Biology subjects

Zang, Y.

Publications and source records attributed to Zang, Y..

40 records · Page 3Linked to original sources

bioRxiv2020

Novel mosaic mice with diverse applications

Gene-deficient mouse models are indispensable for interrogating mammalian gene functions, but the conventional models allow the study of only one or few genes per mouse line, which has been a bottleneck in functional genomics. To confront the challenge, we have combined the CRISPR-Cas and Cre-Lox systems to develop a novel type of mosaic mice termed MARC (Mosaic Animal based on gRNA and Cre) for targeting many genes per mouse but only one gene per cell. This technology employs a transgene comprising a modified U6 promoter upstream of a series of floxed gRNA genes linked together in tandem, with one gRNA expressed per cell following Cre-mediated recombination. At least 61 gRNA genes can be stably maintained in the transgene, and importantly, enables robust proof-of-principle in vivo screens, demonstrating the potential for quickly evaluating the functions of many genes in diverse tissues in a single MARC line. In theory, MARC can also be analyzed by single-cell sequencing, and should enable cost-effective derivation of conventional single-gene-KO lines via simple breeding. Our study establishes MARC as an important addition to the mouse genetics toolbox.

genetics↗

bioRxiv2019

Firing rate-dependent phase responses of Purkinje cells support transient oscillations

Both spike rate and timing can transmit information in the brain. Phase response curves (PRCs) quantify how a neuron transforms input to output by spike timing. They exhibit strong firing-rate adaptation, but its mechanism and relevance for network output are poorly understood. Using our Purkinje cell (PC) model we demonstrate that the rate adaptation is caused by rate-dependent subthreshold membrane potentials efficiently regulating the activation of Na+ channels. Then we use a realistic PC network model to examine how rate-dependent responses synchronize spikes in the scenario of reciprocal inhibition-caused high-frequency oscillations. The changes in PRC cause oscillations and spike correlations only at high firing rates. The causal role of the PRC is confirmed using a simpler coupled oscillator network model. This mechanism enables transient oscillations between fast-spiking neurons that thereby form PC assemblies. Our work demonstrates that rate adaptation of PRCs can spatio-temporally organize the PC input to cerebellar nuclei.

neuroscience↗

bioRxiv2018

Comprehensive analysis of potential immunotherapy genomic biomarkers in 1,000 Chinese patients with cancer

BackgroundTumor mutation burden (TMB), DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI), and PD-L1 amplification (PD-L1 AMP) may predict the efficacy of PD-1/PD-L1 blockade. In this study, we aimed to characterize the distributions of these biomarkers in over 1,000 Chinese patients with cancer.\n\nMethodsTMB, MSI, dMMR, and PD-L1 AMP were determined based on whole-exome sequencing of tumor/blood samples from > 1,000 Chinese patients with cancer.\n\nResultsIncidence rates among 953 Chinese patients with cancer showing high TMB (TMB-H), high MSI (MSI-H), dMMR and PD-L1 AMP were 35%, 4%, 0.53% and 3.79%, respectively. We found higher rates of TMB-H among hepatocellular carcinoma, breast cancer, and esophageal cancer patients than was reported for The Cancer Genome Atlas data. Lung cancer patients with EGFR mutations had significantly lower TMB values than those with wild-type EGFR, and increased TMB was significantly associated with dMMR in colorectal cancer (CRC). The frequency of tumors with MSI-H was highest in CRC (14%) and gastric cancer (4%). PD-L1 AMP occurred most frequently in lung squamous cell carcinoma (14.3%) and HER2-positive breast cancer (8.8%). Most MSI-H and dMMR cases exhibited TMB-H, but the overlap among the other biomarkers was low.\n\nConclusionWhile MSI and dMMR are associated with higher mutational loads, correlations between TMB-H and other biomarkers, between MSI-H and dMMR, and between PD-L1 AMP and other biomarkers were low, indicating different underlying causes of the four biomarkers. Thus, it is recommended that all four biomarkers be assessed for certain cancers before administration of PD-1/PD-L1 blockade treatment.

cancer biology↗

bioRxiv2018

Voltage- and Branch-specific Climbing Fiber Responses in Purkinje Cells

Climbing fibers (CFs) provide instructive signals driving cerebellar learning. However, conflicting experimental studies have been reported about the reliability of CF mediated Ca2+ influx in Purkinje cell (PC) distal dendrites. Mechanisms causing the wide variation in duration and spikelet numbers of complex spikes (CSs) have not been explored systematically. Using a new experimentally validated PC model, we describe the full range of modifiability of CF responses to explain the experimental data and make new predictions. We find voltage state gates the initiation and propagation of dendritic spikes. PC dendrites exhibit inhomogeneous excitability with individual branches as computational units for CF input. Somatic CSs are regulated by voltage state, CF activation phase and instantaneous CF firing rate. Concurrent synaptic inputs can affect CSs by modulating dendritic responses in a spatially precise way. These voltage- and branch-specific CF responses will increase dendritic computational capacity and give PCs an active role in integrating CF signals.

neuroscience↗