Biology subjects

Zheng, L.

Publications and source records attributed to Zheng, L..

12 recordsLinked to original sources

bioRxiv2018

Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia

BackgroundPlacental protein expression plays a crucial biological role during normal and complicated pregnancies. We hypothesized that: (1) circulating pregnancy-associated, placenta-related protein levels throughout gestation reflect the uncomplicated, full-term temporal progression of human gestation, and effectively estimates gestational ages (GAs); (2) pregnancies with underlying placental pathology, such as preeclampsia (PE), are associated with disruptions in this GA estimation in early gestation; (3) malfunctions of this GA estimation can be employed to identify impending PE. In addition, to explore the underlying biology and PE etiology, we set to compare protein gestational patterns of human and mouse, using pregnant heme oxygenase-1 (HO-1) heterozygote (Het) mice, a mouse model reflecting PE-like symptoms.\n\nMethodsSerum levels of circulating placenta-related proteins - leptin (LEP), chorionic somatomammotropin hormone like 1 (CSHL1), elabela (ELA), activin A, soluble fms-like tyrosine kinase 1 (sFlt-1), and placental growth factor (PlGF)- were quantified by ELISA in blood serially collected throughout human pregnancies (20 normal subjects with 66 samples, and 20 PE subjects with 61 samples). Linear multivariate analysis of the targeted serological protein levels was performed to estimate the normal GA. Logarithmic transformed mean-squared errors of GA estimations were used to identify impending PE. Then the human gestational protein patterns were compared to those in the pregnant HO-1 mice.\n\nResultsAn elastic net (EN)-based gestational dating model was developed (R2 = 0.76) and validated (R2 = 0.61) using the serum levels of the 6 proteins at various GAs from women with normal uncomplicated pregnancies (n = 10 for training and n = 6 for validation). In pregnancies complicated by PE (n = 14), the EN model was not (R2 = -0.17) associated with GA at sampling in PE. Statistically significant deviations from the normal GA EN model estimations were observed in PE-associated pregnancies between GAs of 16-30 weeks (P = 0.01). The EN model developed with 5 proteins (ELA excluded due to the lack of robustness of the mouse ELA essay) performed similarly on normal human (R2 = 0.68) and WT mouse (R2 = 0.85) pregnancies. Disruptions of this model were observed in both human PE-associated (human: R2 = 0.27) and mouse HO-1 Het (mouse: R2 = 0.30) pregnancies. LEP out performed sFlt-1 and PlGF in differentiating impending PE at early human and late mouse gestations.\n\nConclusionsAs revealed in both human and mouse GA EN analyses, temporal serological placenta-related protein patterns are tightly regulated throughout normal human pregnancies and can be significantly disrupted in pathologic PE states. LEP changes earlier during gestation than the well-established late GA PE biomarkers (sFlt-1 and PlGF). Our HO-1 Het mouse analysis provides direct evidence of the causative action of HO-1 deficiency in LEP upregulation in a PE-like murine model. Therefore, longitudinal analyses of pregnancy-related protein patterns in sera, may not only help in the exploration of underlying PE pathophysiology but also provide better clinical utility in PE assessment.

molecular biology↗

bioRxiv2018

Crystal Structure of a Natural Light-Gated Anion Channelrhodopsin

The anion channelrhodopsin GtACR1 from the alga Guillardia theta is a potent neuron-inhibiting optogenetics tool. Presented here, its X-ray structure at 2.9 [A] reveals a tunnel traversing the protein from its extracellular surface to a large cytoplasmic cavity. The tunnel is lined primarily by small polar and aliphatic residues essential for anion conductance. A disulfide-immobilized extracellular cap facilitates channel closing and the ion path is blocked mid-membrane by its photoactive retinylidene chromophore and further by a cytoplasmic side constriction. The structure also reveals a novel photoactive site configuration that maintains the retinylidene Schiff base protonated when the channel is open. These findings suggest a new channelrhodopsin mechanism, in which the Schiff base not only controls gating, but also serves as a direct mediator for anion flux.

biochemistry↗

bioRxiv2018

RAD51 AND MITOTIC FUNCTION OF MUS81 ARE ESSENTIAL FOR RECOVERY FROM LOW-DOSE OF CAMPTOTHECIN IN THE ABSENCE OF THE WRN EXONUCLEASE

Stabilisation of the stalled replication fork is crucial to prevent excessive fork reversal or degradation, which can undermine genome integrity. The WRN protein is a human RecQ helicase that participates in the processing and recovery of perturbed replication forks. WRN is unique among the other human RecQ family members to possess exonuclease activity. However, the biological role of the WRN exonuclease is poorly defined, and little is known about an involvement in the response to perturbed replication. Recently, the WRN exonuclease has been linked to protection of stalled forks from MRE11-dependent degradation in response to clinically-relevant nanomolar doses of the Topoisomerase I inhibitor camptothecin. Alternative processing of perturbed forks has been associated to chemoresistance of BRCA-deficient cancer cells, thus, we used WRN exonuclease-deficiency as a model to investigate the fate of perturbed replication forks undergoing degradation, but in a BRCA wild-type condition. We find that, upon nanomolar doses of camptothecin, loss of WRN exonuclease stimulates fork inactivation and accumulation of parental gaps, which engages RAD51. Such alternative mechanism affects reinforcement of CHK1 phosphorylation and causes persistence of RAD51 during recovery from treatment. Notably, in WRN exonuclease-deficient cells, persistence of RAD51 correlates with elevated mitotic phosphorylation of MUS81 at Serine 87, which is essential to avoid accumulation of mitotic abnormalities. Altogether, these findings indicate that aberrant fork degradation, in the presence of a wild-type RAD51 axis, stimulates RAD51-mediated post-replicative repair and engagement of the MUS81 complex to limit genome instability and cell death.\n\nAUTHOR SUMMARYCorrect progression of the molecular machine copying the chromosomes is threatened by multiple causes that induce its delay or arrest. Once the replication machinery is arrested, the cell needs to stabilise it to prevent DNA damage. Many proteins contribute to this task and the Werners syndrome protein, WRN, is one of them.\n\nDefining what happens to replication machineries when they are blocked is highly relevant. Indeed, destabilised replication machineries may form upon treatment with anticancer drugs and influence the efficacy of some of them in specific genetic backgrounds. We used cells that lack one of the two enzymatic functions of WRN, the exonuclease activity, to investigate the fate of destabilised replication machineries. Our data show that they are handled by a repair pathway normally involved in fixing DNA breaks but, in this case, recruited to deal with regions of the genome that are left unreplicated after their destabilisation. This alternative mechanism involves a protein, RAD51, which tries to copy DNA from the sister chromosome. In so doing, however, RAD51 produces a lot of DNA interlinking that requires upregulation of a complex, called MUS81/EME1, which resolves this interlinking prior cell division and prevents accumulation of mitotic defects and cell death.

cell biology↗

bioRxiv2018

Genome-wide identification of functional tRNA-derived fragments in Senescence-accelerated mouse prone 8 brain

tRNA-derived fragments (tRFs) have been linked previously to the development of various diseases, such as cancer and viral infection. However, tRFs seem also related to brain aging and related diseases, especially Alzheimer and Parkinson disease. RNA sequencing, a state-of-the-art technology, has allowed for investigation of tRFs in this field. In this study, we investigated the changes of tRFs in the brains of a senescence-accelerated mouse model, senescence-accelerated mouse prone 8 (SAMP8), that show age-dependent deficits in learning and memory; and a control model, senescence-accelerated mouse resistant 1 (SAMR1), with normal aging, both at 7 months of age. A total of 570 tRF transcripts were discovered. Among these transcripts, 8, including 3 upregulated and 5 downregulated transcripts, were differentially expressed in the SAMP8 mice. Then, we obtained 110 potential target genes in a miRNA-like pattern. GO survey implicated these target genes in the function of various aspects, e.g. postsynaptic density (GO: 0014069). Furthermore, we assessed in detail those tRFs whose miRNA-like pattern was most likely to affect the progression of either Alzheimer and Parkinson disease, such as AS-tDR-011775 acting on Mobp and Park2. In fact, we found the tRFs to be involved in the regulation of gene expression by means other than the miRNA-like pattern. Therefore, these 8 dysregulated tRFs may hold consequences far into the future and can be attractive biomarkers and valid targets. In brief, our study is the first to provide a comprehensive analysis on tRFs in SAMP8 mouse brain, and this breakthrough identified promising new targets for preventing the age-related changes of brain and the therapeutic intervention of Alzheimers and Parkinsons.

neuroscience↗

bioRxiv2018

SSCC: a computational framework for rapid and accurate clustering of large-scale single cell RNA-seq data

Clustering is a prevalent analytical means to analyze single cell RNA sequencing data but the rapidly expanding data volume can make this process computational challenging. New methods for both accurate and efficient clustering are of pressing needs. Here we proposed a new clustering framework based on random projection and feature construction for large scale single-cell RNA sequencing data, which greatly improves clustering accuracy, robustness and computational efficacy for various state-of-the-art algorithms benchmarked on multiple real datasets. On a dataset with 68,578 human blood cells, our method reached 20% improvements for clustering accuracy and 50-fold acceleration but only consumed 66% memory usage compared to the widely-used software package SC3. Compared to k-means, the accuracy improvement can reach 3-fold depending on the concrete dataset. An R implementation of the framework is available from https://github.com/Japrin/sscClust.

bioinformatics↗

bioRxiv2018

Microbial Community Structure and Diversity of Shrimp Paste at Different Fermentation Stages

High-throughput sequencing was used to reveal the highly diverse bacterial populations in shrimp paste at different fermentation stages. We studied three stages of fermentation and obtained 448,916 reads. Using this approach, we revealed the presence of 30 phyla, 55 classes, 86 orders, 206 families and 695 genera of bacteria in the shrimp paste. Shrimp paste in fermentation metaphase had a more diverse microbiota than that in fermentation prophase and fermentation anaphase. Diversity appeared greatest in fermentation anaphase. The four dominant phyla were Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. The most common genera were Psychrobacter, Halomonas, Bacillus, Alteribacillus, and Lactococcus. Their content varied at different stages of fermentation. All the microbiome presented a variety of changes in the microbial diversity of shrimp paste.\n\nImportanceMost research on the microbial diversity of shrimp paste has focused on the shrimp culture environment, or the chemical composition and sensory attributes of the paste. Little research has been conducted on the microbial diversity and composition of shrimp paste. The relationship between microbes and the flavor and quality of shrimp paste has thus been unknown. We therefore analyzed the microbial composition and variation of shrimp paste at different stages of fermentation. The dominant bacteria in fermentation prophase, metaphase, and anaphase were identified. Our preliminary findings give some insight into which microbes contribute to the flavor of shrimp paste and suggest how to improve its flavor. In addition, our findings are relevant to optimizing the production of shrimp paste and guaranteeing its quality and safety.

microbiology↗

bioRxiv2018

Effect of eco-remediation and microbial community using multilayer solar planted floating island (MS-PFI) in the drainage channel

A multilayer solar planted floating island (MS-PFI) planted with Eichhornia crassipes are potential alternatives to traditional PFI. The highest removal rates of suspended solids, total nitrogen, total phosphorus, ammonia nitrogen and chemical oxygen demand was 86%, 75%, 80%, 95% and 84%, respectively. Proteobacteria (average 43.4% of total sequences) and Actinobacteria (19.9%) were the dominant phyla. Numerous genus had obvious differences between influent and effluent water, for instance, 13, 12 and 7 % in effluent water were assigned to the hgcl_clade, Norank_c_Cyanobacteria, and Rhizorhapis, while their relative abundances were decreased to 5, 3 and 0 %. In contrast, a distinct increase among Flavobacterium (10%), Limnohabitans (7%), Alpinimonas (4%), norank_p_Saccharibacteria (4%), Erwinia (3%) after MS-PFI treatment. MS-PFI brings various bacteria involved in contaminant degradation and nutrient removal in biological wastewater treatment systems. An amount of {yen} 1,843 was totally inputted to construct floating bed, which was rarely needed operation and maintenance costs.\n\nImportanceIn-situ micro-polluted water ecological remediation, microorganisms and plants are effective to improve environmental quality and provide essential ecosystem services. Recently, we invent a new multilayer solar with an excellent pollutant removal efficiency. Microbes can decompose or mineralize organic matter effectively, also provide food for aquatic animals and increase nutrients or substances for plants, it is an important part of biogeochemical cycles and energy flows in aquatic ecological systems. However, few study explain the bacteria diversity and its responses between influent and effluent water in a planted floating island. The significance of our study is in identifying-in greater detail-the responses of bacteria in the new MS-PFI. This will greatly enhance our knowledge of bacteria communities, and can be widely used in micro-polluted water remediation.

bioengineering↗

bioRxiv2018

A data mining paradigm for identifying key factors in biological processes using gene expression data

A large volume of biological data is being generated for studying mechanisms of various biological processes. These precious data enable large-scale computational analyses to gain biological insights. However, it remains a challenge to mine the data efficiently for knowledge discovery. The heterogeneity of these data makes it difficult to consistently integrate them, slowing down the process of biological discovery. We introduce a data processing paradigm to identify key factors in biological processes via systematic collection of gene expression datasets, primary analysis of data, and evaluation of consistent signals. To demonstrate its effectiveness, our paradigm was applied to epidermal development and identified many genes that play a potential role in this process. Besides the known epidermal development genes, a substantial proportion of the identified genes are still not supported by gain- or loss-of-function studies, yielding many novel genes for future studies. Among them, we selected a top gene for loss-of-function experimental validation and confirmed its function in epidermal differentiation, proving the ability of this paradigm to identify new factors in biological processes. In addition, this paradigm revealed many key genes in cold-induced thermogenesis using data from cold-challenged tissues, demonstrating its generalizability. This paradigm can lead to fruitful results for studying molecular mechanisms in an era of explosive accumulation of publicly available biological data.

bioinformatics↗

bioRxiv2018

Structure of the receptor-activated human TRPC6 ion channel

TRPC6 is a receptor-activated nonselective cation channel that belongs to the family of canonical transient receptor potential (TRPC) channels. It is activated by diacylglycerol, a lipid second messenger. TRPC6 is involved in many physiological processes and implicated in human genetic diseases. Here we present the structure of human TRPC6 homotetramer in complex with a newly identified high affinity inhibitor BTDM solved by single-particle cryo-electron microscopy to 3.8 [A] resolution. The structure shows a two-layer architecture, in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domain, including N terminal ankyrin repeats and C terminal coiled-coil, contribute to the tetramer assembly. The high affinity inhibitor BTDM wedges between S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening. Our structure uncovers the molecular architecture of TRPC channels and provides a structural basis for understanding the mechanism of these channels.

biophysics↗

bioRxiv2018

Gallic Acid Disrupts Aβ1-42 Aggregation and Rescues Cognitive Decline of APP/PS1 Transgenic Mouse

Alzheimers disease (AD) treatment represents one of the largest unmet medical needs. Developing drugs capable of preventing A{beta} aggregation is an excellent approach to prevent and treat AD. Here, we show that gallic acid (GA), a naturally occurring polyphenolic small molecule rich in grape seeds and fruits, has the capacity to alleviate cognitive decline of APP/PS1 transgenic mouse through reduction of A{beta}1-42 aggregation and neurotoxicity. Oral administration of GA not only improved the spatial reference memory and spatial working memory of early stage AD mice (4-month-old), but also significantly reduced the more severe deficits in spatial learning, reference memory, short-term recognition and spatial working memory of the late stage AD mice (9-month-old). The hippocampal long-term-potentiation (LTP) was also significantly elevated in the GA-treated late stage APP/PS1 AD mice. Atomic force microscopy (AFM), dynamic light scattering (DLS) and thioflavin T (ThT) fluorescence densitometry analyses showed that GA can reduce A{beta}1-42 aggregation from forming toxic oligomers and fibrils. Indeed, pre-incubating GA with oligomeric A{beta}1-42 reduced A{beta} 1-42-mediated intracellular calcium influx and neurotoxicity. Molecular docking studies identified that the 3,4,5-hydroxyle groups of GA were essential in noncovalently stabilizing GA binding to the Lys28-Ala42 salt bridge and the -COOH group is critical for disrupting the salt bridge of A{beta}1-42. The predicated covalent interaction through Schiff-base formation between the carbonyl group of the oxidized product and {varepsilon}-amino group of Lys16 is also critical for the disruption of A{beta}1-42 S-shaped triple-{beta}-motif and toxicity. Together, these studies demonstrated that GA can prevent and protect the AD brain through disrupting A{beta}1-42 aggregation.

neuroscience↗

bioRxiv2017

Cell-autonomous regulation of structural and functional plasticity in inhibitory neurons by excitatory synaptic inputs

Functional circuit assembly is thought to require coordinated development of excitation and inhibition, but whether they are co-regulated cell-autonomously remains unclear. We investigated effects of decreased glutamatergic synaptic input on inhibitory synapses by expressing AMPAR subunit, GluA1 and GluA2, C-terminal peptides (GluA1CTP and GluA2CTP) in developing Xenopus tectal neurons. GluACTP decreased excitatory synaptic inputs and cell-autonomously decreased inhibitory synaptic inputs in excitatory and inhibitory neurons. Visually-evoked excitatory and inhibitory currents decreased proportionately, maintaining excitation/inhibition. GluACTP affected dendrite structure and visual experience-dependent structural plasticity differently in excitatory and inhibitory neurons. Deficits in excitatory and inhibitory synaptic transmission and experience-dependent plasticity manifested in altered visual receptive field properties. Both visual avoidance behavior and learning-induced behavioral plasticity were impaired, suggesting that maintaining excitation/inhibition alone is insufficient to preserve circuit function. We demonstrate that excitatory synaptic dysfunction in individual neurons cell-autonomously decreases inhibitory inputs and disrupts neuronal and circuit plasticity, information processing and learning.

neuroscience↗

bioRxiv2017

Coupling effect of morphology and mechanical properties contributes to the tribological behaviors of snake scales

It is known that the tribological behaviors of snake skins are contributed by the synergistic action of multiple factors, such as surface morphology and mechanical properties, which has inspired fabrication of scale-like surface textures in recent years. However, the coupling effect and mechanism remain to be elucidated. In this work, the morphology and mechanical properties of the scales from different body sections (leading body half, middle trunk and trailing body half) and positions (dorsal, lateral and ventral) of Boa constrictor and Eryx tataricus have been characterized and compared to investigate the corresponding effects on the tribological behaviors and to probe the possible coupling mechanism. The morphological characterizations of scanning electron microscopy and atomic force microscopy have revealed significant differences between the two species with the roughness of scales from Boa constrictor being larger in general. The mechanical properties measured by nanoindentation have corroboratively demonstrated substantial differences in terms of elastic modulus and hardness. Meanwhile, tribological characterizations of scales in different body positions from the two species also exhibit evident anisotropy. Interestingly, the ventral scales manifest higher friction coefficients but lower surface roughness, together with relatively larger elastic modulus and hardness. A \"double-crossed\" hypothesis has been proposed to explain the observed coupling effect of the morphology and mechanical properties on friction, which may afford valuable insights for the design of materials with desirable tribological performance.

animal behavior and cognition↗