Biology subjects

Cao, P.

Publications and source records attributed to Cao, P..

49 records · Page 3Linked to original sources

bioRxiv2021

Modelling The Effect of MUC1 on Influenza Virus Infection Kinetics and Macrophage Dynamics

MUC1 belongs to the family of cell surface (cs-) mucins. Experimental evidence indicates that its presence reduces in vivo influenza viral infection severity. However, the mechanisms by which MUC1 influences viral dynamics and the host immune response are not yet well understood, limiting our ability to predict the efficacy of potential treatments that target MUC1. To address this limitation, we utilize available in vivo kinetic data for both virus and macrophage populations in wildtype and MUC1 knockout mice. We apply two mathematical models of within-host influenza dynamics to this data. The models differ in how they categorise the mechanisms of viral control. Both models provide evidence that MUC1 reduces the susceptibility of epithelial cells to influenza virus and regulates macrophage recruitment. Furthermore, we predict and compare some key infection-related quantities between the two mice groups. We find that MUC1 significantly reduces the basic reproduction number of viral replication as well as the number of cumulative macrophages but has little impact on the cumulative viral load. Our analyses suggest that the viral replication rate in the early stages of infection influences the kinetics of the host immune response, with consequences for infection outcomes, such as severity. We also show that MUC1 plays a strong anti-inflammatory role in the regulation of the host immune response. This study improves our understanding of the dynamic role of MUC1 against influenza infection and may support the development of novel antiviral treatments and immunomodulators that target MUC1.

immunology↗

bioRxiv2020

The SC-SNc pathway boosts appetitive locomotion in predatory hunting

Appetitive locomotion is essential for organisms to approach rewards, such as food and prey. How the brain controls appetitive locomotion is poorly understood. In a naturalistic goal-directed behavior--predatory hunting, we demonstrate an excitatory brain circuit from the superior colliculus (SC) to the substantia nigra pars compacta (SNc) to boost appetitive locomotion. The SC-SNc pathway transmitted locomotion-speed signals to dopamine neurons and triggered dopamine release in the dorsal striatum. Activation of this pathway increased the speed and frequency of approach during predatory hunting, an effect that depended on the activities of SNc dopamine neurons. Conversely, synaptic inactivation of this pathway impaired appetitive locomotion but not defensive or exploratory locomotion. Together, these data revealed the SC as an important source to provide locomotion-related signals to SNc dopamine neurons to boost appetitive locomotion.

neuroscience↗

bioRxiv2020

GEMC1-MCIDAS transcriptional program regulates multiciliogenesis in the choroid plexus and acts as a barrier to tumorigenesis

Multiciliated cells (MCCs) in the brain include the ependymal cells and choroid plexus (CP) epithelial cells. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. However, the mechanisms and functional significance of multiciliogenesis in the CP remain unknown. Deregulated oncogenic signals cause CP carcinoma (CPC), a rare but aggressive pediatric brain cancer. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. NOTCH-driven CP tumors were monociliated, whereas disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of GEMC1 and MCIDAS, early regulators of multiciliogenesis. Consistently, GEMC1-MCIDAS function is essential for multiciliation in the CP, and is critical for correcting multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia. Consistently, CPC driven by deletion of Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal a GEMC1-MCIDAS multiciliation program in the CP critical for inhibiting tumorigenesis, and it may have therapeutic implications for the treatment of CPC.

cancer biology↗

bioRxiv2020

Duple extinguishment of COVID-19: single compound synergized inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokines in vitro/vivo

We firstly disclose single compound yields better therapeutic outcome than Remdesivir in COVID-19 hamster treatments as it is armed with direct inhibition viral replication and intrinsic suppression inflammatory cytokines expression. Crystal data reveals that Au (I), released from Au22Glutathione18 (GA), covalently binds thiolate of Cys145 of SARS-CoV-2 Mpro. GA directly decreases SARS-CoV-2 viral replication (EC50: ~0.24 M) and intrinsically down-regulates NF{kappa}B pathway therefore significantly inhibiting expression of inflammatory cytokines in cells. The lung viral load and inflammatory cytokines in GA-treated COVID-19 transgenic mice are found to be significantly lower than that of control mice. When COVID-19 golden hamsters are treated by GA, the lung inflammatory cytokines levels are significantly lower than that of Remdesivir while their lung viral load are decreased to same level. The pathological results show that GA treatment significantly reduce lung inflammatory injuries when compared to that of Remdesivir-treated COVID-19 golden hamsters. One Sentence SummaryWe found that gold cluster molecule directly inhibits SARS-CoV-2 replication and intrinsically suppresses inflammatory cytokines expression in COVID-19 transgenic mouse and golden hamster model, gold cluster providing a better lung injury protection than Remdesivir in COVID-19 golden hamsters via intranasally dropping administration.

microbiology↗

bioRxiv2020

Mitochondria fragment and reassemble to initiate the formation and development of the nucleus

The function of nuclear-localized mitochondria remains unknown. We found that mitochondria assembled dense particles to fragment and disperse into the particles, which reassembled to initiate nuclear formation and development. Individually-formed nuclei in one single cell were joined together by mitochondrial fragmentation concurrently partitioning cytoplasm to form an intranuclear inclusion (INC), whose creation was not related to herniation or invagination of the cytoplasm. Along with the nuclear transition of a mitochondrion and its neighboring counterparts, the organelle included itself in the nucleus to become nuclear mitochondrion through peripherally assembling of dense particles. New medium reversed the nuclear formation of the organelles to recovery and re-establishment via the return of the particles, which consisted of dense microvesicles (MIVs).

cell biology↗

bioRxiv2020

Modelling within-host macrophage dynamics in influenza virus infection

Human respiratory disease associated with influenza virus infection is of significant public health concern. Macrophages, as part of the front line of host innate cellular defence, have been shown to play an important role in controlling viral replication. However, fatal outcomes of infection, as evidenced in patients infected with highly pathogenic viral strains, are often associated with prompt activation and excessive accumulation of macrophages. Activated macrophages can produce a large amount of pro-inflammatory cytokines, which leads to severe symptoms and at times death. However, the mechanism for rapid activation and excessive accumulation of macrophages during infection remains unclear. It has been suggested that the phenomena may arise from complex interactions between macrophages and influenza virus. In this work, we develop a novel mathematical model to study the relationship between the level of macrophage activation and the level of viral shedding in influenza virus infection. Our model combines a dynamic model of viral infection, a dynamic model of macrophages and the essential interactions between the virus and macrophages. Our model predicts that the level of macrophage activation can be negatively correlated with the level of viral shedding when viral infectivity is sufficiently high. We further identify that temporary depletion of resting macrophages in response to viral infection is a major driver in our model for the negative relationship between macrophage activation and viral shedding, providing new insight into the mechanisms that regulate macrophage activation. Our model serves as a framework to study the complex dynamics of virus-macrophage interactions and provides a mechanistic explanation for existing experimental observations, contributing to an enhanced understanding of the role of macrophages in influenza viral infection.

immunology↗

bioRxiv2020

Evolution of a plant gene cluster in Solanaceae and emergence of metabolic diversity

Plants produce phylogenetically and spatially restricted, as well as structurally diverse specialized metabolites via multistep metabolic pathways. Hallmarks of specialized metabolic evolution include enzymatic promiscuity, recruitment of primary metabolic enzymes and genomic clustering of pathway genes. Solanaceae plant glandular trichomes produce defensive acylsugars, with aliphatic sidechains that vary in length across the family. We describe a tomato gene cluster on chromosome 7 involved in medium chain acylsugar accumulation due to trichome specific acyl-CoA synthetase and enoyl-CoA hydratase genes. This cluster co-localizes with a tomato steroidal alkaloid gene cluster forming a supercluster, and is syntenic to a chromosome 12 region containing another acylsugar pathway gene. We reconstructed the evolutionary events leading to emergence of this gene cluster and found that its phylogenetic distribution correlates with medium chain acylsugar accumulation across the Solanaceae. This work reveals dynamics behind emergence of novel enzymes from primary metabolism, gene cluster evolution and cell-type specific metabolite diversity.

plant biology↗

bioRxiv2019

Modelling the population dynamics of Plasmodium falciparum gametocytes in humans during malaria infection

Every year over two hundred million people are infected with the malaria parasite. Renewed efforts to eliminate malaria has highlighted the potential to interrupt transmission from humans to mosquitoes which is mediated through the gametocytes. Reliable prediction of transmission requires an improved understanding of in vivo kinetics of gametocytes. Here we study the population dynamics of Plasmodium falciparum gametocytes in human hosts by establishing a framework which incorporates improved measurements of parasitaemia in humans, a novel mathematical model of gametocyte dynamics, and model validation using a Bayesian hierarchical inference method. We found that the novel mathematical model provides an excellent fit to the available clinical data from 17 volunteers infected with P. falciparum, and reliably predicts observed gametocyte levels. We estimated the P. falciparums sexual commitment rate and gametocyte sequestration time in humans to be 0.54% (95% credible interval: 0.30-1.00) per life cycle and 8.39 (6.54-10.59) days respectively. Furthermore, we used the data-calibrated model to predict the effects of those gametocyte dynamics parameters on human-to-mosquito transmissibility, providing a method to link within-human host kinetics of malaria infection to epidemiological-scale infection and transmission patterns.

bioinformatics↗

bioRxiv2019

Genomic approaches reveal an endemic sub-population of gray wolves in Southern China

Despite being one of the most widely distributed terrestrial mammals, the history of gray wolves (Canis lupus) in China is not well understood as their habitats have been destroyed with growing economic development. Using six specimens from wolf skins in Chinese Natural History museums, we sequenced their genome using a modified ancient DNA procedure. Using whole genome sequence analysis, we showed that gray wolves from Southern China (SC) derive from a single lineage, distinct from gray wolves from the Tibetan Plateau (Canis lupus chanco) and Northern China, suggesting that SC gray wolves may form a distinct sub-population. Of SC gray wolves, one wolf from Zhejiang carries a genetic component from a canid that must have diverged earlier from other wolves than jackals did, perhaps through gene flow from a population related to or further diverged from wolves than the dhole, a species distributed in Southern China and Southeast Asia. This may indicate that interspecific gene flow likely played an important role in shaping the speciation patterns and population structure in the genus Canis. Our study is the first to survey museum genomes of gray wolves from Southern China, revealing the presence of an endemic population with ancient interspecific gene flow from a population related to the dhole, and highlighting how sequencing the paleogenome from museum specimens can help us to study extinct species.

evolutionary biology↗

bioRxiv2018

Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm

The Hedgehog (Hh) pathway controls embryonic development and postnatal tissue maintenance and regeneration. Inhibition of oligomeric Hh receptor Patched (Ptch) by the secreted and post-translationally modified ligand Hh relieves suppression of the signaling cascades. Here, we report the cryo-EM structure of tetrameric Ptch1 in complex with palmitoylated N-terminal signaling domain of human Sonic hedgehog (ShhNp). The structure shows that four Ptch1 protomers are organized as a loose dimer of dimers and each dimer binds to one ShhNp through two distinct inhibitory interfaces. Ptch1-A binds to ShhNp through the well-characterized Ca2+-mediated interface on the globular domain of ShhNp, and Ptch1-B primarily interacts with the N-terminal peptide and the palmitoyl moiety. Map comparison reveals that the cholesteryl moiety of native ShhN occupies a recently identified extracellular steroid binding pocket in Ptch1-B. Our structure elucidates the tetrameric assembly of Ptch1 and suggests asymmetric mode of actions of the Hh ligands for inhibiting the potential cholesterol transport activity of Ptch1.

biophysics↗

bioRxiv2018

Predicting the Outcomes of New Short-Course Regimens for Multi-Drug Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modelling

Short-course regimens for multi-drug resistant tuberculosis (MDR-TB) are urgently needed. Limited data suggest that the new drug, bedaquiline (BDQ), may have the potential to shorten MDR-TB treatment to less than six months when used in conjunction with standard anti-TB drugs. However, the feasibility of BDQ in shortening MDR-TB treatment duration remains to be established. Mathematical modelling provides a platform to investigate different treatment regimens and predict their efficacy. We developed a mathematical model to capture the immune response to TB inside a human host environment. This model was then combined with a pharmacokinetic-pharmacodynamic model to simulate various short-course BDQ-containing regimens. Our modelling suggests that BDQ could reduce MDR-TB treatment duration to just 18 weeks (four months) while still maintaining a very high treatment success rate (100% for daily BDQ for two weeks, or 95% for daily BDQ for one week during the intensive phase). The estimated time to bacterial clearance of these regimens ranges from 27 to 33 days. Our findings provide the justification for empirical evaluation of short-course BDQ-containing regimens. If short-course BDQ-containing regimens are found to improve outcomes then we anticipate clear cost-savings and a subsequent improvement in the efficiency of national TB programs.

systems biology↗

bioRxiv2018

Investigating the efficacy of triple artemisinin-based combination therapies (TACTs) for treating Plasmodium falciparum malaria patients using mathematical modelling

The first line treatment for uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative co-administered with a longer acting partner drug. However, the spread of Plasmodium falciparum resistant to both artemisinin and its partner drugs poses a major global threat to malaria control activities. Novel strategies are needed to retard and reverse the spread of these resistant parasites. One such strategy is triple artemisinin-based combination therapy (TACT). We developed a mechanistic within-host mathematical model to investigate the efficacy of a TACT (dihydroartemisinin-piperaquine-mefloquine - DHA-PQ-MQ), for use in South-East Asia, where DHA and PQ resistance are now increasingly prevalent. Comprehensive model simulations were used to explore the degree to which the underlying resistance influences the parasitological outcomes. The effect of MQ dosing on the efficacy of TACT was quantified at varying degrees of DHA and PQ resistance. To incorporate interactions between drugs, a novel model is presented for the combined effect of DHA-PQ-MQ, which illustrates how the interactions can influence treatment efficacy. When combined with a standard regimen of DHA and PQ, the administration of three 8.3 mg/kg doses of MQ was sufficient to achieve parasitological efficacy greater than that currently recommended by WHO guidelines.

pharmacology and toxicology↗

bioRxiv2017

WSL5, a pentatricopeptide repeat protein, is essential for chloroplast biogenesis in rice under cold stress

AbstactChloroplasts play an essential role in plant growth and development, and cold has a great effect on chloroplast development. Although many genes or regulators involved in chloroplast biogenesis and development have been isolated and characterized, identification of novel components associated with cold is still lacking. In this study, we reported the functional characterization of white stripe leaf 5 (wsl5) mutant in rice. The mutant developed white-striped leaves during early leaf development and was albinic when planted under cold stress. Genetic and molecular analysis revealed that WSL5 encodes a novel chloroplast-targeted pentatricopeptide repeat protein. RNA-seq analysis showed that expression of nuclear-encoded photosynthetic genes in the mutant was significantly repressed, and expression of many chloroplast-encoded genes was also significantly changed. Notably, the WSL5 mutation caused defects in editing of rpl2 and atpA, and in splicing of rpl2 and rps12. Chloroplast ribosome biogenesis was impaired under cold stress. We propose that WSL5 is required for normal chloroplast development in rice under cold stress.

genetics↗