Biology subjects

Goldman, D.

Publications and source records attributed to Goldman, D..

4 recordsLinked to original sources

bioRxiv2018

Fast, versatile, and quantitative annotation of complex images

We report a generic smartphone app for quantitative annotation of complex images. The app is simple enough to be used by children, and annotation tasks are distributed across app users, contributing to efficient annotation. We demonstrate its flexibility and speed by annotating >30,000 images, including features of rice root growth and structure, stem cell aggregate morphology, and complex worm (C. elegans) postures, for which we show that the speed of annotation is >130-fold faster than state-of-the-art techniques with similar accuracy.

bioengineering↗

bioRxiv2018

Synthetic-evolution reveals that phosphoregulation of the mitotic kinesin-5 Cin8 is constrained

Cdk1 has been found to phosphorylate the majority of its substrates in disordered regions. These phosphorylation sites do not appear to require precise positioning for their function. The mitotic kinesin-5 Cin8 was shown to be phosphoregulated at three Cdk1 sites in disordered loops within its catalytic motor domain. Here, we examined the flexibility of Cin8 phosphoregulation by analyzing the phenotypes of synthetic Cdk1-sites that were systematically generated by single amino-acid substitutions, starting from a phosphodeficient variant of Cin8. Out of 29 synthetic Cdk1 sites that we created, eight were non-functional; 19 were neutral, similar to the phosphodeficient variant; and two gave rise to phosphorylation-dependent spindle phenotypes. Of these two, one site resulted in novel phosphoregulation, and only one site, immediately adjacent to a native Cdk1 site, produced phosphoregulation similar to wild-type. This study shows that, while the gain of a single phosphorylation site can confer regulation and modulate the dynamics of the spindle, to achieve optimal regulation of a mitotic kinesin-5 motor protein, phosphoregulation has to be site-specific and precise.

cell biology↗

bioRxiv2018

Computational assessment of blood flow heterogeneity in dialysis patients’ cardiac ventricles

Dialysis prolongs life but augments cardiovascular mortality. Imaging data suggests that dialysis increases myocardial blood flow (BF) heterogeneity, but its causes remain poorly understood. A biophysical model of human coronary vasculature was used to explain the imaging observations, and highlight causes of coronary BF heterogeneity.\n\nPost-dialysis CT images from patients under control, pharmacological stress (adenosine), therapy (cooled dialysate), and adenosine and cooled dialysate conditions were obtained. The data presented disparate phenotypes. To dissect vascular mechanisms, a 3D human coronary vasculature model was implemented. Simulations were performed to investigate the effects of altered aortic pressure and blood vessel diameters on myocardial BF heterogeneity which was quantified using relative dispersion, fractal dimension, and transmural BF distribution.\n\nImaging showed that stress and therapy potentially increased mean and total BF, while reducing heterogeneity. BF histograms of one patient showed multi-modality. Using the model, it was found that total coronary BF increased as coronary perfusion pressure (CPP) was increased. BF heterogeneity was differentially affected by large or small vessel blocking. BF heterogeneity was found to be inversely related to small blood vessel diameters. Simulation of large artery stenosis indicates that BF became heterogeneous (increase relative dispersion) and gave multi-modal histograms. The total transmural BF as well as transmural BF heterogeneity reduced due to large artery stenosis, generating large patches of very low O_SCPCAPBFC_SCPCAP regions downstream. Blocking of arteries at various orders showed that blocking larger arteries results in multi-modal BF histograms and large patches of low BF, whereas smaller artery blocking results in augmented relative dispersion and fractal dimension. Transmural heterogeneity was also affected. Finally, the effects of augmented aortic pressure in the presence of blood vessel blocking shows differential effects on BF heterogeneity as well as transmural BF.\n\nImproved aortic blood pressure may lead to improved BF. Stress and therapy may be effective if they dilate small vessels. A potential cause for the observed complex BF distributions (multi-modal BF histograms) may indicate existing large vessel stenosis.\n\nThe intuitive BF heterogeneity methods used can be readily used in clinical studies. Further development of the model and methods will permit personalised assessment of patient BF status.

biophysics↗

bioRxiv2017

Do Candidate Genes Affect the Brain’s White Matter Microstructure? Large-Scale Evaluation of 6,165 Diffusion MRI Scans

AbstractSusceptibility genes for psychiatric and neurological disorders - including APOE, BDNF, CLU,CNTNAP2, COMT, DISC1, DTNBP1, ErbB4, HFE, NRG1, NTKR3, and ZNF804A - have been reported to affect white matter (WM) microstructure in the healthy human brain, as assessed through diffusion tensor imaging (DTI). However, effects of single nucleotide polymorphisms (SNPs) in these genes explain only a small fraction of the overall variance and are challenging to detect reliably in single cohort studies. To date, few studies have evaluated the reproducibility of these results. As part of the ENIGMA-DTI consortium, we pooled regional fractional anisotropy (FA) measures for 6,165 subjects (CEU ancestry N=4,458) from 11 cohorts worldwide to evaluate effects of 15 candidate SNPs by examining their associations with WM microstructure. Additive association tests were conducted for each SNP. We used several meta-analytic and mega-analytic designs, and we evaluated regions of interest at multiple granularity levels. The ENIGMA-DTI protocol was able to detect single-cohort findings as originally reported. Even so, in this very large sample, no significant associations remained after multiple-testing correction for the 15 SNPs investigated. Suggestive associations (1.3x10-4 < p < 0.05, uncorrected) were found for BDNF, COMT, and ZNF804A in specific tracts. Meta-and mega-analyses revealed similar findings. Regardless of the approach, the previously reported candidate SNPs did not show significant associations with WM microstructure in this largest genetic study of DTI to date; the negative findings are likely not due to insufficient power. Genome-wide studies, involving large-scale meta-analyses, may help to discover SNPs robustly influencing WM microstructure.

neuroscience↗