Biology subjects

Mori, H.

Publications and source records attributed to Mori, H..

At least 19 recordsLinked to original sources

bioRxiv2026

HPV-Associated Tonsillar Intraepithelial Neoplasia and Oral High-Risk HPV mRNA as a Candidate Biomarker

Early detection of human papillomavirus (HPV)-associated oropharyngeal cancer is an unmet need, as its premalignant lesions remain unestablished. We hypothesized that such lesions exist in individuals with oral high-risk HPV (HR-HPV) mRNA. We preoperatively screened 1,180 individuals undergoing tonsillectomy due to benign conditions and detected five with oral HR-HPV mRNA. Serial sectioning of the entire excised tonsils identified HPV-associated intraepithelial lesions in three of these five individuals. A similar lesion was identified in an additional individual with oral HPV16 infection with unknown oral HR-HPV mRNA status. Intraepithelial lesions in two individuals were HPV16-associated and showed moderate-to-severe atypia, whereas those in the other two individuals were associated with other HR-HPV and showed minimal-to-mild atypia. Based on HPV life cycle, the former were classified as transforming lesions and the latter as productive-to-intermediate lesions. Spatial transcriptomic analysis revealed molecular profiles intermediate between those of normal epithelium and HPV-associated oropharyngeal cancer. These findings establish the first evidence for HPV-associated tonsillar premalignant lesions and suggest oral HR-HPV mRNA as a candidate biomarker.

cancer biology↗

bioRxiv2026

A cuffed CRISPR guide RNA for microRNA activity-dependent genome editing

Cells in multicellular eukaryotic systems are diverse biological units, with characteristics and functions determined by their molecular profiles. CRISPR-Cas9 genome editing has been widely used across biology to modulate gene expression and study gene function. However, there is currently no versatile and scalable method for editing a cells genome in response to endogenous cellular signals. Here, we report the engineering of a CRISPR guide RNA that efficiently confers genome editing in response to the catalytic activity of a target microRNA (miRNA) within a cell. miRNAs are short non-coding RNAs that are widely conserved across eukaryotes and can cleave their target RNA through almost perfect base pairing. In mammals, miRNAs are largely involved in development and homeostasis as well as disease progression and developmental disorders. To leverage these properties for genome editing, we developed a cuffed guide RNA (cgRNA) which is composed of a permutated order of sequence domains from the commonly used single guide RNA (sgRNA). These permutated domains were then concatenated with a miRNA target sequence, yielding a warped guide RNA that is inactive until cleaved by a complementary miRNA. We demonstrated that cgRNA enabled efficient miRNA activity-dependent genome editing in human and mouse cell lines. Biochemical and structural analyses revealed three stages of inhibition of the CRISPR genome-editing pathway for unprocessed cgRNA. Utilizing a lentiviral library of cgRNAs containing miRNA targets covering mouse genome-wide miRNAs, we identified miRNA cleavage activities and their sequence specificities in mouse embryonic stem cells and during smooth muscle cell differentiation. Furthermore, we showed that endogenous mRNA expression could be irreversibly recorded into a DNA sequence using a cgRNA targeted by a synthetic miRNA repeat. cgRNA is a simple, robust, miRNA activity-gated genome editing system that could facilitate the development of cell state-specific genome editing, the mapping of miRNA activity and gene expression landscapes, and the recording of molecularly determined cell states during the long-term progression of multicellular systems.

bioengineering↗

bioRxiv2026

P95-HER2 promotes metastatic progression by biasing MRTFA dependent signaling

Naturally occurring isoforms of the proto-oncogene Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2, HER2) incite unique pathways of tumor progression in mouse models of breast cancer. Although each isoform has been shown to progress to metastasis, the N-terminally truncated isoform (p95) was previously shown to be biased toward early distant dissemination prior to detection. Here we show how HER2 isoforms differentially promote go-or-grow phenotypes through biased utilization of tyrosine autophosphorylation sites in the intracellular tail of HER2. Fluorescently barcoded humanized full-length HER2 (WT), exon-16 splice HER2 isoform (d16), and p95 expressing tumor cell lines were derived from HER2 Crainbow mice, then utilized for a series of functional assays including proliferation, tumor growth rate, cell motility, collective cell migration, cellular morphology, and invasive potential. Quantitative analysis reveals biased tumor cell behaviors across each genotype. WT tumor cells are biased toward proliferation and collective migration, d16 cells are biased toward proliferation and individual motility, and p95 tumor cells are biased toward individual motility and invasion. Single cell analysis reveals a myogenic-like state transition in p95 cells accompanied by an increased nuclear translocation of the Myocardin Related Transcription Factor A (MRTFA). MRTFA knockdown, as well as knockdown of a downstream effector, Transforming growth factor beta 1 induced transcript 1 (TGFB1I1), both inhibit the p95 invasive phenotype. Furthermore, intracellular residue tyrosine 1139 (Y1139) is necessary for MRTFA translocation, and when edited in p95 cells (Y1139F) invasion and motility phenotypes are subsequently lost. Our data illustrate the importance of functionally selective signaling in HER2 and highlight the need for therapeutics that intercept metastasis by targeting HER2 biased signaling.

cell biology↗

bioRxiv2026

Akkermansia muciniphila-derived LPS links gut dysbiosis to pathogenic miR-21 signaling in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a chronic T cell-mediated autoimmune disease characterized by blood-brain barrier (BBB) disruption, neuroinflammation, and demyelination of the central nervous system (CNS). Emerging evidence links gut microbiota to disease pathogenesis, but the microbial factors that regulate pathogenic microRNA (miRNA) programs are largely unknown. Here, using experimental autoimmune encephalomyelitis (EAE, a MS mouse model), we investigated whether gut microbiota exacerbate EAE pathogenesis by modulating host miRNA expression. Antibiotic-induced depletion of the gut microbiota markedly attenuated EAE scores and reduced circulating inflammatory miRNAs, with miR-21 emerging as the dominant pathogenic candidate. Functional inhibition of miR-21 significantly ameliorated disease severity and reduced CNS T-cell infiltration. Mechanistically, miR-21 enhanced IL-17 and GM-CSF production by CD4 T cells and promoted immune-cell entry into the CNS through endothelial activation and blood-brain barrier dysfunction. We identified a transient expansion of Akkermansia muciniphila during the prodromal phase of EAE that positively correlated with circulating miR-21 levels. Colonization of antibiotic-treated mice with A. muciniphila exacerbated EAE and increased serum miR-21, whereas monocolonization of germ-free mice was insufficient to induce systemic miR-21, indicating a requirement for an inflammatory host environment. Further analyses revealed that atypical lipopolysaccharides (LPS) derived from A. muciniphila induce epithelial miR-21 production through coordinated TLR2/TLR4 signaling. Circulating miR-21 subsequently promoted endothelial dysfunction through the TIMP3-ADAM17 pathway, facilitating pathogenic T-cell migration into the CNS. Importantly, circulating miR-21 was also elevated in patients with MS. Collectively, these findings identify a previously unrecognized A. muciniphila-LPS-miR-21 axis linking gut dysbiosis to neuroinflammation and suggest that host-derived miRNAs function as systemic mediators through which microbial signals influence CNS autoimmunity.

immunology↗

bioRxiv2026

Microbe-dependent inter-organ communication regulates germline stem cell proliferation in Drosophila

Animals integrate environmental cues with internal physiological states through inter-organ communication to regulate reproduction. However, how environmental microbes are incorporated into these systemic pathways to control reproductive stem cell proliferation remains poorly understood. Here, we demonstrate that environmental microbes colonizing the gut promote stem cell-mediated oogenesis in Drosophila melanogaster by increasing germline stem cell (GSC) number. This process requires microbial activation of gut metabolic pathways, including glycolysis and the pentose phosphate pathway (PPP), linking microbial cues to organismal physiology. We further show that microbial cues modulate circadian clock gene expression in both the gut and brain, and that circadian gene activity in these tissues is required for microbe-induced increases in GSCs. These metabolic changes promote ecdysone and juvenile hormone signaling in ovarian somatic cells, and single-cell transcriptomic analyses further reveal cell type-specific metabolic and hormonal responses across germline and follicle cell populations. Together, our findings establish that microbe-dependent gut-mediated inter-organ communication integrates metabolism, circadian gene expression, and endocrine signaling to regulate stem cell-mediated reproduction in Drosophila.

developmental biology↗

bioRxiv2026

Adaptation of white adipocytes to cooler temperatures: impacts on energy metabolism and protein acetylation

Adipocytes throughout the body reside in distinct thermal environments. Visceral adipocytes within the body core are maintained near 37 {degrees}C, whereas those in bone marrow, subcutaneous, and dermal depots occupy cooler regions within the peripheral shell. While brown and beige adipocyte responses to cold stress are well characterized, much less is known about how white adipocytes adapt to moderately reduced temperatures below 37 {degrees}C. Our recent work revealed that cultured adipocytes exposed to 31 {degrees}C, a temperature representative of distal adipose regions, exhibit enhanced mitochondrial function, including increased substrate oxidation and ATP turnover, yet the mechanisms underlying this upregulation remain unclear. Here we show that adaptation to cool temperatures leads to a widespread decrease in protein acetylation in both undifferentiated and differentiated adipocytes, independent of nutrient status, and that this change is readily reversible upon rewarming. Subcellular fractionation and immunoblotting demonstrate that the hypoacetylation coincides with a compartment-specific enrichment of acetylated proteins within mitochondria, indicating selective remodeling of the mitochondrial acetylome. Transcriptomic and biochemical analyses reveal that these temperature-dependent changes occur without alterations in acetyltransferase or deacetylase expression, NAD concentration, or acetyl-CoA availability, suggesting regulation through alternative mechanisms affecting acetyl-CoA flux or enzyme activity. Integrative acetyl-proteomic and metabolomic profiling identifies mitochondrial enzymes, including serine hydroxymethyltransferase 2 (SHMT2) and propionyl-CoA carboxylase (PCCA), whose acetylation correlates closely with changes in associated metabolite pools. Together, these findings establish physiologically relevant cooling as a cell-autonomous regulator of mitochondrial protein acetylation and metabolic adaptation in adipocytes.

cell biology↗

bioRxiv2026

Diversity and stability of the gut microbiome of naked mole-rat (Heterocephalus glaber), the longest-lived rodent

The naked mole-rat is a subterranean rodent adapted to extreme hypoxia and low metabolic demands, with an exceptionally long lifespan relative to its small body size, while maintaining reproductive capacity. Using 16S rRNA gene sequencing of 24 samples and whole-metagenome sequencing of 11 samples from individuals up to 15 years of age, we characterized the gut microbiota and showed its complexity and distinctiveness compared with that of other rodents, including mice, squirrels, and rabbits. Although all animals were born and raised in a laboratory setting, the gut microbiota remained taxonomically stable across ages and retained key taxa previously reported in wild naked mole-rats (e.g., Treponema and Desulfovibrio). Metagenome-assembled genomes revealed the presence of archaeal methanogens and termite-gut-associated bacteria (e.g., Methanobacteria within Euryarchaeota and Avelusimicrobium within Elusimicrobiota), together with genes involved in hydrogen metabolism and archaeal methanogenesis. Compared with mice, the naked mole-rat gut microbiota was enriched in carbohydrate-active enzymes targeting plant cell-wall polysaccharides, resembling those found in ruminants. We also detected evidence of flagellates, ciliates, and fungi, which may further contribute to polysaccharide degradation and fermentation, potentially within the enlarged cecum. Together, this comprehensive analysis provides distinctive gut microbial features of the naked mole-rat that may be associated with the naked mole-rats low metabolic rate and exceptional longevity.

microbiology↗

bioRxiv2025

Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating malignancy characterized by limited therapeutic options for advanced disease. Immunotherapy, in particular, has had dismal success rates in the PDAC due to a tumor microenvironment (TME) that contributes to immune exclusion and poor drug delivery. Many cytokines necessary for Natural Killer (NK) and T cell chemotaxis, activation, and cytotoxicity are absent in the PDAC TME. Despite their early success, cytokine therapies have largely failed in the treatment of solid tumors as a result of the lack of efficacy of single cytokine administration and toxicities from systemic delivery. To overcome these limitations, we designed multiplexed mRNA cocktails encoding diverse interleukins, chemokines, and interferons for intratumoral delivery. Administration of a cytokine-encoding mRNA mixture into mice with orthotopically transplanted PDAC tumors achieved robust yet transient cytokine expression locally in the PDAC TME, leading to NK cell and CD8+ T cell immunity and reduced tumor growth and fibrosis in multiple mouse models. Combining cytokine mRNAs with those encoding tumor-associated antigens further activated CD8+ T cell-mediated tumor control and enhanced survival after just a single dose in PDAC-bearing mice. Remarkably, lipid-based nanoparticle (NP) encapsulation of an all-in-one cytokine and antigen mRNA cocktail allowed safe systemic administration and local delivery of these immunogenic signals to autochthonous PDAC tumors in genetically engineered mouse models, culminating in complete tumor responses in 50% of animals. These results suggest that multiplexed mRNA approaches to delivering cytokine signals and antigens generally absent in the TME could pave the way for an effective immunotherapy for PDAC.

cancer biology↗

bioRxiv2025

Trehalose promotes wound healing in vitro by enhancing the migration of human keratinocytes via the VEGF/JNK/PI3K pathway

BackgroundTrehalose is a naturally occurring disaccharide found in invertebrates but cannot be synthesized by vertebrates. We previously reported that high-concentration trehalose induces a transient senescent-like state in fibroblasts, leading to cell cycle arrest and growth factor secretion via CDKN1A/p21, and this process promoted keratinocyte proliferation, enhancing capillary formation and wound closure in vivo. ObjectiveThis study aimed to investigate the effect of trehalose on human keratinocytes. MethodsPreviously published RNA-seq data of cytokine-untreated samples from our group of trehalose-treated human keratinocytes were re-analyzed, and an in vitro scratch assay was performed using cells treated with mitomycin C. ResultsThe trehalose-treated group exhibited increased wound closure. A significantly increased secretion of vascular endothelial growth factor (VEGF) was observed in keratinocytes treated with high-concentration trehalose, which is one of the most crucial molecules inducing angiogenesis in the skin. Significant upregulation of mRNA level and protein secretion of VEGF was confirmed using qPCR and ELISA, respectively. Furthermore, treatment with axitinib, a VEGF receptor inhibitor, significantly suppressed trehalose-induced activation of keratinocyte migration. Additionally, the increase in trehalose-induced migration activity was significantly inhibited by the Jun N-terminal kinase (JNK) inhibitor SP600125 and the PI3K inhibitor LY294002. ConclusionTrehalose promotes wound healing via VEGF secretion from keratinocytes and the PI3K and JNK pathways. The findings of this study may lead to the development of novel therapeutic agents that can alter the wound healing process. IMPORTANTO_LIManuscripts submitted to Review Commons are peer reviewed in a journal-agnostic way. C_LIO_LIUpon transfer of the peer reviewed preprint to a journal, the referee reports will be available in full to the handling editor. C_LIO_LIThe identity of the referees will NOT be communicated to the authors unless the reviewers choose to sign their report. C_LIO_LIThe identity of the referee will be confidentially disclosed to any affiliate journals to which the manuscript is transferred. C_LI GUIDELINESO_LIFor reviewers: https://www.reviewcommons.org/reviewers C_LIO_LIFor authors: https://www.reviewcommons.org/authors C_LI CONTACTThe Review Commons office can be contacted directly at: office@reviewcommons.org

cell biology↗

bioRxiv2025

Extensive clonal reproduction drives liana proliferation following forest fragmentation

Large-scale anthropogenic disturbances, including forest fragmentation, are increasing worldwide. Lianas often proliferate after such events, yet the mechanisms underlying these increases-- particularly their demographic sources--remain unclear. Here, we quantify the extent to which clonal expansion, rather than seed recruitment, accounts for post-disturbance proliferation of Wisteria floribunda (Fabaceae), the dominant liana in the study area. In a 21.6-ha fragmented forest landscape in Japan, we divided the study area into 20 x 20 m grid cells and randomly sampled up to one W. floribunda ramet per cell, and genotyped 273 ramets at 10 microsatellite loci to assign ramets to genets and quantify genet areas and their spatial distribution. Genotyping revealed a substantial contribution of extensive clonal reproduction: 94% of ramets were clonal, resolving into 47 genets. These genets collectively occupied 58% of the 21.6-ha study area, and expansion produced extensive genets--the largest covered 9.5 ha. Several genets spanned multiple forest patches; three multi-patch genets accounted for 43% of all ramets, including one spanning seven patches. Multi-patch genets were concentrated within areas covered by forests prior to fragmentation (odds ratio = 6.83; P < 0.001). These observations indicate that clonal expansion accounts for most post-disturbance proliferation, that some genets attain landscape-scale coverage in a fragmented forest, and that part of this dominance likely reflects legacy effects of genets established prior to fragmentation. Explicitly accounting for clonal contributions and genet spatial scale is critical for accurate prediction of disturbance-driven liana dynamics.

ecology↗

bioRxiv2025

Adaptive selection of p53 mutation metaplastic phenotypes in estrogen-independent progression of ER+ tumors: A mechanism for acquired resistance to hormonal therapy.

Estrogen receptor positive (ER+) subtypes of mammary adenocarcinoma comprise 79% of all breast cancer diagnosis and 67% of all breast cancer mortality. The paucity of models of ER+ mammary cancer that mimic human disease and response to treatment has limited critical preclinical study of mechanisms and new therapies for ER+ breast cancer. The Stat1 knockout, 129S6/SvEvTac-Stat1tm1Rds (Stat1-/-), females develop luminal type FoxA1+, ER+, and PR+ mammary carcinomas after prolonged latencies. Initial studies showed that a cell line derived from a Stat1-/- mammary carcinoma was tumorigenic in syngeneic mice, but non-tumorigenic in ovariectomized (Ovx) mice. Here, data shows that Ovx performed after SSM2 tumors establish growth results in ovarian hormone independent growth. The viable post-Ovx tumors were primarily composed of metaplastic CK14+ basal type cells with a high percentage p53 immunohistochemistry (IHC) positive "mutation pattern", rather than the original luminal type tumors with low percent "wild type" pattern p53. Comparing whole exome sequences of ER+ Stat1-/- mammary tumors before and after Ovx, revealed basal keratins, mesenchymal (EMT) phenotypes, and unique mutation profiles in genes, including Trp53 and Prlr, in the estrogen-independent tumors. Our experimental findings are consistent with the clinical evidence of tumor heterogeneity of ER+ breast cancers in patients in recent whole genome sequencing studies. Similarly, spontaneous Stat1-/- tumors with high percentage p53 "mutation pattern" were more basaloid and grew rapidly after Ovx, while retaining high expression of ER and FoxA1. This study demonstrates that the STAT1-/-, ER+ estrogen dependent breast cancers can become resistant to through clonal selection of mammary cells comprised of metaplastic p53+/CK14+ basaloid cells.

cancer biology↗

bioRxiv2024

Synergistic effects of tRNA modification defects in Escherichia coli K12.

Transfer RNAs (tRNAs) are essential components of the translation machinery and carry numerous post-transcriptional modifications that contribute to decoding accuracy, efficiency and cellular fitness. In Escherichia coli K-12, all tRNA modification pathways have been identified, yet the functional interactions between these pathways remain largely unexplored. Here, we systematically analyze genetic interactions between 29 non-essential tRNA modification genes using a pairwise synthetic lethal screen based on P1 transduction. Most combinations of tRNA modification gene deletions are tolerated during growth in rich medium; however, we identify five synthetically lethal pairs and fifteen additional combinations that display negative genetic interactions. Deletions of truA, which encodes the pseudouridine synthase responsible for modifications at positions 38-40 of multiple tRNAs, show the highest frequency of negative epistasis. Synthetic lethality associated with truA can be complemented by expression of truA in trans and, in specific cases, partially suppressed by overexpression of its tRNA substrates, indicating substrate-specific functional dependencies. Analysis of tRNA abundance by northern blotting and AQRNA-seq demonstrates that loss of individual tRNA modification enzymes does not generally lead to widespread tRNA destabilization. Instead, further phenotypic characterization of viable double mutants reveals condition-dependent growth defects influenced by carbon source, temperature and metabolic stress, as well as toxicity associated with overexpression of specific tRNAs. Together, these results reveal a limited but distinct set of genetic interactions among bacterial tRNA modification pathways and highlight the importance of physiological context in uncovering their cellular roles.

microbiology↗

bioRxiv2024

Automated Harmonization and Large-Scale Integration of Heterogeneous Biomedical Sample Metadata Using Large Language Models

The exponential growth of biomedical data has created an urgent need for efficient integration and analysis of heterogeneous sample metadata across studies. However, current methods for harmonizing and standardizing these metadata are largely manual, time-consuming, and prone to inconsistencies. Here, we present a novel computational framework that leverages large language models (LLMs) to automate the harmonization and large-scale integration of diverse biomedical sample metadata. Our approach combines semantic clustering techniques with LLM-driven natural language processing to extract, interpret, and standardize metadata from various sources, including research papers, supplementary tables, and text data from public databases. We demonstrate the efficacy of our framework by applying it to thousands of human gut microbiome papers, successfully extracting and integrating metadata from over 400,000 samples. Our method achieved a 50% recovery rate of manually curated metadata, significantly outperforming traditional rule-based methods. Furthermore, our framework enabled the creation of a unified, searchable database of standardized metadata, facilitating cross-study analyses and revealing previously obscured patterns in microbiome composition across diverse populations and conditions. The scalability and adaptability of our approach suggest its potential applicability to a wide range of biomedical fields, potentially accelerating meta-analyses and fostering new insights from existing data. This work represents a significant advancement in biomedical data integration, offering a powerful tool for researchers to unlock the full potential of accumulated scientific knowledge.

bioinformatics↗

bioRxiv2024

Clonal reproduction as a driver of liana proliferation following large-scale disturbances in temperate forests

Large-scale disturbances significantly impact forest dynamics, structure, and biodiversity. Lianas (woody vines) proliferate rapidly after such events, likely due to clonal reproduction. Understanding this process is challenging due to the need for precise disturbance history and accurate estimation of whether individuals originate from clonal reproduction, seed reproduction, or pre-existing vegetation. This study examines whether clonal reproduction drives liana proliferation following large natural disturbances. We analyzed the dominant liana species (Trachelospermum asiaticum var. asiaticum; Apocynaceae) in temperate forests on a volcanic island. The study included young forests recovering from a volcanic eruption 22 years ago and old-growth forests unaffected by eruptions for over 800 years. We established six 10 m x 10 m quadrats (three in each forest type), divided into 1 m - 1 m grids, and sampled 587 individuals. Genetic structure was assessed using 11 newly developed nuclear microsatellite markers. Significant clonal expansion was observed in both forest types, but stem density and genetic diversity varied markedly. Old-growth forests had 14 times more stem density and five times more genets (clones) than young forests, with greater genet intermingling and higher clonal diversity. This indicates that clonal reproduction results in high abundance and complex spatial genetic structures of the liana species in old-growth forests. Our analysis revealed that a few genets, newly recruited via seed dispersal in early succession stages, rapidly expanded through extensive clonal reproduction, leading to long-term liana proliferation. This study highlights the importance of understanding and quantifying clonality in predicting liana population dynamics after large-scale disturbances.

ecology↗

bioRxiv2024

DFAST_QC: Quality Assessment and Taxonomic Identification Tool for Prokaryotic Genomes

MotivationAccurate taxonomic assignments of genomic data are crucial across various biological databases. With a rapid increase in submitted genomes in recent years, ensuring precise classification is important to maintain database integrity. Mislabeled genomes can confuse researchers, hinder analyses, and produce false results. Therefore, there is a critical need for computationally efficient tools that ensure accurate taxonomic classification for data to be deposited into genomic databases. ResultsHere we introduce DFAST_QC, a quality control and taxonomic classification tool of prokaryotic genomes based on NCBI and GTDB taxonomies. We benchmarked DFAST_QCs performance against NCBI taxonomy assignments, showing high consistency with them. Our results demonstrate that DFAST_QC achieves high consistency to NCBI taxonomy classification. Availability and implementationDFAST_QC is implemented in Python and is available both as a web service (https://dfast.ddbj.nig.ac.jp/dqc) and as a stand-alone command line tool. The source code is available under the GPLv3 license at: https://github.com/nigyta/dfast_qc, and the conda package is also available from Bioconda. The data and scripts used for the benchmarking process are publicly available on GitHub (https://github.com/Mohamed-Elmanzalawi/DFAST_QC_Benchmark). Contactyt@nig.ac.jp Supplementary informationSupplementary data are available at Bioinformatics online.

genomics↗

bioRxiv2024

Parasitoid wasp venoms degrade Drosophila imaginal discs for successful parasitism

Parasitoid wasps, one of the most diverse and species-rich animal taxa on Earth, produce venoms that manipulate host development and physiology to exploit host resources. However, mechanisms of venom action remain poorly understood. Here, we show that infection of host Drosophila by the endoparasitoid wasp, Asobara japonica, triggers imaginal disc degradation (IDD) by inducing apoptosis, autophagy, and mitotic arrest, leading to impaired host metamorphosis. A multi-omics approach identified two venom proteins of A. japonica necessary for IDD. Knockdown experiments targeting the venom genes revealed that in concert with host immune suppression, IDD is essential for successful parasitism. Our study highlights a venom-mediated hijacking strategy of the parasitoid wasp that allows host larvae to grow, but ultimately kills the hosts.

developmental biology↗

bioRxiv2024

Control of Physiologic Glucose Homeostasis via the Hypothalamic Modulation of Gluconeogenic Substrate Availability

The brain augments glucose production during fasting, but the mechanisms are poorly understood. Here, we show that Cckbr-expressing neurons in the ventromedial hypothalamic nucleus (VMNCckbr cells) prevent low blood glucose during fasting through sympathetic nervous system (SNS)-mediated augmentation of adipose tissue lipolysis and substrate release. Activating VMNCckbr neurons mobilized gluconeogenic substrates without altering glycogenolysis or gluconeogenic enzyme expression. Silencing these cells (CckbrTetTox animals) reduced fasting blood glucose, impaired lipolysis, and decreased circulating glycerol (but not other gluconeogenic substrates) despite normal insulin, counterregulatory hormones, liver glycogen, and liver gluconeogenic gene expression. Furthermore, {beta}3-adrenergic adipose tissue stimulation in CckbrTetTox animals restored lipolysis and blood glucose. Hence, VMNCckbr neurons impact blood glucose not by controlling islet or liver physiology, but rather by mobilizing gluconeogenic substrates. These findings establish a central role for hypothalamic and SNS signaling during normal glucose homeostasis and highlight the importance of gluconeogenic substrate mobilization during physiologic fasting.

physiology↗

bioRxiv2024

Extracellular vesicle-mediated secretion of chlorophyll biosynthetic intermediates in the cyanobacterium Leptolyngbya boryana

Extracellular vesicles (EVs) are derived from the outer membrane (OM) in Gram-negative bacteria and have diverse physiological functions such as toxin transport, extracellular signal transduction, nutrient acquisition, and horizontal gene transfer. EV-mediated secretion of monovinyl protochlorophyllide (MV-Pchlide), the chlorophyll a (Chl) biosynthetic intermediate, was previously reported in a mutant lacking dark-operative Pchlide reductase in the cyanobacterium Leptolyngbya boryana. This study showed a detailed characterization of EVs from the wild-type (WT) of L. boryana grown under photoautotrophic and dark heterotrophic conditions, focusing on the accumulation of Chl intermediates. WT L. boryana cells produce two types of EVs, low-density EVs (L-EVs) and high-density EVs (H-EVs), both under light and dark conditions. L-EVs and H-EVs showed distinct morphological features and protein compositions. L-EVs from cells grown under both light and dark conditions commonly contained carotenoids, myxol glycoside, and zeaxanthin, as major pigments. Based on the protein compositions of EVs and other cellular membrane fractions, L-EVs and H-EVs are probably derived from low-density OM and high-density OM interacting with cell walls, respectively. Fluorescence detection of pigments was applied to EVs, and the three Chl intermediates, protoporphyrin IX, demetallated Mg-protoporphyrin IX monomethyl ester, pheophorbide, and were commonly detected both L-EVs from light- and dark-grown cells, whereas L-EVs from dark-grown cells contained additional MV-Pchlide and MV-protopheophorbide. These Chl intermediates appear to transfer from the thylakoid membrane to L-EVs via an unknown transport system. Cyanobacterial EVs may play a novel function in alleviating the accumulation of Chl intermediates in cells.

microbiology↗