Biology subjects

Liang, T.

Publications and source records attributed to Liang, T..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Acetyl-CoA Synthetase Mutations S868G and V949I Do Not Confer Resistance to Antimalarial Drugs in vitro in Plasmodium falciparum.

Plasmodium falciparum acetyl-CoA synthetase (PfACAS) protein is an important source of acetyl-CoA. We detected the mutations S868G and V949I in PfACAS by whole-genome sequencing analysis in some recrudescent parasites after antimalarial treatment with artesunate and dihydroartemisinin-piperaquine, suggesting that they may confer drug resistance. Using CRISPR/Cas9 technology, we engineered parasite lines carrying the PfACAS S868G and V949I mutations in two genetic backgrounds and evaluated their susceptibility to antimalarial drugs in vitro. The results demonstrated that PfACAS S868G and V949I mutations alone or in combination were not enough to provide resistance to antimalarial drugs.

microbiology↗

bioRxiv2023

SARS-CoV-2 spike protein induces the cytokine release syndrome by stimulating T cells to produce more IL-2

Cytokine release syndrome (CRS) is one of the leading causes of mortality in COVID-19 patients caused by the SARS-CoV-2 coronavirus. However, the mechanism of CRS induced by SARS-CoV-2 is vague. This study shows that dendritic cells loaded with spike protein of SARS-CoV-2 stimulate T cells to release much more IL-2, which subsequently cooperates with spike protein to facilitate peripheral blood mononuclear cells to release IL-1{beta}, IL-6, and IL-8. These effects are achieved via IL-2 stimulation of NK cells to release TNF- and IFN-{gamma}, as well as T cells to release IFN-{gamma}. Mechanistically, IFN-{gamma} and TNF- enhance the transcription of CD40, and the interaction of CD40 and its ligand stabilizes the membrane expression of TLR4 which serves as a receptor of spike protein on the surface of monocytes. As a result, there is a constant interaction between spike protein and TLR4, leading to continuous activation of NF-{kappa}B. Furthermore, TNF- also activates NF-{kappa}B signaling in monocytes, which further cooperates with IFN-{gamma} and spike protein to modulate NF-{kappa}B-dependent transcription of CRS-related inflammatory cytokines. Targeting TNF-/IFN-{gamma} in combination with TLR4 may represent a promising therapeutic approach for alleviating CRS in individuals with COVID-19.

immunology↗

bioRxiv2023

Melatonin alleviates valproic acid-induced neural tube defects by modulating Src/PI3K/ERK signaling and oxidative stress

Neural tube defects (NTDs) represent a developmental disorder of the nervous system that can lead to significant disability in children and impose substantial social burdens. Valproic acid (VPA), a widely prescribed first-line antiepileptic drug for epilepsy and various neurological conditions, has been associated with a fourfold increase in the risk of NTDs when used during pregnancy. Consequently, urgent efforts are required to identify innovative prevention and treatment approaches for VPA-induced NTDs. Studies have demonstrated that the disruption in the delicate balance between cell proliferation and apoptosis is a crucial factor contributing to NTDs induced by VPA. Encouragingly, our current data reveal that melatonin (MT) exerts significant inhibition on apoptosis while promoting the restoration of neuroepithelial cells proliferation impaired by VPA. Moreover, further investigations demonstrate that MT substantially reduces the incidence of neural tube malformations resulting from VPA exposure, primarily achieved by suppressing apoptosis through the modulation of intracellular reactive oxygen species levels. In addition, the Src/PI3K/ERK signaling pathway appears to play a pivotal role in VPA-induced NTDs, with a significant inhibition observed in the affected samples. Notably, MT treatment successfully reinstates the Src/PI3K/ERK signals, thereby offering a potential underlying mechanism for MTs protective effects against VPA-induced NTDs. In summary, our current study substantiates the considerable protective potential of MT in mitigating VPA-triggered NTDs, thereby offering valuable strategies for the clinical management of VPA-related birth defects.

developmental biology↗

bioRxiv2023

Statistically inferred neuronal connections in subsampled neural networks strongly correlate with spike train covariance

Statistically inferred neuronal connections from observed spike train data are often skewed from ground truth by factors such as model mismatch, unobserved neurons, and limited data. Spike train covariances, sometimes referred to as "functional connections," are often used as a proxy for the connections between pairs of neurons, but reflect statistical relationships between neurons, not anatomical connections, and moreover are not casual. Connections inferred by maximum likelihood inference, by contrast, can be constrained to be causal. However, we show in this work that the inferred connections in spontaneously active networks modeled by stochastic leaky integrate-and-fire networks strongly reflect covariances between neurons, not causal information, when many neurons are unobserved or when neurons are weakly coupled. This phenomenon occurs across different network structures, including random networks and balanced excitatory-inhibitory networks.

neuroscience↗

bioRxiv2022

Experimental study of modified human tendon stem cells to promote graft ligamentation and tendon-bone healing after anterior cruciate ligament reconstruction

Restoring the normal structure and function of injured tendons is one of the biggest challenges faced by the Department of Orthopedics and Sports Medicine. Tendon-derived stem cells (TDSCs), a new type of pluripotent stem cells with multidirectional differentiation potential, are expected to be promising cell seeds for the treatment of tendon injury and tendon-bone healing in the future. In this study, tendon stem cells were successfully isolated from human tissues, which were positive for markers CD44, CD90, and CD105, and exhibited clonality and multilineage differentiation ability. Analysis of single-cell sequencing results and mass spectrometry identification results showed that there were differences in protein expression during CTGF-induced TDSC tendon differentiation. Reverse Co-IP, qPCR, WB, and immunofluorescence detection all confirmed that CTGF directly interacts with KIT, thereby mediating the transcription factor HES1 to regulate the Wnt/{beta}-catenin signaling pathway (GSK3{beta}, {beta}-catenin, TCF4). ChIP-qPCR and dual-luciferase reporter gene assays indicated that HES1 regulates stem cell differentiation by directly regulating the expression of GSK3{beta} in the Wnt/{beta}-catenin pathway. Rats were treated with TDSCs overexpressing the KIT gene after repair surgery. This method had a more ideal recovery effect than other methods through animal behavioral scores, mechanical properties testing, and HE staining tissue observation. This study found that the use of modified human tendon stem cells (hTDSC) could promote graft ligamentization and tendon-bone healing after ACL reconstruction, which could provide an effective way for faster and better recovery from tendon injury.

cell biology↗

bioRxiv2022

Human endogenous retrovirus activation contributes to biliary atresia pathogenesis through re-education of resident macrophages

Biliary atresia (BA) is a life-threatening neonatal fibro-inflammatory disease characterized by hepatic fibrosis, cirrhosis, and end-stage liver failure. BA is also the most frequent indication of pediatric liver transplantation globally. Despite the devastating condition of BA, the pathogenesis mechanism is unknown. Viral infection has been suggested to be associated with BA, but definitive evidence to support this hypothesis is not available. To elucidate the virus-associated pathogenesis mechanism of BA and to understand the immune ecosystem, we performed single-cell transcriptomic and proteomic profiling of BA livers. We detected human endogenous virus (HERV) in infants with BA and their parents. HERV was mainly found in FOLR2+ resident macrophages, T cells, and NK cells. In addition, HERV activation re-educated the fetal-derived FOLR2+ resident macrophages, and reactive oxygen species scavenging neutrophil recruitment was impaired in patients with BA and HERV+, due to FOLR2+ resident macrophage re-education. Furthermore, we showed depletion of FOLR2+ resident macrophage and N-acetylcysteine treatment could rescue the liver damage in BA. Overall, our study revealed the HERV-associated immunopathology mechanism of BA. These results contribute to potential diagnosis and immunotherapy strategies for BA.

pathology↗

bioRxiv2021

Camel nanobodies broadly neutralize SARS-CoV-2 variants

With the emergence of SARS-CoV-2 variants, there is urgent need to develop broadly neutralizing antibodies. Here, we isolate two VHH nanobodies (7A3 and 8A2) from dromedary camels by phage display, which have high affinity for the receptor-binding domain (RBD) and broad neutralization activities against SARS-CoV-2 and its emerging variants. Cryo-EM complex structures reveal that 8A2 binds the RBD in its up mode and 7A3 inhibits receptor binding by uniquely targeting a highly conserved and deeply buried site in the spike regardless of the RBD conformational state. 7A3 at a dose of [≥]5 mg/kg efficiently protects K18-hACE2 transgenic mice from the lethal challenge of B.1.351 or B.1.617.2, suggesting that the nanobody has promising therapeutic potentials to curb the COVID-19 surge with emerging SARS-CoV-2 variants. One-Sentence SummaryDromedary camel (Camelus dromedarius) VHH phage libraries were built for isolation of the nanobodies that broadly neutralize SARS-CoV-2 variants.

immunology↗

bioRxiv2021

A novel PD-L1-targeted shark VNAR single domain-based CAR-T strategy for treating breast cancer and liver cancer

Chimeric antigen receptor (CAR)-T cell therapy shows great potency against hematological malignancies, whereas it remains difficult to treat solid tumors mainly due to lack of appropriate antigenic targets and immunosuppressive tumor microenvironment (TME). Checkpoint molecule PD-L1 is widely overexpressed on multiple tumor types, and the PD-1/PD-L1 interaction is a key mediator of immunosuppression in TME. Here, we isolated anti-PD-L1 single domain antibodies from a newly constructed semi-synthetic nurse shark VNAR phage library. We found that one VNAR, B2, showed cross-reactivity to human, mouse, and canine PD-L1 antigens, and it partially blocked the interaction of human PD-1 to PD-L1. Furthermore, CAR (B2) T cells specifically lysed human breast cancer and liver cancer cells by targeting constitutive and inducible expression of PD-L1, and also hindered tumor metastasis. Importantly, the combination of CAR (B2) T cells with CAR-T cells targeting liver cancer-specific antigen GPC3 regress liver tumors in mice. We concluded that PD-L1-targeted shark VNAR single domain-based CAR-T therapy is a novel strategy to treat breast cancer and liver cancer. This provides a rationale for potential use of CAR (B2) T cells as a monotherapy or combination with a tumor-specific therapy in clinical studies.

cancer biology↗

bioRxiv2021

Evolution of innate behavioral strategies through competitive population dynamics

Many organism behaviors are innate or instinctual and have been "hard-coded" through evolution. Current approaches to understanding these behaviors model evolution as an optimization problem in which the traits of organisms are assumed to optimize an objective function representing evolutionary fitness. Here, we use a mechanistic birth-death dynamics approach to study the evolution of innate behavioral strategies in a population of organisms in silico. In particular, we performed agent-based stochastic simulations and mean-field analyses of organisms exploring random environments and competing with each other to find locations with plentiful resources. We find that when organism density is low, the mean-field model allows us to derive an effective objective function, predicting how the most competitive phenotypes depend on the exploration-exploitation trade-off between the scarcity of high-resource sites and the increase in birth rate those sites offer organisms. However, increasing organism density alters the most competitive behavioral strategies and precludes the existence of a well-defined objective function. Moreover, there exists a range of densities for which the coexistence of many phenotypes persists for evolutionarily long times.

animal behavior and cognition↗

bioRxiv2020

Fate mapping analysis reveals a novel dermal migratory Langerhans-like cell population

Dendritic cells residing in the skin represent a large family of antigen presenting cells, ranging from long-lived Langerhans cells (LC) in the epidermis to various distinct classical dendritic cell subsets in the dermis. Through genetic fate mapping analysis and single cell RNA sequencing we have identified a novel separate population of LC-independent CD207+CD326+ LClike cells in the dermis that homed at a slow rate to the LNs. These LClike cells were long-lived and radioresistant but, unlike LCs, they were gradually replenished by bone-marrow-derived precursors under steady state. LClike cells together with cDC1s were the main migratory CD207+CD326+ cell fractions present in the LN and not, as currently assumed, LCs, which were barely detectable, if at all. These findings bring new insights into the dynamism of cutaneous dendritic cells and opens novel avenues in the development of treatments to cure inflammatory skin disorders.

immunology↗

bioRxiv2020

Controlling Cellular Arrangements via Stretched Bioprinting

Bioprinting is a common method to replicate geometrical architecture of native tissues. However, it usually fails to modulate cellular arrangements, which is critical for the tissues functionality. To our knowledge, no method has successfully addressed this challenge. Here, we report a method of controlling cellular orientation during the bioprinting process by integrating a stretch process into a modified bioprinting frame. We demonstrate that the cellular orientation is a result of cells sensing and responding to the tensile stress, instead of shear stress or topographical patterns. Moreover, our method shows a potent capability to induce myoblast differentiation, fusion and maturation without the presence of differentiation medium. As a potential clinical application, we demonstrate that aligned myofibers directly printed onto injured muscle in vivo, can not only repair the structure of damaged tissue, but also recover the muscle functionalities effectively. This study shows that the new method can produce tissues with precise control of cellular arrangements and more clinically viable functionalities. Significance StatementDue to no method could reproduce the exact cellular arrangements of native tissues in engineered tissues, tissue engineering facing difficult in fabricating 3D tissues that possess desirable biological and mechanical functionalities for biomedical applications. For the first time, we report a method of controlling cellular orientation during 3D bio-printing process. This method can be used to produce engineered tissues with controlled cellular arrangement with several different cell types. Moreover, this method shows a potent capability of fabricating fully mature and aligned myofibers in vitro in the absence of differentiation medium. As potential clinical applications, with this method, engineered tissues could be directly printed in vivo with high efficacy of tissue repair and function recovery.

cell biology↗

bioRxiv2020

Visualization of individual cell division history in complex tissues

The division potential of individual stem cells and the molecular consequences of successive rounds of proliferation remain largely unknown. We developed an inducible cell division counter (iCOUNT) that reports cell division events in human and mouse tissues in vitro and in vivo. Analysing cell division histories of neural stem/progenitor cells (NSPCs) in the developing and adult brain, we show that iCOUNT allows for novel insights into stem cell behaviour. Further, we used single cell RNA-sequencing (scRNA-seq) of iCOUNT-labelled NSPCs and their progenies from the developing mouse cortex and forebrain-regionalized human organoids to identify molecular pathways that are commonly regulated between mouse and human cells, depending on individual cell division histories. Thus, we developed a novel tool to characterize the molecular consequences of repeated cell divisions of stem cells that allows an analysis of the cellular principles underlying tissue formation, homeostasis, and repair. HighlightsO_LIiCOUNT reports previous cell divisions in mouse and human cells in vitro C_LIO_LIiCOUNT detects cell division biographies in complex mouse tissues in vivo C_LIO_LIiCOUNT allows for the analysis of human neural stem/progenitor cells in human forebrain organoids C_LIO_LISingle cell RNA-sequencing of iCOUNT cells derived from the mouse developing cortex and human forebrain organoids identifies molecular consequences of previous rounds of cell divisions C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/266171v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@144b085org.highwire.dtl.DTLVardef@a10b2forg.highwire.dtl.DTLVardef@e57053org.highwire.dtl.DTLVardef@1316c11_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Cross-neutralization antibodies against SARS-CoV-2 and RBD mutations from convalescent patient antibody libraries

The emergence of coronavirus disease 2019 (COVID-19) pandemic led to an urgent need to develop therapeutic interventions. Among them, neutralizing antibodies play crucial roles for preventing viral infections and contribute to resolution of infection. Here, we describe the generation of antibody libraries from 17 different COVID-19 recovered patients and screening of neutralizing antibodies to SARS-CoV-2. After 3 rounds of panning, 456 positive phage clones were obtained with high affinity to RBD (receptor binding domain). Then the positive clones were sequenced and reconstituted into whole human IgG for epitope binning assays. After that, all 19 IgG were classified into 6 different epitope groups or Bins. Although all these antibodies were shown to have ability to bind RBD, the antibodies in Bin2 have more superiority to inhibit the interaction between spike protein and angiotensin converting enzyme 2 receptor (ACE2). Most importantly, the antibodies from Bin2 can also strongly bind with mutant RBDs (W463R, R408I, N354D, V367F and N354D/D364Y) derived from SARS-CoV-2 strain with increased infectivity, suggesting the great potential of these antibodies in preventing infection of SARS-CoV-2 and its mutations. Furthermore, these neutralizing antibodies strongly restrict the binding of RBD to hACE2 overexpressed 293T cells. Consistently, these antibodies effectively neutralized pseudovirus entry into hACE2 overexpressed 293T cells. In Vero-E6 cells, these antibodies can even block the entry of live SARS-CoV-2 into cells at only 12.5 nM. These results suggest that these neutralizing human antibodies from the patient-derived antibody libraries have the potential to become therapeutic agents against SARS-CoV-2 and its mutants in this global pandemic.

immunology↗

bioRxiv2020

SARS-CoV-2 proteome microarray for mapping COVID-19 antibody interactions at amino acid resolution

COVID-19 has quickly become a worldwide pandemic, which has significantly impacted the economy, education, and social interactions. Understanding the humoral antibody response to SARS-CoV-2 proteins may help identify biomarkers that can be used to detect and treat COVID-19 infection. However, no immuno-proteomics platform exists that can perform such proteome-wide analysis. To address this need, we created a SARS-CoV-2 proteome microarray to analyze antibody interactions at amino acid resolution by spotting peptides 15 amino acids long with 5-amino acid offsets representing full-length SARS-CoV-2 proteins. Moreover, the array processing time is short (1.5 hours), the dynamic range is ~2 orders of magnitude, and the lowest limit of detection is 94 pg/mL. Here, the SARS-CoV-2 proteome array reveals that antibodies commercially available for SARS-CoV-1 proteins can also target SARS-CoV-2 proteins. These readily available reagents could be used immediately in COVID-19 research. Second, IgM and IgG immunogenic epitopes of SARS-CoV-2 proteins were profiled in the serum of ten COVID-19 patients. Such epitope biomarkers provide insight into the immune response to COVID-19 and are potential targets for COVID-19 diagnosis and vaccine development. Finally, serological antibodies that may neutralize viral entry into host cells via the ACE2 receptor were identified. Further investigation into whether these antibodies can inhibit the propagation of SARS-CoV-2 is warranted. Antibody and epitope profiling in response to COVID-19 is possible with our peptide-based SARS-COV-2 proteome microarray. The data gleaned from the array could provide invaluable information to the scientific community to understand, detect, and treat COVID-19.

biochemistry↗

bioRxiv2020

Multiple approaches for massively parallel sequencing of HCoV-19 genomes directly from clinical samples

COVID-19 has caused a major epidemic worldwide, however, much is yet to be known about the epidemiology and evolution of the virus. One reason is that the challenges underneath sequencing HCoV-19 directly from clinical samples have not been completely tackled. Here we illustrate the application of amplicon and hybrid capture (capture)-based sequencing, as well as ultra-high-throughput metatranscriptomic (meta) sequencing in retrieving complete genomes, inter-individual and intra-individual variations of HCoV-19 from clinical samples covering a range of sample types and viral load. We also examine and compare the bias, sensitivity, accuracy, and other characteristics of these approaches in a comprehensive manner. This is, to date, the first work systematically implements amplicon and capture approaches in sequencing HCoV-19, as well as the first comparative study across methods. Our work offers practical solutions for genome sequencing and analyses of HCoV-19 and other emerging viruses.

genomics↗

bioRxiv2020

Separation or Integration of Sequential Arrays in VWM Depends On the interval Between Them

The visual information can be stored as either "active" representations in the active state or "activity-silent" representations in the passive state during the retention period in visual working memory (VWM). Catering to the dynamic nature of visual world, we explored how the temporally dynamic visual input was stored in VWM. In the current study, the memory arrays were presented sequentially, and the contralateral delay activity (CDA), an electrophysiological measure, was used to identify whether the memory representations were transferred into the passive state. Participants were instructed to encode two sequential arrays and retrieve them respectively, with two conditions of interval across the two arrays: 400ms and 800ms. These results provided strong evidence for the state-separated storage of two sequential arrays in different neural states if the interval between them was long enough, and the concurrent storage of them in the active state if the interval was relatively short. This conclusion was valid only when the participants encountered the task for the first time. Once participants have formed their mindset, they would apply the same storage mode to the subsequently extended or shortened interval condition.

neuroscience↗

bioRxiv2019

For running or burying -- The toe fringe of Phrynocephalus mystaceus is important

Toe fringe is the most typical morphological feature of lizards adapted to sandy environments, and toe fringe is suitable for testing the adaptive convergence suggested by form-environment correlations. Phrynocephalus mystaceus mainly lives in dune habitats, has a developed bilateral toe fringe, and exhibits fast sand-diving behavior for predator avoidance. We tested the effects of resecting the medial and bilateral toe fringes on the locomotor performance and sand-diving performance of P. mystaceus. The results showed that the individuals that had their medial toe fringe removed exhibited significantly faster sprint speeds than the unresected and all resected individuals (P <0.05). The results of stepwise regression analysis show that the relative area of the toe fringe is an important morphological feature that affects locomotor performance. The sand-burial performance scores of the unresected individuals were significantly greater than those of the resected individuals (P <0.05). The results of stepwise regression analysis show that the relative area of toe fringe and the axilla-groin length are the main morphological features that affect the sand-diving performance of P. mystaceus. After the bilateral toe fringe was removed, a significant negative correlation between locomotor and sand-diving performance was observed (P <0.05). Taken together, these results provide experimental evidence that toe fringe is positively associated with the locomotor and sand-diving performance of P. mystaceus.

animal behavior and cognition↗

bioRxiv2018

Risk Factors Associated with Dengue Virus Infection in Guangdong Province: a Community-based Case-control Study

BackgroundDengue fever is a mosquito-borne infectious disease, and it is now still epidemic in China, especially in Guangdong Province. Owing to the absence of dengue vaccination, effective preventive measure is critical for controlling of dengue fever. This study aimed to explore the individual risk factors of dengue virus infection in Guangdong Province, as well as to provide a scientific basis for prevention and supervision of dengue fever in future.\n\nMethodsA case-control study including 237 cases and 237 controls was performed. The data was collected from the epidemiological questionnaires. Univariate analysis was used for preliminary screening of 28 variables potentially related to dengue virus infection, and an unconditioned logistic regression analysis was used for multivariate analysis to analysis those statistically significant variables.\n\nResultsMultivariate analysis of the result showed three independent risk factors: activities in the park (odd ratio [OR]= 1.70, 95%CI 1.03 to 2.83), outdoor sports (OR= 1.67, 95%CI 1.07 to 2.62), and poor indoor daylight quality (OR= 2.27, 95%CI 1.00 to 5.15); and two protective factors: two persons per room (OR=0.43, 95%CI 0.28 to 0.67), three persons and above per room (OR=0.43, 95%CI 0.22 to 0.86), using air-condition (OR=0.43, 95%CI 0.20 to 0.93).\n\nConclusionThese results are conducive to learn the risk factors for dengue virus infection in Guangdong Province. It is crucial to provide effective and efficient strategy to improve environmental protection and anti-mosquito measures. In addition, more systematic studies are needed to explore the other potential risk factors for dengue fever infection.\n\nAuthor summaryDengue fever, one of the mosquito-borne infectious diseases, is mainly transmitted by Aedes aegypti in Asia and Southeast Asia countries. Since 1978, the incidence of dengue fever has markedly increased in China especially in Guangdong province. In order to formulate the effective prevention and control measures, we explored the risk factors of dengue virus infection in Guangdong Province by conducting a case-control study. In this study, 237 patients with dengue virus infection and 237 participants without dengue virus infection were included. Then through these questionnaires and data analysis, we found that activities in the park, outdoor sports, and poor indoor daylight quality significantly contributed to the residents risk of dengue virus infection. On the other hand, we observed that using air-condition and using anti-mosquito measures were effective personal prevention interventions.

scientific communication and education↗