Biology subjects

Liang, J.

Publications and source records attributed to Liang, J..

At least 199 records · Page 11Linked to original sources

bioRxiv2020

Neuronal lipolysis participates in PUFA-mediated neural function and neurodegeneration

Lipid droplets (LDs) are dynamic cytoplasmic organelles present in most eukaryotic cells. The appearance of LDs in neurons is not usually observed under physiological conditions, but is associated with neural diseases. It remains unclear how LD dynamics is regulated in neurons and how the appearance of LDs affects neuronal functions. We discovered that mutations of two key lipolysis genes atgl-1 and lid-1 lead to LD appearance in neurons of Caenorhabditis elegans. This neuronal lipid accumulation protects neurons from hyperactivation-triggered neurodegeneration, with a mild decrease in touch sensation. We also discovered that reduced biosynthesis of polyunsaturated fatty acids (PUFAs) causes similar effects, synergistically with decreased lipolysis. Furthermore, we demonstrated that these changes in lipolysis and PUFA biosynthesis increase PUFA partitioning toward triacylglycerol, and reduced incorporation of PUFAs into phospholipids increases neuronal protection. Together, these results suggest the crucial role of neuronal lipolysis in regulating neural functions and neurodegeneration cell-autonomously. HighlightsO_LINeuronal lipolysis prevents LD accumulation in neurons. C_LIO_LIDefective neuronal lipolysis leads to touch sensation defect. C_LIO_LIBlocking neuronal lipolysis alleviates neurodegeneration. C_LIO_LINeuronal lipolysis and de novo PUFA biosynthesis have a synergistic effect in neurodegeneration. C_LIO_LIThe incorporation of PUFAs into phospholipids promotes neurodegeneration. C_LI

cell biology↗

bioRxiv2020

Response of Asplenium nidus to Drought Stress and Identification of Drought Tolerance Genes

To explore how Asplenium nidus responds to drought stress, and to mine drought-responsive genes for Asplenium nidus, we conducted a pot experiment in the IOT smart greenhouse. We measured a series of physiological and biochemical indexes for drought-treated plants, and analyzed the expression of drought-responsive genes in Asplenium nidus by RT-qPCR. The results show that the Asplenium nidus is a species with drought tolerance. Asplenium nidus inhibits plant photosynthesis and reduces life activities by limiting stomatal opening to adapt to drought. To resist drought stress, the Asplenium nidus changes the osmotic potential by increasing the proline content to maintain normal metabolic activities and prevents the damage of active oxygen by increasing the enzyme activities of SOD and POD. Based on the analysis of the relative expression levels of genes, AVP1-2 and AVP1-4 may be drought-resistant genes in Asplenium nidus. This study lays the foundation for in-depth research on drought tolerance mechanisms and drought-resistant gene mining of Asplenium nidus.

genetics↗

bioRxiv2020

The effects of seasonal climate variability on dengueannual incidence in Hong Kong: A modellingstudy

In recent years, dengue has been rapidly spreading and growing in the tropics and subtropics. Located in southern China, Hong Kongs subtropical monsoon climate may favour dengue vector populations and increase the chance of disease transmissions during the rainy summer season. An increase in local dengue incidence has been observed in Hong Kong ever since the first case in 2002, with an outbreak reaching historically high case numbers in 2018. However, the effects of seasonal climate variability on recent outbreaks are unknown. As the local cases were found to be spatially clustered, we developed a Poisson generalized linear mixed model using pre-summer monthly total rainfall and mean temperature to predict annual dengue incidence (the majority of local cases occur during or after the summer months), over the period 2002-2018 in three pre-defined areas of Hong Kong. Using leave-one-out cross-validation, 5 out of 6 observations of area-specific outbreaks during the major outbreak years 2002 and 2018 were able to be predicted. 42 out of a total of 51 observations (82.4%) were within the 95% confidence interval of the annual incidence predicted by our model. Our study found that the rainfall before and during the East Asian monsoon (pre-summer) rainy season is negatively correlated with the annual incidence in Hong Kong while the temperature is positively correlated. Hence, as mosquito control measures in Hong Kong are intensified mainly when heavy rainfalls occur during or close to summer, our study suggests that a lower-than-average intensity of pre-summer rainfall should also be taken into account as an indicator of increased dengue risk.

ecology↗

bioRxiv2020

Counteracting Genome Instability by p53-dependent Mintosis

Entosis was proposed to promote aneuploidy and genome instability by cell-in-cell mediated engulfment in tumor cells. We reported here, in epithelial cells, that entosis coupled with mitotic arrest functions to counteract genome instability by targeting aneuploid mitotic progenies for engulfment and elimination. We found that the formation of cell-in-cell structures associated with prolonged mitosis, which was sufficient to induce entosis. This process was controlled by the tumor suppressor p53 (wild type) that upregulates Rnd3 expression in response to DNA damages associated with prolonged metaphase. Rnd3 compartmentalized RhoA activities accumulated during prolonged metaphase to drive cell-in-cell formation. Remarkably, this prolonged mitosis-induced entosis (mintosis) selectively targets non-diploid progenies for internalization, blockade of which increased aneuploidy. Thus, our work uncovered a heretofore unrecognized mechanism of mitotic surveillance for entosis, which eliminates newly-born abnormal daughter cells in a p53-depedent way to maintain genome integrity.

cell biology↗

bioRxiv2019

IRAK1-mediated coincidence detection of microbial signals licenses inflammasome activation

The innate immune system signals through various higher order signaling complexes called supramolecular organizing centers (SMOCs), which typically organize components of a single pathway. While innate immune signaling pathways have been largely characterized using single receptor stimuli, responses to pathogens require the coordinated engagement of multiple pathways. Here, we report an IRAK1-containing SMOC formed specifically when multiple receptors are activated, which recruits select components of the TLR, MAPK and inflammasome pathways. This allows for signal flux redistribution from TLRs to inflammasomes and facilitates inflammasome licensing through an MKK7-JNK axis, which is defective in Irak1-/- mice. Furthermore, this defect in Irak1-/- mice manifests in increased susceptibility to inflammasome-sensitive pathogens and diminished IL1 production from inflammasomes after co-TLR priming. Thus, IRAK1 SMOCs form a multi-pathway coordinating hub for coincidence detection of microbial signals, which may be employed by innate immune cells as a threat assessment and thresholding mechanism for inflammasome activation.

immunology↗

bioRxiv2019

CHROMATIX: computing the functional landscape of many-body chromatin interactions in transcriptionally active loci

Chromatin interactions are important for gene regulation and cellular specialization. Emerging evidence suggests many-body spatial interactions can play important roles in condensing super-enhancer regions into a cohesive transcriptional apparatus. Chromosome conformation studies using Hi-C are limited to pairwise, population-averaged interactions; therefore, not suitable for direct assessment of many-body interactions. We describe a computational model, CHROMATIX, that reconstructs structural ensembles based on Hi-C data and identifies significant many-body interactions. For a diverse set of highly-active transcriptional loci with at least 2 super-enhancers, we detail the many-body functional landscape and show DNase-accessibility, POLR2A binding, and decreased H3K27me3 are predictive of interaction-enriched regions.

bioinformatics↗

bioRxiv2019

High-Resolution Single-Cell Models of Ensemble Chromatin Structures during Drosophila Embryogenesis from Population Hi-C

Single-cell chromatin studies provide insights into how chromatin structure relates to functions of individual cells. However, balancing high-resolution and genome wide-coverage remains challenging. We describe a computational method for the reconstruction of large 3D-ensembles of single-cell (sc) chromatin conformations from population Hi-C that we apply to study embryogenesis in Drosophila. With minimal assumptions of physical properties and without adjustable parameters, our method generates large ensembles of chromatin conformations via deep-sampling. Our method identifies specific interactions, which constitute 5-6% of Hi-C frequencies, but surprisingly are sufficient to drive chromatin folding, giving rise to the observed Hi-C patterns. Modeled sc-chromatins quantify chromatin heterogeneity, revealing significant changes during embryogenesis. Furthermore, >50% of modeled sc-chromatin maintain topologically associating domains (TADs) in early embryos, when no population TADs are perceptible. Domain boundaries become fixated during development, with strong preference at binding-sites of insulator-complexes upon the mid-blastula transition. Overall, high-resolution 3D-ensembles of sc-chromatin conformations enable further in-depth interpretation of population Hi-C, improving understanding of the structure-function relationship of genome organization.

genomics↗

bioRxiv2019

Transcription imparts architecture, function, and logic to enhancer units

Distal enhancers remain one of the least understood regulatory elements with pivotal roles in development and disease. We used massively parallel reporter assays to perform functional comparisons of two leading enhancer models and find that gene-distal transcription start sites (TSSs) are robust predictors of enhancer activity with higher resolution and specificity than histone modifications. We show that active enhancer units are precisely delineated by active TSSs, validate that these boundaries are sufficient to capture enhancer function, and confirm that core promoter sequences are required for this activity. Finally, we assay pairs of adjacent units and find that their cumulative activity is best predicted by the strongest unit within the pair. Synthetic fusions of enhancer units demonstrate that adjacency imposes winner-takes-all logic, revealing a simple design for a maximum-activity filter of enhancer unit outputs. Together, our results define fundamental enhancer units and a principle of non-cooperativity between adjacent units.

genomics↗

bioRxiv2019

Cross-species machine learning improves diagnostic classification of human psychiatric disorders

Psychiatric disorders often exhibit shared (co-morbid) symptoms, raising controversies over accurate diagnosis and the overlap of their neural underpinnings. Because the complexity of data generated by clinical studies poses a formidable challenge, we have pursued a reductionist framework using brain imaging data of a transgenic primate model of autism spectrum disorder (ASD). Here we report an interpretable cross-species machine learning approach which extracts transgene-related core regions in the monkey brain to construct the classifier for diagnostic classification in humans. The cross-species classifier based on core regions, mainly distributed in frontal and temporal cortex, identified from the transgenic primate model, achieved an accuracy of 82.14% in one clinical ASD cohort obtained from Autism Brain Imaging Data Exchange (ABIDE-I), significantly higher than the human-based classifier (61.31%, p < 0.001), which was validated in another independent ASD cohort obtained from ABIDE-II. Such monkey-based classifier generalized to achieve a better classification in obsessive-compulsive disorder (OCD) cohorts, and enabled parsing of differential connections to right ventrolateral prefrontal cortex being attributable to distinct traits in patients with ASD and OCD. These findings underscore the importance of investigating biologically homogeneous samples, particularly in the absence of real-world data adequate for deconstructing heterogeneity inherited in the clinical cohorts.\n\nOne Sentence SummaryFeatures learned from transgenic monkeys enable improved diagnosis of autism-related disorders and dissection of their underlying circuits.

neuroscience↗

bioRxiv2019

Hedgehog pathway activation through conformational blockade of the Patched sterol conduit

Activation of the Hedgehog pathway may have therapeutic value for improved bone healing, taste receptor cell regeneration, and alleviation of colitis or other conditions. Systemic pathway activation, however, may be detrimental and therapeutic application has been difficult for lack of agents amenable to tissue targeting. We have developed a novel agonist, a conformation-specific nanobody against the Hedgehog receptor Patched1. This nanobody potently activates the Hedgehog pathway in vitro and in vivo by stabilizing an alternative conformation of a Patched1 \"switch helix\", as revealed by cryo-EM structure determination. Although this conformation likely constitutes part of the transport cycle, nanobody-trapping disrupts the cycle and prevents substrate movement through the Patched1 sterol conduit. Our conformation-selective nanobody approach provides a new route to the development of transporter-related pharmacologic agents and may be generally applicable to the study of other transporters.

biophysics↗

bioRxiv2019

DEEP LEARNING-ENABLED POINT-OF-CARE SENSING USING MULTIPLEXED PAPER-BASED SENSORS

We present a deep learning-based framework to design and quantify point-of-care sensors. As its proof-of-concept and use-case, we demonstrated a low-cost and rapid paper-based vertical flow assay (VFA) for high sensitivity C-Reactive Protein (hsCRP) testing, a common medical test used for quantifying the degree of inflammation in patients at risk of cardio-vascular disease (CVD). A machine learning-based sensor design framework was developed for two key tasks: (1) to determine an optimal configuration of immunoreaction spots and conditions, spatially-multiplexed on a paper-based sensing membrane, and (2) to accurately infer the target analyte concentration based on the signals of the optimal VFA configuration. Using a custom-designed mobile-phone based VFA reader, a clinical study was performed with 85 human serum samples to characterize the quantification accuracy around the clinically defined cutoffs for CVD risk stratification. Results from blindly-tested VFAs indicate a competitive coefficient of variation of 11.2% with a linearity of R2 = 0.95; in addition to the success in the high-sensitivity CRP range (i.e., 0-10 mg/L), our results further demonstrate a mitigation of the hook-effect at higher CRP concentrations due to the incorporation of antigen capture spots within the multiplexed sensing membrane of the VFA. This paper-based computational VFA that is powered by deep learning could expand access to CVD health screening, and the presented machine learning-enabled sensing framework can be broadly used to design cost-effective and mobile sensors for various point-of-care diagnostics applications.

bioengineering↗

bioRxiv2019

Whole-Genome Association Analyses of Sleep-disordered Breathing Phenotypes in the NHLBI TOPMed Program

Sleep-disordered breathing (SDB) is a common disorder associated with significant morbidity. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program we report the first whole-genome sequence analysis of SDB. We identified 4 rare gene-based associations with SDB traits in 7,988 individuals of diverse ancestry and 4 replicated common variant associations with inclusion of additional samples (n=13,257). We identified a multi-ethnic set-based rare-variant association (p = 3.48 x 10-8) on chromosome X with ARMCX3. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Results highlighted associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis and HIF1A-mediated hypoxic response.

genetics↗

bioRxiv2019

Paired design of ATP bioluminescence method and colony counting method: whether it is suitable for evaluating the disinfection effect of environmental surface?

ATP bioluminescence method has been used as a on-site rapid detection method in nosocomial infections control more and more. In this study, a paired design between four methods/detectors were performed to detect the environmental surface after disinfection. Two methods were ATP bioluminescence method and colony counting method (C), and ATP bioluminescence method included three kinds of detectors (B, P and N). Every surface was performed by two methods/detectors. ATP content per surface from ICU had no statistically significant difference with internal medicine wards of B and P, of which p was 0.435 and 0.260. By Spearman rank correlation coefficients, with the exception of better correlation between ATP content detected by B and P, the correlation between the remaining methods/detectors was poor or had no correlation. And the differences between detectors are statistically significant. Therefor, ATP bioluminescence method may not be suitable for the evaluation of disinfection effect, but be more appropriate for evaluating the cleanliness of environmental surface.

microbiology↗

bioRxiv2019

Multiple Cross Displacement Amplification Coupled with Gold Nanoparticles-Based Lateral Flow Biosensor for Detection of the Mobilized Colistin Resistance Gene mcr-1

Fast dissemination of the mobilized colistin resistance (mcr) gene mcr-1 in Enterobacteriaceae causes a huge threat to the treatment of severe infection. In the current report, a multiple cross displacement amplification (MCDA) coupled with the detection of amplified products by gold nanoparticles-based lateral flow biosensor (LFB) assay (MCDA-LFB) was established to identify the mcr-1 gene with simpleness, rapidity, specificity and sensitivity. The MCDA-LFB assay was performed at a isothermal temperature (63{degrees}C) for only 30 min during the amplification stage, and the reaction products were directly identified by using LFB which obtained the result with 2 min. The entire process of experiments, from templates extraction to result judging, was accomplished less than 60 min. For the analytical specificity of this method, all of the 16 mcr-1-producing strains were positive, and all of the non-mcr-1 isolates got the negative results. The sensitivity of mcr-1-MCDA-LFB assay was as little as 600 fg of plasmid DNA per reaction in pure culture, and approximately 4.5x103 CFU/mL (~4.5 CFU/reaction) in fecal samples spiked with 100 l of strains. Therefore, this technique established in the present study is suitable for the surveillance of mcr-1 gene in clinic and livestock industry.

molecular biology↗

bioRxiv2019

Tumor establishment requires tumor autonomous and non autonomous decoupling of EGF signaling from apoptosis

SummaryIn healthy adult organs, robust feedback mechanisms control cell turnover to enforce homeostatic equilibrium between cell division and death [1, 2]. Nascent tumors must subvert these mechanisms to achieve cancerous overgrowth [3-7]. Elucidating the nature of this subversion can reveal how cancers become established and may suggest strategies to prevent tumor progression. In adult Drosophila intestine, a well-studied model of homeostatic cell turnover, the linchpin of cell equilibrium is feedback control of the EGF protease Rhomboid (Rho). Expression of Rho in apoptotic cells enables them to secrete EGFs, which stimulate nearby stem cells to undergo replacement divisions [8]. As in mammals, loss of adenomatous polyposis coli (APC) causes Drosophila intestinal stem cells to form adenomas [9]. Here we demonstrate that Drosophila APC-/- tumors trigger widespread Rho expression in non-apoptotic cells, resulting in chronic EGF signaling. Initially, nascent APC-/- tumors induce rho in neighbor wild-type cells via acute, non-autonomous activation of JNK. During later growth and multilayering, APC-/- tumors induce rho in tumor cells by autonomous downregulation of E-cadherin (E-cad) and consequent activity of p120-catenin. This sequential dysregulation of tumor non-autonomous and -autonomous EGF signaling converts tissue-level feedback into feed-forward activation that drives cancerous overgrowth. Since Rho, EGFR, and E-cad are associated with colorectal cancer in humans [10-17], our findings may shed light on how human colorectal tumors progress.

developmental biology↗

bioRxiv2019

Visual interference can help and hinder memory: Measuring memory fidelity using a novel circular shape space

Although we can all agree that interference induces forgetting, there is surprisingly little consensus regarding what type of interference most likely disrupts memory. We previously proposed that the similarity of interference differentially impacts the representational detail of color memory. Here, we extend this work by applying the Validated Circular Shape Space (Li et al., 2020) for the first time to a continuous retrieval task, in which we quantified both the visual similarity of distracting information as well as the representational detail of shape memory. We found that the representational detail of memory was systematically and differentially altered by the similarity of distracting information. Dissimilar distractors disrupted both fine- and coarse-grained information about the target, akin to memory erasure. In contrast, similar distractors disrupted fine-grained target information but increased reliance on coarse-grained information about the target, akin to memory blurring. Notably, these effects were consistent across two mixture models that each implemented a different scaling metric (either angular distance or perceived target similarity), as well as a parameter-free analysis that did not fit the mixture model. These findings suggest that similar distractors will help memory in cases where coarse-grained information is sufficient to identify the target. In other cases where precise fine-grained information is needed to identify the target, similar distractors will impair memory. As these effects have now been observed across both stimulus domains of shape and color, and were robust across multiple scaling metrics and methods of analyses, we suggest that these results provide a general set of principles governing how the nature of interference impacts forgetting.

neuroscience↗

bioRxiv2019

MaXLinker: proteome-wide cross-link identifications with high specificity and sensitivity

Protein-protein interactions play a vital role in nearly all cellular functions. Hence, understanding their interaction patterns and three-dimensional structural conformations can provide crucial insights about various biological processes and underlying molecular mechanisms for many disease phenotypes. Cross-linking mass spectrometry has the unique capability to detect protein-protein interactions at a large scale along with spatial constraints between interaction partners. However, the current cross-link search algorithms follow an "MS2-centric" approach and, as a result, suffer from a high rate of mis-identified cross-links (~15%). We address this urgent problem, by designing a novel "MS3-centric" approach for cross-link identification and implemented it as a search engine called MaXLinker. MaXLinker significantly outperforms the current state of the art search engine with up to 18-fold lower false positive rate. Additionally, MaXLinker results in up to 31% more cross-links, demonstrating its superior sensitivity and specificity. Moreover, we performed proteome-wide cross-linking mass spectrometry using K562 cells. Employing MaXLinker, we unveiled the most comprehensive set of 9,319 unique cross-links at 1% false discovery rate, comprising 8,051 intraprotein and 1,268 interprotein cross-links. Finally, we experimentally validated the quality of a large number of novel interactions identified in our study, providing a conclusive evidence for MaXLinkers robust performance.

systems biology↗

bioRxiv2018

Premeiotic and meiotic failures associate with hybrid male sterility in the Anopheles gambiae complex

Hybrid male sterility contributes to speciation by restricting gene flow between related taxa. Detailed cytological characterizations of reproductive organs in hybrid males is important for identifying phenotypes that can help guide searches of speciation genes. To investigate possible cellular causes of hybrid male sterility, we performed crosses between closely related species of the Anopheles gambiae complex: An. merus with An. gambiae or An. coluzzii. We demonstrate that hybrid male sterility in African malaria mosquitoes involves two defects in the reciprocal crosses: a premeiotic arrest of germline stem cells in degenerate testes and a failure of the reductional meiotic division of primary spermatocytes in normal-like testes. The premeiotic arrest in degenerate testes of hybrids is accompanied by a strong suppression of meiotic and postmeiotic genes. Unlike pure species, sex chromosomes in normal-like testes of F1 hybrids are largely unpaired during meiotic prophase I and all chromosomes show various degrees of insufficient condensation. Instead of entering reductional division in meiosis I, primary spermatocytes prematurely undergo an equational mitotic division producing nonmotile diploid sperm. Thus, our study identified cytogenetic errors in interspecies hybrids that arise during the early stages of postzygotic isolation.

evolutionary biology↗