Biology subjects

Iida, T.

Publications and source records attributed to Iida, T..

14 recordsLinked to original sources

bioRxiv2026

Generalized Morphogenesis Theory: A Flow-Inertia Modeling Framework for Cross-Scale Dynamics of Dissipative Structures

Understanding structural similarities across dynamical systems at different scales remains a central problem in nonlinear science [1, 3]. Here we propose a modeling framework for cross-scale morphogenetic dynamics, termed Generalized Morphogenesis Theory (GMT), based on a flow-inertia formulation: O_FD O_INLINEFIG[Formula 1]C_INLINEFIGM_FD(1)C_FD where S denotes system state, E environmental input, F (E, S) a driving function, and {micro}(S) an inertia function representing resistance to change. This formulation provides a structural representation that encompasses several classical dynamical models--including Newtonian relaxation, logistic growth, and reaction-diffusion systems [13]--under appropriate parameterizations. Non-dimensionalization reveals a small set of control parameters governing regime transitions. Empirical validation is performed across two independent scales. At the organism scale, crop growth time-series datasets from multiple species exhibit consistent multiplicative dynamics F (E, S) = f (E) {middle dot} S, statistically preferred over additive alternatives in 5 of 6 independently tested systems ({Delta}AIC ranging from +2 to +891; R2 up to 0.98). Independently estimated inertia time constants agree in two plant systems (cucumber:{tau} = 3.7 days, CV=3.3%; maize:{tau} = 36.8 days, CV=17.3%), with the 10-fold ratio consistent with structural complexity differences. At the molecular scale, publicly available perturbation transcriptomics datasets (Perturb-seq) show directional response structures consistent with the proposed flow-inertia decomposition (93% causal direction agreement across three independent datasets; p < 10-25). Across domains, recurrent dynamical motifs are organized into 12 canonical design patterns, derived from a 2 x 2 x 3 orthogonal structure (4 elementary operations x 3 temporal scales), associated with stability classes and bifurcation conditions. These results suggest that the flow-inertia formulation functions as a domain-independent structural modeling principle for dissipative morphogenesis.

systems biology↗

bioRxiv2025

Netrin-1 promotes pancreatic tumorigenesis and innervation through NEO1.

Nerves have been shown to regulate cancer progression. However, a clear demonstration of a role for axon guidance molecules in pancreatic tumorigenesis, innervation, and metastasis has been lacking. Using murine KrasG12D-mutant pancreatic organoids, we screened axon guidance molecules by qRT-PCR, identified Ntn1 upregulation, and then verified its in vivo upregulation during pancreatic tumorigenesis in humans and mice. NTN1 and its receptor NEO1 were upregulated in epithelial cells by the Kras mutation and {beta}-adrenergic signaling, in part, through the MAPK pathway. Ex-vivo culture of celiac ganglia showed that NTN1 promoted the axonogenesis of sympathetic neurons through the nerve NEO1 receptor. In the Pdx1-Cre;LSL-KrasG12D/+ model, Ntn1 knockout decreased sympathetic innervation and the development of pancreatic intraepithelial neoplasia. Treatment of pancreatic tumor organoids with recombinant NTN1 enhanced cell growth, epithelial-mesenchymal transition (EMT), and cancer stemness with the upregulation of ZEB1 and SOX9 through NEO1-mediated activation of focal adhesion kinase (FAK). In Pdx1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+mice, Ntn1 knockout reduced innervation, FAK phosphorylation, and the features of EMT and stemness to extend mouse survival. In a liver metastasis model of PDAC (pancreatic ductal adenocarcinoma), treatment with a NTN1-neutralizing antibody or tumoral knockdown of Neo1 reduced ZEB1 and SOX9 and decreased tumor progression. In contrast, Ntn1 overexpression promoted innervation and the progression of PDAC liver metastasis. These data suggest that the NTN1/NEO1 axis is a key regulator of PDAC progression, directly influencing cancer cell stemness and EMT, while indirectly promoting tumor growth through nerves. Inhibiting the NTN1/NEO1 axis could represent a potential therapeutic approach for PDAC. Statement of SignificanceNTN1 promotes pancreatic tumorigenesis and metastasis directly and indirectly through nerves, highlighting the importance of tumor cell-nerve crosstalk in cancer. NTN1 blockade could represent a promising strategy for treating PDAC liver metastasis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/666009v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@ca611corg.highwire.dtl.DTLVardef@ad9264org.highwire.dtl.DTLVardef@1661c00org.highwire.dtl.DTLVardef@b86798_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

High-resolution Cryo-EM visualises hydrated type I and IV pilus structures from enterotoxigenic Escherichia coli

To efficiently colonise intestinal epithelium, enteric pathogens utilise a wide variety of pilus filaments, including those synthesised by the chaperone-usher or type IV pilus assembly pathway. Despite the importance of these filaments as potential drug and vaccine targets, their large size and dynamic nature present challenges for atomic-resolution structural determination. Here, we used cryo-electron microscopy (cryo-EM) and whole genome sequencing to identify and determine the structures of type I and IV pili expressed in enterotoxigenic Escherichia coli. The well-defined cryo-EM maps at resolutions of 2.20 and 1.78 [A] for Type I and Type IV pilus, respectively, facilitated de novo structural modelling for these filaments, revealing side chain structures in detail. Further, we resolved thousands of hydrated water molecules around and within the inner core of the filaments, functioning as a buffer to stabilise the otherwise metastable subunit assembly. The high-resolution structures offer novel insights into the subunit-subunit interactions, providing important clues to understand pilus assembly, stability, and flexibility.

microbiology↗

bioRxiv2022

Direct Observation of Stepping Rotation of V-ATPase Reveals Rigid Coupling between Vo and V1 Motors

V-ATPases are rotary motor proteins which convert chemical energy of ATP into electrochemical potential of ions across the cell membrane. V-ATPases consist of two rotary motors, Vo and V1, and Enterococcus hirae V-ATPase (EhVoV1) actively transports Na+ in Vo (EhVo) by using torque generated by ATP hydrolysis in V1 (EhV1). Here, we observed ATP-driven stepping rotation of detergent-solubilized EhVoV1 wild-type, aE634A, and BR350K mutants under the various Na+ and ATP concentrations ([Na+] and [ATP], respectively) by using a 40-nm gold nanoparticle as a low-load probe. When [Na+] was low and [ATP] was high, under the condition that only Na+ binding to EhVo is the rate-limiting, wild-type and aE634A exhibited 10-pausing positions reflecting 10-fold symmetry of the EhVo rotor and almost no backward steps. Duration time before forward steps was inversely proportional to [Na+], confirming that Na+ binding triggers the steps. When both [ATP] and [Na+] were low, under the condition that both Na+ and ATP bindings are rate-limiting, aE634A exhibited 13-pausing positions reflecting 10- and 3-fold symmetries of EhVo and EhV1, respectively. Distribution of duration time before forward step was well fitted by a sum of two exponential decay functions with distinct time constants. Furthermore, frequent backward steps smaller than 36{degrees} were observed. Small backward steps were also observed during long, three ATP cleavage pauses of BR350K. These results indicate that EhVo and EhV1 do not share pausing positions and Na+ and ATP bindings occur at different angles, and the coupling between EhVo and EhV1 is not elastic but rigid. Significance StatementV-ATPases are ion pumps consisting of two rotary motor proteins Vo and V1, and actively transport ions across the cell membrane by using chemical energy of ATP. To understand how V-ATPases transduce the energy in the presence of structural symmetry mismatch between Vo and V1, we simultaneously visualized rotational pauses and forward and backward steps of Vo and V1 coupled with ion transport and ATP hydrolysis reaction, respectively. Our results indicate rigid coupling of a V-ATPase which has multiple peripheral stalks, in contrast to elastic coupling of F-ATPases with only one peripheral stalk, which work as ATP synthase. Our high-speed/high-precision single-molecule imaging of rotary ATPases in action will pave the way for a comprehensive understanding of their energy transduction mechanisms.

biophysics↗

bioRxiv2021

Conversion of cancer-associated fibroblasts from pro- to antitumor improves the sensitivity of pancreatic cancer to chemotherapeutics

Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we show that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, non-natural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment.

cancer biology↗

bioRxiv2021

CBL-C E3 ubiquitin ligase acts as a host defense to mediate ubiquitin-proteasomal degradation of enteropathogenic Escherichia coli Tir protein

Translocated intimin receptor (Tir) is an essential bacterial factor for enteropathogenic Escherichia coli (EPEC) to establish Tir-intimin interaction-mediated adherence to the epithelial cell and to form actin pedestal structures beneath the adherent bacteria. However, it remains unclear how the host cells eliminate Tir protein after infection. Here we show that intracellular translocated Tir is degraded via the host ubiquitin- proteasome system. We found that host CBL-C, an E3 ubiquitin-protein ligase, bound to and ubiquitinated the 454 tyrosine-phosphorylated Tir protein. Tir ubiquitination leads to proteasome-dependent degradation and attenuated EPEC colonization of the epithelial cell. Using Citrobacter rodentium, a mouse model for EPEC, we demonstrated that infection with C. rodentium mutant expressing a tyrosine- phenylalanine-substituted Tir (CBL-C resistant) showed increased bacterial loads in the colon and lethality compared with infection with C. rodentium expressing wild-type Tir. These results indicate that CBL-C is a critical host defense factor that determines the fate of cytosolic Tir and terminates bacterial colonization. Graphical Abstracts O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/434331v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@d28d7borg.highwire.dtl.DTLVardef@146b7e6org.highwire.dtl.DTLVardef@1d36d14org.highwire.dtl.DTLVardef@19e6b25_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2020

Diagnosis of central serous chorioretinopathy by deep learning analysis of en face images of choroidal vasculature

PurposeTo classify central serous chorioretinopathy (CSC) by deep learning (DL) analyses of en face images of choroidal vasculature obtained by optical coherence tomography (OCT) and to analyze the regions of interest for DL from heatmaps. MethodsOne-hundred eyes were studied; 53 eyes with CSC and 47 normal eyes. Volume scans of 12x12 mm square were obtained at the same time as the OCT angiographic (OCTA) scans (Plex Elite 9000 Swept-Source OCT(R), Zeiss). High-quality en face images of the choroidal vasculature of the segmentation slab of one-half of the subfoveal choroidal thickness were created for the analyses. The entire 100 en face images were divided into 80 for training (100 times) and 20 for validation. The Neural Network Console (NNC) developed by Sony and the Keras-Tensorflow backend developed by Google were used as the software for the classification with 16 layers of convolutional neural networks. The active region of the heatmap based on the feature quantity extracted by DL was also evaluated as the percentages with gradient-weighted class activation mapping implementation in Keras. ResultsIn the 20 eyes used for validation including 8 eyes with CSC, the accuracy rate of the validation was 100% (20/20) for NNC and 95% (19/20) for Keras. This difference was not significant (P=0.33). The mean active region in the heatmap image was 12.5% in CSC eyes which was significantly lower than the 79.8% in normal eyes (P<0.01). ConclusionsCSC can be automatically classified with high accuracy from en face images of the choroidal vasculature by DLs with different programs, convolutional layer structures, and small data sets. Heatmap analyses showed that DL focused on the area occupied by the choroidal vessels and their uniformity. We conclude that DL can help in the diagnosis of CSC.

biophysics↗

bioRxiv2020

De Novo Design of Allosteric Control into Rotary Motor V1-ATPase by Restoring Lost Function

Protein complexes exert various functions through allosterically controlled cooperative work. De novo design of allosteric control into protein complexes provides understanding of their working principles and potential tools for synthetic biology. Here, we hypothesized that an allosteric control can be created by restoring lost functions of pseudo-enzymes contained as subunits in protein complexes. This was demonstrated by computationally de novo designing ATP binding ability of the pseudo-enzyme subunits in a rotary molecular motor, V1-ATPase. Single molecule experiments with solved crystal structures revealed that the designed V1 is allosterically accelerated than the wild-type by the ATP binding to the created allosteric site and the rate is tunable by modulating the binding affinity. This work opened up an avenue for programming allosteric control into proteins exhibiting concerted functions.

biophysics↗

bioRxiv2020

Neural correlates of temporal presentness in theprecuneus: a crosslinguistic fMRI study based on speech stimuli

AbstractsThe position of any event in time could be either present, past, or future. This temporal discrimination is vitally important in our daily conversations, but it remains elusive how the human brain distinguishes among the past, present, and future. To address this issue, we searched for neural correlates of presentness, pastness, and futurity, each of which is automatically evoked when we hear sentences such as it is raining now, it rained yesterday, or it will rain tomorrow. Here, we show that sentences that evoked presentness activated the bilateral precuneus more strongly than those that evoked pastness or futurity. Interestingly, this contrast was shared across native speakers of Japanese, English, and Chinese, languages which vary considerably in their verb tense systems. The results suggest that the precuneus serves as a key region that provides the origin, the Now, to our time perception irrespective of differences in tense systems across languages.

neuroscience↗

bioRxiv2020

Helicobacter small RNA regulates host adaptation and carcinogenesis

Type-1 carcinogenic Helicobacter pylori that is known to evolve during long-term infection, enters the stomach orally and causes gastric cancer using the carcinogenic protein CagA1. However, little is known about the adaptation mechanisms of H. pylori when the environment changes from the outside to the inside of the living body. Here we show that small non-coding RNA HPnc4160 is a crucial novel RNA molecule of H. pylori that negatively regulates bacterial-host adaptation and gastric cancer. H. pylori isolated from gerbils stomachs eight weeks post-infection acquired mutations in the increased number of T-repeats within the upstream region of the HPnc4160 coding region, which leads to reduced HPnc4160 expression levels that also seen in cancer patients-derived H. pylori. By comparing RNA-seq and iTRAQ analysis between wild-type and hpnc4160 deficient mutant strains, we identified eight targets of HPnc4160 including cagA and unknown factors. Mice infection experiment revealed that the hpnc4160 deficient mutant had a higher number of colonized bacteria in the mice stomach than the wild-type strain, indicating that reduced expression levels of HPnc4160 was important for bacterial host adaptation. The expression level of HPnc4160 was lower in the clinical isolates derived from gastric cancer patients compared with non-cancer-derived strains, while the mRNA expression levels of target factors were higher. Our findings highlight the first discovery that HPnc4160 is an important small RNA for bacteria to adapt to the host environment leading to gastric carcinogenesis.

microbiology↗

bioRxiv2019

Soil prokaryotes associated with decreasing pathogen density during anaerobic soil disinfestation

Anaerobic soil disinfestation (ASD) is a chemical-independent method that can reduce pathogens. Although soil microbes play essential roles in ASD, the relationship between the microbial community structure and disinfestation efficiency remains unclear. To this end, we investigated changes in the microbial community and pathogen density during a period of ASD under field conditions for 14 days in a greenhouse using three different substrates. Soil samples were collected at 0, 3, 7, and 14 days after ASD treatment. The pathogen densities were analyzed by real-time polymerase chain reactions, prokaryotic community analysis was conducted using unidirectional pyrosequencing, and the factors related to pathogen density were statistically analyzed. The pathogen density rapidly decreased by >90% at 3 days after treatment and then slowly decreased until day 14, but the rate of decrease differed among the substrates. The microbial communities became altered after 3 days and recovered to their original state on day 14. The dipyridyl reaction, microbial diversity, richness, and community structure were not correlated with pathogen density. The most negatively correlated operational taxonomic units with pathogen density were Clostridia and Bacilli, both belonging to Firmicutes. These results suggested that the growth of specific microbes, but not the changes in microbial community structure, might be important for ASD disinfestation efficiency.

microbiology↗

bioRxiv2019

Comparison of prokaryotic communities between the fields showing different disinfestation effects by anaerobic soil disinfestation

Anaerobic soil disinfestation (ASD) is a chemical-independent fumigation method used for reducing the abundance of pathogens at soil depths of <40 cm. However, its disinfestation efficiency is unstable under field conditions. The microbial community reflects the soil environment and is a good indicator of soil health. Therefore, soil with a good disinfestation efficiency may have a unique microbial community. The aim of the present study was to compare the prokaryotic communities among soils obtained from 17 geographically different greenhouses that experienced tomato bacterial wilt but exhibited different disinfestation efficiencies after ASD treatment with the same substrate. In the present study, soil prokaryotic communities in the field, which indicate difference in disinfestation effects after ASD treatment among several fields, were compared using next-generation sequencing. The prokaryotic communities in the fields showing different disinfestation effects were roughly separated into sampling fields. The relative abundances of Betaproteobacteria and Clostridia were significantly increased in well-disinfested fields. Overall, 25 operational taxonomic units (OTUs) were specifically increased in various well-disinfested soils and 18 OTUs belonged to phylogenetically diversified Clostridia. Other OTUs belonged to aerobic bacteria and were not previously detected in sample collected from ASD-treated fields. The results showed that the changes to the prokaryotic communities did not affect ASD efficiency, whereas changes in the abundance of specific microbes in the community were related to disinfestation.

microbiology↗

bioRxiv2019

A NMF-based approach to discover overlooked differentially expressed gene regions from single-cell RNA-seq data

Single-cell RNA sequencing has enabled researchers to quantify the transcriptomes of individual cells, infer cell types, and investigate differential expression among cell types, which will lead to a better understanding of the regulatory mechanisms of cell states. Transcript diversity caused by phenomena such as aberrant splicing events have been revealed, and differential expression of previously unannotated transcripts might be overlooked by annotation-based analyses. Accordingly, we have developed an approach to discover overlooked differentially expressed (DE) gene regions that complements annotation-based methods. We applied our algorithm to two datasets and discovered several intriguing DE transcripts, including a transcript related to the modulation of neural stem/progenitor cell differentiation.

bioinformatics↗

bioRxiv2018

Bile Acid Biosynthesis Avoiding Cholesterol

Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have investigated the bile acid content of plasma and urine from patients with a defect in cholesterol biosynthesis, i.e. Smith-Lemli-Opitz syndrome (SLOS), resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography - mass spectrometry (LC-MS) we have identified a novel pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC. This pathway also proceeds to a minor extent in healthy individuals. Monitoring of the pathway products could provide a rapid diagnostic for SLOS while elevated levels of pathway intermediates could be responsible for some of the features of the disease. Importantly, intermediates in the pathway are modulators of the activity of Smoothened, an oncoprotein that mediates Hedgehog signalling during embryogenesis and regeneration of postembryonic tissue.

biochemistry↗