before-after studies, interrupted time series, and quasi-experimental studies. We screened in duplicate, then extracted data and appraised risk of bias in duplicate with a pre-tested form. We conducted random-effects meta-analysis and Bayesian network meta-analysis. FINDINGS: We included 52 studies of duration 5 years or less with 1 108 541 children, and four long-term studies 8-10 years after mass deworming programmes with more than 160 000 children. Overall risk of bias was moderate. Mass deworming for soil-transmitted helminths compared with controls led to little to no improvement in weight over a period of about 12 months (0·99 kg, 95% credible interval [CrI] -0·09 to 0·28; moderate certainty evidence) or height (0·07 cm, 95% CrI -0·10 to 0·24; moderate certainty evidence), little to no difference in proportion stunted (eight fewer per 1000 children, 95% CrI -48 to 32; high certainty evidence), cognition measured by short-term attention (-0·23 points on a 100 point scale, 95% CI -0·56 to 0·14; high certainty evidence), school attendance (1% higher, 95% CI -1 to 3; high certainty evidence), or mortality (one fewer per 1000 children, 95% CI -3 to 1; high certainty evidence). We found no data on quality of life and little evidence of adverse effects. Mass deworming for schistosomiasis might slightly increase weight (0·41 kg, 95% CrI -0·20 to 0·91) and has little to no effect on height (low certainty evidence) and cognition (moderate certainty evidence). Our analyses do not suggest indirect benefits for untreated children from being exposed to treated children in the community. We are uncertain about effects on long-term economic productivity (hours worked), cognition, literacy, and school enrolment owing to very low certainty evidence. Results were consistent across sensitivity and subgroup analyses by age, worm prevalence, baseline nutritional status, infection status, impact on worms, infection intensity, types of worms (ascaris, hookworm, or trichuris), risk of bias, cluster versus individual trials, compliance, and attrition. INTERPRETATION: Mass deworming for soil-transmitted helminths with or without deworming for schistosomiasis had little effect. For schistosomiasis, mass deworming might be effective for weight but is probably ineffective for height, cognition, and attendance. Future research should assess which subset of children do benefit from mass deworming, if any, using individual participant data meta-analysis. FUNDING: Canadian Institutes of Health Research and WHO

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an

Sampling free energy surfaces as slices by combining umbrella sampling and metadynamics.

Metadynamics (MTD) is a very powerful technique to sample high-dimensional free energy landscapes, and due to its self-guiding property, the method has been successful in studying complex reactions and conformational changes. MTD sampling is based on filling the free energy basins by biasing potentials and thus for cases with flat, broad, and unbound free energy wells, the computational time to sample them becomes very large. To alleviate this problem, we combine the standard Umbrella Sampling (US) technique with MTD to sample orthogonal collective variables (CVs) in a simultaneous way. Within this scheme, we construct the equilibrium distribution of CVs from biased distributions obtained from independent MTD simulations with umbrella potentials. Reweighting is carried out by a procedure that combines US reweighting and Tiwary-Parrinello MTD reweighting within the Weighted Histogram Analysis Method (WHAM). The approach is ideal for a controlled sampling of a CV in a MTD simulation, making it computationally efficient in sampling flat, broad, and unbound free energy surfaces. This technique also allows for a distributed sampling of a high-dimensional free energy surface, further increasing the computational efficiency in sampling. We demonstrate the application of this technique in sampling high-dimensional surface for various chemical reactions using ab initio and QM/MM hybrid molecular dynamics simulations. Further, to carry out MTD bias reweighting for computing forward reaction barriers in ab initio or QM/MM simulations, we propose a computationally affordable approach that does not require recrossing trajectories. © 2016 Wiley Periodicals, Inc

Value of Minimum Apparent Diffusion Coefficient on Magnetic Resonance Imaging as a Biomarker for Predicting Progression of Disease Following Surgery and Radiotherapy in Glial Tumors from a Tertiary Care Center in Northern India

Purpose: Studies have shown that cellularity of glial tumors are inversely correlated to minimum apparent diffusion coefficient (ADC) values derived on diffusion-weighted imaging (DWI). The purpose of this prospective exploratory study was to evaluate whether temporal change in “minimum ADC” values during follow-up predict progressive disease in glial tumors post radiotherapy and surgery. Materials and Methods: Adult patients of glial tumors, subjected to surgery followed by Radiotherapy (RT), were included in the study. Serial conventional magnetic resonance imaging with DWI at the following time points – presurgery, pre-RT, post-RT imaging at 3, 7, and 15 months were done. For “minimum ADC” values, multiple regions of interest (ROI) were identified on ADC maps derived from DWI. A mean of 5 minimum ADC values was chosen as “minimum ADC” value. The correlation was drawn between histology and minimum ADC values and time trends were studied. Results: Fourteen patients were included in this study. Histologies were low-grade glioma (LGG) - 5, anaplastic oligodendroglioma (ODG) -5, and glioblastoma multiforme (GBM) - 4. Minimum ADC values were significantly higher in LGG and GBM than ODG. Presurgery, the values were 0.812, 0.633, and 0.787 × 10−3 mm2/s for LGG, ODG, and GBM, respectively. DWI done at the time of RT planning showed values of 0.786, 0.636, 0.869 × 10−3 mm2/s, respectively. During follow-up, the increasing trend of minimum ADC was observed in LGG (P = 0.02). All these patients were clinically and radiologically stable. Anaplastic ODGs, however, showed an initial increase followed by the fall of minimum ADC in all the 5 cases (P = 0.00). Four of the five cases developed progressive disease subsequently. In all the 4 GBM cases, a consistent fall of minimum ADC values was observed (P = 0.00), and they all progressed in spite of RT. Conclusions: The DWI-derived minimum ADC values are an important yet simple quantitative tool to assess the treatment response and disease progression before they are evident on conventional imaging during the follow-up of glial tumors