Biology subjects

Li, C.

Publications and source records attributed to Li, C..

At least 793 records · Page 44Linked to original sources

bioRxiv2021

Integrative Omics Analysis Reveals the Immunomodulatory Effects of the Parasitic Dinoflagellate Hematodinium on Crustacean Immunity

Parasitic dinoflagellates in genus Hematodinium have caused substantial economic losses to multiple commercially valuable marine crustaceans around the world. In the present study, comprehensive omics approaches (miRNA transcriptomics, iTRAQ-based proteomics) were applied to investigate the host-parasite interaction between hemocytes from Portunus trituberculatus and Hematodinium perezi. The parasitic dinoflagellate remodeled the miRNome and proteome of hemocytes from challenged hosts, modulated the host immune response at both post-transcriptional and translational levels and caused post-transcriptional regulation to the host immune response. Multiple important cellular and humoral immune-related pathways (ex. Apoptosis, Endocytosis, ECM-receptor interaction, proPO activation pathway, Toll- like signaling pathway, Jak-STAT signaling pathway) were significantly affected by Hematodinium parasites. Through modulation of the host miRNome, the host immune responses of nodulation, proPO activation and antimicrobial peptides were significantly suppressed. Cellular homeostasis was imbalanced via post-transcriptional dysregulation of the phagosome, peroxisome, and lysosome pathways. Cellular structure and communication was seriously impacted by post-transcriptional downregulation of ECM-receptor interaction and focal adhesion pathways. Author summaryThe parasitic dinoflagellate Hematodinium infects many economically important marine crustaceans. Recent efforts to better understand the life cycle and biology of the parasite have improved our understanding of the disease ecology. However, studies on the host-parasite interaction, especially how Hematodinium parasites evade the host immune response are lacking. To address this shortfall, we used miRNA transcriptomics and iTRAQ-based proteomic approaches to explore the immune responses of Portunus trituberculatus when challenged with Hematodinium perezi. Striking changes in the miRNome and proteome of hemocytes were observed, and the parasite exhibited multifaceted immunomodulatory effects and potential immune-evasion mechanisms in this crustacean host.

immunology↗

bioRxiv2021

A live attenuated influenza virus-vectored intranasal COVID-19 vaccine provides rapid, prolonged, and broad protection against SARS-CoV-2 infection

Remarkable progress has been made in developing intramuscular vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, they are limited with respect to eliciting local immunity in the respiratory tract, which is the primary infection site for SARS-CoV-2. To overcome the limitations of intramuscular vaccines, we constructed a nasal vaccine candidate based on an influenza vector by inserting a gene encoding the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2, named CA4-dNS1-nCoV-RBD (dNS1-RBD). A preclinical study showed that in hamsters challenged 1 day and 7 days after single-dose vaccination or 6 months after booster vaccination, dNS1-RBD largely mitigated lung pathology, with no loss of body weight, caused by either the prototype-like strain or beta variant of SARS-CoV-2. Lasted data showed that the animals could be well protected against beta variant challenge 9 months after vaccination. Notably, the weight loss and lung pathological changes of hamsters could still be significantly reduced when the hamster was vaccinated 24 h after challenge. Moreover, such cellular immunity is relatively unimpaired for the most concerning SARS-CoV-2 variants. The protective immune mechanism of dNS1-RBD could be attributed to the innate immune response in the nasal epithelium, local RBD-specific T cell response in the lung, and RBD-specific IgA and IgG response. Thus, this study demonstrates that the intranasally delivered dNS1-RBD vaccine candidate may offer an important addition to fight against the ongoing COVID-19 pandemic, compensating limitations of current intramuscular vaccines, particularly at the start of an outbreak.

pathology↗

bioRxiv2021

Key Factors Governing Initial Stages of Lipid Droplet Formation

Lipid droplets (LDs) are neutral lipid storage organelles surrounded by a phospholipid (PL) monolayer. LD biogenesis from the endoplasmic reticulum (ER) is driven by phase separation of neutral lipids, overcoming surface tension and membrane deformation. However, the core biophysics of the initial steps of LD formation remain relatively poorly understood. Here, we use a tunable, phenomenological coarse-grained (CG) model to study triacylglycerol (TG) nucleation in a bilayer membrane. We show that PL rigidity has a strong influence on TG lensing and membrane remodeling: When membrane rigidity increases, TG clusters remain more planar with high anisotropy but a minor degree of phase nucleation. This finding is confirmed by free energy sampling simulations that calculate the potential of mean force (PMF) as a function of the degree of nucleation and anisotropy. We also show that asymmetric tension, controlled by the number of PLs on each membrane leaflet, determines the budding direction. A TG lens buds in the direction of the monolayer containing excess PLs to allow for better PL coverage of TG, consistent with reported experiments. Finally, two governing mechanisms of the LD growth, Ostwald ripening and merging, are observed. Taken together, this study characterizes the interplay between two thermodynamic quantities during the initial LD phases, the TG bulk free energy and membrane remodeling energy.

biophysics↗

bioRxiv2021

Scaling between DNA and cell size governs bacterial growth homeostasis and resource allocation

Bacteria maintain a stable cell size and a certain DNA content through proliferation as described by classic growth laws. How cells behave when this inherent scaling is broken, however, has rarely been interrogated. Here we engineered Escherichia coli cells with extremely low DNA contents using a tunable synthetic tool CRISPRori that temporarily inhibited chromosome replication initiation. A detailed mechanistic model coupling DNA replication, cell growth, and division revealed a fundamental DNA-centric growth law, which was validated by two observations. First, lineage dynamics were robust to large CRISPRori perturbations with division cycles rapidly restoring through a timer mechanism rather than the adder rule. Second, cellular growth transitioned into a linear regime at low DNA-cytoplasm ratios. Experiments and theory showed that in this regime, cellular resource was redirected to plasmid-borne gene expression. Together with the ability of CRISPRori to bi-directionally modulate plasmid copy numbers, these findings suggest a novel strategy for bio-production enhancement.

systems biology↗

bioRxiv2021

Transcriptome analysis of SARS-CoV-2 naive and recovered individuals vaccinated with inactivated vaccine

The urgent approval of the use of the inactivated COVID-19 vaccine is essential to reduce the threat and burden of the epidemic on global public health, however, our current understanding of the host immune response to inactivated vaccine remains limited. Herein, we performed serum IgG antibody detection and transcriptomics analysis on 20 SARS-CoV-2 naive individuals who received multiple doses of inactivated vaccine and 5 SARS-CoV-2 recovered individuals who received single dose of inactivated vaccine. Our research revealed the important role of many innate immune pathways after vaccination, identified a significant correlation with the third dose of booster vaccine and proteasome-related genes, and found that SARS-CoV-2 recovered individuals can produces a strong immune response to a single dose of inactivated vaccine. These results help us understand the reaction mechanism of the hosts molecular immune system to the inactivated vaccine, and provide a basis for the choice of vaccination strategy.

microbiology↗

bioRxiv2021

Sleep Need, the Key Regulator of Sleep Homeostasis, Is Indicated and Controlled by Phosphorylation of Threonine 221 in Salt Inducible Kinase 3

Sleep need drives sleep and plays a key role in homeostatic regulation of sleep. So far sleep need can only be inferred by animal behaviors and indicated by electroencephalography (EEG). Here we report that threonine 221 (T221) of the salt inducible kinase 3 (SIK3) was important for the catalytic activity and stability of SIK3. T221 phosphorylation in the mouse brain indicates sleep need: more sleep resulting in less phosphorylation and less sleep more phosphorylation during daily sleep/wake cycle and after sleep deprivation (SD). Sleep need was reduced in SIK3 loss of function (LOF) mutants and by T221 mutation to alanine (T221A). Sleep rebound after SD was also decreased in SIK3 LOF and T221A mutant mice. Other kinases such as SIK1 and SIK2 or other sites in SIK3 do not fulfil criteria to be both an indicator and a controller of sleep need. Our results reveal SIK3 T221 phosphorylation as the first and only chemical modification which indicates and controls sleep need.

neuroscience↗

bioRxiv2021

Repetition Probability Effects for Words Depend on Language Knowledge

The magnitude of repetition suppression (RS), measured by fMRI, is modulated by the probability of repetitions (P(rep)) for various sensory stimulus categories. It has been suggested that for visually presented simple letters this P(rep) effect depends on the prior practices of the participants with the stimuli. Here we tested further if previous experiences affect the neural mechanisms of RS, leading to the modulatory effects of stimulus P(rep), for more complex lexical stimuli as well. We measured the BOLD signal in the Visual Word Form Area (VWFA) of native Chinese and German participants and estimated the P(rep) effects for Chinese characters and German words. The results showed a significant P(rep) effect for stimuli of the mother tongue in both participant groups. Interestingly, Chinese participants, learning German as a second language, also showed a significant P(rep) modulation of RS for German words while the German participants who had no prior experiences with the Chinese characters showed no such effects. Our findings suggest that P(rep) effects on RS are manifest for visual word processing as well, but only for words of a language with which participants are highly familiar. These results support further the idea that predictive processes, estimated by P(rep) modulations of RS, require prior experiences.

neuroscience↗

bioRxiv2021

Microglia ferroptosis is prevalent in neurodegenerative disease and regulated by SEC24B

Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinsons Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS). One prominent feature of affected brain regions are iron-loaded microglia, but how iron overload influences microglia physiology and disease response is poorly understood. Here we show that microglia are highly susceptible to ferroptosis, an iron-dependent form of cell death. In a tri-culture of human iPSC-derived neurons, astrocytes, and microglia, under ferroptosis-inducing conditions, microglia undergo a drastic shift in cell state, with increased ferritin levels, disrupted glutathione homeostasis, and altered cytokine signaling. Similar ferroptosis-associated signature (FAS) microglia were uncovered in PD, and the signature was also found in a large cohort of PD patient blood samples, raising the possibility that ferroptosis can be identified clinically. We performed a genome-wide CRISPR screen which revealed a novel regulator of ferroptosis, the vesicle trafficking gene SEC24B. A small molecule screen also nominated several candidates which blocked ferroptosis, some of which are already in clinical use. These data suggest that ferroptosis sits at the interface of cell death and inflammation, and inhibition of this process in microglia and other brain cells may provide new ways for treating neurodegenerative disease.

neuroscience↗

bioRxiv2021

Blood pressure and the kidney cortex transcriptome response to high sodium diet challenge in female nonhuman primates

Blood pressure (BP) is influenced by genetic variation and sodium intake. Ninety percent of Americans consume more than the AHA recommended amount of sodium. Studies on the impact of genetic variation and sodium intake on BP in nonhuman primates (NHP) to date have focused on males. We hypothesized that variation in renal transcriptional networks correlate with BP response to high dietary sodium in female baboons. Sodium-naive female baboons (n=7) were fed a low-sodium (LS) diet for 6 weeks followed by a high sodium (HS) diet for 6 weeks. Sodium intake, serum 17 betaestradiol, and ultrasound-guided kidney biopsies for RNA-Seq BP were collected at the end of each diet. BP was continuously measured for 64-hour periods throughout the study by implantable telemetry devices. On the LS diet, Na+ intake and serum 17 beta-estradiol concentration correlated with BP. Kidney transcriptomes differed by diet; analysis by unbiased weighted gene co-expression network analysis revealed modules of genes correlated with BP on the HS diet. Cell type composition of renal biopsies was consistent among all animals for both diets. Network analysis of module genes showed causal networks linking hormone receptors, proliferation and differentiation, methylation, hypoxia, insulin and lipid regulation, and inflammation as regulators underlying variation in BP on the HS diet. Our results show variation in BP correlated with novel kidney gene networks with master regulators PPARG and MYC in female baboons on a HS diet. Identification of mechanisms underlying regulators that influence BP will inform better therapies towards greater precision medicine for women.

genomics↗

bioRxiv2021

Elevated Hoxb5b expands vagal neural crest pool and blocks enteric neuronal development in zebrafish

Neural crest cells (NCCs) are a migratory, transient, and multipotent stem cell population essential to vertebrate embryonic development, contributing to numerous cell lineages in the adult organism. While great strides have been made in elucidating molecular and cellular events that drive NCC specification, comprehensive knowledge of the genetic factors that orchestrate NCC developmental programs is still far from complete. We discovered that elevated Hoxb5b levels promoted an expansion of zebrafish NCCs, which persisted throughout multiple stages of development. Correspondingly, elevated Hoxb5b also specifically expanded expression domains of the vagal NCC markers foxd3 and phox2bb. Increases in NCCs were most apparent after pulsed ectopic Hoxb5b expression at early developmental stages, rather than later during differentiation stages, as determined using a novel transgenic zebrafish line. The increase in vagal NCCs early in development led to supernumerary Phox2b+ enteric neural progenitors, while leaving many other NCC-derived tissues without an overt phenotype. Surprisingly, these NCC-derived enteric progenitors failed to expand properly into sufficient quantities of enterically fated neurons and stalled in the gut tissue. These results suggest that while Hoxb5b participates in vagal NCC development as a driver of progenitor expansion, the supernumerary, ectopically localized NCC fail to initiate expansion programs in timely fashion in the gut. All together, these data point to a model in which Hoxb5b regulates NCCs both in a tissue specific and temporally restricted manner.

developmental biology↗

bioRxiv2021

Total parenteral nutrition drives glucose metabolism disorders by modulating gut microbiota and its metabolites

The occurrence of glucose metabolism disorders is a potentially fatal complication of total parenteral nutrition (TPN). However, the mechanisms of TPN-associated glucose metabolism disorders remain unclarified. Given that the glucose metabolism was related to gut microbiome and TPN could induce the gut microbiota dysbiosis, we hypothesized that gut microbiota and its metabolites played the important roles in TPN-associated glucose metabolism disorders. By performing a cohort study of 256 type 2 IF patients given PN, we found that H-PN (PN>80%) patients exhibited insulin resistance and a higher risk of complications. Then, TPN and microbiome transfer mice model showed that TPN promoted glucose metabolism disorders by inducing gut microbiota dysbiosis; 16S rRNA sequencing demonstrated that the abundance of Lactobacillaceae was decreased in mice model and negatively correlated with HOMA-IR and lipopolysaccharide level in TPN patients. Untargeted metabolomics found that indole-3-acetic acid (IAA) was decreased in TPN mice, and the serum level was also decreased in H-PN patients. Furthermore, GLP-1 secretion regulated by IAA and aryl hydrocarbon receptor was reduced in TPN mice and patients; IAA or liraglutide completely prevented glucose metabolism disorders in TPN mice. In conclusion, TPN drives glucose metabolism disorders by inducing alteration of gut microbiota and its metabolites.

microbiology↗

bioRxiv2021

A deep learning-based framework for estimating fine-scale germline mutation rates

Germline mutation rates are essential for genetic and evolutionary analyses. Yet, estimating accurate fine-scale mutation rates across the genome is a great challenge, due to relatively few observed mutations and intricate relationships between predictors and mutation rates. Here we present MuRaL (Mutation Rate Learner), a deep learning framework to predict mutation rates at the nucleotide level using only genomic sequences as input. Harnessing human germline variants for comprehensive assessment, we show that MuRaL achieves better predictive performance than current state-of-the-art methods. Moreover, MuRaL can build models with relatively few training mutations and a moderate number of sequenced individuals, and can leverage transfer learning to further reduce data and time demands. We apply MuRaL to produce genome-wide mutation rate maps for four representative species - Homo sapiens, Macaca mulatta, Arabidopsis thaliana and Drosophila melanogaster, demonstrating its high applicability. As an example, we use improved mutation rate estimates to stratify human genes into distinct groups which are enriched for different functions, and highlight that many developmental genes are subject to high mutational burden. The open-source software and generated mutation rate maps can greatly facilitate related research.

genomics↗

bioRxiv2021

Bicolor angelfish (Centropyge bicolor) provides the first chromosome-level genome of the Pomacanthidae family

The Bicolor Angelfish, Centropyge bicolor, is a tropical coral reef fish. It is named for its striking two-color body. However, a lack of high-quality genomic data means little is known about the genome of this species. Here, we present a chromosome-level C. bicolor genome constructed using Hi-C data. The assembled genome is 650 Mbp in size, with a scaffold N50 value of 4.4 Mbp, and a contig N50 value of 114 Kbp. Protein-coding genes numbering 21,774 were annotated. Our analysis will help others to choose the most appropriate de novo genome sequencing strategy based on resources and target applications. To the best of our knowledge, this is the first chromosome-level genome for the Pomacanthidae family, which might contribute to further studies exploring coral reef fish evolution, diversity and conservation.

genomics↗

bioRxiv2021

Combinatorial tumor suppressor inactivation efficiently initiates lung adenocarcinoma with therapeutic vulnerabilities

Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most common subtype. Many oncogenes and tumor suppressor genes are altered in this cancer type and the discovery of oncogene mutations has led to the development of targeted therapies that have improved clinical outcomes. However, a large fraction of lung adenocarcinomas lacks mutations in known oncogenes, and the genesis and treatment of these oncogene-negative tumors remain enigmatic. Here, we perform iterative in vivo functional screens using quantitative autochthonous mouse model systems to uncover the genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Through the generation of hundreds of diverse combinations of tumor suppressor alterations, we demonstrate that the inactivation of suppressors of the RAS and PI3K pathways drive the development of oncogene-negative lung adenocarcinoma. Human genomic data and histology identified RAS/MAPK and PI3K pathway activation as a common event in oncogene- negative human lung adenocarcinomas. We demonstrate that these Onc-negativeRAS/PI3K tumors and related cell lines are vulnerable to pharmacological inhibition of these signaling axes. These results transform our understanding of this prevalent yet understudied subtype of lung adenocarcinoma.

cancer biology↗

bioRxiv2021

High Resolution Nanostructure with Two-stages of Exponential Energy Dissipation at the Ultrathin Osteochondral Interface Tissue of Human Knee Joint

Cartilage adheres to subchondral bone via a specific osteochondral interface tissue where forces are transferred from soft cartilage to hard bone without fatigue damage over a lifetime of load cycles. However, the fine structure and mechanical properties of osteochondral interface tissue remain unclear. Here, we identified an ultrathin [~]20-30 m calcified region with two-layered micro-nano structures of osteochondral interface tissue in human knee joint, which exhibited characteristic biomolecular compositions and complex nanocrystals assembly. Within this region, an exponential increase of modulus (3 orders of magnitude) was conducive to the force transmission which was verified by finite element simulations. The nanoscale heterogeneity of hydroxyapatite, along with enrichment of elastic-responsive protein-titin which is usually present in muscle, endowed the osteochondral tissue with excellent energy dissipation and fatigue resistance properties. Our results provide potential design for high-performance interface materials for osteochondral interface regeneration and functional coatings.

bioengineering↗

bioRxiv2021

The genome of the camphor tree and the genetic and climatic relevance of the top-geoherbalism in this medicinal plant

Camphor tree (Cinnamomum camphora (L.) J. Presl), a species in the magnoliid family Lauraceae, is known for its rich volatile oils and is used as a medical cardiotonic and as a scent in many perfumed hygiene products. Here, we present a high-quality chromosome-scale genome of C. camphora with a scaffold N50 of 64.34 Mb and an assembled genome size of 755.41 Mb. Phylogenetic inference revealed that the magnoliids are a sister group to the clade of eudicots and monocots. Comparative genomic analyses identified two rounds of ancient whole-genome duplication (WGD). Tandem duplicated genes exhibited a higher evolutionary rate, a more recent evolutionary history and a more clustered distribution on chromosomes, contributing to the production of secondary metabolites, especially monoterpenes and sesquiterpenes, which are the principal essential oil components. Three-dimensional analyses of the volatile metabolites, gene expression and climate data of samples with the same genotype grown in different locations showed that low temperature and low precipitation during the cold season modulate the expression of genes in the terpenoid biosynthesis pathways, especially TPS genes, which facilitates the accumulation of volatile compounds. Our study lays a theoretical foundation for policy-making regarding the agroforestry applications of camphor tree.

genomics↗

bioRxiv2021

Lin28a rejuvenates muscle stem cells via mitochondrial optimization

The well-conserved correlation between juvenility and tissue regeneration was first discussed by Charles Darwin. Ectopic Lin28 is known to play an important role in somatic reprogramming and tissue regeneration, but endogenous Lin28s role in tissue homeostasis and juvenility had remained unclear. Through lineage tracing, we found that a rare subset of muscle stem cells (MuSCs) expressing Lin28a can respond to acute injury by proliferating as Pax3+ or Pax7+ MuSCs, and contribute to all types of myofibers during muscle regeneration. Compared with conventional Pax7+ MuSCs, Lin28a+ MuSCs express more Pax3 and show enhanced myogenicity in vitro. In terms of the epigenetic clock, adult Lin28a+ MuSCs lie between adult Pax7+ MuSCs and embryonic Pax7+ myoblasts according to their DNA methylation profiles. We found that Lin28a+ MuSCs upregulate several embryonic limb bud mesoderm transcription factors and could maintain a juvenile state with enhanced stem cell self-renewal and stress-responsiveness in vitro and in vivo. When combined with telomerase and TP53 inhibition to biomimic mouse Lin28a+ MuSCs, we found that Lin28a can rejuvenate and dedifferentiate aged human primary myoblasts into engraftable, self-renewing MuSCs. Mechanistic studies revealed that Lin28a activated the HIF1A pathway by optimizing mitochondrial ROS (mtROS), thereby rejuvenating MuSC self-renewal and muscle regeneration. Our findings connect the stem cell factor Lin28, mtROS metabolism and stress response pathways to the process of stem cell rejuvenation and tissue regeneration.

cell biology↗

bioRxiv2021

Endothelial Cell-Specific Molecule-1 Inhibits Albuminuria in Diabetic Mice

Diabetic kidney disease (DKD) is the most common cause of kidney failure in the world, and novel predictive biomarkers and molecular mechanisms of disease are needed. Endothelial cell-specific molecule-1 (Esm-1) is a secreted proteoglycan that attenuates inflammation. We previously identified that a glomerular deficiency of Esm-1 associates with more pronounced albuminuria and glomerular inflammation in DKD-susceptible relative to DKD-resistant mice, but its contribution to DKD remains unexplored. In this study, we show that lower circulating Esm-1 predicts progressive stages of albuminuria in patients with diabetes. In DKD-susceptible mice, Esm-1 inversely correlates with albuminuria and glomerular leukocyte infiltration. Using hydrodynamic tail-vein injection, we show that over-expression of either mouse or human Esm-1 reduces diabetes-induced albuminuria relative to saline-injected controls independent of leukocyte infiltration. Using a complementary approach, we find that constitutive deletion of Esm-1 in DKD-resistant mice increases the degree of diabetes-induced albuminuria versus wild-type controls. Mechanistically, over-expression of Esm-1 attenuates diabetes-induced podocyte injury. By glomerular RNAseq, we identify that Esm-1 attenuates diabetes-induced up-regulation of interferon-stimulated genes, and Esm-1 inhibits expression of kidney disease-promoting and interferon-related genes, including Ackr2 and Cxcl11. In conclusion, we demonstrate that Esm-1 protects against diabetes-induced albuminuria, and podocytopathy, possibly through select interferon signaling.

immunology↗