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Yamashita, Y.

Publications and source records attributed to Yamashita, Y..

At least 19 recordsLinked to original sources

A hierarchical generative model reveals enhanced latent precision of brain-body interaction dynamics during interoceptive attention

Brain-body interactions (BBIs) are fundamental to cognition and mental health, but their continuous multimodal dynamics remain difficult to extract. Previous approaches have been largely observational, and few frameworks enable these interacting processes to be modeled within an integrated generative system. Here, we applied a Predictive-Coding-Inspired Variational RNN (PV-RNN) to simultaneous EEG, ECG, and respiration recordings obtained from 33 participants during exteroceptive and interoceptive attention. The model learned a temporal hierarchy spanning modality-specific dynamics, multimodal associative integration, and sequence-level global states, and accurately reconstructed unseen physiological sequences. Specifically, the intermediate associative layer successfully captured the core complexities of BBI by extracting multiscale, nonlinear, and bidirectional coupling dynamics with variable temporal lags. Furthermore, the estimated precision (inverse variance) of latent variables representing BBI dynamics within this multimodal associative layer increased significantly during interoceptive attention. The magnitude of this condition-dependent precision enhancement correlated positively with subjective adaptive body controllability and negatively with psychiatric vulnerabilities, including rumination and trait anxiety. These findings identify a latent physiological signature of interoceptive attention and establish hierarchical generative modeling as an interpretable framework for extracting continuous BBI dynamics and linking multimodal physiology to cognitive and clinical characteristics.

neuroscience↗

Synergistic and Redundant Information Dynamics Exhibit Dissociable Alterations Across Major Psychiatric Disorders

Deficits in neural information integration are hypothesized to underlie diverse psychiatric symptoms, yet the specific patterns of alteration across different disorders remain unclear. In this study, we decomposed information dynamics between brain regions into synergistic and redundant components using a recent information-theoretical approach based on the idea of Partial Information Decomposition applied to resting-state fMRI data from patients with schizophrenia (SZ), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). Our analysis revealed distinct disorder-specific profiles: SZ and ASD exhibited a widespread reduction in synergy, whereas ADHD showed a contrasting increase. Furthermore, ASD was uniquely characterized by a significant reduction in redundancy. Meta-analytic functional annotation using NeuroSynth associated synergy with higher-order cognitive functions and redundancy with lower-level sensorimotor processing. To investigate multivariate organization of these patterns that distinguish psychiatric diagnoses, we employed Linear Discriminant Analysis (LDA). This analysis demonstrated that synergy and redundancy partially capture distinct dimensions of network variation, exhibiting substantial complementarity in their multivariate structure. While redundancy overlapped considerably with correlation-based connectivity, synergy reflected additional structure not fully represented by conventional measures. Together, these findings indicate that decomposing information dynamics provides complementary perspectives on large-scale network organization, offering a refined framework for characterizing psychiatric disorders.

neuroscience↗

Structural basis for color tuning and passive ion conductance in red-shifted pump-fold channelrhodopsin ChR024

ChR024 is a cation-conducting channelrhodopsin with a red-shifted absorption spectrum, recently discovered from a previously unidentified clade through machine-learning-guided gene mining. Due to its unique position in the phylogenetic tree and distinctive spectral properties, it serves as an important model for elucidating rhodopsin evolution and for engineering optogenetic tools with enhanced performance, but its structure and function remain poorly understood. Here, we present cryo-electron microscopy structures of ChR024 in detergent micelles and lipid nanodiscs at resolutions of 3.22 and 2.45 [A], respectively. The structures reveal an architecture strikingly similar to that of ion-pumping rhodopsins, even more so than other pump-like channelrhodopsins such as ChRmine. Structural, theoretical, and spectroscopic analyses uncover a unique color-tuning mechanism, in which charged residues close and distant from the retinal chromophore cooperatively modulate the pKa of the Schiff base counterion and thereby determine the absorption maximum wavelength. Finally, comparative structural analysis of channel- and pump-type rhodopsins, combined with electrophysiology, provides insights into the molecular boundary between these two functional classes and demonstrates the conversion of an outward proton pump into a light-gated channel. Together, these findings illuminate diverse mechanisms of color tuning and functional specification within the rhodopsin family, paving the way for the rational engineering of next-generation optogenetic tools.

biophysics↗

Metabolism of L-threonate, an ascorbate degradation product, requires a protein with L-threonate metabolizing domains in Arabidopsis

L-Threonate is one of the major degradation products of ascorbate in plants. While bacteria can utilize L-threonate as a sole carbon source by converting it to dihydroxyacetone phosphate, a glycolysis intermediate, through a three- or four-step metabolic pathway, the corresponding processes in plants remain uncharacterized. Remarkably, an Arabidopsis gene encodes a unique protein containing domains homologous to all three enzymes involved in the bacterial three-step pathway. We designated this protein as L-threonate metabolizing domains (LTD) and investigated its functional role in plant L-threonate metabolism. Despite extensive efforts, recombinant expression of LTD was unsuccessful, likely due to its large protein size. Therefore, a reverse genetic approach was employed, using ltd knockout Arabidopsis lines to explore LTD function. Under continuous dark conditions, where ascorbate degradation is facilitated, LTD transcription was significantly upregulated, leading to increased L-threonate dehydrogenase (LtnD) activity. Knockout lines of LTD exhibited no detectable LtnD activity under both light and dark conditions, alongside elevated levels of L-threonate compared to wild-type plants. These results indicate that LTD is essential for L-threonate metabolism in Arabidopsis. The LTD gene is highly conserved among land plants but is absent in green algae, providing a hypothesis that the rise in ascorbate concentrations during plant evolution necessitated a more active metabolism of ascorbate degradation products.

plant biology↗

Hypomorphic Lig4 gene mutation in mice predisposes to Th1-skewing intestinal inflammation

Dysregulation of DNA double-strand break (DSB) repair leads to adaptive immunodeficiency, whereas the remaining lymphocytes are aberrantly activated and provoke inflammations. However, no model mice were available to consistently manifest inflammation under defective DSB repair. We generated mutant mice carrying a missense mutation p.W447C in the gene encoding DNA ligase IV (LIG4), critical for DSB repair. Lig4W447C/W447C mice showed growth retardation and severe intestinal inflammations under adaptive immunodeficiency. The inflammations were featured by marked infiltration of T helper type 1 (Th1) cells and macrophages and was dependent on lymphocytes. When Ifng was deleted, Th2 and Th17 instead of Th1 cells drove the inflammations. Lig4W447C/W447C mice showed expansion of oligoclonal T cells with T cell receptor repertoire skewed towards more proximal 3 V and 5 J gene segments. Thus, our novel hypomorphic Lig4 mutant mice show that defective DSB repair leads to Th1-dependent intestinal inflammations under severe adaptive immunodeficiency.

immunology↗

Flexible value coding in the mesolimbic dopamine system depending on internal water and sodium balance

Homeostatic imbalances elicit strong cravings, such as thirst and salt appetite, to restore equilibrium. Although midbrain dopaminergic neurons are known to encode the value of foods, their nutritional state-dependency remains unknown. Here, we show that the activity of the dopaminergic mesolimbic pathway flexibly expresses the positive and negative values of water and salt depending on the internal state in mice. Mice showed behavioral preference and aversion to water and salt depending on their internal water and sodium balance. Fiber photometry recordings revealed that dopamine neurons in the ventral tegmental area and dopamine release in the nucleus accumbens flexibly showed bidirectional excitatory and inhibitory responses to water and salt intake in a state-dependent manner. Furthermore, these dopaminergic and behavioral responses could be simulated by a homeostatic reinforcement learning model. Our results demonstrate the nutritional state-dependency of value coding in mesolimbic dopamine systems, providing new insights into neural circuits underlying homeostatic regulation of appetitive and avoidance behaviors.

neuroscience↗

Harmonizing Inter-Site Differences in T1-Weighted Images Using CycleGAN

IntroductionWhen neuroimaging studies using magnetic resonance imaging (MRI) are conducted across multiple centers, they often encounter inter-site differences in MRI equipment and protocols leading to biases and confounding effects in MRI measurements. There are existing techniques for correcting these site effects, i.e., harmonization, but they have limitations, including the need for preprocessing of MRI data, which involves processes such as spatial normalization. Deep learning-based methods have emerged as potential alternatives that can handle site effects without the need for preprocessing steps. In this study, we propose a novel method based on the generative adversarial network (GAN) framework, CycleGAN, that effectively addresses inter-site differences in T1-weighted images with minimal preprocessing requirements. We compare the harmonization efficacy of CycleGAN with that of the commonly used method ComBat. MethodsWe trained the proposed CycleGAN method and the comparative ComBat method using data from 40 subjects at each of two sites. To evaluate the effectiveness of the two methods, we used data from nine subjects who underwent imaging at both sites. We assessed harmonization performance at the image level using the structural similarity index (SSIM) and peak signal-to-noise ratio (PSNR). Additionally, we evaluated harmonization results at the feature level by analyzing regional cortical thickness and volume data. Cohens d was employed to quantify the differences between feature values. ResultsAt the image level, the ComBat method decreased the median baseline SSIM value from 0.86 (interquartile range [IQR], 0.02) to 0.84 (IQR, 0.02), whereas the proposed CycleGAN method maintained the SSIM value at 0.86 (IQR, 0.02). For PSNR, the baseline value was 18.33 (IQR, 1.78), which decreased to 15.30 (IQR, 2.20) after applying ComBat, but increased to 19.58 (IQR, 3.12) with the proposed CycleGAN method. These findings indicate that CycleGAN preserved the structural and signal similarity of the images. At the feature level, the effect size for cortical thickness decreased from 0.97 (IQR, 1.79) to 0.91 (IQR, 1.54) after applying ComBat, whereas the proposed CycleGAN method yielded an effect size of 1.05 (IQR, 1.14). For cortical volume, the effect size decreased from 0.95 (IQR, 1.78) to 0.69 (IQR, 1.00) after applying ComBat, and decreased to 0.88 (IQR, 0.74) with the CycleGAN method. Compared with baseline, Cohens d was significantly lower with both ComBat (p = 0.000002) and CycleGAN (p = 0.028) with no significant difference between the two methods, indicating similar performance of the two methods under the study conditions. ConclusionThe results underscore the ability of CycleGAN to harmonize data without explicit normalization and emphasize the potential impact of the normalization process on harmonization procedures. Our findings suggest that CycleGAN holds promise as a harmonization technique in multi-site neuroimaging studies.

neuroscience↗

Cellular Responses to Photothermal Therapy: Heat-Induced ERK Signaling and Intercellular Communication in Solid Tumors

Nanoparticle-mediated photothermal therapy (PTT) shows promise as a standalone cancer treatment but faces clinical challenges due to inconsistent efficacy. Its translation is further hindered by a limited understanding of plasmon-induced heat effects, such as stress responses and intercellular signaling. Here, we investigate how plasmon-induced local heating affects cellular behavior and fate within tumor spheroids by focusing on the activity of the extracellular signal-regulated kinase (ERK). Spheroids were prepared from HeLa cells that express a FRET-based ERK sensor, and ERK activity changes under photothermal stimuli were tracked using a deep-learning program, 3DeeCellTracker. Gold nanostars were used as highly efficient photothermal transducers. Our results revealed significant alterations in ERK signaling patterns upon photothermal stimulation compared to spontaneous ERK activity in untreated spheroids, including changes in the activation frequency, timing, and duration. Notably, photothermal-induced ERK activity propagated across neighboring cells within the spheroid, suggesting intercellular communication. Furthermore, analysis of cell death and division further demonstrated that laser power modulates cellular fate during photothermal therapy. This study provides insights for predicting the therapeutic effects of PPT and guides the rational design of next-generation photothermal strategies. Additionally, our approach demonstrates the potential of FRET-based biosensors and deep-learning tools as powerful methods to study the effects of various therapeutic stimuli on solid tumors at the single-cell level.

cancer biology↗

Immunological characterization of peritoneal exudate cells in liver cirrhosis patients

BACKGROUND AND AIMSLiver cirrhosis (LC) is the end stage of liver fibrosis caused by various chronic liver diseases. Patients with LC often develop ascites containing peritoneal exudate cells (PECs). However, those cells have not been fully immunologically characterized. In this study, we clarify immune cell profiles of PECs from patients with LC. APPROACH AND RESULTSPECs were collected from patients with LC or patients receiving continuous ambulatory peritoneal dialysis (CAPD) as a non-cirrhotic control and subjected to single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (RNA-seq) and flowcytometry analyses. Analysis of scRNA-seq revealed that dendritic cells (DCs) and macrophages were major populations in CAPD patient-derived PECs, while those cells were decreased and T cells were most abundant in LC patient-derived PECs. Notably, FCGR3A-expressing macrophages were dominant over DCs and GATA6-expressing macrophages in LC patient-derived PECs. Bulk RNA-seq analysis further clarified expression of a set of genes was up- or down-regulated along with LC severity. Especially, expression of T cell signature genes was featured by its increase at Child-Pugh class B, but decrease at Child-Pugh class C. Flowcytometry analysis showed increase of T cells, decrease of DCs and macrophages, and increased expression of CD16 and CD163 in CD1cintCD14high cells corresponding to FCGR3A-expressing macrophages in LC patient-derived PECs. CONCLUSIONSIn LC patient-derived PECs, myeloid and T cell populations and their gene expression profiles were fluctuated with severity. Our findings should contribute to further development of diagnosis or therapeutic maneuver for LC.

immunology↗

Implication of S-1 biomarkers on aging and prognosis in elderly patients with lung cancer treated by adjuvant S-1 chemotherapy: Accompanying results of the Setouchi Lung Cancer Group Study 1201

BACKGROUNDSThe management of elderly patients presents several challenges due to age-related declines; however recent recommendations advocate for age not being the sole determinant for adjuvant treatment decisions in patients with non-small cell lung cancer (NSCLC). Aging may alter expression levels of 5-fluorouracil (5-FU) biomarkers. METHODSExpression changes with aging were explored using The Cancer Genome Atlas (TCGA) database. 5-FU-related biomarker expressions, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase, epidermal growth factor receptor (EGFR), and excision repair cross-complementation group-1 (ERCC1), were assessed by the quantitative reverse-transcription PCR assays in 89 NSCLCs elderly patients ([&ge;] 75 years old) receiving adjuvant S-1, an oral fluoropyrimidine agent, therapy in a SLCG1201 trial. RESULTS: TCGA database analysis (n=955) indicated decreased TS expression with aging, particularly in those 75 or older. In the SCLG1201 trial, univariate analysis revealed that high EGFR and low TS expressions correlated with favorable recurrence-free survival (RFS)(p=0.0264) and overall survival (OS)(p=0.0365), respectively. Multivariable analysis confirmed pathological stage as an independent prognostic factor for both RFS and OS (p=0.0052 and 0.0352, respectively). EGFR mutant tumors (n=27) showed significantly higher DPD (p=0.0066) and EGFR (p<0.0001) expressions, and lower TS(p=0.0125) and ERCC1(p=0.0015) expressions. CONCLUSIONDespite pathological stage being an independent prognostic factor, high EGFR and low TS expressions may predict better clinical outcomes in elderly NSCLC patients using adjuvant S-1. The age-related decrease in TS expression supports the potential benefit of 5-FU-based therapy in them compared to younger patients. Further research is warranted to validate these clinical implications.

pharmacology and toxicology↗

Parasitic-plant parasite utilizes flowering pathways at unconventional stages to form stem-derived galls

Galls induced by various organisms exhibit diverse morphological and physiological characteristics, involving complex plant-insect interactions. Most transcriptome analyses to date have focused on leaf-derived galls. To better understand gall formation mechanisms, we investigated stem-derived galls induced by the weevil Smicronyx madaranus on the parasitic plant Cuscuta campestris at gene expression, cellular, and physiological levels. RNA-seq across four developmental stages identified differentially expressed genes and associated gene ontology terms. Consistent with histological observations, genes related to cell division and the cell cycle were upregulated early but decreased as the gall matured. Similar to leaf-derived galls, we found high expression of PLETHORA and meristem-related homeobox genes in early gall development, suggesting that stem cell induction and maintenance are involved in various gall types. Like leaf- derived galls, the expression of genes related to floral organ development increased through the gall development. However, their expression patterns were dramatically different: downstream genes in the flowering pathway were highly expressed at the initial gall stage, whereas upstream genes were highly expressed later. This suggests that the weevil might activate the flowering pathway at unconventional stages, potentially rerouting the typical flowering cascade to influence gall development. Unlike the decrease in photosynthesis-related genes in leaf-derived galls, we observed an increase in these genes in galls formed on the stem of the holoparasitic plant. Shading experiments confirmed that photosynthesis is crucial for both gall growth and the weevil. This study highlights how gall-inducers can co-opt host resources and genetic pathways, offering new insights into the complexity of plant-insect interactions.

plant biology↗

Heterogeneous Appetite Patterns in Depression: Computational Modeling of Nutritional Interoception, Reward Processing, and Decision-Making

Accurate interoceptive processing in decision-making is essential to maintain homeostasis and overall health. Disruptions in this process have been associated with various psychiatric conditions, including depression. Recent studies have focused on nutrient homeostatic dysregulation in depression for effective subtype classification and treatment. Neurophysiological studies have associated changes in appetite in depression with altered activation of the mesolimbic dopamine system and interoceptive regions, such as the insular cortex, suggesting that disruptions in reward processing and interoception drive changes in nutrient homeostasis and appetite. This study aimed to explore the potential of computational psychiatry in addressing these issues. Using a homeostatic reinforcement learning model formalizing the link between internal states and behavioral control, we investigated the mechanisms by which altered interoception affects homeostatic behavior and reward system activity via simulation experiments. Simulations of altered interoception demonstrated behaviors similar to those of depression subtypes, such as appetite dysregulation. Specifically, reduced interoception led to decreased reward system activity and increased punishment, mirroring the neuroimaging study findings of decreased appetite in depression. Conversely, increased interoception was associated with heightened reward activity and impaired goal-directed behavior, reflecting an increased appetite. Furthermore, effects of interoception manipulation were compared with traditional reinforcement learning parameters (e.g., inverse temperature {beta} and delay discount{gamma} ), which represent cognitive-behavioral features of depression. The results suggest that disruptions in these parameters contribute to depressive symptoms by affecting the underlying homeostatic regulation. Overall, this study findings emphasize the importance of integrating interoception and homeostasis into decision-making frameworks to enhance subtype classification and facilitate the development of effective therapeutic strategies.

systems biology↗

Digital Twin Brain Simulator: Harnessing Primate ECoG Data for Real-Time Consciousness Monitoring and Virtual Intervention

At the forefront of bridging computational brain modeling with personalized medicine, this study introduces a novel, real-time, electrocorticogram (ECoG) simulator based on the digital twin brain concept. Utilizing advanced data assimilation techniques, specifically a Variational Bayesian Recurrent Neural Network model with hierarchical latent units, the simulator dynamically predicts ECoG signals reflecting real-time brain latent states. By assimilating broad ECoG signals from Macaque monkeys across awake and anesthetized conditions, the model successfully updated its latent states in real-time, enhancing the precision of ECoG signal simulations. Behind the successful data assimilation, a self-organization of latent states in the model was observed, reflecting brain states and individuality. This self-organization facilitated simulation of virtual drug administration and uncovered functional networks underlying changes in brain function during anesthesia. These results show that the proposed model is not only capable of simulating brain signals in real-time with high accuracy, but is also useful for revealing underlying information processing dynamics.

neuroscience↗

Future shapes present: autonomous goal-directed and sensory-focused mode switching in a Bayesian allostatic network model

Trade-offs between moving to achieve goals and perceiving the surrounding environment highlight the complexity of continually adapting behaviors. The need to switch between goal-directed and sensory-focused modes, along with the goal emergence phenomenon, challenges conventional optimization frameworks, necessitating heuristic solutions. In this study, we propose a Bayesian recurrent neural network framework for homeostatic behavior adaptation via hierarchical multimodal integration. In it, the meta-goal of "minimizing predicted future sensory entropy" underpins the dynamic self-organization of future sensorimotor goals and their precision regarding the increasing sensory uncertainty due to unusual physiological conditions. We demonstrated that after learning a hierarchical predictive model of a dynamic environment through random exploration, our Bayesian agent autonomously switched self-organized behavior between goal-directed feeding and sensory-focused resting. It increased feeding before anticipated food shortages, explaining predictive energy regulation (allostasis) in animals. Our modeling framework opens new avenues for studying brain information processing and anchoring continual behavioral adaptations.

neuroscience↗

Integration of shoot-derived polypeptide signals by root TGA transcription factors is essential for survival under fluctuating nitrogen environments

Unlike plants in the field, which experience significant temporal fluctuations in environmental conditions, plants in the laboratory are typically grown in controlled, stable environments. Therefore, signaling pathways evolved for survival in continuously fluctuating environments often remain functionally latent in laboratory settings. Here, we show that TGA1 and TGA4 act as hub transcription factors through which the expression of genes involved in high-affinity nitrate uptake are regulated in response to shoot-derived phloem mobile polypeptides, CEP DOWNSTREAM 1 (CEPD1), CEPD2 and CEPD-like 2 (CEPDL2) as nitrogen (N) deficiency signals, and Glutaredoxin S1 (GrxS1) to GrxS8 as N sufficiency signals. CEPD1/2/CEPDL2 and GrxS1-S8 competitively bind to TGA1/4 in roots, with the former acting as transcription coactivators that enhance the uptake of nitrate, while the latter function as corepressor complexes together with TOPLESS to limit nitrate uptake. Arabidopsis plants deficient in TGA1/4 maintain basal nitrate uptake and exhibit growth similar to wild-type plants in a stable N environment, but were impaired in regulation of nitrate acquisition in response to shoot N demand, leading to defective growth under continuously fluctuating N environments where rhizosphere nitrate ions switch periodically between deficient and sufficient states. TGA1/4 are crucial transcription factors that enable plants to survive under fluctuating and challenging N environmental conditions.

plant biology↗

Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice

Animals have the innate ability to select optimal defensive behaviors with appropriate intensity in response to predator threats within specific contexts. Such innate behavioral decisions are thought to be computed in the medial hypothalamic nuclei, which contain neural populations that directly control defensive behavioral outputs. The vomeronasal organ (VNO) serves as a primary sensory channel for detecting predator cues by relaying signals to the medial hypothalamic nuclei, particularly the ventromedial hypothalamus (VMH), via the medial amygdala (MeA) and bed nucleus of the stria terminalis (BNST). Here, we demonstrate that cat saliva contains predator cues that signal the imminence of predator threat and modulate the intensity of freezing behavior through the VNO in mice. Cat saliva activates neurons expressing the V2R-A4 subfamily of sensory receptors, suggesting that specific receptor groups are responsible for inducing the freezing behavior. The number of VNO neurons activated in response to saliva correlates with both the freshness of saliva and the intensity of freezing behavior. In contrast, the downstream neurons in the accessory olfactory bulb (AOB) and the defensive behavioral circuit are activated to a similar extent by fresh and old saliva. Strikingly, however, the number of VMH neurons activated by fresh, but not old, saliva positively correlates with the intensity of freezing behavior. Detailed analysis of the spatial distribution of neurons responding to fresh and old saliva, as well as the overlap of those activated within the same individual mice, revealed that fresh and old saliva predominantly activate distinct neuronal populations within the VMH. Collectively, this study suggests that there is an accessory olfactory circuit in mice that is specifically tuned to time-sensitive components of cat saliva, which optimizes their defensive behavior to maximize their chance of survival according to the imminence of threat.

neuroscience↗

The conserved upstream ORF of the Arabidopsis ANAC082 gene mediates translational upregulation in response to nucleolar stress

Perturbations in ribosome biogenesis cause a type of cellular stress called nucleolar or ribosomal stress, which triggers adaptive responses in both animal and plant cells. The Arabidopsis ANAC082 transcription factor has been identified as a key mediator of the plant nucleolar stress response. The 5'-untranslated region (5'-UTR) of ANAC082 mRNA contains an upstream ORF (uORF) encoding an evolutionarily conserved amino acid sequence. Here, we report that this uORF mediates the upregulation of ANAC082 translation in response to nucleolar stress. When transgenic Arabidopsis plants containing a luciferase reporter gene under the control of the ANAC082 promoter and 5'-UTR were treated with reagents that induced nucleolar stress, translation of the reporter gene was enhanced in a uORF sequence-dependent manner. Additionally, we examined the effect of an endoplasmic reticulum (ER) stress-inducing reagent on reporter gene expression because the closest homolog of ANAC082 in Arabidopsis, ANAC103, is involved in the ER stress response. However, the ANAC082 uORF did not respond to ER stress. Interestingly, although ANAC103 has a uORF with an amino acid sequence similar to that of the ANAC082 uORF, the C-terminal sequence critical for regulation is not well conserved among ANAC103 homologs in Brassicaceae. Transient expression assays revealed that unlike the ANAC082 uORF, the ANAC103 uORF does not exert a sequence-dependent regulatory effect. Altogether, our findings suggest that the ANAC082 uORF is important for the nucleolar stress response but not for the ER stress response, and that for this reason, the uORF sequence-dependent translational regulation was lost in ANAC103 during evolution.

plant biology↗

Deep learning generates custom-made logistic regression models for explaining how breast cancer subtypes are classified

Differentiating the intrinsic subtypes of breast cancer is crucial for deciding the best treatment strategy. Deep learning can predict the subtypes from genetic information more accurately than conventional statistical methods, but to date, deep learning has not been directly utilized to examine which genes are associated with which subtypes. To clarify the mechanisms embedded in the intrinsic subtypes, we developed an explainable deep learning model called a point-wise linear (PWL) model that generates a custom-made logistic regression for each patient. Logistic regression, which is familiar to both physicians and medical informatics researchers, allows us to analyze the importance of the feature variables, and the PWL model harnesses these practical abilities of logistic regression. In this study, we show that analyzing breast cancer subtypes is clinically beneficial for patients and one of the best ways to validate the capability of the PWL model. First, we trained the PWL model with RNA-seq data to predict PAM50 intrinsic subtypes and applied it to the 41/50 genes of PAM50 through the subtype prediction task. Second, we developed a deep enrichment analysis method to reveal the relationships between the PAM50 subtypes and the copy numbers of breast cancer. Our findings showed that the PWL model utilized genes relevant to the cell cycle-related pathways. These preliminary successes in breast cancer subtype analysis demonstrate the potential of our analysis strategy to clarify the mechanisms underlying breast cancer and improve overall clinical outcomes.

cancer biology↗