Biology subjects

Mori, K.

Publications and source records attributed to Mori, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Independent evolution of flavour and parthenocarpy in fig, one of the earliest domesticated fruit trees

Domestication often modifies multiple traits in concert, but whether fruit quality and reproductive mode share a genetic basis in perennial crops has not been tested at multi-omics resolution. In fig (Ficus carica), one of the earliest domesticated fruit trees and a crop with archaeobotanical evidence of cultivation over 11,000 years ago, domestication yielded both distinctive flavour and parthenocarpy, fruit development without pollination. We integrated whole-genome resequencing, transcriptomics, volatile and metabolite profiling, and taste sensor data across a diverse accession panel, using Bayesian GWAS/TWAS and multi-omics factor analysis. Flavour emerges as an integrated sensory system led by aroma, which modulates taste through cross-modal interactions, with sugar-acid balance as a secondary axis; these quality traits map to numerous independent loci. Parthenocarpy instead traces to a single perfectly concordant chromosome 04 haplotype (Eden) centred on FcMYB101-like, carrying a selective-sweep signature and a derived allele fixed in cultivated figs but rare across the genus. Flavour and reproductive mode thus evolved along separate genomic trajectories, allowing each to be improved independently.

plant biology↗

bioRxiv2026

AI-enabled rhodopsin design for blue-light enhanced bacterial growth

We developed an AI-guided design pipeline that generated and validated non-natural microbial rhodopsins with spectral properties not yet known in nature. The pipeline comprised a three-stage in silico design, a genetic algorithm (GA) for sequence generation, a stacked LASSO and XGBoost machine-learning (ML) regressor for spectral prediction and fitness ranking, and a Markov-based sequence plausibility filter to enforce proton pumping like characteristics. Four candidate rhodopsins (APR1, APR2, APR6, and APR7) targeting blue light absorption were designed and AlphaFold3 structural modelling predicted retinal binding pocket architecture consistent with outward proton-pumping function. Experimental characterisation confirmed that all four variants absorbed light at [~]410 nm and significantly promoted the growth of Cupriavidus necator under blue light illumination. This study demonstrates that AI-enabled design can engineer proteins with no natural precedent, generating light-harvesting rhodopsins with novel spectral properties while preserving biological function, marking a significant advance in programmable synthetic biology.

Synthetic Biology↗

bioRxiv2026

A computational account of how positive performance bias supports cognitive effort

The willingness to exert cognitive effort is essential but is constrained by the subjective cost of effort. Although effortful tasks are often avoided, positive bias about ones own performance may help sustain engagement with cognitive demands. Here, participants completed an effort-based decision-making task and reported trial-by-trial predictions of their own performance, allowing us to quantify performance prediction error (PPE) as the discrepancy between subjective and objective accuracy. The results showed that PPE was predominantly positive and increased with effort level, indicating greater overestimation under higher cognitive demands. Using a computational model, we show that choices were best explained by a learning model in which rewarded trials accompanied by positive PPE decreased subsequent sensitivity to effort. A confidence-based control model did not provide a better account of choices, suggesting that this effect was better captured by positive performance bias than by confidence alone. Our findings provide a computational account of how biased self-evaluation may attenuate the subjective cost of cognitive effort and extend the positive bias literature to the task need for cognitive effort.

neuroscience↗

bioRxiv2026

RPL38 controls 60S ribosomal subunit homeostasis to regulate start-codon stringency and frame selection during C9ORF72 RAN translation

Translation initiation depends on stringent start-codon recognition, yet how ribosomal states modulate initiation stringency remains incompletely defined. Repeat-associated non-AUG (RAN) translation is a non-canonical initiation pathway that generates toxic dipeptide repeat proteins in C9ORF72-associated frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS). Here, we performed a dual-luciferase reporter-based siRNA screen to identify factors that differentially regulate canonical AUG-initiated and C9ORF72 RAN translation. We identified the 60S ribosomal protein RPL38 as a key determinant of translational output. RPL38 depletion selectively suppressed AUG-dependent translation while relatively preserving near-cognate-initiated RAN translation, resulting in a dose-dependent increase in the RAN-to-AUG translation ratio. Polysome profiling showed a selective reduction in large ribosomal subunit abundance without impaired subunit joining, consistent with defective 60S subunit homeostasis. Substitution of a near-cognate CUG start codon with AUG rendered translation sensitive to RPL38 depletion, supporting a role for ribosomal subunit availability in modulating initiation stringency. Graded RPL38 depletion altered frame usage within C9ORF72 repeat RNA. Consistent with these findings, RPL38 knockdown in the Drosophila eye enhanced GR-frame RAN translation while suppressing canonical AUG-dependent translation. Collectively, these findings identify 60S ribosomal subunit availability as a key determinant of start-codon stringency and frame selection in pathological C9ORF72 RAN translation.

molecular biology↗

bioRxiv2025

Energy Landscape Analysis with Automated Region-of-Interest Selection via Genetic Algorithms

Understanding brain dynamics is essential for advancing cognitive and clinical neuroscience. Energy landscape analysis (ELA), based on the pairwise maximum entropy model, is a powerful framework to characterize brain activity as transitions among discrete states defined by regional activity patterns. However, traditional ELA relies on the subjective manual selection of a small subset of regions of interest (ROIs) from whole-brain parcellations to satisfy mathematical constraints, which limits the scope and reproducibility of ELA results due to subjective subset selection. To overcome this, we developed ELA/GAopt, a meta-framework that utilizes a genetic algorithm to automate the selection of ROI combinations from the entire atlas search space by optimizing a user-defined objective function. In this study, we implemented a representative objective function balancing model fitting accuracy with the inter-individual variability of model parameters. We applied ELA/GAopt to three independent resting-state functional magnetic resonance imaging datasets. In Scenario 1, using the Creativity dataset (OpenNeuro: ds002330, n = 61), the ROI sets identified by ELA/GAopt achieved significantly higher objective function values and pattern reproducibility than randomly selected ROI sets (p < 0.05). Additional validation with the large-scale Human Connectome Project Young Adult (HCP-YA) dataset (n = 270) confirmed the robustness of our framework in high-dimensional settings. Stability analysis using Jaccard and Hamming metrics demonstrated that ELA/GAopt consistently identified reproducible ROI subsets across independent optimization runs. In Scenarios 2-4, we analyzed data from the Autism Brain Imaging Data Exchange II dataset using a site-disjoint validation design to mitigate findings were robust against multi-site artifacts. ELA/GAopt identified ASD-specific dynamics, where participants tend to visit local minima characterized by global co-activation of selected ROIs within sensory-motor and visual networks. These signatures were replicated in an independent cohort consisting of different scanning sites. Furthermore, ROI sets optimized for one group (ASD or typically developing controls) did not generalize to the other, highlighting distinct neurodynamic architectures. These results demonstrate that ELA/GAopt provides a reproducible, data-driven pathway for characterizing condition-specific brain dynamics, serving as a methodological basis for future, harmonization-aware and externally validated biomarker studies.

neuroscience↗

bioRxiv2025

Tim-3 Promotes Early Differentiation of Tbet+ Effector T Cells During Acute Viral Infection

The transmembrane protein Tim-3 has received significant attention in recent years as a possible immunotherapy target. This is due to its robust expression on dysfunctional, exhausted, T cells found in the settings of cancer and chronic infection and biochemical evidence suggesting an inhibitory function of Tim-3. However, numerous clinical trials of putative Tim-3 blocking antibodies have yielded modest benefits, at best, in clinical trials for various cancers. Thus, there is a need to more fully understand the function of Tim-3 in vivo. Here we have studied the function of Tim-3 early during a T cell response to LCMV Armstrong, which causes an acute viral infection in mice. We show that Tim-3 is rapidly expressed after infection and that the expression of Tim-3 is associated with acquisition of a type I effector phenotype, including expression of T-bet and downregulation of Tcf-1, by both CD4+ and CD8+ T cells. In addition, we demonstrate that knockout or cytoplasmic truncation of Tim-3 attenuates the acquisition of the effector program by T cells after LCMV Armstrong infection. Together, these data help to clarify the role of Tim-3 during acute infection.

immunology↗

bioRxiv2024

Involvement of Hepatitis B Core-Related Antigen in Viral Genome Integration in Patients With Prior Hepatitis B Virus Infection

BackgroundThe incidence of non-B non-C hepatocellular carcinoma (NBNC-HCC), which is negative for hepatitis B surface antigen and hepatitis C virus antibodies, is on the rise. Relatively high numbers of NBNC-HCC patients are hepatitis B core antibody (HBcAb) positive, suggesting that previous HBV infection may play a role in NBNC-HCC development, though the exact mechanisms are unclear. This study aimed to investigate whether HBV genomes are integrated into the host genome of HBcAb-positive NBNC-HCC cases and how these integrations may contribute to cancer development and progression. MethodsHBV detection PCR using HBV-specific primers on DNA extracted from HBcAb-positive NBNC-HCC tissue samples was performed. Positive samples were further examined for HBV integration sites using viral DNA-capture sequencing. Additionally, hepatitis B core-related antigen (HBcrAg) serum levels were measured to assess whether they could be predictive for HBV detection PCR results. ResultsAmong 90 HBcAb-positive NBNC-HCC samples, HBV genome amplification was detected in 18 samples, and elevated HBcrAg levels were associated with the HBV detection PCR results. Seventeen of these samples exhibited HBV integration. The HBV genome was integrated near the TERT gene in 7 samples, resulting in significantly increased TERT mRNA levels; in the KMT2B gene (2 samples); and downstream of LOC441666 (2 samples). ConclusionThe integration sites we identified in our samples have been previously reported in HBV-related HCC, suggesting that HBV integration may also contribute to hepatocarcinogenesis in HBcAb-positive NBNC-HCC. Furthermore, HBcrAg could serve as a potential, noninvasive marker for detecting HBV integration in these cases.

microbiology↗

bioRxiv2024

Carotenoid pigments enhance rhodopsin-mediated phototrophy by light-harvesting and photocycle-accelerating

Microbial rhodopsins, photoreceptor proteins widely distributed in marine microorganisms, receive large amount of light energy that sustains marine ecosystems. Although rhodopsins generally harbor retinal as their only chromophore, a recent study reported that carotenoid antennae transfer light energy to the retinal in proteorhodopsins, proton pump rhodopsins abundant in marine environments. Here, using marine bacterial isolates, we detected energy transfer from a carotenoid (myxol) to retinal not only in proteorhodopsin but also in the chloride ion-pumping rhodopsin. Carotenoid binding improved the light utilization efficiency of the proteorhodopsin by accelerating the photocycle, together with facilitating light-harvesting. The carotenoid-binding ability is conserved in rhodopsins of the phylum Bacteroidota, which are widely transcribed in the photic zone. These findings suggest that the distribution of carotenoid-binding rhodopsins is more taxon-specific than previously thought, thus underscoring the importance of carotenoid-binding rhodopsins that provide an extended light utilization strategy in the environmental adaptation of marine bacteria.

microbiology↗

bioRxiv2024

Hope for Others: Research Results from the University of Pittsburgh Rapid Autopsy Program for Breast Cancer

Breast cancer affects 1/8 of women throughout their lifetimes, with over 90% of cancer deaths being caused by metastasis. However, metastasis poses unique challenges to research, as complex changes in the microenvironment in different metastatic sites and difficulty obtaining tissue for study hinder the ability to examine in depth the changes that occur during metastasis. Rapid autopsy programs thus fill a unique need in advancing metastasis research. Here, we describe our protocol and processes for establishing and improving the US-based Hope for OTHERS (Our Tissue Helping Enhance Research and Science) program for organ donation in metastatic breast cancer. As of August 2024, we consented 114 patients and performed 37 autopsies, from which we collected 551 unique metastatic frozen tumor samples, 1244 FFPE blocks, 90 longitudinal liquid biopsy samples and developed 14 patient-derived organoid and 8 patient-derived xenograft models. We report in-depth clinical and histopathological information and discuss extensive new research and novel findings in patient outcomes, metastatic phylogeny, and factors in successful living model development. Our results reveal key logistical and protocol improvements that are uniquely beneficial to certain programs based on identifiable features, such as working closely with patient advocates, methods to rescue RNA quality in cases where tissue quality may degrade due to time delays, as well as guidelines and future expansions of our program. Statement of SignificanceRapid autopsy programs are unique research settings with huge potential for studying metastatic cancer, however, they have complex research challenges. Our work provides a valuable resource in advancing this field of research.

cancer biology↗

bioRxiv2024

Mitochondrial Dysfunction and ER Stress in CB1 Receptor Antagonist-Induced Apoptosis in Human Neuroblastoma SH-SY5Y Cells

Cannabinoid receptor type 1 (CB1R) is the key modulator of neuronal viability. In particular, CB1R antagonists provide neuroprotective effects on neurotoxicity caused by e.g. neuronal injury. However, the underlying mechanisms and potential limitations of CB1R antagonism remain unclear. Here we investigated the impact of environmental conditions on CB1R antagonist effects. Unexpectedly, we have found that cell-permeable CB1R antagonists, rimonabant and AM251, induced significant cell death in human neuroblastoma SH-SY5Y cells under serum-free conditions. Mitochondrial morphological analysis revealed mitochondrial swelling characterized by their network fragmentation and cristae reduction. Additionally, phosphoproteomics analysis showed an upregulation of phosphorylated EIF2AK3 (also known as PERK), leading to the activation of the eIF2/ATF4/CHOP pathway, indicative of endoplasmic reticulum (ER) stress. Rimonabant and AM251 treatment also triggered caspase-dependent apoptosis, evidenced by the detection of cleaved caspase 3 and cleaved PARP. These results suggest that cell-permeable CB1R antagonists promote apoptosis via mitochondrial dysfunction and ER stress under serum-free conditions in SH-SY5Y cells. Our findings indicate that while CB1R antagonists may be neuroprotective in certain conditions, they may also pose a neurotoxic risk in environments characterized by cellular stress or nutrient deprivation.

pharmacology and toxicology↗

bioRxiv2024

Nobiletin, a Polymethoxyflavonoid, Activates the Desuccinylase Activity of SIRT5 and Prevents the Development of Heart Failure

Nobiletin is a natural compound useful for the prevention and treatment of several diseases. However, the precise role of nobiletin in heart failure is unclear. Nobiletin treatment prevents pressure overload- and myocardial infarction-induced heart failure. Using affinity purification of biotinylated nobiletin from rat heart cell lysates, we identified sirtuin 5 (SIRT5) as a novel nobiletin-binding protein. Nobiletin enhanced the desuccinylase activity of SIRT5 in vitro. Compared to wild-type mice, SIRT5-overexpressing transgenic mice resisted pressure overload-induced systolic dysfunction. Conversely, SIRT5 knockout disrupted the nobiletin-mediated therapeutic effects on heart failure in mice. SIRT5 desuccinylated p300 at lysine 1568 and reduced the histone acetyltransferase (HAT) activity of p300. The desuccinylated p300 mutant suppressed the phenylephrine-induced cardiomyocyte hypertrophic responses. These findings suggest that nobiletin prevents heart failure development through SIRT5-dependent inhibition of p300-HAT activity. Nobiletin, a nontoxic dietary compound, is a potential therapeutic agent for heart failure in humans.

molecular biology↗

bioRxiv2023

UGGT1/2-mediated reglucosylation of N-glycan competes with ER-associated degradation of unstable and misfolded glycoproteins

How the fate (folding versus degradation) of glycoproteins is determined in the endoplasmic reticulum (ER) is an intriguing question. Monoglucosylated glycoproteins are recognized by lectin chaperones to facilitate their folding, whereas glycoproteins exposing well-trimmed mannoses are subjected to glycoprotein ER-associated degradation (gpERAD); we have elucidated how mannoses are sequentially trimmed by EDEM family members (George et al., 2020, 2021 eLife). Although reglucosylation by UGGT was previously reported to have no effect on substrate degradation, here we directly tested this notion using cells with genetically disrupted UGGT1/2. Strikingly, the results showed that UGGT1 delayed the degradation of misfolded substrates and unstable glycoproteins including ATF6. An experiment with a point mutant of UGGT1 indicated that the glucosylation activity of UGGT1 was required for the inhibition of early glycoprotein degradation. These and overexpression-based competition experiments suggested that the fate of glycoproteins is determined by a tug-of-war between structure formation by UGGT1 and degradation by EDEMs. We further demonstrated the physiological importance of UGGT1, since ATF6 cannot function properly without UGGT1. Thus, our work strongly suggests that UGGT1 is a central factor in ER protein quality control via regulation of both glycoprotein folding and degradation.

cell biology↗

bioRxiv2023

Characterization and contribution of RPE senescence to Age-related macular degeneration in Tnfrsf10 knock out mice

BackgroundRetinal pigment epithelial cells (RPE) play vital role in the pathogenesis of age-related macular degeneration (AMD). Our laboratory has shown that RPE cellular senescence contributed to the pathophysiology of experimental AMD, and SASP members are involved in this process. Recently, we presented confirmatory evidence to earlier GWAS studies that dysregulation of tumor necrosis factor receptor superfamily 10A (TNFRSF10A) dysregulation leads to AMD development and is linked to RPE dysfunction. This study aims to investigate the contribution of RPE senescence to AMD pathophysiology using TNFRSF10A silenced human RPE (hRPE) cells and Tnfrsf10 KO mice. MethodsSub-confluent primary hRPE cells and TNFRSF10A silenced hRPE were exposed to stress-induced premature senescence with H2O2 (500 M, 48h), and senescence-associated markers ({beta}gal, p16, and p21) were analyzed by RT-PCR and WB analysis. The effect of H2O2-induced senescence in non-silenced and silenced hRPE on OXPHOS and glycolysis was determined using Seahorse XF96 analyzer. Male C57BL/6J Tnfrsf10 KO (Tnfrsf10-/-) mice were used to study the regulation of senescence by TNFRSF10A in vivo. Expression of p16 and p21 in control and KO mice of varying ages were determined by RT-PCR, WB, and immunostaining analysis. ResultsThe senescence-associated p16 and p21 showed a significant (p < 0.01) upregulation with H2O2 induction at the gene (1.8- and 3-fold) and protein (3.2- and 4-fold) levels in hRPE cells. The protein expression of p16 and p21 was further significantly increased by co-treatment with siRNA (p < 0.05 vs. H2O2). Mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) (pmol/min/total DNA) increased with senescence induction by H2O2 for 48h in control RPE, and knockdown of TNFRSF10A caused a further increase in OCR and ECAR. In addition, co-treatment with PKC activator significantly improved all parameters. Similarly, in vivo studies showed upregulation of p16 and p21 by RT-PCR, WB, and immunostaining analysis in RPE/choroid of Tnfrsf10 KO mice. When subjected to examination across distinct age groups, namely young (1-3 months), middle (6-9 months), and old (12-15 months) mice, a discernible age-related elevation in the expression of p16 and p21 was observed. ConclusionsOur findings suggest that TNRSF10A is a regulator of regulates in RPE senescence. Further work on elucidating pathways of senescence will facilitate the development of new therapeutic targets for AMD.

pathology↗

bioRxiv2023

Transcriptomics elucidates metabolic regulation and functional promoters in the basidiomycete red yeast Xanthophyllomyces dendrorhous CBS 6938

Transcriptomics is a powerful approach for functional genomics and systems biology, yet it can also be used for genetic part discovery. Genetic part discovery has never been more necessary, as advances in synthetic biology increase the number of tractable organisms that need tunable gene expression for genetic circuits and metabolic pathways. Therefore, approaches are needed to assess a tractable organism and obtain a convenient set of genetic parts to support future research. Here, we describe a genomic and transcriptomic approach to derive a modular integrative part library with constitutive and regulated promoters in the basidiomycete yeast Xanthophyllomyces dendrorhous CBS 6938. X. dendrorhous is currently the sole biotechnologically relevant organism in the Tremellomycete family - it produces large amounts of astaxanthin, especially under oxidative stress and exposure to light. Particularly for this yeast, there are not large libraries of parts from related organisms that could be transferred. They must be derived. To do this, a contiguous genome was first obtained through combined short read and long read sequencing. Then, differential gene expression (DGE) analysis using transcriptomics was performed, comparing oxidative stress and exposure to different wavelengths of light. This revealed a set of putative light-responsive regulators that mediate a complex survival response to ultraviolet (UV) where X. dendrorhous upregulates aromatic amino acid and tetraterpenoid biosynthesis and downregulates central carbon metabolism and respiration. The DGE data was then used to derive 26 constitutive and regulated gene expression elements from the genome. The gene expression elements were designed to be compatible with a new modular cloning system for X. dendrorhous which includes integration sites, terminators, selection markers, and reporters. Each element was characterized by luciferase assay of an integrated gene expression cassette. Notably, a novel promoter from a hypothetical gene that has 9-fold activation upon UV exposure was characterized. This study defines an advanced modular genetic part collection for engineering the basidiomycete X. dendrorhous CBS 6938 while simultaneously discovering potential targets for increasing tetraterpenoid biosynthesis. Further, it demonstrates that -omics-to-parts workflows can simultaneously provide useful genomic data and advance genetic tools for nonconventional microbes, particularly those without a related model organism. This approach will be broadly useful in current efforts to engineer diverse microbes. KEY POINTSO_LIOmics-to-parts can be applied to non-model organisms for rapid "onboarding". C_LIO_LI26 promoters native to X. dendrorhous were identified. C_LIO_LIOmics revealed unique photobiology in X. dendrorhous. C_LI

synthetic biology↗

bioRxiv2023

The orientation of choroidal macrophage polarization significantly influences the development of myopia in murine models

Myopia is a primary contributor to visual impairment and has emerged as a global public health concern. Evidence indicates that one of the main structural features of myopia is the corresponding decrease in choroidal thickness, and choroidal macrophages play an important role in maintaining the choroidal thickness. Nevertheless, the effect of choroidal macrophages on myopia remains unclear. Here, we discovered that the continuous intraperitoneal injection of clodronate liposomes depleted choroidal macrophages and leads to myopia, which confirmed that the presence of choroidal macrophages plays an important role in myopia development. Subsequently, based on the phenotypic characteristics of macrophages, experiments were designed to study the effects of different polarization directions of macrophages on myopia development. We found that lipopolysaccharides (LPS) injection can induce the polarization of choroidal M1 macrophages, thinning the choroidal thickness and resulting in myopia. Conversely, IL-4 or IL-13 injection causes choroidal M2 macrophage polarization, thickens the choroid, and suppresses the progression of myopia. Additionally, we demonstrated that the opposite effects of M1 and M2 macrophages on myopia development may be related to their impacts on choroidal thickness, inflammation, and oxidative stress response. These findings establish that choroidal macrophages are critically important in the development of myopia and provide new strategies for the development of myopic therapies.

immunology↗

bioRxiv2023

Sexually dimorphic dynamics of the microtubule network in medaka (Oryzias latipes) germ cells

Oogenesis is the process through which ovarian germ cells enter meiosis and acquire essential characteristics of an egg, such as an increase in follicular size and deposition of maternal factors. In vertebrates, however, the pathways that initiate oogenic processes after germ cell sex determination remain elusive. Here we report a dome-shaped microtubule structure that is maintained during oogenesis. This structure is established in primordial germ cells and maintained in gonocytes and stem-type germ cells in a foxl3-independent manner. dmrt1 is required for disruption of the dome structure in differentiating spermatogonia. In addition, the dome structure accumulates mitochondria and Golgi apparatus, and is replaced by the Balbiani body, an oocyte-specific aggregate producing animal-vegetal polarity, suggesting a role for this structure in organelle transfer and oocyte polarization. Our findings show the presence of a pathway regulating a sexually dimorphic microtubule network independent of germ cell feminization by foxl3. Summary StatementA dome-shaped microtubule structure leading to oocyte polarity was identified in germ cells. Genetic pathways involved in the formation and destabilization of the structure during germ cell sex determination were clarified.

developmental biology↗

bioRxiv2023

Ultrasensitive detection of circulating LINE-1 ORF1p as a specific multi-cancer biomarker

Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. While proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1, L1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible detectable expression in corresponding normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore the potential of ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10-17 M) ORF1p concentrations in patient plasma samples across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multi-analyte panel, and provides early therapeutic response monitoring in gastric and esophageal cancers. Together, these observations nominate ORF1p as a multi-cancer biomarker with potential utility for disease detection and monitoring. Statement of SignificanceLINE-1 ORF1p transposon protein is pervasively expressed in many cancers and a highly specific biomarker of multiple common, lethal carcinomas and their high-risk precursors in tissue and blood. Ultrasensitive ORF1p assays from as little as 25 L plasma are novel, rapid, cost-effective tools in cancer detection and monitoring.

cancer biology↗

bioRxiv2022

Blue light promotes ascorbate synthesis by deactivating the PAS/LOV photoreceptor that inhibits GDP-L-galactose phosphorylase

Ascorbate (vitamin C) is one of the most essential antioxidants in fresh fruits and vegetables. To get insights into the regulation of ascorbate metabolism in plants, a mutant producing ascorbate-enriched fruits was studied. The causal mutation, identified by a mapping-by-sequencing strategy, corresponded to a knock-out recessive mutation in a new class of photoreceptor named PAS/LOV protein (PLP, Solyc05g07020), which acts as a negative regulator of ascorbate biosynthesis in tomato. This trait was confirmed by CRISPR/Cas9 gene editing, and further found in all plant organs, including fruit that accumulated 2-3 times more ascorbate than in the WT. The functional characterization revealed that PLP interacted with the two isoforms of GDP-L-galactose phosphorylase (GGP), known as the controlling step of the L-galactose pathway of ascorbate synthesis. The interaction with GGP occurred in the cytoplasm and the nucleus, but was abolished when PLP was mutated. These results were confirmed by an optogenetic approach using an animal cell system, which additionally demonstrated that blue light modulated the PLP-GGP interaction. Assays performed in vitro with heterologously expressed GGP and PLP showed that PLP is a non-competitive inhibitor of GGP that is inactivated after blue light exposure. This discovery sheds light on the light-dependent regulation of ascorbate metabolism in plants.

plant biology↗