From microscopy data to in silico environments for in vivo-oriented simulations

In our previous study, we introduced a combination methodology of Fluorescence Correlation Spectroscopy (FCS) and Transmission Electron Microscopy (TEM), which is powerful to investigate the effect of intracellular environment to biochemical reaction processes. Now, we developed a reconstruction method of realistic simulation spaces based on our TEM images. Interactive raytracing visualization of this space allows the perception of the overall 3D structure, which is not directly accessible from 2D TEM images. Simulation results show that the diffusion in such generated structures strongly depends on image post-processing. Frayed structures corresponding to noisy images hinder the diffusion much stronger than smooth surfaces from denoised images. This means that the correct identification of noise or structure is significant to reconstruct appropriate reaction environment in silico in order to estimate realistic behaviors of reactants in vivo. Static structures lead to anomalous diffusion due to the partial confinement. In contrast, mobile crowding agents do not lead to anomalous diffusion at moderate crowding levels. By varying the mobility of these non-reactive obstacles (NRO), we estimated the relationship between NRO diffusion coefficient (Dnro) and the anomaly in the tracer diffusion (α). For Dnro=21.96 to 44.49 μ m2/s, the simulation results match the anomaly obtained from FCS measurements. This range of the diffusion coefficient from simulations is compatible with the range of the diffusion coefficient of structural proteins in the cytoplasm. In addition, we investigated the relationship between the radius of NRO and anomalous diffusion coefficient of tracers by the comparison between different simulations. The radius of NRO has to be 58 nm when the polymer moves with the same diffusion speed as a reactant, which is close to the radius of functional protein complexes in a cell.ISSN:1687-4145ISSN:1687-415

Stellar contents and star formation in the young star cluster Be 59

We present $UBVI_C$ CCD photometry of the young open cluster Be 59 with the aim to study the star formation scenario in the cluster. The radial extent of the cluster is found to be $\sim$ 10 arcmin (2.9 pc). The interstellar extinction in the cluster region varies between $E(B-V) \simeq$ 1.4 to 1.8 mag. The ratio of total-to-selective extinction in the cluster region is estimated as $3.7\pm0.3$. The distance of the cluster is found to be $1.00\pm0.05$ kpc. Using near-infrared colours and slitless spectroscopy, we have identified young stellar objects (YSOs) in the open cluster Be 59 region. The ages of these YSOs range between $<1$ Myr to $\sim$ 2 Myr, whereas the mean age of the massive stars in the cluster region is found to be $\sim$ 2 Myr. There is evidence for second generation star formation outside the boundary of the cluster, which may be triggered by massive stars in the cluster. The slope of the initial mass function, $\Gamma$, in the mass range $2.5 < M/M_\odot \le 28$ is found to be $-1.01\pm0.11$ which is shallower than the Salpeter value (-1.35), whereas in the mass range $1.5 < M/M_\odot \le 2.5$ the slope is almost flat. The slope of the K-band luminosity function is estimated as $0.27\pm0.02$, which is smaller than the average value ($\sim$0.4) reported for young embedded clusters. Approximately 32% of H$\alpha$ emission stars of Be 59 exhibit NIR excess indicating that inner disks of the T-Tauri star (TTS) population have not dissipated. The MSX and IRAS-HIRES images around the cluster region are also used to study the emission from unidentified infrared bands and to estimate the spatial distribution of optical depth of warm and cold interstellar dust.Comment: Accepted for the publication in MNRAS, 39 pages, 26 Figures, 8 Table

Causal relevance of different blood pressure traits on risk of cardiovascular diseases: GWAS and Mendelian randomisation in 100,000 Chinese adults

Elevated blood pressure (BP) is major risk factor for cardiovascular diseases (CVD). Genome-wide association studies (GWAS) conducted predominantly in populations of European ancestry have identified >2,000 BP-associated loci, but other ancestries have been less well-studied. We conducted GWAS of systolic, diastolic, pulse, and mean arterial BP in 100,453 Chinese adults. We identified 128 non-overlapping loci associated with one or more BP traits, including 74 newly-reported associations. Despite strong genetic correlations between populations, we identified appreciably higher heritability and larger variant effect sizes in Chinese compared with European or Japanese ancestry populations. Using instruments derived from these GWAS, multivariable Mendelian randomisation demonstrated that BP traits contribute differently to the causal associations of BP with CVD. In particular, only pulse pressure was independently causally associated with carotid plaque. These findings reinforce the need for studies in diverse populations to understand the genetic determinants of BP traits and their roles in disease risk

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

An immune clock of human pregnancy

The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies

From microscopy data to in silico environments for in vivo-oriented simulations

In our previous study, we introduced a combination methodology of Fluorescence Correlation Spectroscopy (FCS) and Transmission Electron Microscopy (TEM), which is powerful to investigate the effect of intracellular environment to biochemical reaction processes. Now, we developed a reconstruction method of realistic simulation spaces based on our TEM images. Interactive raytracing visualization of this space allows the perception of the overall 3D structure, which is not directly accessible from 2D TEM images. Simulation results show that the diffusion in such generated structures strongly depends on image post-processing. Frayed structures corresponding to noisy images hinder the diffusion much stronger than smooth surfaces from denoised images. This means that the correct identification of noise or structure is significant to reconstruct appropriate reaction environment in silico in order to estimate realistic behaviors of reactants in vivo. Static structures lead to anomalous diffusion due to the partial confinement. In contrast, mobile crowding agents do not lead to anomalous diffusion at moderate crowding levels. By varying the mobility of these non-reactive obstacles (NRO), we estimated the relationship between NRO diffusion coefficient (Dnro) and the anomaly in the tracer diffusion (α). For Dnro=21.96 to 44.49 μ m²/s, the simulation results match the anomaly obtained from FCS measurements. This range of the diffusion coefficient from simulations is compatible with the range of the diffusion coefficient of structural proteins in the cytoplasm. In addition, we investigated the relationship between the radius of NRO and anomalous diffusion coefficient of tracers by the comparison between different simulations. The radius of NRO has to be 58 nm when the polymer moves with the same diffusion speed as a reactant, which is close to the radius of functional protein complexes in a cell

Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease.

Funder: Government Department of BusinessFunder: Energy and Industrial Strategy (BEIS)Funder: Vice-Chancellor Fellowship from the University of BristolFunder: Shanghai Thousand Talents ProgramFunder: Academy of Medical Sciences (AMS) Springboard AwardFunder: BBSRC Innovation fellowshipFunder: NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of BristolBACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of 25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.This research has been conducted using the UK Biobank resource under Application Numbers ‘40135’ and ‘15825’. J.Z. is funded by a Vice-Chancellor Fellowship from the University of Bristol. This research was also funded by the UK Medical Research Council Integrative Epidemiology Unit [MC_UU_00011/1, MC_UU_00011/4 and MC_UU_00011/7]. J.Z. is supported by the Academy of Medical Sciences (AMS) Springboard Award, the Wellcome Trust, the Government Department of Business, Energy and Industrial Strategy (BEIS), the British Heart Foundation and Diabetes UK [SBF006\1117]. This study was funded/supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (G.D.S., T.R.G. and R.E.W.). This study received funding from the UK Medical Research Council [MR/R013942/1]. J.Z., Y.M.Z. and T.R.G are funded by a BBSRC Innovation fellowship. J.Z. is supported by the Shanghai Thousand Talents Program. Y.M.Z. is supported by the National Natural Science Foundation of China [81800636]. H.Z. is supported by the Training Program of the Major Research Plan of the National Natural Science Foundation of China [91642120], a grant from the Science and Technology Project of Beijing, China [D18110700010000] and the University of Michigan Health System–Peking University Health Science Center Joint Institute for Translational and Clinical Research [BMU2017JI007]. N.F. is supported by the National Institutes of Health awards R01-MD012765, R01-DK117445 and R21-HL140385. R.C. is funded by a Wellcome Trust GW4 Clinical Academic Training Fellowship [WT 212557/Z/18/Z]. The Trøndelag Health Study (the HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. M.C.B. is supported by the UK Medical Research Council (MRC) Skills Development Fellowship [MR/P014054/1]. S.F. is supported by a Wellcome Trust PhD studentship [WT108902/Z/15/Z]. Q.Y. is funded by a China Scholarship Council PhD scholarship [CSC201808060273]. Y.C. was supported by the National Key R&D Program of China [2016YFC0900500, 2016YFC0900501 and 2016YFC0900504]. The China Kadoorie Biobank baseline survey and the first resurvey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust [202922/Z/16/Z, 088158/Z/09/Z and 104085/Z/14/Z]. Japan-Kidney-Biobank was supported by AMED under Grant Number 20km0405210. P.C.H. is supported by Cancer Research UK [grant number: C18281/A19169]. A.K. was supported by DFG KO 3598/5–1. N.F. is supported by NIH awards R01-DK117445, R01-MD012765 and R21-HL140385. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health

Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings

Epigenetic regulation of centromeric chromatin: old dogs, new tricks?

The assembly of just a single kinetochore at the centromere of each sister chromatid is essential for accurate chromosome segregation during cell division. Surprisingly, despite their vital function, centromeres show considerable plasticity with respect to their chromosomal locations and activity. The establishment and maintenance of centromeric chromatin, and therefore the location of kinetochores, is epigenetically regulated. The histone H3 variant CENP-A is the key determinant of centromere identity and kinetochore assembly. Recent studies have identified many factors that affect CENP-A localization, but their precise roles in this process are unknown. We build on these advances and on new information about the timing of CENP-A assembly during the cell cycle to propose new models for how centromeric chromatin is established and propagated