Biology subjects

Jin, Y.

Publications and source records attributed to Jin, Y..

At least 127 records · Page 7Linked to original sources

bioRxiv2023

KRAS inhibition activates an actionable CD24 do-not-eat-me signal in pancreas cancer

KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C- driven PDAC model. Compared to the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a hot tumor immune microenvironment. Immunoprofiling revealed that CD24, a dont eat me signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRASG12D-driven PDAC. Together, this study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. SignificanceGeneration of an autochthonous KRASG12C-driven pancreatic cancer model enabled elucidation of specific effects of KRASG12C during tumor development, revealing CD24 as an actionable adaptive mechanism in cancer cells induced upon KRASG12C inhibition.

cancer biology↗

bioRxiv2023

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer

KRASG12C inhibitors including adagrasib and sortorasib have shown clinical promise in targeting KRASG12C-mutated lung cancers, however, most patients eventually develop drug resistance. In lung adenocarcinoma patients with co-occurring KRASG12C and STK11/LKB1 mutations, we found a high squamous gene signature at baseline significantly correlated with poor adagrasib response. Through integrative studies of Lkb1-deficient KRASG12Cand KrasG12D lung cancer mouse models and/or organoids treated with KRAS inhibitors, we found tumor cells invoked a lineage plasticity program: adeno-to-squamous transition (AST) that mediated resistance to KRAS inhibition. Transcriptomic and epigenomic analyses revealed {Delta}Np63 drives AST and modulates response to KRAS inhibition. We identified an intermediate high-plasticity cell state with distinct gene expression program marked by Krt6a upregulation. Notably, higher KRT6A expression at baseline correlated with shorter overall survival in KRAS-mutant patients receiving adagrasib. These data support the role of AST in KRAS inhibitor resistance and provide predictive biomarker for KRAS-targeted therapies in lung cancer.

cancer biology↗

bioRxiv2023

Nuclear Lipid Droplets Exit to the Cytoplasm: A Novel Mechanism of non-nuclear pore-dependent material exchange

In cellular biology, the extrusion of large molecular complexes from the nucleus has consistently represented a considerable challenge. In this investigation, we reveal a hitherto unexplored mechanism facilitating the efflux of nuclear lipid droplets (nLDs) from the nucleus directly into the cytoplasm, a process integral to comprehending cellular processes and nuclear dynamics. Through high-throughput sequencing, immunoprecipitation, and immunofluorescence experimentation, we demonstrated that the type I nucleoplasmic reticulum engages with nLDs, enabling the dynamic protein Rab8as transfer to the nLDs and fostering their translocation to the nuclear membrane. Phosphorylation of LMNA/C at the S392 site, adjacent to the nLD-nuclear membrane contact site, induces local depolymerization of lamins, creating an aperture that enables gradual nuclear exit of nLDs. Following this, nLDs, carrying DNA fragments, are released into the cytoplasm through budding and subsequently undergo autophagy-mediated degradation. Furthermore, we demonstrate that RhoA-PKC signaling enhances nLD movement and LMNA/C phosphorylation, while its inhibition impedes nuclear nLD efflux. Our groundbreaking investigation illuminates non-nuclear pore-dependent mechanisms of material exchange and offers fresh perspectives on nuclear metabolic pathways. In Brief O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/556761v1_ufig1.gif" ALT="Figure 1"> View larger version (107K): org.highwire.dtl.DTLVardef@38a213org.highwire.dtl.DTLVardef@1898caorg.highwire.dtl.DTLVardef@d7270forg.highwire.dtl.DTLVardef@14582a2_HPS_FORMAT_FIGEXP M_FIG C_FIG In this study, Jin et al. elucidate a novel mechanism for the expulsion of nuclear lipid droplets (nLDs) from the nucleus. They demonstrate that the activation of RhoA within the nucleus recruits Rab8a to the surface of nLDs. Concurrently, PKC phosphorylation triggers the phosphorylation of LMNA/C at the S392 site, leading to a localized depolymerization of lamins. This creates an aperture that allows for the gradual exit of nLDs from the nucleus. The efflux process of nLDs involves three sequential steps: rupture of the nuclear fibril layer, fusion of nLDs with the inner nuclear membrane (INM), and subsequent fusion with the outer nuclear membrane (ONM). This enables nLDs to enter the cytoplasm, shedding light on a previously unknown process of large molecular entity expulsion from the nucleus.

molecular biology↗

bioRxiv2023

Linking genomic prediction for muscle fat content in Atlantic salmon to underlying changes in lipid metabolism regulation

Muscle fat content is an important production trait in Atlantic salmon (Salmo salar) because it influences the flavor, texture, and nutritional properties of the fillet. Genomic selection can be applied to alter muscle fat content, however how such selection changes the underlying molecular physiology of these animals is unknown. Here, we examine the link between genomic prediction and underlying molecular physiology by correlating genomic breeding values for fat content to liver gene expression in 184 fish. We found that Salmon with higher genomic breeding values had higher expression of genes in lipid metabolism pathways. This included key lipid metabolism genes hmgcrab, fasn-b, fads2d5, and fads2d6, and lipid transporters fatp2f, fabp7b, and apobc. We also found several regulators of lipid metabolism with negative correlation to genomic breeding vales, including pparg-b, fxr-a, and fxr-b. A quantitative trait loci analysis for variation in gene expression levels (eQTLs) for 167 trait associated genes found that 71 genes had at least one eQTL, and that most were trans eQTLs. Closer examination revealed distinct eQTL clustering on chromosomes 3 and 6, indicating the presence of putative common regulator in these regions. Taken together, these results suggest that increased fat content in high genomic breeding value salmon is associated with elevated lipid synthesis, elevated lipid transport, and reduced glycerolipid breakdown; and that this is at least partly achieved by selection on genetic variants that impact the function of top-level transcription factors involved in liver metabolism. Our study sheds light on how genomic selection alters lipid content in Atlantic salmon, and the results could be used to prioritize SNPs to improve the efficiency of genomic selection in the future.

genomics↗

bioRxiv2023

Impact of Yaq-001, a non-absorbable, engineered carbon bead of controlled porosity in rodent models of cirrhosis and acute on chronic liver failure

ObjectiveTranslocation of gut bacterial lipopolysaccharide (LPS) is associated with complications of cirrhosis. Current strategies to target bacterial translocation are limited to antibiotics with risk of resistance. This study aims to explore therapeutic potential of a non-absorbable, engineered carbon bead, Yaq-001 in cirrhosis and acute-on-chronic liver failure (ACLF) models. DesignThe performance of Yaq-001 was evaluated in in vitro studies. Two-rodent models of cirrhosis (4-week, bile duct ligation (BDL): Sham (n=36); Sham-Yaq-001 (n=30); BDL (n=37); BDL-Yaq-001 (n=44)) and ACLF (BDL-LPS: Sham-LPS (n=9); Sham-LPS-Yaq-001 (n=10); BDL-LPS (n=16); BDL-LPS-Yaq-001(n=12)). The treated-groups received Yaq-001 for 2-weeks. Samples were collected for assessment of organ and immune function, transcriptomics, microbiome composition and metabolomics. ResultsIn vitro, Yaq-001 exhibited rapid adsorption kinetics for endotoxin and bile acids without exerting an antibiotic effect. In vivo, Yaq-001 produced significant improvement in ALT, ammonia, liver cell death, portal pressure, markers of systemic inflammation and renal function in BDL animals. Yaq-001-treated ACLF animals had significantly better survival, ALT, portal pressure, brain water and creatinine. Ex-vivo LPS-induced reactive oxygen species production in portal venous monocytes and Kupffer cell populations was diminished with Yaq-001 treatment. Transcriptome analysis demonstrated a significant modulation of inflammation, cell death and senescence pathways in the liver, kidneys, brain and colon of Yaq-001-treated BDL rats. Yaq-001 impacted positively on the microbiome composition with significant modulation of Family Porphyromonadaceae and Genus Barnesiella. Urinary 1HNMR analysis suggested a shift in metabolomic signature in Yaq-001-treated BDL rats. ConclusionsThis study provides strong pre-clinical rationale for developing Yaq-001 for treatment of patients with cirrhosis. Significance of this studyO_ST_ABSWhat is already known on this topic?C_ST_ABSCurrent strategies to target bacterial translocation in cirrhosis are limited to antibiotics with risk of resistance. Yaq-001 is an insoluble, non-absorbable, non-antibiotic, engineered carbon bead of tailored porosities, which works as an adsorbent in the gut and is completely excreted after oral administration. What this study adds?O_LIYaq-001 rapidly adsorbs endotoxin, ammonia and bile acids without influencing bacterial growth kinetics in vitro. C_LIO_LIYaq-001 reduces mortality of ACLF animals and impacts positively on markers of gut permeability, liver injury, portal pressure, brain and kidneys in rodent models of cirrhosis and ACLF. C_LIO_LIYaq-001 administration was associated with positive impact on the composition of the gut microbiota, reduction in severity of endotoxemia and ammonia, which significantly reduced the severity of inflammation, cell death, signaling pathways and LPS sensitivity. C_LI How this study might affect research, practice or policy?The data provide the pre-clinical rationale to proceed to clinical trials in patients with cirrhosis aiming to prevent the occurrence of complications.

animal behavior and cognition↗

bioRxiv2023

A 3D microtumour system that faithfully represents ovarian cancer minimal residual disease

BackgroundBulk cancer and minimal residual disease (MRD) are characterised by different molecular drivers and therefore necessitate different therapeutic strategies. However, there are currently no 3D models that can faithfully recapitulate MRD ex vivo for therapy development. MethodsA microfluidic technique was implemented to construct 3D microtumours, in which tumour cells, either by themselves or with fibroblasts, were encapsulated in viscous hydrogels. The 3D microtumours were analysed for their response to first-line chemotherapeutics and characterised through RNA-Seq, by comparing them to both 2D cultures and clinical samples. ResultsOur microfluidic platform guarantees the fabrication of 3D microtumours of tailorable size and cell content, which recreate key features of tumours such as hypoxia, characteristic organization of the cytoskeleton and a dose-response to chemotherapeutics close to the physiological range. The 3D microtumours were also used to examine non-genetic heterogeneity in ovarian cancer and could fully reflect the recently described "Oxford Classic" five molecular signatures. The gene expression profile of 3D microtumours following chemotherapy treatment closely resembled that of MRD in ovarian cancer patients, showing the upregulation of genes involved in fatty acid metabolism. We demonstrate that these 3D microtumours are ideal for drug development by showing how they support the identification of a promising inhibitor of fatty acid oxidation, perhexiline, which specifically targets chemotherapy-resistant MRD ovarian cancer cells and not bulk cancer cells. ConclusionWe have obtained the first 3D model of ovarian cancer MRD by using microtumours generated through microfluidics. This system is ideal for high-throughput drug screening and, given its versatility, it can be readily extended to additional types of cancer, as well as accommodate multiple cell types to generate complex tumour microenvironments.

cancer biology↗

bioRxiv2023

Competition between stochastic neuropeptide signals calibrates the rate of satiation

We investigated how transmission of hunger- and satiety-promoting neuropeptides, NPY and MSH, is integrated at the level of intracellular signaling to control feeding. Receptors for these peptides use the second messenger cAMP, but the messengers spatiotemporal dynamics and role in energy balance are controversial. We show that AgRP axon stimulation in the paraventricular hypothalamus evokes probabilistic and spatially restricted NPY release that triggers stochastic cAMP decrements in downstream MC4R-expressing neurons (PVHMC4R). Meanwhile, POMC axon stimulation triggers stochastic, MSH-dependent cAMP increments. NPY and MSH competitively control cAMP, as reflected by hunger-state-dependent differences in the amplitude and persistence of cAMP transients evoked by each peptide. During feeding bouts, elevated MSH release and suppressed NPY release cooperatively sustain elevated cAMP in PVHMC4R neurons, thereby potentiating feeding-related excitatory inputs and promoting satiation across minutes. Our findings highlight how state-dependent integration of opposing, quantal peptidergic events by a common biochemical target calibrates energy intake.

neuroscience↗

bioRxiv2023

The unique properties of Big tau in the visual system

Tau is a microtubule associated protein that plays important roles in regulating the properties of microtubules and axonal transport, as well as tauopathies associated with toxic aggregates leading to neurodegenerative diseases. It is encoded by the MAPT gene forming multiple isoforms by alternative splicing of exons 2/3 at the N-terminal and exon 10 which determines the numbers of microtubule binding repeats (3R or 4R). The high molecular weight (MW) tau isoform termed Big tau contains an additional large exon 4a generating a long projecting domain and expressed as a 110 kDa protein. Big tau was originally discovered in the peripheral nervous system but later found in selective CNS areas that project to the periphery as well as in the cerebellum and the visual system. However, there is a gap of knowledge in understanding the expression patterns and the role of Big tau during normal neuronal development and pathological conditions relative to the common low MW isoforms. Here we investigated the properties of Big tau in the retina and optic nerve and in particular its unique isoform structure as a middle MW of 90kDa and its distribution in retinal ganglion cells and axons of the optic nerve. We discovered that Big tau expresses the 4a exon as well as exons 6 and 10 (4R), lacking exons 2/3 but sharing the extensive phosphorylation characteristic of other tau isoforms. Importantly, early in development the visual system expresses only the low MW isoform (3R) switching to both the low and middle MW isoforms (4R) in adult retinal ganglion neurons and their corresponding axons. This is a unique structure and expression pattern of Big tau likely associated with different properties than what has been previously described, requiring more research to elucidate the detailed roles of Big tau in the visual system.

neuroscience↗

bioRxiv2023

Single cell transcriptomics unveiled that early life BDE-99 exposure reprogrammed the gut-liver axis to promote a pro-inflammatory metabolic signature in male mice at late adulthood

Polybrominated diphenyl ethers (PBDEs) are a class of legacy flame retardants that bioaccumulate in the environment, raising global health concerns. The gut microbiome is an important regulator of liver including xenobiotic biotransformation, nutrient homeostasis, and immune regulation. Using bulk RNA-Seq, we recently showed that neonatal exposure to BDE-99, a human breast milk-enriched PBDE congener, up-regulated pro-inflammation- and down-regulated drug metabolism-related genes predominantly in males in young adulthood. However, it remains unknown whether such dysregulation persists into late adulthood, how various cell types in the liver contribute to the hepatotoxicity, and to what extent gut microbiome is involved in BDE-99 mediated developmental reprogramming of the liver. To address these knowledge gaps, male C57BL/6 mouse pups were orally exposed to corn oil (10 ml/kg) or BDE-99 (57 mg/kg) once daily from postnatal days 2-4. At 15 months of age, single cell transcriptomics (scRNA-seq) in liver showed that neonatal BDE-99 exposure down-regulated key xenobiotic- and fatty acid metabolizing enzymes and up-regulated genes involved in microbial influx in hepatocytes. Neonatal BDE-99 exposure also led to a persistent increase in the hepatic proportion of neutrophils, a predicted increase of macrophage migration inhibitory factor (MIF) signaling, which activates macrophage populations, as well as histopathological abnormalities of the liver in 15 months of age. The BDE-99 mediated hepatic reprogramming is associated with decreased intestinal tight junction protein (Tjp) transcripts, persistent dysbiosis of the gut microbiome, and dysregulation of inflammation-related fatty acid metabolites. ScRNA-seq in germ-free (GF) mice demonstrated the necessity of a normal gut microbiome in maintaining hepatic immunotolerance. Fecal microbiome transplant to GF mice using large intestinal microbiome from adults that were neonatally exposed to BDE-99 down-regulated Tjp transcripts and up-regulated several cytokines in the large intestine. In conclusion, neonatal BDE-99 exposure reprogrammed the cell type-specific gene expression and cell-cell communication networks in liver towards a pro-inflammation with compromised metabolic functions at late adulthood. Importantly, gut microbiome is necessary in promoting immunotolerance in the liver, and BDE-99-mediated pro-inflammatory signaling may be partly due to the dysregulated gut environment.

pharmacology and toxicology↗

bioRxiv2023

CellStitch: 3D Cellular Anisotropic Image Segmentation via Optimal Transport

BackgroundSpatial mapping of transcriptional states provides valuable biological insights into cellular functions and interactions in the context of the tissue. Accurate 3D cell segmentation is a critical step in the analysis of this data towards understanding diseases and normal development in situ. Current approaches designed to automate 3D segmentation include stitching masks along one dimension, training a 3D neural network architecture from scratch, and reconstructing a 3D volume from 2D segmentations on all dimensions. However, the applicability of existing methods is hampered by inaccurate segmentations along the non-stitching dimensions, the lack of high-quality diverse 3D training data, and inhomogeneity among different dimensions; as a result, they have not been widely used in practice. MethodsTo address these challenges, we formulate the problem of finding cell correspondence across layers with a novel optimal transport (OT) approach. We propose CellStitch, a flexible pipeline that segments cells from 3D images without requiring large amounts of 3D training data. We further extend our method to interpolate internal slices from highly anisotropic cell images to recover isotropic cell morphology. ResultsWe evaluated the performance of CellStitch through eight 3D plant microscopic datasets with diverse anisotropic levels and cell shapes. CellStitch substantially outperforms the state-of-the art methods on anisotropic images, and achieves comparable segmentation quality against competing methods in isotropic setting. We benchmarked and reported 3D segmentation results of all the methods with instance-level precision, recall and average precision (AP) metrics. ConclusionThe proposed OT-based 3D segmentation pipeline outperformed the existing state-of-the-art methods on different datasets with nonzero anisotropy, providing high fidelity recovery of 3D cell morphology from microscopic images.

bioinformatics↗

bioRxiv2023

In Vivo Tissue Distribution of Microplastics and Systemic Metabolomic Alterations After Gastrointestinal Exposure

Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. Plastic debris slowly degrades into microplastics (MPs) that can ultimately be inhaled or ingested by both animals and humans. A growing body of evidence indicates that MPs can cross the gut barrier and enter into the lymphatic and systemic circulation leading to accumulation in tissues such as the lungs, liver, kidney, and brain. The impacts of mixed MPs exposure on tissue function through metabolism remains largely unexplored. To investigate the impact of ingested MPs on target metabolomic pathways, mice were subjected to either polystyrene microspheres or a mixed plastics (5 {micro}m) exposure consisting of polystyrene, polyethylene and the biodegradability and biocompatible plastic, poly-(lactic-co-glycolic acid). Exposures were performed twice a week for four weeks at a dose of either 0, 2, or 4 mg/week via oral gastric gavage. Our findings demonstrate that, in mice, ingested MPs can pass through the gut barrier, be translocated through the systemic circulation, and accumulate in distant tissues including the brain, liver, and kidney. Additionally, we report on the metabolomic changes that occur in the colon, liver and brain which show differential responses that are dependent on dose and type of MPs exposure. Lastly, our study provides proof of concept for identifying metabolomic alterations associated with MPs exposure and adds insight into the potential health risks that mixed MPs contamination may pose to humans.

pharmacology and toxicology↗

bioRxiv2023

Beclin1-Deficient Adipocytes Promote Tumor Progression by YAP/TAZ-dependent Adipocyte Transformation

Adipocytes are crucial components of the tumor microenvironment (TME) that play a prominent role in supporting tumor growth. However, the characteristics of cancer-associated adipocytes (CAAs) that contribute to the pro-tumorigenic niche remain to be fully established. Here, we used adipocyte-specific Beclin1 KO (BaKO) mice to investigate the role of maladaptive adipocytes in promoting tumor progression. BECN1-deficient adipocytes exhibited downregulation of adipogenic markers and activation of YAP/TAZ signaling, similar to the traits observed in CAAs. Thus, we generated adipocyte-specific Becn1/Yap1/Taz KO mice, which exhibit markedly restored phenotypes in adipose tissue, resulting in tumor regression compared to that in BaKO. Further, we observed dysregulation of the BECN1-YAP/TAZ axis in the adipose tissue of mice fed a high-fat diet (HFD). Treatment with the YAP/TAZ inhibitor, verteporfin, suppressed tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Our findings provide insights into CAA formation and its significance in determining malignant TME, thereby suggesting a potential dual therapeutic strategy simultaneously targeting adipocyte homeostasis and cancer growth.

biochemistry↗

bioRxiv2023

Transcript errors generate a continuous stream of amyloid and prion-like proteins in human cells

Aging is characterized by the accumulation of amyloid and prion-like proteins. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that transcript errors generate amyloid and prion-like proteins in a wide variety of human cell types, including stem cells, brain organoids, and fully differentiated neurons. Intriguingly, some of these proteins are identical to proteins previously implicated in familial cases of amyloid diseases, raising the possibility that both familial and non-familial cases are caused by identical mutant proteins. However, transcript errors also generate amyloid proteins that have not been observed before, suggesting that aging cells are exposed to a second class of pathogenic proteins we are currently unaware of. Finally, we show that transcript errors are readily generated by DNA damage, a hallmark of human aging and a staple of multiple proteotoxic diseases, including Alzheimers disease. Together, these observations greatly expand our understanding of mutagenesis in human aging and disease and suggest a new mechanism by which amyloid diseases can develop.

molecular biology↗

bioRxiv2023

Ebola Virus Sequesters IRF3 in Viral Inclusion Bodies to Evade Host Antiviral Immunity

Viral inclusion bodies (IBs) commonly form during the replication of Ebola virus (EBOV) in infected cells, but their role in viral immune evasion has rarely been explored. Here, we found that interferon regulatory factor 3 (IRF3), but not TANK-binding kinase 1 (TBK-1) or I{kappa}B kinase epsilon (IKK{varepsilon}), was recruited and sequestered in viral IBs when the cells were infected by EBOV transcription- and replication-competent virus-like particles (trVLPs). NP/VP35-induced IBs formation was critical for IRF3 recruitment and sequestration, probably through interaction with STING. Consequently, the association of TBK1 and IRF3, which plays a vital role in type I interferon (IFN-I) induction, was blocked by EBOV trVLPs infection. Additionally, IRF3 phosphorylation and nuclear translocation induced by Sendai virus (SeV) or poly(I:C) stimulation were suppressed by EBOV trVLPs. Furthermore, downregulation of STING significantly attenuated VP35-induced IRF3 accumulation in IBs. Coexpression of the viral proteins by which IBs-like structures formed was much more potent in antagonizing IFN-I than expression of the IFN-I antagonist VP35 alone. These results suggested a novel immune evasion mechanism by which EBOV evades host innate immunity. Impact statementEbola virus VP35 protein evades host antiviral immunity by interacting with STING to sequester IRF3 into inclusion bodies and inhibit type-I interferon production.

microbiology↗

bioRxiv2023

Duckweed evolution: from land back to water

Terrestialization is supposedly an important evolutionary process plant experience. However, directions of land back to water acquired little attention. Here we integrate multiproxy evidence to elucidate the evolution of duckweed. Three genera of duckweed show chronologically gradient degeneration in roots structure and stomatal function and decrease in lignocellulose content, accompanied by gradual contraction in relevant gene numbers and/or decline in transcription. The gene numbers in the main phytohormonal pathway are also gradually decreased. The co-action of auxin and rhizoid development gene causes a gradual decrease in adventitious roots. The significant expansion of the flavonoid pathway is also related to the adaptation of duckweed to floating growth. This study reconstructs the evolution history of duckweeds from land back to water, reverse to that of early land plants. SummaryWith terrestrialization being the popularly acknowledged plant evolutionary process, little is known about the evolution of higher plant from land back to water. Here we integrate multiproxy evidence to elucidate the gradual reverse evolution of duckweed. Three genera of duckweed show chronologically gradient degeneration in the structure of roots, the function of stomata, and decrease in lignocellulose content, accompanied by gradient contraction in relevant gene numbers and/or decline in transcript expression. The gene numbers in the main phytohormonal pathway are also gradually decreased. The co-action of auxin and rhizoid development gene causes a gradual decrease in adventitious roots. The significant expansion of the flavonoid pathway is also highly related to the adaptation of duckweed to floating growth. Our study combined with the fossil evidence reconstruct the evolution history of duckweeds from land back to water, reverse to that of early land plants. This study reconstructed the process of how a land plant returns to water, a reverse evolutionary approach which is different from what we studied in textbook about plant terrestrialization. This finding could be helpful for us to deeply and widely understand the adaptation of plant to the environment, and to expand and deepen the knowledge of evolution theory.

evolutionary biology↗

bioRxiv2023

Artificially cultivated duckweed: a high-efficiency starch producer

The increasing demand for starch has been a social struggle. We report a new technology that efficiently produces starch from duckweed. Although Landoltia punctata has a dramatic contraction of gene families, its starch content and productivity reached 72.2% (dry basis) and 10.4 g m-2 d-1 in 10 days, equivalent to a yield of 38.0 t ha-1 y-1 under nutrient limitation and CO2 elevation treatment. Meanwhile, we also examined the mechanism of duckweeds high starch accumulation. This is exhibited in the regulation of DNA methylation and transcription factors as well as the significantly up-regulated transcription levels and the increased enzyme activities of key genes in starch biosynthesis. Meantime, while nitrogen redistribution was enhanced, sucrose biosynthesis and transportation, and lignocellulose biosynthesis were all reduced. These alterations led to a reduction in lignocellulose and protein content and ultimately an increase in an accumulation of starch in the chloroplast. This work demonstrates duckweeds potential of being a highly efficient starch producer.

plant biology↗

bioRxiv2023

Coupling of Slack and NaV1.6 sensitizes Slack to quinidine blockade and guides anti-seizure strategy development

Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidines blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6s N-and C-termini binding to Slacks C-terminus, and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slacks C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of "Slack as an isolated target" for anti-epileptic drug discovery efforts, and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/532982v3_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1127858org.highwire.dtl.DTLVardef@19ad9f4org.highwire.dtl.DTLVardef@15b5542org.highwire.dtl.DTLVardef@13a86b4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Cell-free multi-omics analysis reveals tumor status-informative signatures in gastrointestinal cancer patients' plasma

During cancer development, hosts tumorigenesis and immune signals are released to and informed by circulating molecules, like cell-free DNA (cfDNA) and RNA (cfRNA) in blood. However, these two kinds of molecules are still not systematically compared in gastrointestinal cancer. Here, we profiled 4 types of cell-free omics data from colorectal and stomach cancer patients, and assayed 15 types of genomic, epi-genomic, and transcriptomic variations. First, we demonstrated that the multi-omics data were more capable of detecting cancer genes than the single-omics data, where cfRNAs were more sensitive and informative than cfDNAs in terms of detection ratio, variation type, altered number, and enriched functional pathway. Moreover, we revealed several peripheral immune signatures that were suppressed in cancer patients and originated from specific circulating and tumor-microenvironment cells. Particularly, we defined a {gamma}{delta}-T-cell score and a cancer-associated-fibroblast (CAF) score using the cfRNA-seq data of 143 cancer patients. They were informative of clinical status like cancer stage, tumor size, and survival. In summary, our work reveals the cell-free multi-molecular landscape of colorectal and stomach cancer, and provides a potential monitoring utility in blood for the personalized cancer treatment.

systems biology↗