Biology subjects

He, F.

Publications and source records attributed to He, F..

131 records · Page 8Linked to original sources

bioRxiv2018

Parametric and Non-parametric Gradient Matching for Network Inference

Reverse engineering of gene regulatory networks from time series gene-expression data is a challenging problem, not only because of the vast sets of candidate interactions but also due to the stochastic nature of gene expression. To avoid the computational cost of large-scale simulations, a two-step Gaussian process interpolation based gradient matching approach has been proposed to solve differential equations approximately. Based on this gradient matching approach, we evaluate the fits of parametric as well as non-parametric candidate models to the data under various settings for different inference objectives. We also use model averaging, based on the Bayesian Information Criterion (BIC), in order to combine the different inferences. We found that parametric methods can provide comparable, and often improved inference compared to non-parametric methods; the latter, however, require no kinetic information and are computationally more efficient.\n\nThe code used in this work is available at https://github.com/ld2113/Final-Project.

systems biology↗

bioRxiv2017

Defining the Layers of a Sensory Cilium with STORM and Cryo-Electron Nanoscopies

Primary cilia are cylindrical organelles extending from the surface of most animal cells that have been implicated in a host of signaling and sensory functions. Genetic defects in their component molecules, known as \"ciliopathies\" give rise to devastating symptoms, ranging from defective development, to kidney disease, to progressive blindness. The detailed structures of these organelles and the true functions of proteins encoded by ciliopathy genes are poorly understood because of the small size of cilia and the limitations of conventional microscopic techniques. We describe the combination of cryo-electron tomography, enhanced by sub-tomogram averaging, with super-resolution stochastic reconstruction microscopy (STORM) to define substructures and subdomains within the light-sensing rod sensory cilium of the mammalian retina. Longitudinal and radial domains are demarcated by structural features such as the axoneme and its connections to the ciliary membrane, and are correlated with molecular markers of these compartments, including Ca2+-binding protein centrin-2 in the lumen of the axoneme, acetylated tubulin forming the axoneme, the glycocalyx extending outward from the surface of the plasma membrane, and molecular residents of the space between axoneme and ciliary membrane, including Arl13B, intraflagellar transport proteins, BBS5, and syntaxin-3. Within this framework we document that deficiencies in the ciliopathy proteins BBS2, BBS7 and BBS9 lead to inappropriate accumulation of proteins in rod outer segments while largely preserving their sub-domain localization within the connecting cilium region, but alter the distribution of syntaxin-3 clusters.

cell biology↗

bioRxiv2017

Unexpected CRISPR off-target mutation pattern in vivo are not typicallygermline-like

To the EditorSchaefer et al.1 (referred to as Study_1) recently presented the provocative conclusion that CRISPR-Cas9 nuclease can induce many unexpected off-target mutations across the genome that arise from the sites with poor homology to the gRNA. As Wilson et al.2 pointed out, however, the selection of a co-housed mouse as the control is insufficient to attribute the observed mutation differences between the CRISPR-treated mice and control mice. Therefore, the causes of these mutations need to be further investigated. In 2015, Iyer et al.3 (referred to as Study_2) used Cas9 and a pair of sgRNAs to mutate the Ar gene in vivo and off-target mutations were investigated by comparison the control mice and the offspring of the modified mice. After analyzing the whole genome sequencing (WGS) of the offspring and the control mice, they claimed that off-target mutations are rare from CRISPR-Cas9 engineering. Notably, their study only focused on indel off-target mutations. We re-analyzed the WGS data of these two studies and detected both single nucleotide variants (SNVs) and indel mutations.

genetics↗

bioRxiv2017

Convergence of Wnt, Growth Factor and Trimeric G protein signals on Daple

Cellular proliferation, differentiation, and morphogenesis are shaped by multiple signaling cascades; their concurrent dysregulation plays an integral role in cancer progression and is a common feature of many malignancies. Three such cascades that contribute to the oncogenic potential are the Wnt/Frizzled(FZD), growth factor-receptor tyrosine kinases (RTKs), and G-proteins/GPCRs. Here we identify Daple, a modulator of trimeric G-proteins and a Dishevelled (Dvl)-binding protein as an unexpected point of convergence for all three cascades. Daple-dependent activation of Gi and enhancement of non-canonical Wnt signals is not just triggered by Wnt5a/FZD to suppress tumorigenesis, but also hijacked by growth factor-RTKs to stoke tumor progression. Phosphorylation of Daple by both RTKs and non-RTKs triggers Gi activation and potentiates non-canonical Wnt signals that trigger epithelial-mesenchymal transition. In patients with colorectal cancers, concurrent upregulation of Daple and the prototype RTK, EGFR, carried poor prognosis. Thus, this work defines a novel growth factor{leftrightarrow}G-protein{leftrightarrow}Wnt crosstalk paradigm in cancer biology.

cancer biology↗

bioRxiv2017

Signature Of Co-Evolution Between Defense And Vegetative Lifespan Strategies In Arabidopsis thaliana

The selective impact of pathogen epidemics on host defenses can be strong but remains transient. By contrast, life-history shifts can durably and continuously modify the balance between costs and benefits of immunity, which arbitrates the evolution of host defenses. Their impact on the evolutionary dynamics of host immunity, however, has seldom been documented. Optimal investment into immunity is expected to decrease with shortening lifespan, because a shorter life decreases the probability to encounter pathogens or enemies. Here, we document that in natural populations of Arabidopsis thaliana, the expression levels of immunity genes correlate positively with flowering time, which in annual species is a proxy for lifespan. Using a novel genetic strategy based on bulk-segregants, we partitioned flowering time-dependent from - independent immunity genes and could demonstrate that this positive co-variation can be genetically separated. It is therefore not explained by the pleiotropic action of some major regulatory genes controlling both immunity and lifespan. Moreover, we find that immunity genes containing variants reported to impact fitness in natural field conditions are among the genes whose expression co-varies most strongly with flowering time. Taken together, these analyses reveal that natural selection has likely assorted alleles promoting lower expression of immunity genes with alleles that decrease the duration of vegetative lifespan in A. thaliana and vice versa. This is the first study documenting a pattern of variation consistent with the impact that selection on flowering time is predicted to have on diversity in host immunity.

evolutionary biology↗