Biology subjects

Zhu, D.

Publications and source records attributed to Zhu, D..

7 recordsLinked to original sources

bioRxiv2018

Insulin-Producing Cells Monitor the Temperature and Compensate for Cold-Induced Sleep in Drosophila

Sleep is regulated by environmental factors including temperature, but the neural circuits that receive the sensory signal and mediate the regulation remain unclear. We examined how cold could influence Drosophila sleep patterns and its neural mechanism. The results showed that Drosophila has more sleep duration, less sleep latency and deeper sleep depth under cold condition. We identified the Insulin-producing Cells (IPCs) can be activated by cold, and receive the cold signal from the 11216 cold-sensing neuron without a direct synaptic connection. Elevation of IPCs sensitivity to cold impairs the sleep-promoting effect of cold while blocking of IPCs enhance the effect mostly on sleep circadian, suggesting that the cold activated IPCs have a compensative role in sleep regulation. Our finding revealed a potential neural circuit that help maintain sleep circadian in detrimental environment and may give new insight to the complicated sleep regulation mechanism.

neuroscience↗

bioRxiv2018

The Enzymes that beyond Non-Oxidative Glycolysis

High yield is an important objective of cell factory. One or several genes cloned into the bacterial may make the synthetic pathway much more optimal, so can increase the yield. But the global benefit enzymes are rare, which can increase the yields of many chemical products for a cell factory such as E.coli. Two of these kinds of global benefit enzymes are the famous enzymes, D-fructose-6-phosphate D-erythrose-4-phosphate-lyase and D-Xylulose 5-phosphate D-glyceraldehyde-3-phosphate-lyase, of non-oxidative glycolysis (NOG) published in Nature, which can improve the utilization ratio of carbon. We expect to find other global benefit enzymes. We use an integrated model, which integrated in silico model of E.coli and KEGG. By computation, we analyze the effect of adding each reaction from KEGG on the theoretical yields of several products with E.coli and find 83 enzymes that may be potentially global benefit enzymes. By comparison, we find about 30 of the 83 enzymes are better in improving the theoretical yields than the two enzymes of NOG.\n\nIn order to compare the global benefit enzymes with NOG, as an example, we select \"Glycerol:NADP+ oxidoreductase\" (GNO) which can increase the supply of NADPH in E.coli. But To increase the supply of reducing power, such as NADPH will probably increase the yield of chemicals in a cell factory. We use flux balance analysis method to testify our assumption. By comparing the maximum yields of 80 products produced by E.coli with respectively using GNO and NOG, we find GNO has better performance in the product production of E.coli. So GNO is a global benefit enzyme which can increase the yields of many chemical products in E.coli.

synthetic biology↗

bioRxiv2018

Stimulus-responsive self-assembly of enzymatic fractal structures by computational design

Fractal topologies, which are statistically self-similar over multiple length scales, are pervasive in nature. The recurrence of patterns at increasing length scales in fractal-shaped branched objects, e.g., trees, lungs, and sponges, results in high effective surface areas, and provides key functional advantages, e.g., for molecular trapping and exchange. Mimicking these topologies in designed protein-based assemblies will provide access to novel classes of functional biomaterials for wide ranging applications. Here, we describe a modular, multi-scale computational design method for the reversible self-assembly of proteins into tunable supramolecular fractal-like topologies in response to phosphorylation. Computationally-guided atomic-resolution modeling of fusions of symmetric, oligomeric proteins with Src homology 2 (SH2) binding domain and its phosphorylatable ligand peptide was used to design iterative branching leading to fractal-like assembly formation by enzymes of the atrazine degradation pathway. Structural characterization using various microscopy techniques and Cryo-electron tomography revealed a variety of dendritic, hyperbranched, and sponge-like topologies which are self-similar over three decades ([~]10nm-10m) of length scale, in agreement with models from multi-scale computational simulations. We demonstrate control over mesoscale topology (by linker design), formation dynamics, and functional enhancements due to dynamic multi-component assemblies constructed with three atrazine degradation pathway enzymes. The described design method should enable the construction of a variety of novel, spatiotemporally responsive catalytic biomaterials featuring fractal topologies.

biophysics↗

bioRxiv2018

Sub-voxel light-sheet microscopy for high-resolution, high-throughput volumetric imaging of large biomedical specimens

A key challenge when imaging whole biomedical specimens is how to quickly obtain massive cellular information over a large field of view (FOV). Here, we report a sub-voxel light-sheet microscopy (SLSM) method enabling high-throughput volumetric imaging of mesoscale specimens at cellular-resolution. A non-axial, continuous scanning strategy is used to rapidly acquire a stack of large-FOV images with three-dimensional (3-D) nanoscale shifts encoded. Then by adopting a sub-voxel-resolving procedure, the SLSM method models these low-resolution, cross-correlated images in the spatial domain and iteratively recovers a 3-D image with improved resolution throughout the sample. This technique can surpass the optical limit of a conventional light-sheet microscope by more than three times, with high acquisition speeds of gigavoxels per minute. As demonstrated by quick reconstruction (minutes to hours) of various samples, e.g., 3-D cultured cells, an intact mouse heart, mouse brain, and live zebrafish embryo, the SLSM method presents a high-throughput way to circumvent the tradeoff between intoto mapping of large-scale tissue (>100 mm3) and isotropic imaging of single-cell (~1-m resolution). It also eliminates the need of complicated mechanical stitching or precisely modulated illumination, using a simple light-sheet setup and fast graphics-processing-unit (GPU)-based computation to achieve high-throughput, high-resolution 3-D microscopy, which could be tailored for a wide range of biomedical applications in pathology, histology, neuroscience, etc.

bioengineering↗

bioRxiv2018

Single-cell transcriptome analysis reveals estrogen signaling augments the mitochondrial folate pathway to coordinately fuel purine and polyamine synthesis in breast cancer cells

Estrogen regulates diverse physiological effects and drives breast tumor progression by directly activating estrogen receptor (ER). However, due to the stochastic nature of gene transcription and the resulting heterogeneous cellular response, it is important to investigate estrogen-stimulated gene expression profiles at the single-cell level in order to fully understand how ER regulates transcription in breast cancer cells. In this study, we performed single-cell transcriptome analysis on ER-positive breast cancer cell lines following 17{beta}-estradiol stimulation. Overall, we observed robust gene expression diversity between individual cells. Moreover, we found over two thirds of the genes in breast cancer cells displayed a bimodal expression pattern, which caused averaging artifacts and masked the identification of potential estrogen-regulated genes. We overcame this issue by reconstructing a dynamic estrogen-responsive transcriptional network from discrete time points into a pseudotemporal continuum. Pathway analysis of the differentially expressed genes derived from the pseudotemporal analysis showed an estrogen-stimulated metabolic switch that favored biosynthesis and cell proliferation but reduced estrogen degradation. In addition, we identified folate-mediated one-carbon metabolism as a novel estrogen-regulated pathway in breast cancer cells. Notably, estrogen stimulation reprogramed this pathway through the mitochondrial folate pathway to coordinately fuel polyamine and de novo purine synthesis. Finally, we showed AZIN1 and PPAT, key regulators in the above pathways, are direct ER target genes and essential for breast cancer cell survival and growth. In summary, our single-cell study illustrated a dynamic transcriptional heterogeneity in ER-positive breast cancer cells in response to estrogen stimulation and uncovered a novel mechanism of an estrogen-mediated metabolic switch.

genomics↗

bioRxiv2018

Long Noncoding RNA-Maternally Expressed Gene 3 Contributes to Hypoxic Pulmonary Hypertension

The expression and function of long noncoding RNAs (lncRNAs) in the development of hypoxic pulmonary hypertension, especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs) are largely unknown. Here, we characterized the expression of lncRNA-maternally expressed gene 3 (lncRNA-MEG3) was significantly increased and primarily located in the cytoplasm of PASMCs by hypoxia. LncRNA-MEG3 knockdown by lung-specific delivery of small interfering RNAs (siRNAs) significantly prevented the development of hypoxic pulmonary hypertension in vivo. Silencing of lncRNA-MEG3 by siRNAs and gapmers attenuated PASMC responses to hypoxia in vitro. Mechanically, we found that lncRNA-MEG3 acts as a molecular sponge of microRNA-328 (miR-328); upon hypoxia, lncRNA-MEG3 interacts and sequesters miR-328, leading to the upregulation of insulin-like growth factor 1 receptor (IGF1R). Additionally, higher expression of lncRNA-MEG3 and IGF1R, and lower expression of miR-328 were observed in PASMCs of iPAH patients. These data provide insight into the contribution of lncRNA-MEG3 in hypoxia pulmonary hypertension. Upregulation of lncRNA-MEG3 sequesters cytoplasmic miR-328, eventually leading to the expression of IGF1R, revealing a regulatory mechanism by lncRNAs in hypoxia-induced PASMC proliferation.

molecular biology↗

bioRxiv2017

Motor selection dynamics in FEF explain the reaction time variance of saccades to single targets

In studies of voluntary movement, a most elemental quantity is the reaction time (RT) between the onset of a visual stimulus and a saccade toward it. However, this RT demonstrates extremely high variability, which in spite of extensive research remains unexplained. It is well established that, when a visual target appears, oculomotor activity gradually builds up until a critical level is reached, at which point a saccade is triggered. Here, we further characterize the dynamics of this rise-to-threshold process based on computational work and single-neuron recordings from the frontal eye field (FEF) of behaving monkeys. We find that the baseline activity, build-up rate, and threshold level show strong, nonlinear co-dependencies that explain the distinct RT distributions observed experimentally. The results indicate that intrinsic randomness contributes little to saccade variance, which results mainly from an intricate, fundamentally deterministic mechanism of motor conflict resolution that has subtle yet highly characteristic manifestations.

neuroscience↗