Biology subjects

Ma, Y.

Publications and source records attributed to Ma, Y..

At least 343 records · Page 19Linked to original sources

bioRxiv2022

Epigenetic reprogramming of melanoma cell state through fatty acid β-oxidation and Toll like receptor 4 signaling

Tumor cells respond to a host of factors from the local microenvironment. Microenvironmental fatty acids can be used by melanoma cells for fuel, but their effects on transcription and epigenetics are still unclear. Here, we show that the fatty acid {beta}-oxidation (FAO) pathway integrates signaling and epigenetics to drive melanoma progression. Using transgenic zebrafish and human cell lines, we find that octanoate, a medium-chain fatty acid, increases tumorigenesis. Octanoate is metabolized via the FAO/ACLY axis into acetyl-CoA, leading to increased histone acetylation. Transcriptomic and epigenetic analyses demonstrate a convergence of inflammatory gene signatures in octanoate-treated melanoma cells. This signature is mediated by TLR4/MyD88 signaling, which is activated by saturated fatty acids like octanoate. Genetic inactivation of either FAO enzymes or TLR4/MyD88 inhibits alterations in histone acetylation, and rescues octanoate-tumor promoting effects. Together, these data demonstrate clear evidence linking fatty acid metabolism and epigenetics to melanoma pathogenesis through TLR4 signaling.

cancer biology↗

bioRxiv2022

Metabolic interactions control the spread of plasmid-encoded functional novelty during microbial range expansion

Surface-associated microbial communities are omnipresent on Earth. As individuals grow and divide within these communities, they undergo range expansion during which different cell-types arrange themselves across space to form spatial patterns (referred to as spatial self-organization). Metabolic interactions are important determinants of the spatial self-organization process, where they direct the spatial positionings of different cell-types. We hypothesized here a previously unexplored consequence of metabolic interactions; by directing the spatial positionings of different cell-types, they also control the horizontal spread of functional novelty during range expansion. We focused on a form of functional novelty of critical importance to human health - the conjugative transfer and proliferation of plasmid-encoded antibiotic resistance. We performed range expansion experiments and spatially-explicit individual-based computational simulations with pairs of strains of the bacterium Pseudomonas stutzeri, where one strain was a plasmid donor and the other a potential recipient. We then imposed a competitive or resource cross-feeding interaction between them. We found that interactions that increase the spatial intermixing of strains also increase plasmid conjugation. We further directly linked these effects to spatial intermixing itself. We finally showed that the ability of plasmid recipients to proliferate is determined by their spatial positionings. Our results demonstrate that metabolic interactions are indeed important determinants of the horizontal spread of functional novelty during microbial range expansion, and that the spatial positionings of different cell-types need to be considered when predicting the proliferation and fate of plasmid-encoded traits.

ecology↗

bioRxiv2022

Dynamin forms liquid-like condensates at synapses to support ultrafast endocytosis

Endocytosis at synapses is accelerated by the pre-accumulation of Dynamin 1xA at the endocytic zone by Syndapin 1. However, it is unclear how these proteins support the ultrafast kinetics of endocytosis. Here we report that these proteins phase separate at the presynaptic endocytic zone where ultrafast endocytosis takes place. Specifically, the proline-rich motif of Dynamin 1xA interacts with the Src-Homology 3 domain of Syndapin 1 and forms liquid-like condensates. Single-particle tracking of Dynamin 1xA molecules at synapses shows that their diffusion slows down substantially when they are in the condensates, indicating the presence of molecular crowding and intermolecular interaction. When Dynamin 1xA is mutated to disrupt its interaction with Syndapin 1 the condensates do not form. Thus, the liquid-like assembly of these endocytic proteins provides a catalytic platform for ultrafast endocytosis.

neuroscience↗

bioRxiv2022

Modeling the effects of genetic and diet induced obesity on melanoma progression in zebrafish.

Obesity is a rising concern and associated with an increase in numerous cancers often in a sex-specific manner. Preclinical models are needed to deconvolute the intersection between obesity, sex, and cancer. We have generated a zebrafish system that can be used as a platform for studying these factors. We studied how germline overexpression of AgRP along with a high-fat diet (HFD) affects melanomas dependent on BRAFV600E. This revealed an increase in tumor incidence and area in male obese fish, but not females, consistent with the clinical literature. This is dependent on the somatic mutations, as male tumors generated with an RB1 mutation are sensitive to obesity, but this is not observed with PTEN. These data indicate that both germline and somatic mutations contribute to obesity related effects in melanoma. Given the rapid genetic tools available in the zebrafish, this provides a high-throughput system to dissect the interactions of genetics, diet, sex, and host factors in obesity-related cancers. Summary StatementDue to the rising incidence of obesity, there is a corresponding increased occurrence of obesity related cancers, which is often described to be dependent on sex. Here we developed a model to investigate the intersection between obesity, sex, and cancer.

cancer biology↗

bioRxiv2022

A global atlas of substrate specificities for the human serine/threonine kinome

Protein phosphorylation is one of the most widespread post-translational modifications in biology. With the advent of mass spectrometry-based phosphoproteomics, more than 200,000 sites of serine and threonine phosphorylation have been reported, of which several thousand have been associated with human diseases and biological processes. For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein Ser/Thr kinases encoded in the human genome is responsible. Here, we utilize synthetic peptide libraries to profile the substrate sequence specificity of nearly every functional human Ser/Thr kinase. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. Our kinome-wide dataset was used to computationally annotate and identify the most likely protein kinases for every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites where the protein kinases involved have been previously identified, our predictions were in excellent agreement. When this approach was applied to examine the signaling response of tissues and cell lines to hormones, growth factors, targeted inhibitors, and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the full extent of substrate specificity of the human Ser/Thr kinome, illuminate cellular signaling responses, and provide a rich resource to link unannotated phosphorylation events to biological pathways.

systems biology↗

bioRxiv2022

Nucleoli and the nucleoli-centromere association are dynamic during normal development and in cancer

Centromeres are known to cluster around nucleoli in drosophila and mammalian cells. However, the functional significance of nucleoli-centromere interaction remains underexplored. We hypothesize that if this conserved interaction is functionally important, it should be dynamic under different physiological and pathological conditions. We examined the nucleolar structure and centromeres at various differentiation stages using cell culture models. The results show dynamic changes of nucleolar number, area, and nucleoli-centromere interactions at differentiation stages and in cancer cells. Embryonic stem cells usually have a single large nucleolus, which associates with a high percentage of centromeres. As cells differentiate into intermediate states, the nucleolar number increases and the association with centromeres decreases. In terminally differentiated cells, including myotubes, neurons and keratinocytes, the number of nucleoli and their association with centromeres are at the lowest. Cancer cells demonstrate the pattern of nucleoli number and nucleoli-centromere association that is akin to proliferative less differentiated cell types, suggesting that nucleolar reorganization and changes in nucleoli-centromere interactions may help facilitate malignant transformation. This idea is supported in a case of pediatric rhabdomyosarcoma, in which induced differentiation inhibits cell proliferation and reduces nucleolar number and centromere association. These findings suggest active roles of nucleolar structure in centromere function and genome organization critical for cellular function in both normal development and cancer.

cell biology↗

bioRxiv2022

Lipid droplets are a metabolic vulnerability in melanoma

Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the pigmented cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved in human melanoma specimens. This state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt oxidative metabolism and slow melanoma growth in vivo. Because the pigmented cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.

cancer biology↗

bioRxiv2022

A Self-Healing, Viscoelastic Hydrogel Promotes Healing of Brain Lesions

Brain lesions can arise from traumatic brain injury, infection, and craniotomy. Although injectable hydrogels show promise for promoting healing of lesions and health of surrounding tissue, enabling cellular ingrowth and restoring neural tissue continue to be challenging. We hypothesized that these challenges arise in part from viscoelastic mismatch between the hydrogel and the brain parenchyma, and tested this hypothesis by developing and evaluating a self-healing hydrogel that mimicked both the composition and viscoelasticity of native brain parenchyma. The hydrogel was crosslinked by dynamic boronate ester bonds between phenylboronic acid grafted hyaluronic acid (HA-PBA) and dopamine grafted gelatin (Gel-Dopa). This HA-PBA/Gel-Dopa hydrogel could be injected into a lesion cavity in a shear-thinning manner with rapid hemostasis, high tissue adhesion and efficient self-healing. We tested this in an in vivo mouse model of brain lesions and found the hydrogel to support neural cell infiltration, decrease astrogliosis and glial scars, and close the lesions. The results suggest a role for viscoelasticity in brain lesion healing, and motivate additional experimentation in larger animals as the technology progresses towards potential application in humans.

bioengineering↗

bioRxiv2022

Mapping the risks of China's global coastal development to marine socio-ecological systems

Rapid coastal development continues to jeopardize the integrity of marine socio-ecological systems. China is now the largest bilateral creditor in the world, committing nearly half a trillion US dollars to overseas development finance since 2008. Meanwhile, there are growing concerns over the impacts of this boom in Chinese development finance on marine systems. Here, we quantify the risks of coastal development projects financed by China to marine biodiversity and coastal Indigenous communities. Ports present the greatest impact risks to marine systems, in terms of both magnitude and area at risk, with power plants, roads, and other facilities presenting relatively high localized risks. Risks are most prominent in Africa and the Caribbean, with coastal Indigenous communities in Western and Central Africa particularly vulnerable to the potential negative impacts of development. All projects present some risk to threatened marine species and potential critical habitats, but few present high risks to nearby marine protected areas. Most projects present additional risks to ecosystems that are already under increasing human pressures, but some are likely to introduce new risks to relatively intact ecosystems. "Bluing" future coastal development projects in Chinas overseas development finance portfolio will require more social and environmental safeguards, higher standards for host-country impact assessments, and greater integration of land-sea risk mitigation and management approaches.

ecology↗

bioRxiv2022

G6PD Inhibition Sensitizes Ovarian Cancer Cells to Oxidative Stress in the Metastatic Omental Microenvironment

Ovarian cancer (OC) is the most lethal gynecological malignancy, with aggressive metastatic disease responsible for the majority of ovarian cancer related deaths. In particular, OC tumors preferentially metastasize to and proliferate rapidly in the omentum. Here, we show metastatic OC cells experience increased oxidative stress in the omental microenvironment. Metabolic reprogramming, including upregulation of the pentose phosphate pathway (PPP), a key cellular redox homeostasis mechanism, allows OC cells to compensate for this challenge. Inhibition of G6PD, the rate-limiting enzyme of the PPP, reduces tumor burden in pre-clinical models of OC, suggesting this adaptive metabolic dependency is important for OC omental metastasis. HighlightsO_LIThe omental microenvironment poses a high oxidative stress metastatic niche for ovarian cancer cells. C_LIO_LIG6PD, a key enzyme involved in redox homeostasis and the rate-limiting enzyme of the pentose phosphate pathway (PPP) is upregulated in omental metastasis. C_LIO_LIInhibition of G6PD increases oxidative stress and cytotoxicity in the omental microenvironment. C_LIO_LIPharmacological G6PD inhibition reduces omental metastases in vivo. C_LI

cancer biology↗

bioRxiv2022

Sequence characterization of the complete chloroplast genome of Eupatorium fortunei

Eupatorium fortunei has been utilized as herbal medicine to cure various diseases in various regions of the world especially China, Korea, and other Asian countries. The available literature shows Eupatorium fortunei contain anti-metastatic, anti-angiogenic, anti-bacterial, and anti-oxidant, along with compounds to cure human cancer. In present study, Eupatorium fortunei was used as an experimental material, and its genome was sequenced based on high-throughput sequencing technology. We assembled the complete chloroplast genome of Eupatorium fortunei and obtained NCBI accession number (OK545755). We analyzed chloroplast genome structure of Eupatorium fortunei and systematic analysis was conducted, including the size of the entire genome sequence, genome volume, large single-copy (LSC), small single-copy (SSC), inverted repeat region (IR)-LSC/SSC boundaries, etc. The obtained results showed that chloroplast genome of Eupatorium fortunei is a typical tetrad structure with a total length of 152,401 bp and a sum of 133 annotated genes, including eight ribosomal RNA (rRNA)-encoding genes, 37 transfer RNA (tRNA)-encoding genes, 87 protein-encoding genes, and one pseudo-gene. A sum of 29 Single Sequence Repeats (SSR)s were identified for mono-nucleotide, di-nucleotide and tri-nucleotide microsatellites with mono-nucleotides in majority. The phylogenetic analysis revealed that Eupatorium fortunei is more closely related to Litothamnus nitidus and belongs to the same branch. The genome assembly and analysis of the chloroplast genome of Eupatorium fortunei provides more accurate evidence for further taxonomic identification and localization of Asteraceae/Compositae plant.

bioinformatics↗

bioRxiv2022

Structural insights into the viral proteins binding by TRIM7 reveal a general C-terminal glutamine recognition mechanism

The E3 ligase TRIM7 has emerged as a critical player in viral infection and pathogenesis. A recent study found that TRIM7 inhibits human enteroviruses through ubiquitination and proteasomal degradation of viral 2BC protein by targeting the 2C moiety of 2BC protein. Here, we report the crystal structures of TRIM7 in complex with 2C, where the C-terminal region of 2C is inserted into a positively charged groove of the TRIM7 PRY-SPRY domain. Structure-guided biochemical studies revealed the C-terminus glutamine residue of 2C as the primary determinant for TRIM7 binding. Such a glutamine-end motif binding mechanism can be successfully extended to other substrates of TRIM7. More importantly, leveraged by this finding, we were able to identify norovirus and SARS-CoV-2 proteins, and physiological proteins, as new TRIM7 substrates. We further show that TRIM7 may function as a restriction factor to promote the degradation of the viral proteins of norovirus and SARS-CoV-2, thereby restoring the Type I interferon immune response and inhibiting viral infection. Several crystal structures of TRIM7 in complex with SARS-CoV-2 proteins are also determined, and a conserved C-terminus glutamine-specific interaction is observed. These findings unveil a common recognition mode by TRIM7, providing the foundation for further mechanistic characterization of antiviral and cellular functions of TRIM7.

biochemistry↗

bioRxiv2022

A photoswitchable ligand targeting β1-adrenoceptor enables light-control of the cardiac rhythm

Catecholamine-triggered {beta}-adrenoceptor ({beta}-AR) signaling is essential for the correct functioning of the heart. Although both {beta}1- and {beta}2-AR subtypes are expressed in cardiomyocytes, drugs selectively targeting {beta}1-AR have proven this receptor as the main target for the therapeutic effects of beta blockers in heart. Here, we report a new strategy for the spatiotemporal control of {beta}1-AR activation by means of light-regulated drugs with a high level of {beta}1-/{beta}2-AR selectivity. All reported molecules allow for an efficient real time optical control of receptor function in vitro. Moreover, using confocal microscopy we demonstrate that the binding of our best hit, pAzo-2, can be reversibly photocontrolled. Strikingly, pAzo-2 also enables a dynamic cardiac rhythm management on alive zebrafish larvae using light, thus highlighting the therapeutic and research potential of the developed photoswitches. Overall, this work provides the first proof of precise control of the therapeutic target {beta}1-AR in native environments using light.

pharmacology and toxicology↗

bioRxiv2022

Transcriptional circuitry of NKX2-1 and SOX1 defines an unrecognized lineage subtype of small cell lung cancer

RationaleThe current molecular classification of small cell lung cancer (SCLC) based on expression of four lineage transcription factors still leaves its major subtype SCLC-A as a heterogeneous group, necessitating more precise characterization of lineage subclasses. ObjectivesTo refine the current SCLC classification with epigenomic profiles and to identify features of the re-defined SCLC subtypes. MethodsWe performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines. Functional significance was evaluated by cell growth, apoptosis and xenograft using CRISPR-Cas9-mediated deletion. The specific cistromic profiles by ChIP-seq and its functional transcriptional partners using co-immunoprecipitation followed by mass spectrometry were determined. Rb1fl/flTrp53fl/fl and Rb1fl/flNkx2-1fl/fl mouse models were engineered to explore the function of Nkx2-1 in tumor initiation and differentiation. H3K27ac profiles were analyzed to reveal 6 human SCLC specimen and 20 mice tumors epigenomic landscapes. Measurements and Main ResultsWe identified an epigenomic subclusters of the major SCLC-A subtype, named SCLC-A and SCLC-A{sigma}. SCLC-A was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-A. We further found maintenance of this neural identity in SCLC-A is mediated by collaborative transcriptional activity with another neuronal transcriptional factor SOX1. ConclusionsWe comprehensively describe an additional epigenomic heterogeneity of the major SCLC-A subtype, and define SCLC-A subtype by the core regulatory circuitry representing NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.

molecular biology↗

bioRxiv2022

Ascorbic acid derived carbon dots promote circadian rhythm and contribute to attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children, and ADHD patients always display circadian abnormalities. While, the ADHD drugs currently used in clinic have strong side effects, such as psychosis, allergic reactions and heart problems. Here, we demonstrated carbon dots derived from the ascorbic acid (VCDs) could strongly rescue the hyperactive and impulsive behaviour of a zebrafish ADHD disease model caused by per1b mutation. VCDs prolonged the circadian period of zebrafish for more than half an hour. In addition, the amplitude and circadian phase were also changed. The dopamine level was specifically increased, which may be caused by stimulation of the dopaminergic neuron development in the midbrain. Notably, it was found that the serotonin level was not altered by VCDs treatments. Also, the gene transcriptome effects of VCDs were discussed in present work. Our results provided the dynamic interactions of carbon dots with circadian system and dopamine signaling pathway, which illustrates a potential application of degradable and bio-safe VCDs for the treatment of the attention deficient and hyperactive disorder through circadian intervention. Brief summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/482578v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@198eeforg.highwire.dtl.DTLVardef@1f714f7org.highwire.dtl.DTLVardef@819d8eorg.highwire.dtl.DTLVardef@18ef9cb_HPS_FORMAT_FIGEXP M_FIG C_FIG

animal behavior and cognition↗

bioRxiv2022

The NOD/RIPK2 signaling pathway contributes to osteoarthritis susceptibility

Introductory paragraphOsteoarthritis (OA) is a debilitating disease characterized by loss of homeostasis of the joint with consequent remodeling of tissue architecture1. The molecular pathways that limit disease onset or progression are unknown2-5, and consequently no disease-modifying drugs are available1,6-9. We sought genes that contribute to dominant forms of hereditary OA with the aim of identifying pathways whose activity level contributes to OA susceptibility. We found seven independent alleles affecting the NOD/RIPK2 pathway. To determine if altered signaling is sufficient to confer heightened OA susceptibility, mice carrying the OA-associated hyperactive Ripk2104Asp allele were generated. Knees of heterozygous Ripk2104Asp mice exhibit no overt signs of joint remodeling. Nevertheless, the mice respond to injury with markedly advanced post-traumatic OA. Uninjured heterozygous Ripk2104Asp mice appear primed to develop OA: their knees exhibit elevated NOD/RIPK2 pathway activity, localized inflammation, and altered expression of extracellular matrix genes linked to OA. In contrast to the joint, the mice display no evidence of systemic elevated inflammation. Elevated NOD/RIPK2 signaling confers vulnerability to OA.

genetics↗

bioRxiv2022

Normal Reproductive function in male mice lacking pituitary kisspeptin receptor.

The anterior pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) regulate gonadal development, gametogenesis and the secretion of the gonadal steroid hormones. The gonadotroph is primarily regulated by hypothalamic secretion of gonadotropin-releasing hormone (GnRH) from neurons of the rostral hypothalamus and is mediated by GnRH receptor signaling. Kisspeptin (KISS1)/kisspeptin receptor (KISS1R) signaling in GnRH neurons plays an essential role in reproductive function. As the kisspeptin receptor is present in the pituitary, kisspeptin signaling via the Kiss1r may regulate reproductive function at the level of pituitary. Using Cre/Lox technology, we deleted the Kiss1r gene in pituitary gonadotropes (PKiRKO). PKiRKO male and females have normal genital development, puberty onset, and fertility. Females have normal LH, FSH and estradiol while males had significantly increased basal serum FSH levels with no differences in basal serum LH, or testosterone levels. Overall, these findings indicate that the pituitary KISS1R does not play a role in male reproduction.

physiology↗

bioRxiv2022

DNA origami as a nanomedicine for targeted rheumatoid arthritis therapy through reactive oxygen species and nitric oxide scavenging

High levels of reactive oxygen species (ROS) and nitric oxide (NO) generated by M1 macrophages induce inflammation in the development of rheumatoid arthritis (RA). The eliminating of ROS and NO therefore represents an alternative strategy for RA treatment. Because DNA molecules possess ROS- and endogenous NO-scavenging capability, herein, we develop a nanomedicine based on triangular DNA origami nanostructures for targeted RA treatment. We showed that folic acid-modified triangular DNA origami nanostructures (FA-tDONs) could reduce ROS and NO simultaneously inside proinflammatory M1 macrophages, leading to their polarization into anti-inflammatory M2 subtype. Further in vivo studies confirmed that FA-tDONs could actively target inflamed joints in collagen-induced arthritis (CIA) mice, attenuate inflammatory cytokines and alleviate disease progression. This work demonstrated that DNA origami itself could act as a potential nanomedicine for targeted RA treatment.

bioengineering↗