Multi-frame demosaicing for the Quad Bayer CFA in the color difference domain.

Recently, imaging systems with submicron image sensors have been increasingly adopting the Quad Bayer color filter array (CFA) owing to its high sensitivity under low illumination conditions when pixel binning techniques are employed. Conversely, under sufficient illumination conditions, direct demosaicing methods are required for the Quad Bayer color filter array to obtain a full-resolution color image. However, the Quad Bayer color filter array is more susceptible to aliasing artifacts because of its structural disadvantages compared to the Bayer color filter array. In this paper, we propose the multi-frame demosaicing method to address this problem. The proposed method assesses local spatial contributions within local windows at each pixel to reconstruct the lost spatial resolution caused by aliasing. Additionally, we utilize the color difference domain to exploit inter-channel correlations, aiming to alleviate color artifacts and enhance spatial resolution. The experimental results demonstrate that our proposed method outperforms other methods, both quantitatively and qualitatively, including single-frame-based demosaicing methods and another multi-frame demosaicing method with pixel binning techniques.

Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.

Systematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types.

The complexity of the tumor microenvironment poses significant challenges in cancer therapy. Here, to comprehensively investigate the tumor-normal ecosystems, we perform an integrative analysis of 4.9 million single-cell transcriptomes from 1070 tumor and 493 normal samples in combination with pan-cancer 137 spatial transcriptomics, 8887 TCGA, and 1261 checkpoint inhibitor-treated bulk tumors. We define a myriad of cell states constituting the tumor-normal ecosystems and also identify hallmark gene signatures across different cell types and organs. Our atlas characterizes distinctions between inflammatory fibroblasts marked by AKR1C1 or WNT5A in terms of cellular interactions and spatial co-localization patterns. Co-occurrence analysis reveals interferon-enriched community states including tertiary lymphoid structure (TLS) components, which exhibit differential rewiring between tumor, adjacent normal, and healthy normal tissues. The favorable response of interferon-enriched community states to immunotherapy is validated using immunotherapy-treated cancers (n = 1261) including our lung cancer cohort (n = 497). Deconvolution of spatial transcriptomes discriminates TLS-enriched from non-enriched cell types among immunotherapy-favorable components. Our systematic dissection of tumor-normal ecosystems provides a deeper understanding of inter- and intra-tumoral heterogeneity.

scLENS: data-driven signal detection for unbiased scRNA-seq data analysis.

High dimensionality and noise have limited the new biological insights that can be discovered in scRNA-seq data. While dimensionality reduction tools have been developed to extract biological signals from the data, they often require manual determination of signal dimension, introducing user bias. Furthermore, a common data preprocessing method, log normalization, can unintentionally distort signals in the data. Here, we develop scLENS, a dimensionality reduction tool that circumvents the long-standing issues of signal distortion and manual input. Specifically, we identify the primary cause of signal distortion during log normalization and effectively address it by uniformizing cell vector lengths with L2 normalization. Furthermore, we utilize random matrix theory-based noise filtering and a signal robustness test to enable data-driven determination of the threshold for signal dimensions. Our method outperforms 11 widely used dimensionality reduction tools and performs particularly well for challenging scRNA-seq datasets with high sparsity and variability. To facilitate the use of scLENS, we provide a user-friendly package that automates accurate signal detection of scRNA-seq data without manual time-consuming tuning.

Inflammatory response in dairy cows caused by heat stress and biological mechanisms for maintaining homeostasis.

Climate change increases global temperatures, which is lethal to both livestock and humans. Heat stress is known as one of the various livestock stresses, and dairy cows react sensitively to high-temperature stress. We aimed to better understand the effects of heat stress on the health of dairy cows and observing biological changes. Individual cows were divided into normal (21-22 °C, 50-60% humidity) and high temperature (31-32 °C, 80-95% humidity), respectively, for 7-days. We performed metabolomic and transcriptome analyses of the blood and gut microbiomes of feces. In the high-temperature group, nine metabolites including linoleic acid and fructose were downregulated, and 154 upregulated and 72 downregulated DEGs (Differentially Expressed Genes) were identified, and eighteen microbes including Intestinimonas and Pseudoflavonifractor in genus level were significantly different from normal group. Linoleic acid and fructose have confirmed that associated with various stresses, and functional analysis of DEG and microorganisms showing significant differences confirmed that high-temperature stress is related to the inflammatory response, immune system, cellular energy mechanism, and microbial butyrate production. These biological changes were likely to withstand high-temperature stress. Immune and inflammatory responses are known to be induced by heat stress, which has been identified to maintain homeostasis through modulation at metabolome, transcriptome and microbiome levels. In these findings, heat stress condition can trigger alteration of immune system and cellular energy metabolism, which is shown as reduced metabolites, pathway enrichment and differential microbes. As results of this study did not include direct phenotypic data, we believe that additional validation is required in the future. In conclusion, high-temperature stress contributed to the reduction of metabolites, changes in gene expression patterns and composition of gut microbiota, which are thought to support dairy cows in withstanding high-temperature stress via modulating immune-related genes, and cellular energy metabolism to maintain homeostasis.

Integrative analysis of spatial and single-cell transcriptome data from human pancreatic cancer reveals an intermediate cancer cell population associated with poor prognosis.

BACKGROUND: Recent studies using single-cell transcriptomic analysis have reported several distinct clusters of neoplastic epithelial cells and cancer-associated fibroblasts in the pancreatic cancer tumor microenvironment. However, their molecular characteristics and biological significance have not been clearly elucidated due to intra- and inter-tumoral heterogeneity. METHODS: We performed single-cell RNA sequencing using enriched non-immune cell populations from 17 pancreatic tumor tissues (16 pancreatic cancer and one high-grade dysplasia) and generated paired spatial transcriptomic data from seven patient samples. RESULTS: We identified five distinct functional subclusters of pancreatic cancer cells and six distinct cancer-associated fibroblast subclusters. We deeply profiled their characteristics, and we found that these subclusters successfully deconvoluted most of the features suggested in bulk transcriptome analysis of pancreatic cancer. Among those subclusters, we identified a novel cancer cell subcluster, Ep_VGLL1, showing intermediate characteristics between the extremities of basal-like and classical dichotomy, despite its prognostic value. Molecular features of Ep_VGLL1 suggest its transitional properties between basal-like and classical subtypes, which is supported by spatial transcriptomic data. CONCLUSIONS: This integrative analysis not only provides a comprehensive landscape of pancreatic cancer and fibroblast population, but also suggests a novel insight to the dynamic states of pancreatic cancer cells and unveils potential therapeutic targets.

Distinct features of B cell receptors in neuromyelitis optica spectrum disorder among CNS inflammatory demyelinating diseases.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) stands out among CNS inflammatory demyelinating diseases (CIDDs) due to its unique disease characteristics, including severe clinical attacks with extensive lesions and its association with systemic autoimmune diseases. We aimed to investigate whether characteristics of B cell receptors (BCRs) differ between NMOSD and other CIDDs using high-throughput sequencing. METHODS: From a prospective cohort, we recruited patients with CIDDs and categorized them based on the presence and type of autoantibodies: NMOSD with anti-aquaporin-4 antibodies, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) with anti-myelin oligodendrocyte glycoprotein antibodies, double-seronegative demyelinating disease (DSN), and healthy controls (HCs). The BCR features, including isotype class, clonality, somatic hypermutation (SHM), and the third complementarity-determining region (CDR3) length, were analyzed and compared among the different disease groups. RESULTS: Blood samples from 33 patients with CIDDs (13 NMOSD, 12 MOGAD, and 8 DSN) and 34 HCs were investigated for BCR sequencing. Patients with NMOSD tended to have more activated BCR features compare to the other disease groups. They showed a lower proportion of unswitched isotypes (IgM and IgD) and a higher proportion of switched isotypes (IgG), increased clonality of BCRs, higher rates of SHM, and shorter lengths of CDR3. Notably, advanced age was identified as a clinical factor associated with these activated BCR features, including increased levels of clonality and SHM rates in the NMOSD group. Conversely, no such clinical factors were found to be associated with activated BCR features in the other CIDD groups. CONCLUSIONS: NMOSD patients, among those with CIDDs, displayed the most pronounced B cell activation, characterized by higher levels of isotype class switching, clonality, SHM rates, and shorter CDR3 lengths. These findings suggest that B cell-mediated humoral immune responses and characteristics in NMOSD patients are distinct from those observed in the other CIDDs, including MOGAD. Age was identified as a clinical factor associated with BCR activation specifically in NMOSD, implying the significance of persistent B cell activation attributed to anti-aquaporin-4 antibodies, even in the absence of clinical relapses throughout an individual's lifetime.

Prognostic Performance of Sequential Organ Failure Assessment, Acute Physiology and Chronic Health Evaluation III, and Simplified Acute Physiology Score II Scores in Patients with Suspected Infection According to Intensive Care Unit Type.

We investigated the prognostic performance of scoring systems by the intensive care unit (ICU) type. This was a retrospective observational study using data from the Marketplace for Medical Information in the Intensive Care IV database. The primary outcome was in-hospital mortality. We obtained Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) III, and Simplified Acute Physiology Score (SAPS) II scores in each ICU type. Prognostic performance was evaluated with the area under the receiver operating characteristic curve (AUROC) and was compared among ICU types. A total of 29,618 patients were analyzed, and the in-hospital mortality was 12.4%. The overall prognostic performance of APACHE III was significantly higher than those of SOFA and SAPS II (0.807, [95% confidence interval, 0.799-0.814], 0.785 [0.773-0.797], and 0.795 [0.787-0.811], respectively). The prognostic performance of SOFA, APACHE III, and SAPS II scores was significantly different between ICU types. The AUROC ranges of SOFA, APACHE III, and SAPS II were 0.723-0.826, 0.728-0.860, and 0.759-0.819, respectively. The neurosurgical and surgical ICUs had lower prognostic performance than other ICU types. The prognostic performance of scoring systems in patients with suspected infection is significantly different according to ICU type. APACHE III systems have the highest prediction performance. ICU type may be a significant factor in the prognostication.

Acoustofluidic lysis of cancer cells and Raman spectrum profiling.

The lysis of cancer cells inside a sessile droplet was performed using traveling surface acoustic waves (SAWs) without any chemical reagents. Raman spectrum profiling was then carried out to explore detailed cell-derived data. The Rayleigh waves formed by an interdigital transducer were made to propagate along the surface of an LiNbO3 substrate. Polystyrene microparticles (PSMPs) were used to establish mechanical cell lysis effectively, and gold nanoparticles (AuNPs) were added to enhance the Raman signals from the lysed cells by SAWs. The lysis efficiency was evaluated according to the size and concentration of the PSMPs in experiments where the frequency was varied. Lysis occurred mainly by mechanical collision using PSMPs in a high-frequency domain, and the lysis efficiency was improved by increasing the application time and the energy density of the SAWs. Raman signals from the lysed cells were greatly enhanced by nanogaps formed by the AuNPs, which were evenly distributed irrespective of the SAWs through the frequency-independent behavior of the AuNPs. Finally, detailed Raman spectra of MDA-MB-231, malignant breast cancer cells, were acquired, and various organic matter-derived peaks were observed. The 95% confidence region for cells subjected to lysis was more widely distributed than that of cells not subjected to lysis. The proposed SAW platform is expected to facilitate the detection of small quantities and to be applied in biomedical applications.

Yolk sac cell atlas reveals multiorgan functions during human early development.

The extraembryonic yolk sac (YS) ensures delivery of nutritional support and oxygen to the developing embryo but remains ill-defined in humans. We therefore assembled a comprehensive multiomic reference of the human YS from 3 to 8 postconception weeks by integrating single-cell protein and gene expression data. Beyond its recognized role as a site of hematopoiesis, we highlight roles in metabolism, coagulation, vascular development, and hematopoietic regulation. We reconstructed the emergence and decline of YS hematopoietic stem and progenitor cells from hemogenic endothelium and revealed a YS-specific accelerated route to macrophage production that seeds developing organs. The multiorgan functions of the YS are superseded as intraembryonic organs develop, effecting a multifaceted relay of vital functions as pregnancy proceeds.

Cryobiopsy: A Breakthrough Strategy for Clinical Utilization of Lung Cancer Organoids.

One major challenge associated with lung cancer organoids (LCOs) is their predominant derivation from surgical specimens of patients with early-stage lung cancer. However, patients with advanced lung cancer, who are in need of chemotherapy, often cannot undergo surgery. Therefore, there is an urgent need to successfully generate LCOs from biopsy specimens. Conventional lung biopsy techniques, such as transthoracic needle biopsy and forceps biopsy, only yield small amounts of lung tissue, resulting in a low success rate for culturing LCOs from biopsy samples. Furthermore, potential complications, like bleeding and pneumothorax, make it difficult to obtain sufficient tissue. Another critical issue is the overgrowth of normal lung cells in later passages of LCO culture, and the optimal culture conditions for LCOs are yet to be determined. To address these limitations, we attempted to create LCOs from cryobiopsy specimens obtained from patients with lung cancer (n = 113). Overall, the initial success rate of establishing LCOs from cryobiopsy samples was 40.7% (n = 46). Transbronchial cryobiopsy enables the retrieval of significantly larger amounts of lung tissue than bronchoscopic forceps biopsy. Additionally, cryobiopsy can be employed for peripheral lesions, and it is aided via radial endobronchial ultrasonography. This study significantly improved the success rate of LCO culture and demonstrated that the LCOs retained characteristics that resembled the primary tumors. Single-cell RNA sequencing confirmed high cancer cell purity in early passages of LCOs derived from patients with advanced lung cancer. Furthermore, the three-dimensional structure and intracellular components of LCOs were characterized using three-dimensional holotomography. Finally, drug screening was performed using a specialized micropillar culture system with cryobiopsy-derived LCOs. LCOs derived from cryobiopsy specimens offer a promising solution to the critical limitations of conventional LCOs. Cryobiopsy can be applied to patients with lung cancer at all stages, including those with peripheral lesions, and can provide sufficient cells for LCO generation. Therefore, we anticipate that cryobiopsy will serve as a breakthrough strategy for the clinical application of LCOs in all stages of lung cancer.

A Pilot Study Evaluating LV Diastolic Function with M-Mode Measurement of Mitral Valve Movement in the Parasternal Long Axis View.

This pilot study aimed to develop a new, reliable, and easy-to-use method for the evaluation of diastolic function through the M-mode measurement of mitral valve (MV) movement in the parasternal long axis (PSLA), similar to E-point septal separation (EPSS) used for systolic function estimation. Thirty healthy volunteers from a tertiary emergency department (ED) underwent M-mode measurements of the MV anterior leaflet in the PSLA view. EPSS, A-point septal separation (APSS), A-point opening length (APOL), and E-point opening length (EPOL) were measured in the PSLA view, along with the E and A velocities and e' velocity in the apical four-chamber view. Correlation analyses were performed to assess the relationship between M-mode and Doppler measurements, and the measurement time was evaluated. No significant correlations were found between M-mode and Doppler measurements in the study. However, M-mode measurements exhibited high reproducibility and faster acquisition, and the EPOL value consistently exceeded the APOL value, resembling the E and A pattern. These findings suggest that visually assessing the M-mode pattern on the MV anterior leaflet in the PSLA view may be a practical approach to estimating diastolic function in the ED. Further investigations with a larger and more diverse patient population are needed to validate these findings.

AXL+SIGLEC6+ dendritic cells in cerebrospinal fluid and brain tissues of patients with autoimmune inflammatory demyelinating disease of CNS.

Inflammatory demyelinating disease of the CNS (IDD) is a heterogeneous group of autoimmune diseases, and multiple sclerosis is the most common type. Dendritic cells (DCs), major antigen-presenting cells, have been proposed to play a central role in the pathogenesis of IDD. The AXL+SIGLEC6+ DC (ASDC) has been only recently identified in humans and has a high capability of T cell activation. Nevertheless, its contribution to CNS autoimmunity remains still obscure. Here, we aimed to identify the ASDC in diverse sample types from IDD patients and experimental autoimmune encephalomyelitis (EAE). A detailed analysis of DC subpopulations using single-cell transcriptomics for the paired cerebrospinal fluid (CSF) and blood samples of IDD patients (total n = 9) revealed that three subtypes of DCs (ASDCs, ACY3+ DCs, and LAMP3+ DCs) were overrepresented in CSF compared with their paired blood. Among these DCs, ASDCs were also more abundant in CSF of IDD patients than in controls, manifesting poly-adhesional and stimulatory characteristics. In the brain biopsied tissues of IDD patients, obtained at the acute attack of disease, ASDC were also frequently found in close contact with T cells. Lastly, the frequency of ASDC was found to be temporally more abundant in acute attack of disease both in CSF samples of IDD patients and in tissues of EAE, an animal model for CNS autoimmunity. Our analysis suggests that the ASDC might be involved in the pathogenesis of CNS autoimmunity.

A virtual memory CD8+ T cell-originated subset causes alopecia areata through innate-like cytotoxicity.

Virtual memory T (TVM) cells are a T cell subtype with a memory phenotype but no prior exposure to foreign antigen. Although TVM cells have antiviral and antibacterial functions, whether these cells can be pathogenic effectors of inflammatory disease is unclear. Here we identified a TVM cell-originated CD44super-high(s-hi)CD49dlo CD8+ T cell subset with features of tissue residency. These cells are transcriptionally, phenotypically and functionally distinct from conventional CD8+ TVM cells and can cause alopecia areata. Mechanistically, CD44s-hiCD49dlo CD8+ T cells could be induced from conventional TVM cells by interleukin (IL)-12, IL-15 and IL-18 stimulation. Pathogenic activity of CD44s-hiCD49dlo CD8+ T cells was mediated by NKG2D-dependent innate-like cytotoxicity, which was further augmented by IL-15 stimulation and triggered disease onset. Collectively, these data suggest an immunological mechanism through which TVM cells can cause chronic inflammatory disease by innate-like cytotoxicity.

Scalable, solvent-free transparent film-based air filter with high particulate matter 2.5 filtration efficiency.

Over the course of the COVID-19 pandemic, people have realized the importance of wearing a mask. However, conventional nanofiber-based face masks impede communication between people because of their opacity. Moreover, it remains challenging to achieve both high filtration performance and transparency through fibrous mask filters without using harmful solvents. Herein, scalable transparent film-based filters with high transparency and collection efficiency are fabricated in a facile manner by means of corona discharging and punch stamping. Both methods improve the surface potential of the film while the punch stamping procedure generates micropores in the film, which enhances the electrostatic force between the film and particulate matter (PM), thereby improving the collection efficiency of the film. Moreover, the suggested fabrication method involves no nanofibers and harmful solvents, which mitigates the generation of microplastics and potential risks for the human body. The film-based filter provides a high PM2.5 collection efficiency of 99.9 % while maintaining a transparency of 52 % at the wavelength of 550 nm. This enables people to distinguish the facial expressions of a person wearing a mask composed of the proposed film-based filter. Moreover, the results of durability experiments indicate that the developed film-based filter is anti-fouling, liquid-resistant, microplastic-free and foldability.

Kernel Estimation Using Total Variation Guided GAN for Image Super-Resolution.

Various super-resolution (SR) kernels in the degradation model deteriorate the performance of the SR algorithms, showing unpleasant artifacts in the output images. Hence, SR kernel estimation has been studied to improve the SR performance in several ways for more than a decade. In particular, a conventional research named KernelGAN has recently been proposed. To estimate the SR kernel from a single image, KernelGAN introduces generative adversarial networks(GANs) that utilize the recurrence of similar structures across scales. Subsequently, an enhanced version of KernelGAN, named E-KernelGAN, was proposed to consider image sharpness and edge thickness. Although it is stable compared to the earlier method, it still encounters challenges in estimating sizable and anisotropic kernels because the structural information of an input image is not sufficiently considered. In this paper, we propose a kernel estimation algorithm called Total Variation Guided KernelGAN (TVG-KernelGAN), which efficiently enables networks to focus on the structural information of an input image. The experimental results show that the proposed algorithm accurately and stably estimates kernels, particularly sizable and anisotropic kernels, both qualitatively and quantitatively. In addition, we compared the results of the non-blind SR methods, using SR kernel estimation techniques. The results indicate that the performance of the SR algorithms was improved using our proposed method.

Effect of Coating Thickness on Abrasion and Cutting Performance of NCD-Coated Ball Endmills on Graphite Machining.

Nano-crystalline diamond (NCD) coating to improve the performance of cutting tools, as the coating thickness varies, the cutting performance and lifespan of the tool varies because the radius of its cutting edge and coating surface roughness are altered. Therefore, an in-depth analysis on the impact of the variations in coating thickness on the cutting tool abrasion and quality of machined surface is necessary. In this study, two NCD ball endmills were coated with 8 and 12 µm thicknesses, and the tool abrasion and roughness of the machined plane were observed after milling. Furthermore, the morphology of the coated surface and abrased cutting edge were observed using a 3D confocal microscope. Consequently, we observed that individual nodules were formed on the continuous aggregates as the coating thickness increased, which increased the coated surface roughness. The two damage modes of the aggregation determined the dominant abrasion that occurred on the cutting edges of both types of coating thicknesses. Delamination and crater wear caused a sharp increase in the roughness of the machined surface. In summary, the increase in coating thickness delayed the delamination of the coating but increased the roughness of the cutting edge, which reduced the machined surface roughness.

Single-cell mapping of combinatorial target antigens for CAR switches using logic gates.

Identification of optimal target antigens that distinguish cancer cells from normal surrounding tissue cells remains a key challenge in chimeric antigen receptor (CAR) cell therapy for tumors with intratumoral heterogeneity. In this study, we dissected tissue complexity to the level of individual cells through the construction of a single-cell expression atlas that integrates ~1.4 million tumor, tumor-infiltrating normal and reference normal cells from 412 tumors and 12 normal organs. We used a two-step screening method using random forest and convolutional neural networks to select gene pairs that contribute most to discrimination between individual malignant and normal cells. Tumor coverage and specificity are evaluated for the AND, OR and NOT logic gates based on the combinatorial expression pattern of the pairing genes across individual single cells. Single-cell transcriptome-coupled epitope profiling validates the AND, OR and NOT switch targets identified in ovarian cancer and colorectal cancer.

Catecholamine induces Kupffer cell apoptosis via growth differentiation factor 15 in alcohol-associated liver disease.

Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the ß2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.