Exploiting molecular dynamics in Nested Sampling simulations of small peptides

Nested Sampling (NS) is a parameter space sampling algorithm which can be used for sampling the equilibrium thermodynamics of atomistic systems. NS has previously been used to explore the potential energy surface of a coarse-grained protein model and has significantly outperformed parallel tempering when calculating heat capacity curves of Lennard-Jones clusters. The original NS algorithm uses Monte Carlo (MC) moves; however, a variant, Galilean NS, has recently been introduced which allows NS to be incorporated into a molecular dynamics framework, so NS can be used for systems which lack efficient prescribed MC moves. In this work we demonstrate the applicability of Galilean NS to atomistic systems. We present an implementation of Galilean NS using the Amber molecular dynamics package and demonstrate its viability by sampling alanine dipeptide, both in vacuo and implicit solvent. Unlike previous studies of this system, we present the heat capacity curves of alanine dipeptide, whose calculation provides a stringent test for sampling algorithms. We also compare our results with those calculated using replica exchange molecular dynamics (REMD) and find good agreement. We show the computational effort required for accurate heat capacity estimation for small peptides. We also calculate the alanine dipeptide Ramachandran free energy surface for a range of temperatures and use it to compare the results using the latest Amber force field with previous theoretical and experimental results.We acknowledge support from the Leverhulme Trust (Grant F/00 215/BL(NSB, CV and DLW)) and the EPSRC (Grants EP/J020281/1(DLW), EP/J010847/1 (GC) and a Doctoral Training Award (RJB)).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.cpc.2015.12.00

Scale dependence of cirrus heterogeneity effects. Part II: MODIS NIR and SWIR channels

In a context of global climate change, the understanding of the radiative role of clouds is crucial. On average, ice clouds such as cirrus have a significant positive radiative effect, but under some conditions the effect may be negative. However, many uncertainties remain regarding the role of ice clouds on Earth's radiative budget and in a changing climate. Global satellite observations are particularly well suited to monitoring clouds, retrieving their characteristics and inferring their radiative impact. To retrieve ice cloud properties (optical thickness and ice crystal effective size), current operational algorithms assume that each pixel of the observed scene is plane-parallel and homogeneous, and that there is no radiative connection between neighboring pixels. Yet these retrieval assumptions are far from accurate, as real radiative transfer is 3-D. This leads to the plane-parallel and homogeneous bias (PPHB) plus the independent pixel approximation bias (IPAB), which impacts both the estimation of top-of-the-atmosphere (TOA) radiation and the retrievals. An important factor that determines the impact of these assumptions is the sensor spatial resolution. High-spatial-resolution pixels can better represent cloud variability (low PPHB), but the radiative path through the cloud can involve many pixels (high IPAB). In contrast, low-spatial-resolution pixels poorly represent the cloud variability (high PPHB), but the radiation is better contained within the pixel field of view (low IPAB). In addition, the solar and viewing geometry (as well as cloud optical properties) can modulate the magnitude of the PPHB and IPAB. In this, Part II of our study, we simulate TOA 0.86 and 2.13 µm solar reflectances over a cirrus uncinus scene produced by the 3DCLOUD model. Then, 3-D radiative transfer simulations are performed with the 3DMCPOL code at spatial resolutions ranging from 50&thinsp;m to 10&thinsp;km, for 12 viewing geometries and nine solar geometries. It is found that, for simulated nadir observations taken at resolution higher than 2.5&thinsp;km, horizontal radiation transport (HRT) dominates biases between 3-D and 1-D reflectance calculations, but these biases are mitigated by the side illumination and shadowing effects for off-zenith solar geometries. At resolutions coarser than 2.5&thinsp;km, PPHB dominates. For off-nadir observations at resolutions higher than 2.5&thinsp;km, the effect that we call THEAB (tilted and homogeneous extinction approximation bias) due to the oblique line of sight passing through many cloud columns contributes to a large increase of the reflectances, but 3-D radiative effects such as shadowing and side illumination for oblique Sun are also important. At resolutions coarser than 2.5&thinsp;km, the PPHB is again the dominant effect. The magnitude and resolution dependence of PPHB and IPAB is very different for visible, near-infrared and shortwave infrared channels compared with the thermal infrared channels discussed in Part I of this study. The contrast of 3-D radiative effects between solar and thermal infrared channels may be a significant issue for retrieval techniques that simultaneously use radiative measurements across a wide range of solar reflectance and infrared wavelengths.</p

Trans-mitochondrial coordination of cristae at regulated membrane junctions

Reminiscent of bacterial quorum sensing, mammalian mitochondria participate in inter-organelle communication. However, physical structures that enhance or enable interactions between mitochondria have not been defined. Here we report that adjacent mitochondria exhibit coordination of inner mitochondrial membrane cristae at inter-mitochondrial junctions (IMJs). These electron-dense structures are conserved across species, resistant to genetic disruption of cristae organization, dynamically modulated by mitochondrial bioenergetics, independent of known inter-mitochondrial tethering proteins mitofusins and rapidly induced by the stable rapprochement of organelles via inducible synthetic linker technology. At the associated junctions, the cristae of adjacent mitochondria form parallel arrays perpendicular to the IMJ, consistent with a role in electrochemical coupling. These IMJs and associated cristae arrays may provide the structural basis to enhance the propagation of intracellular bioenergetic and apoptotic waves through mitochondrial networks within cells

Influence of cloud retrieval errors due to three-dimensional radiative effects on calculations of broadband shortwave cloud radiative effect

We investigate how cloud retrieval errors due to the three-dimensional (3D) radiative effects affect broadband shortwave (SW) cloud radiative effects (CREs) in shallow cumulus clouds. A framework based on the combination of large eddy simulations (LESs) and radiative transfer (RT) models was developed to simulate both one-dimensional (1D) and 3D radiance, as well as SW broadband fluxes. Results show that the broadband SW fluxes reflected at top of the domain, transmitted at the surface, and absorbed in the atmosphere, computed from the cloud retrievals using 1D RT (F1D∗), can provide reasonable broadband radiative energy estimates in comparison with those derived from the true cloud fields using 1D RT (F1D). The difference between these 1D-RT-simulated fluxes (F1D∗, F1D) and the benchmark 3D RT simulations computed from the true cloud field (F3D) depends primarily on the horizontal transport of photons in 3D RT, whose characteristics vary with the sun's geometry. When the solar zenith angle (SZA) is 5°, the domain-averaged F1D∗ values are in excellent agreement with the F3D, all within 7 % relative CRE bias. When the SZA is 60°, the CRE differences between calculations from F1D∗ and F3D are determined by how the cloud side-brightening and darkening effects offset each other in the radiance, retrieval, and broadband fluxes. This study suggests that although the cloud property retrievals based on the 1D RT theory may be biased due to the 3D radiative effects, they still provide CRE estimates that are comparable to or better than CREs calculated from the true cloud properties using 1D RT.</p

Helical Chirality: a Link between Local Interactions and Global Topology in DNA

DNA supercoiling plays a major role in many cellular functions. The global DNA conformation is however intimately linked to local DNA-DNA interactions influencing both the physical properties and the biological functions of the supercoiled molecule. Juxtaposition of DNA double helices in ubiquitous crossover arrangements participates in multiple functions such as recombination, gene regulation and DNA packaging. However, little is currently known about how the structure and stability of direct DNA-DNA interactions influence the topological state of DNA. Here, a crystallographic analysis shows that due to the intrinsic helical chirality of DNA, crossovers of opposite handedness exhibit markedly different geometries. While right-handed crossovers are self-fitted by sequence-specific groove-backbone interaction and bridging Mg2+ sites, left-handed crossovers are juxtaposed by groove-groove interaction. Our previous calculations have shown that the different geometries result in differential stabilisation in solution, in the presence of divalent cations. The present study reveals that the various topological states of the cell are associated with different inter-segmental interactions. While the unstable left-handed crossovers are exclusively formed in negatively supercoiled DNA, stable right-handed crossovers constitute the local signature of an unusual topological state in the cell, such as the positively supercoiled or relaxed DNA. These findings not only provide a simple mechanism for locally sensing the DNA topology but also lead to the prediction that, due to their different tertiary intra-molecular interactions, supercoiled molecules of opposite signs must display markedly different physical properties. Sticky inter-segmental interactions in positively supercoiled or relaxed DNA are expected to greatly slow down the slithering dynamics of DNA. We therefore suggest that the intrinsic helical chirality of DNA may have oriented the early evolutionary choices for DNA topology

Hepatitis B virus (HBV) viral load, liver and renal function in adults treated with tenofovir disoproxil fumarate (TDF) vs. untreated:a retrospective longitudinal UK cohort study

Abstract Background Current clinical guidelines recommend treating chronic hepatitis B virus (HBV) infection in a minority of cases, but there are relatively scarce data on evolution or progression of liver inflammation and fibrosis in cases of chronic HBV (CHB) that do not meet treatment criteria. We aimed to assess the impact of TDF on liver disease, and the risk of renal impairment in treated CHB patients in comparison to untreated patients. Methods We studied a longitudinal ethnically diverse CHB cohort in the UK attending out-patient clinics between 2005 and 2018. We examined TDF treatment (vs. untreated) as the main exposure, with HBV DNA viral load (VL), ALT, elastography scores and eGFR as the main outcomes, using paired tests and mixed effects model for longitudinal measurements. Additionally, decline of eGFR during follow-up was quantified within individuals by thresholds based on clinical guidelines. Baseline was defined as treatment initiation for TDF group and the beginning of clinical follow-up for untreated group respectively. Results We included 206 adults (60 on TDF, 146 untreated), with a median ± IQR follow-up duration of 3.3 ± 2.8 years. The TDF group was significantly older (median age 39 vs. 35 years, p = 0.004) and more likely to be male (63% vs. 47%, p = 0.04) compared to the untreated group. Baseline difference between TDF and untreated groups reflected treatment eligibility criteria. As expected, VL and ALT declined significantly over time in TDF-treated patients. Elastography scores normalised during treatment in the TDF group reflecting regression of inflammation and/or fibrosis. However, 6/81 (7.4%) of untreated patients had a progression of fibrosis stage from F0-F1 to F2 or F3. There was no evidence of difference in rates or incidence of renal impairment during follow-up in the TDF vs. untreated group. Conclusions Risk of liver inflammation and fibrosis may be raised in untreated patients compared to those receiving TDF, and TDF may benefit a larger percentage of the CHB population

Bimodal distribution and set point HBV DNA viral loads in chronic infection:retrospective analysis of cohorts from the UK and South Africa

CITATION: Downs, L. O. 2020. Bimodal distribution and set point HBV DNA viral loads in chronic infection : retrospective analysis of cohorts from the UK and South Africa. Wellcome Open Research, 14(5):113, doi: 10.12688/wellcomeopenres.15941.2.The original publication is available at: https://pubmed.ncbi.nlm.nih.govENGLISH ABSTRACT: Hepatitis B virus (HBV) viral load (VL) is used as a biomarker to assess risk of disease progression, and to determine eligibility for treatment. While there is a well recognised association between VL and the expression of the viral e-antigen protein, the distributions of VL at a population level are not well described. We here present cross-sectional, observational HBV VL data from two large population cohorts in the UK and in South Africa, demonstrating a consistent bimodal distribution. The right skewed distribution and low median viral loads are different from the left-skew and higher viraemia in seen in HIV and hepatitis C virus (HCV) cohorts in the same settings. Using longitudinal data, we present evidence for a stable 'set-point' VL in peripheral blood during chronic HBV infection. These results are important to underpin improved understanding of HBV biology, to inform approaches to viral sequencing, and to plan public health interventions.Publisher's versio

Bimodal distribution and set point HBV DNA viral loads in chronic infection:retrospective analysis of cohorts from the UK and South Africa

CITATION: Downs, L. O. 2020. Bimodal distribution and set point HBV DNA viral loads in chronic infection : retrospective analysis of cohorts from the UK and South Africa. Wellcome Open Research, 14(5):113, doi: 10.12688/wellcomeopenres.15941.2.The original publication is available at: https://pubmed.ncbi.nlm.nih.govENGLISH ABSTRACT: Hepatitis B virus (HBV) viral load (VL) is used as a biomarker to assess risk of disease progression, and to determine eligibility for treatment. While there is a well recognised association between VL and the expression of the viral e-antigen protein, the distributions of VL at a population level are not well described. We here present cross-sectional, observational HBV VL data from two large population cohorts in the UK and in South Africa, demonstrating a consistent bimodal distribution. The right skewed distribution and low median viral loads are different from the left-skew and higher viraemia in seen in HIV and hepatitis C virus (HCV) cohorts in the same settings. Using longitudinal data, we present evidence for a stable 'set-point' VL in peripheral blood during chronic HBV infection. These results are important to underpin improved understanding of HBV biology, to inform approaches to viral sequencing, and to plan public health interventions.Publisher's versio

Incidence, risk factors, and effect on allograft survival of glomerulonephritis post-transplantation in a United Kingdom population: cohort study

BACKGROUND: Post-transplant glomerulonephritis (PTGN) has been associated with inferior long-term allograft survival, and its incidence varies widely in the literature. METHODS: This is a cohort study of 7,623 patients transplanted between 2005 and 2016 at four major transplant UK centres. The diagnosis of glomerulonephritis (GN) in the allograft was extracted from histology reports aided by the use of text-mining software. The incidence of the four most common GN post-transplantation was calculated, and the risk factors for disease and allograft outcomes were analyzed. RESULTS: In total, 214 patients (2.8%) presented with PTGN. IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and membranoproliferative/mesangiocapillary GN (MPGN/MCGN) were the four most common forms of post-transplant GN. Living donation, HLA DR match, mixed race, and other ethnic minority groups were associated with an increased risk of developing a PTGN. Patients with PTGN showed a similar allograft survival to those without in the first 8 years of post-transplantation, but the results suggest that they do less well after that timepoint. IgAN was associated with the best allograft survival and FSGS with the worst allograft survival. CONCLUSIONS: PTGN has an important impact on long-term allograft survival. Significant challenges can be encountered when attempting to analyze large-scale data involving unstructured or complex data points, and the use of computational analysis can assist

Establishing a colorectal cancer research database from routinely collected health data: the process and potential from a pilot study.

OBJECTIVE: Colorectal cancer is a common cause of death and morbidity. A significant amount of data are routinely collected during patient treatment, but they are not generally available for research. The National Institute for Health Research Health Informatics Collaborative in the UK is developing infrastructure to enable routinely collected data to be used for collaborative, cross-centre research. This paper presents an overview of the process for collating colorectal cancer data and explores the potential of using this data source. METHODS: Clinical data were collected from three pilot Trusts, standardised and collated. Not all data were collected in a readily extractable format for research. Natural language processing (NLP) was used to extract relevant information from pseudonymised imaging and histopathology reports. Combining data from many sources allowed reconstruction of longitudinal histories for each patient that could be presented graphically. RESULTS: Three pilot Trusts submitted data, covering 12 903 patients with a diagnosis of colorectal cancer since 2012, with NLP implemented for 4150 patients. Timelines showing individual patient longitudinal history can be grouped into common treatment patterns, visually presenting clusters and outliers for analysis. Difficulties and gaps in data sources have been identified and addressed. DISCUSSION: Algorithms for analysing routinely collected data from a wide range of sites and sources have been developed and refined to provide a rich data set that will be used to better understand the natural history, treatment variation and optimal management of colorectal cancer. CONCLUSION: The data set has great potential to facilitate research into colorectal cancer