Biology subjects

Qin, Z.

Publications and source records attributed to Qin, Z..

90 records · Page 5Linked to original sources

bioRxiv2020

A Single Chromosome Strain of S. cerevisiae Exhibits Diminished Ethanol Metabolism and Tolerance.

This study characterized the growth, metabolism, and transcriptional profile of a S. cerevisiae strain with a single large chromosome that was constructed via successive chromosomal fusions. The single chromosome strain exhibited a longer lag phase, increased doubling time, and lower final biomass concentration compared with a wildtype strain when grown on YPD. These phenotypes were amplified when ethanol was added to the medium or used as the sole carbon source. RNAseq analysis showed diminished induction of genes involved in diauxic shift, ethanol metabolism, fatty-acid {beta}-oxidation, and methylglyoxal catabolism during growth on ethanol compared to the reference strain. Enzyme-constrained metabolic modeling predicted that decreased flux through these poorly induced enzymes results in diminished ATP formation and decreased biomass accumulation observed. Together, these observations suggest that switch-like control of carbon source dependent gene expression in S. cerevisiae requires genome arrangement into multiple chromosomes.

systems biology↗

bioRxiv2020

Computational investigation of protein photoinactivation by molecular hyperthermia

To precisely control protein activity in a living system is a challenging yet long-pursued objective in biomedical sciences. Recently we have developed a new approach named molecular hyperthermia (MH) to photoinactivate protein activity of interest without genetic modification. MH utilizes nanosecond laser pulse to create nanoscale heating around plasmonic nanoparticles to inactivate adjacent protein in live cells. Here we use a numerical model to study important parameters and conditions for MH to efficiently inactivate proteins in nanoscale. To quantify the protein inactivation process, the impact zone is defined as the range where proteins will be inactivated by nanoparticle localized heating. Factors that reduce the MH impact zone include stretching the laser pulse duration, temperature-dependent thermal conductivity (versus constant properties), and non-spherical nanoparticle geometry. In contrast, the impact zone is insensitive to temperature-dependent material density and specific heat, as well as thermal interface resistance based on reported data. The low thermal conductivity of cytoplasm increases the impact zone. Different proteins with various Arrhenius kinetic parameters have significantly different impact zones. This study provides guidelines to design the protein inactivation process in MH.

bioengineering↗

bioRxiv2020

Adaptive optics two-photon endomicroscopy enables deep brain imaging at synaptic resolution over large volumes

Optical deep brain imaging in vivo at high resolution has remained a great challenge over the decades. Two-photon endomicroscopy provides a minimally invasive approach to image buried brain structures, once it is integrated with a gradient refractive index (GRIN) lens embedded in the brain. However, its imaging resolution and field of view are compromised by the intrinsic aberrations of the GRIN lens. Here, we develop a two-photon endomicroscopy by adding adaptive optics based on the direct wavefront sensing, which enables recovery of diffraction-limited resolution in deep brain imaging. A new precompensation strategy plays a critical role to correct aberrations over large volumes and achieve rapid random-access multiplane imaging. We investigate the neuronal plasticity in the hippocampus, a critical deep brain structure, and reveal the relationship between the somatic and dendritic activity of pyramidal neurons.

neuroscience↗

bioRxiv2020

The effect of a novel powerful ABA mimic on the improvement of color in grapes and its mechanism

Pigment content is an important quality attribute in the grape industry, and anthocyanins are the major fruit pigments. iso-PhABA is a novel and excellent ABA analog capable of the antimetabolic inactivation of ABA. In this study, we found that iso-PhABA improved the coloration of grape berries more obviously than ABA at concentrations of 2 mg/L and 5 mg/L in two grape varieties in China. iso-PhABA treatment enhanced the anthocyanin content in the two grape varieties; specifically, the anthocyanin and delphinidin contents increased in both the Jufeng and Xiahei varieties. An enzymatic activity test showed that iso-PhABA significantly promoted four key enzyme activities catalyzing anthocyanin biosynthesis. We also determined the affinity between iso-PhABA and ABA receptors using ABA as a control. The results indicated that iso-PhABA had significantly to moderately higher affinities for some ABA receptors, including PYR1, PYL2, PYL1, PYL3 and PYL10, which resulted in higher inhibition of the PP2C HAB1 in the presence of iso-PhABA than in the presence of ABA. iso-PhABA treatment increased the content of soluble sugars and grape yield without any apparent accompanying adverse effects on the quality of the grapes.

biochemistry↗

bioRxiv2020

Isopropoxy benzene guanidine kills Staphylococcus aureus without detectable resistance

Antibiotic resistance is a serious public health crisis. The challenge caused by Staphylococcus aureus infections clearly urges the development of novel antimicrobial therapy. Drug repurposing has emerged as an alternative approach to rapidly identify effective drugs against multidrug-resistant bacteria. Recently, substituted benzene guanidine compounds have been used as leading structures to discover new promising drugs in both synthetic and medicinal chemistry. We investigated the antimicrobial activity of an analog of substituted benzene guanidine compounds (isopropoxy benzene guanidine) and further explored its antibacterial mechanism against S. aureus. Isopropoxy benzene guanidine had a MIC of 0.125-4g/ml against S. aureus and displayed potent activity against S. aureus by disrupting cell membrane. Unlike conventional antibiotics, repeated use of isopropoxy benzene guanidine had a low probability of resistance section. The most substantial isopropoxy benzene guanidine-induced changes occurred in transcript levels of membrane transport functions-regulated genes, and genes involved in purine- and pyrimidine-synthesis pathway and virulence factors. Furthermore, in vivo studies demonstrated that isopropoxy benzene guanidine is capable of treating invasive MRSA infections. These findings provided strong evidence that isopropoxy benzene guanidine represents a new chemical lead for novel antibacterial agent against multidrug-resistant S. aureus infections.

microbiology↗

bioRxiv2020

Schistosoma Japonicum infection in Treg-specific USP21 knock-out mice

USP21, an E3 de-ubiquitin enzyme playing vital roles in physiological activities, is important for Treg cells to maintain immune homeostasis and control immune tolerance. To understand its diverse functions and potential mechanism is essential for disease development. We, using the USP21 gene-conditional knock-out mice model of Schistosoma Japonicum infection, found more cercariae developed into adults, and more eggs deposited in the liver in KO mice. However, immunohistochemistry showed the degree and the area of egg granuloma and liver fibrosis were both reduced. This suggested knock-out USP21 did affect the immunoregulation between schistosomes and the host. In KO mice the content of IFN-gamma and IL-4, and the expression of anti-SEA IgG and anti-SWAP IgG both increased in the liver, spleen and blood by flow cytometry, while the content of IL-10, lL-17A, IL-23, IL-9 and the expression of USP21 and anti-SEA IgM decreased. This indicated USP21-knockout-Tregs promoted both Th1-type and Th2-type immunity and inhibited other immunities during schistosomes infection, which disordered the host immunity. This study revealed the immunomodulatory of USP21 and preliminarily suggests it might be essential to regulate the complex immune network between the host and schistosomes. USP21 provides a new possible target for schistosomiasis treatment in the future. Author summarySchistosomiasis is a common neglected tropical disease that affects more than 230 million people worldwide. Therefore, the study on the mechanism of immune interaction between schistosomas and the host is not only helpful for the understanding of immune homeostasis, but also helpful for the further development of the treatment of schistosomiasis. Ubiquitin Specific Protease 21(USP21) has been shown to be involved in the regulation of many biological processes, such as maintaining immune homeostasis and regulating cell growth. Here, we observed that the specific deletion of USP21 led to the decrease of mices ability to resist schistosomes infection and promoted the survival of schistosomes. It was also proved that unstable regulatory T cells would produce polarization phenomenon and promote differentiation to helper T cells, which would lead to disorder of immune response in mice. However, this process reduced the serious immune pathological damage caused by egg granuloma. Our findings reveal that USP21 may be an important molecule regulating immune interaction between Schistosoma japonicum and the host.

immunology↗

bioRxiv2019

Na2CO3-Responsive Photosynthetic and ROS Scavenging Mechanisms in Chloroplasts of Alkaligrass Revealed by Phosphoproteomics

Alkali-salinity exerts severe osmotic, ionic and high-pH stresses to plants. To understand the alkali-salinity responsive mechanisms underlying photosynthetic modulation and reactive oxygen species (ROS) homeostasis, physiological and diverse quantitative proteomics analyses of alkaligrass (Puccinellia tenuiflora) under Na2CO3 stress were conducted. In addition, Western blot, real-time PCR, and transgenic techniques were applied to validate the proteomic results and test the functions of the Na2CO3-responsive proteins. A total of 104 and 102 Na2CO3-responsive proteins were identified in leaves and chloroplasts, respectively. In addition, 84 Na2CO3-responsive phosphoproteins were identified, including 56 new phosphorylation sites in 56 phosphoproteins from chloroplasts, which are crucial for the regulation of photosynthesis, ion transport, signal transduction and energy homeostasis. A full-length PtFBA encoding an alkaligrass chloroplastic fructose-bisphosphate aldolase (FBA) was overexpressed in wild-type cells of cyanobacterium Synechocystis sp. Strain PCC 6803, leading to enhanced Na2CO3 tolerance. All these results indicate that thermal dissipation, state transition, cyclic electron transport, photorespiration, repair of photosystem (PS) II, PSI activity, and ROS homeostasis were altered in response to Na2CO3 stress, and they have improved our understanding of the Na2CO3-responsive mechanisms in halophytes.

plant biology↗

bioRxiv2019

Nonlinear mechanics of lamin filaments and the meshwork topology build an emergent nuclear lamina

The nuclear lamina - a meshwork of intermediate filaments termed lamins - functions as a mechanotransduction interface between the extracellular matrix and the nucleus via the cytoskeleton. Although lamins are primarily responsible for the mechanical stability of the nucleus in multicellular organisms, in situ characterization of lamin filaments under tension has remained elusive. Here, we apply an integrative approach combining atomic force microscopy, cryo-electron tomography, network analysis, and molecular dynamics simulations to directly measure the mechanical response of single lamin filaments in its three-dimensional meshwork. Endogenous lamin filaments portray non-Hookean behavior - they deform reversibly under a force of a few hundred picoNewtons and stiffen at nanoNewton forces. The filaments are extensible, strong and tough, similar to natural silk and superior to the synthetic polymer Kevlar(R). Graph theory analysis shows that the lamin meshwork is not a random arrangement of filaments but the meshwork topology follows small world properties. Our results suggest that the lamin filaments arrange to form a robust, emergent meshwork that dictates the mechanical properties of individual lamin filaments. The combined approach provides quantitative insights into the structure-function organization of lamins in situ, and implies a role of meshwork topology in laminopathies.

biophysics↗

bioRxiv2019

Evolution from total variation to nonlinear sparsifying transform for sparse-view CT image reconstruction

Sparse-view CT has been widely studied as an effective strategy for reducing radiation dose to patients. However, the conventional image reconstruction algorithms, such as filtered back-projection method and classical algebraic reconstruction techniques, can no longer be competent in the image reconstruction task of sparse-view CT. A new principle, called compressed sensing (CS), has been therefore developed to provide an effective solution for the ill-posed inverse problem of sparse-view CT image reconstruction. Total variation (TV) minimization, which is most extensively studied among the existing CS techniques, has been recognized as a powerful tool for dealing with this difficult problem in image reconstruction community. However, in recent years, the drawbacks of TV are being increasingly reported, which are appearance of patchy artifacts, depict of incorrect object boundaries, and loss in image textures or smooth intensity changes. These degradations appear especially in reconstructing actual CT images with complicated intensity changes. In order to address these drawbacks, a series of advanced algorithms using nonlinear sparsifying transform (NLST) have been proposed very recently. The NLST-based CS is based on a different framework from the TV, and it achieves an improvement in image quality. Since it is a relatively newly proposed idea, within the scope of our knowledge, there exist few literatures that discusses comprehensively how the image quality improvement occurs in comparison with the conventional TV method. In this study, we investigated the image quality differences between the conventional TV minimization and the NLST-based CS, as well as image quality differences among different kinds of NLST-based CS algorithms in the sparse-view CT image reconstruction. More specifically, image reconstructions of actual CT images of different body parts were carried out to demonstrate the image quality differences.

bioinformatics↗

bioRxiv2019

The effect of overnight consolidation in the perceptual learning of non-native tonal contrasts

Sleep-mediated overnight consolidation was found to facilitate perceptual learning by promoting learners generalization across talkers in their perception of novel segmental categories. Lexical tone differs from most segmental contrasts in that it is highly variable across talkers, and displays dynamic change over time. It remains unclear whether a similar (or a larger) effect of overnight consolidation would be found for perceptual learning of novel tonal contrasts. Thus, this study aims to examine whether overnight consolidation facilitates generalization across talkers in the discrimination and identification of novel Cantonese level tones by Mandarin listeners. Two groups of Mandarin listeners were perceptually trained either in the morning or in the evening. Listeners were trained in a tone identification (ID) task using stimuli produced by a trained talker. Their development was then tested in the ID and AX discrimination tasks using stimuli produced by trained and untrained talkers in three posttests following training: immediately after training, 12-hour delay, and 24-hour delay. While the evening group slept between the first and second posttests, the morning group did not. The results of accuracy rates in the ID task showed that while Mandarin listeners trained in the evening showed an improved trend, predicted by their individual sleep time, in identifying the level tones produced by both the trained and untrained talkers, Mandarin listeners trained in the morning showed a declining trend. In contrast, the results of d-prime scores in the AX discrimination task did not show different developmental patterns between the two groups. Consistent with previous studies on segmental learning, the finding suggests that overnight consolidation might have assisted the evening trainees formation of a more abstract (talker-independent) representation of novel tone categories in memory traces. The results are discussed regarding the features of lexical tones to shed light on the mechanism of phonetic learning.

neuroscience↗

bioRxiv2019

Single Cell Profiling Reveals Sex, Lineage and Regional Diversity in the Mouse Kidney

Chronic kidney disease affects 10% of the population with notable differences in ethnic and sex-related susceptibility to kidney injury and disease. Kidney dysfunction leads to significant morbidity and mortality, and chronic disease in other organ systems. A mouse organ-centered understanding underlies rapid progress in human disease modeling, and cellular approaches to repair damaged systems. To enhance an understanding of the mammalian kidney, we combined anatomy-guided single cell RNA sequencing of the adult male and female mouse kidney with in situ expression studies and cell lineage tracing. These studies reveal cell diversity and marked sex differences, distinct organization and cell composition of nephrons dependent on the time of nephron specification, and lineage convergence, in which contiguous functionally-related cell types are specified from nephron and collecting system progenitor populations. A searchable database integrating findings to highlight gene-cell relationships in a normal anatomical framework will facilitate study of the mammalian kidney.

genetics↗

bioRxiv2019

Artificial intelligence method to design and fold alpha-helix structural proteins from the primary amino acid sequence

The development of rational techniques to discover new proteins for use in variety of applications ranging from agriculture to biotechnology remains an outstanding materials design problem. The key barrier is to design a sequence to fold into a predictable structure to achieve a certain material function. Focused on alpha-helical proteins, we report a Multi-scale Neighborhood-based Neural Network (MNNN) model to learn how a specific amino acid sequence folds into a protein structure. The algorithm predicts the protein structure without using a template or co-evolutional information at a maximum error of 2.1 [A]. We find that the prediction accuracy is higher than other models and the prediction consumes less than six orders of magnitude time than ab initio folding methods. We demonstrate that MNNN can predict the structure of an unknown protein that agrees with experiments, and our model hence shows a great advantage in the rational design of de novo proteins.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC=\"FIGDIR/small/660639v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (66K):\norg.highwire.dtl.DTLVardef@8771fcorg.highwire.dtl.DTLVardef@4c7255org.highwire.dtl.DTLVardef@e63f1eorg.highwire.dtl.DTLVardef@39e4ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2019

Angiocrine FSTL1 insufficiency leads to atrial and vein wall fibrosis via SMAD3 activation

Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. Here we show that loss of follistatin-like protein 1 (FSTL1) in endothelial cells (Fstl1ECKO) led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice with Fstl1 deletion in smooth muscle cells or hematopoietic cells. We further showed that there was excessive alpha-smooth muscle actin (SMA) associated with atrial endocardia, heart valves, veins and microvessels after the endothelial FSTL1 deletion. Consistently, there was an increase of collagen deposition as demonstrated in livers of Fstl1ECKO mutants. The SMAD3 phosphorylation was significantly enhanced and pSMAD3 staining was colocalized with SMA in vein walls, suggesting the activation of TGF{beta} signaling in vascular mural cells of Fstl1ECKO mice. The findings imply that endothelial FSTL1 is critical for the homeostasis of atria and veins and its insufficiency may favor cardiovascular fibrosis leading to heart failure.

developmental biology↗

bioRxiv2019

Aromatic polyketide biosynthesis: fidelity, evolution and engineering

We report the formicapyridines which are structurally and biosynthetically related to the pentacyclic fasamycin and formicamycin aromatic polyketides but comprise a rare pyridine moiety. These new compounds are trace level metabolites formed by derailment of the major biosynthetic pathway. Inspired by evolutionary logic we show that rational mutation of a single gene in the biosynthetic gene cluster leads to a significant increase both in total formicapyridine production and their enrichment relative to the fasamycins/formicamycins. Our observations broaden the polyketide biosynthetic landscape and identify a non-catalytic role for ABM superfamily proteins in type II polyketide synthase assemblages for maintaining biosynthetic pathway fidelity.

bioengineering↗

bioRxiv2018

RT States: systematic annotation of the human genome using cell type-specific replication timing programs

The replication timing (RT) program has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows to characterize the RT program in the entire human genome in a high-throughput and high-resolution fashion. These experiments suggest that RT changes dynamically during development in coordination with gene activity. Since RT is such a fundamental biological process, we believe that an effective quantitative profile of the local RT program from a diverse set of cell types in various developmental stages and lineages can provide crucial biological insights for a genomic locus. In the present study, we explored recurrent and spatially coherent combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We found that a Hidden Markov Model with 15 hidden states provide a good model to describe these genome-wide RT profiling data. Each of the hidden state represents a unique combination of RT profiles across different cell types which we refer to as \"RT states\". To understand the biological properties of these RT states, we inspected their relationship with chromatin states, gene expression, functional annotation and 3D chromosomal organization. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome.\n\nAUTHOR SUMMARYThe replication timing (RT) program is an important cellular mechanism and has been linked to many key biological processes including cell fate commitment, 3D chromatin organization and transcription regulation. Significant technology progress now allows us to characterize the RT program in the entire human genome. Results from these experiments suggest that RT changes dynamically across different developmental stages. Since RT is such a fundamental biological process, we believe that the local RT program from a diverse set of cell types in various developmental stages can provide crucial biological insights for a genomic locus. In the present study, we explored combinatorial profiles from 42 RT programs collected from multiple lineages at diverse differentiation states. We developed a statistical model consist of 15 \"RT states\" to describe these genome-wide RT profiling data. To understand the biological properties of these RT states, we inspected the relationship between RT states and other types of functional annotations of the genome. We found that the newly defined RT states possess interesting genome-wide functional properties that add complementary information to the existing annotation of the human genome.

bioinformatics↗

bioRxiv2018

Low frequency ultrasound enhances chemotherapy sensitivity and induces autophagy in human paclitaxel resistance prostate cancer PC-3R cells through the ERs-mediated PI3K/Akt/mTOR signaling pathway

Sonodynamic therapy (SDT) as an emerging tumor-assisting method has attracted a great deal of interest in tumor therapy research in recent years. However, autophagy has been observed in several cancer cells treated with SDT and its role and mechanism are not clear. In the present study, we have investigated the effect of low frequency ultrasound on paclitaxel(PTX) resistance prostate cancer PC-3R cells and demonstrated that low frequency ultrasound could induce cancer cell apoptosis, inhibit the expression of multiple drug resistance genes (MRP3, MRP7 and P-glycoprotein) and reverse drug resistance; we further found that low frequency ultrasound induced autophagy in PC-3R cells. Our results demonstrated that low frequency ultrasound enhanced chemotherapy sensitivity and induced autophagy in PC-3R cells by inhibiting the PI3K/AKT/mTOR pathway. Moreover, we observed that low frequency ultrasound-induced cell autophagy was correlated with endoplasmic reticulum stress (ERs). 4-phenylbutyric acid (4-PBA) - mediated protection against ERs clearly implicated ERs in the activation of autophagy and cell apoptosis. In addition, the results showed that ERs served as an upstream effector of the PI3K/AKT/mTOR pathway. More importantly, we observed that inhibition of low frequency ultrasound-induced autophagy enhanced ERs and improved the role of low frequency ultrasound in reversing drug resistance. Over all, our findings provide new insights into the molecular mechanisms underlying low frequency ultrasound-mediated reversal of drug resistance and autophagy in PC-3R cells and support autophagy as a potential agent for enhancing anti-cancer effect of SDT.

cancer biology↗

bioRxiv2018

Lysyl oxidase inhibition drives the transdifferentiation from lung adenocarcinoma to squamous cell carcinoma in mice

LKB1 is frequently mutated in human non-small cell lung cancer (NSCLC) and Lkb1 deletion in mice triggered the lung adenocarcinoma (ADC) to squamous cell carcinoma (SCC) transdifferentiation (AST) through lysyl oxidase (LOX)-dependent extracellular matrix remodeling. Here we show that pharmacological inhibition of lysyl oxidase in KrasG12D/Trp53L/L mouse model, which is known to produce lung ADC only, triggers the ADC-to-SCC transdifferentiation independent of LKB1 status. Treatments of two different inhibitors of lysyl oxidase decrease collagen deposition and promote redox accumulation, and eventually trigger the AST. Importantly, these transited SCC show strong resistance to lysyl oxidase inhibition in stark contrast to ADC. Collectively, these findings establish a new AST mouse model independent of LKB1 inactivation status.

cancer biology↗

bioRxiv2018

In situ structures of periplasmic flagella reveal a distinct cytoplasmic ATPase complex in Borrelia burgdorferi

Periplasmic flagella are essential for the distinct morphology and motility of spirochetes. A flagella-specific Type III secretion system (fT3SS) composed of a membrane-bound export apparatus and a cytosolic ATPase complex is responsible for the assembly of the periplasmic flagella. Here, we combine cryo-electron tomography and mutagenesis approaches to characterize the fT3SS machine in the Lyme disease spirochete Borrelia burgdorferi. We define the fT3SS machine by systematically characterizing mutants lacking key component genes. We discover that a distinct cytosolic ATPase complex is attached to the flagellar C-ring through multiple spoke-like linkers. The ATPase complex not only strengthens structural rigidity of the C-ring, but also undergoes conformational changes in concert with flagellar rotation. Our studies provide structural framework to uncover the unique mechanisms underlying assembly and rotation of the periplasmic flagella and may provide the bases for the development of novel therapeutic strategies against several pathogenic spirochetes.

microbiology↗