Gut Microbiota-Derived Butyrate Induces Epigenetic and Metabolic Reprogramming in Myeloid-Derived Suppressor Cells to Alleviate Primary Biliary Cholangitis.

BACKGROUND & AIMS: Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC. METHODS: We measured fecal short-chain fatty acids levels using targeted gas chromatography-mass spectrometry and analyzed circulating MDSCs using flow cytometry in 2 independent PBC cohorts. Human and murine MDSCs were differentiated in vitro in the presence of butyrate, followed by transcriptomic, epigenetic (CUT&Tag-seq and chromatin immunoprecipitation-quantitative polymerase chain reaction), and metabolic (untargeted liquid chromatography-mass spectrometry, mitochondrial stress test, and isotope tracing) analyses. The in vivo role of butyrate-MDSCs was evaluated in a 2-octynoic acid-bovine serum albumin-induced cholangitis murine model. RESULTS: Decreased butyrate levels and defective MDSC function were found in patients with incomplete response to ursodeoxycholic acid, compared with those with adequate response. Butyrate induced expansion and suppressive activity of MDSCs in a manner dependent on PPARD-driven fatty acid ß-oxidation (FAO). Pharmaceutical inhibition or genetic knockdown of the FAO rate-limiting gene CPT1A abolished the effect of butyrate. Furthermore, butyrate inhibited HDAC3 function, leading to enhanced acetylation of lysine 27 on histone H3 at promoter regions of PPARD and FAO genes in MDSCs. Therapeutically, butyrate administration alleviated immune-mediated cholangitis in mice via MDSCs, and adoptive transfer of butyrate-treated MDSCs also displayed protective efficacy. Importantly, reduced expression of FAO genes and impaired mitochondrial physiology were detected in MDSCs from ursodeoxycholic acid nonresponders, and their impaired suppressive function was restored by butyrate. CONCLUSIONS: We identify a critical role for butyrate in modulation of MDSC homeostasis by orchestrating epigenetic and metabolic crosstalk, proposing a novel therapeutic strategy for treating PBC.

Itaconate inhibits CD103 + T RM cells and alleviates hepatobiliary injury in mouse models of primary sclerosing cholangitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease characterized by the infiltration of intrahepatic tissue-resident memory CD8 + T cells (T RM ). Itaconate has demonstrated therapeutic potential in modulating inflammation. An unmet need for PSC is the reduction of biliary inflammation, and we hypothesized that itaconate may directly modulate pathogenic T RM . APPROACH AND RESULTS: The numbers of intrahepatic CD103 + T RM were evaluated by immunofluorescence in PSC (n = 32), and the serum levels of itaconate in PSC (n = 64), primary biliary cholangitis (PBC) (n = 60), autoimmune hepatitis (AIH) (n = 49), and healthy controls (n = 109) were determined by LC-MS/MS. In addition, the frequencies and immunophenotypes of intrahepatic T RM using explants from PSC (n = 5) and healthy donors (n = 6) were quantitated by flow cytometry. The immunomodulatory properties of 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) on CD103 + T RM were studied in vitro. Finally, the therapeutic potential of itaconate was studied by the administration of 4-OI and deficiency of immune-responsive gene 1 (encodes the aconitate decarboxylase producing itaconate) in murine models of PSC. Intrahepatic CD103 + T RM was significantly expanded in PSC and was positively correlated with disease severity. Serum itaconate levels decreased in PSC. Importantly, 4-OI inhibited the induction and effector functions of CD103 + T RM in vitro. Mechanistically, 4-OI blocked DNA demethylation of RUNX3 in CD8 + T cells. Moreover, 4-OI reduced intrahepatic CD103 + T RM and ameliorated liver injury in murine models of PSC. CONCLUSIONS: Itaconate exerted immunomodulatory activity on CD103 + T RM in both in vitro and murine PSC models. Our study suggests that targeting pathogenic CD103 + T RM with itaconate has therapeutic potential in PSC.

Epidemiologic and genetic associations between primary biliary cholangitis and extrahepatic rheumatic diseases.

Patients with primary biliary cholangitis (PBC) commonly experience extrahepatic rheumatic diseases. However, the epidemiologic and genetic associations as well as causal relationship between PBC and these extrahepatic conditions remain undetermined. In this study, we first conducted systematic review and meta-analyses by analyzing 73 studies comprising 334,963 participants across 17 countries and found strong phenotypic associations between PBC and rheumatic diseases. Next, we utilized large-scale genome-wide association study summary data to define the shared genetic architecture between PBC and rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Sjögren's syndrome (SS). We observed significant genetic correlations between PBC and each of the four rheumatic diseases. Pleiotropy and heritability enrichment analysis suggested the involvement of humoral immunity and interferon-associated processes for the comorbidity. Of note, we identified four variants shared between PBC and RA (rs80200208), SLE (rs9843053), and SSc (rs27524, rs3873182) using cross-trait meta-analysis. Additionally, several pleotropic loci for PBC and rheumatic diseases were found to share causal variants with gut microbes possessing immunoregulatory functions. Finally, Mendelian randomization revealed consistent evidence for a causal effect of PBC on RA, SLE, SSc, and SS, but no or inconsistent evidence for a causal effect of extrahepatic rheumatic diseases on PBC. Our study reveals a profound genetic overlap and causal relationships between PBC and extrahepatic rheumatic diseases, thus providing insights into shared biological mechanisms and novel therapeutic interventions.

P4HA2 induces hepatic ductular reaction and biliary fibrosis in chronic cholestatic liver diseases.

BACKGROUNDS: Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in the cholangiocyte pathology of cholestatic liver diseases. METHODS: We studied humans with primary biliary cholangitis (PBC) and Primary sclerosing cholangitis (PSC), P4HA2 -/- mice injured by DDC, and P4HA2 -/- /MDR2 -/- double knockout mice. A parallel study was performed in patients with PBC, PSC, and controls using immunohistochemistry and immunofluorescence. In the murine model, the level of ductular reaction and biliary fibrosis were monitored by histology, qPCR, immunohistochemistry, and Western blotting. Expression of Yes1 Associated Transcriptional Regulator (YAP) phosphorylation was measured in isolated mouse cholangiocytes. The mechanism of P4HA2 was explored in RBE and 293T cell lines by using qPCR, Western blot, immunofluorescence, and co-immunoprecipitation. RESULTS: The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. Cholestatic patients with more severe liver injury correlated with levels of P4HA2 in the liver. In P4HA2 -/- mice, there was a significantly reduced level of ductular reaction and fibrosis compared with controls in the DDC-induced chronic cholestasis. Decreased liver fibrosis and ductular reaction were observed in P4HA2 -/- /MDR2 -/- mice compared with MDR2 -/- mice. Cholangiocytes isolated from P4HA2 -/- /MDR2 -/- mice displayed a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cell proliferation by inducing SAV1 degradation, eventually resulting in the activation of YAP. CONCLUSIONS: P4HA2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC.

Altered faecal microbiome and metabolome in IgG4-related sclerosing cholangitis and primary sclerosing cholangitis.

OBJECTIVE: Multiple clinical similarities exist between IgG4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC), and while gut dysbiosis has been extensively studied in PSC, the role of the gut microbiota in IgG4-SC remains unknown. Herein, we aimed to evaluate alterations of the gut microbiome and metabolome in IgG4-SC and PSC. DESIGN: We performed 16S rRNA gene amplicon sequencing of faecal samples from 135 subjects with IgG4-SC (n=34), PSC (n=37) and healthy controls (n=64). A subset of the samples (31 IgG4-SC, 37 PSC and 45 controls) also underwent untargeted metabolomic profiling. RESULTS: Compared with controls, reduced alpha-diversity and shifted microbial community were observed in IgG4-SC and PSC. These changes were accompanied by differences in stool metabolomes. Importantly, despite some common variations in the microbiota composition and metabolic activity, integrative analyses identified distinct host-microbe associations in IgG4-SC and PSC. The disease-associated genera and metabolites tended to associate with the transaminases in IgG4-SC. Notable depletion of Blautia and elevated succinic acid may underlie hepatic inflammation in IgG4-SC. In comparison, potential links between the microbial or metabolic signatures and cholestatic parameters were detected in PSC. Particularly, concordant decrease of Eubacterium and microbiota-derived metabolites, including secondary bile acids, implicated novel host-microbial metabolic pathways involving cholestasis of PSC. Interestingly, the predictive models based on metabolites were more effective in discriminating disease status than those based on microbes. CONCLUSIONS: Our data reveal that IgG4-SC and PSC possess divergent host-microbe interplays that may be involved in disease pathogenesis. These data emphasise the uniqueness of IgG4-SC.

NUDT1 promotes the accumulation and longevity of CD103+ TRM cells in primary biliary cholangitis.

BACKGROUND & AIMS: Pyruvate dehydrogenase (PDC)-E2 specific CD8+ T cells play a leading role in biliary destruction in PBC. However, there are limited data on the characterization of these autoantigen-specific CD8+ T cells, particularly in the liver. Herein, we aimed to identify pathogenic intrahepatic CD8+ T-cell subpopulations and investigate their immunobiology in PBC. METHODS: Phenotypic and functional analysis of intrahepatic T-cell subsets were performed by flow cytometry. CD103+ TRM cell frequency was evaluated by histological staining. The transcriptome and metabolome were analyzed by RNA-seq and liquid chromatography-mass spectrometry, respectively. Cytotoxicity of TRM cells against cholangiocytes was assayed in a 3D organoid co-culture system. Moreover, the longevity (long-term survival) of TRM cells in vivo was studied by 2-octynoic acid-BSA (2OA-BSA) immunization, Nudt1 conditional knock-out and adoptive co-transfer in a murine model. RESULTS: Intrahepatic CD103+ TRM (CD69+CD103+CD8+) cells were significantly expanded, hyperactivated, and potentially specifically reactive to PDC-E2 in patients with PBC. CD103+ TRM cell frequencies correlated with clinical and histological indices of PBC and predicted poor ursodeoxycholic acid response. NUDT1 blockade suppressed the cytotoxic effector functions of CD103+ TRM cells upon PDC-E2 re-stimulation. NUDT1 overexpression in CD8+ T cells promoted tissue-residence programming in vitro; inhibition or knockdown of NUDT1 had the opposite effect. Pharmacological blockade or genetic deletion of NUDT1 eliminated CD103+ TRM cells and alleviated cholangitis in mice immunized with 2OA-BSA. Significantly, NUDT1-dependent DNA damage resistance potentiates CD8+ T-cell tissue-residency via the PARP1-TGFßR axis in vitro. Consistently, PARP1 inhibition restored NUDT1-deficient CD103+ TRM cell durable survival and TGFß-Smad signaling. CONCLUSIONS: CD103+ TRM cells are the dominant population of PDC-E2-specific CD8+ T lymphocytes in the livers of patients with PBC. The role of NUDT1 in promoting pathogenic CD103+ TRM cell accumulation and longevity represents a novel therapeutic target in PBC. LAY SUMMARY: Primary biliary cholangitis (PBC) is a rare inflammatory condition of the bile ducts. It can be treated with ursodeoxycholic acid, but a large percentage of patients respond poorly to this treatment. Liver-infiltrating memory CD8+ T cells recognizing the PDC-E2 immunodominant epitope are critical in the pathogenesis of PBC. We identifed the key pathogenic CD8+ T cell subset, and worked out the mechanisms of its hyperactivation and longevity, which could be exploited therapeutically.

The Clinical Significance of Hepatic CD69+ CD103+ CD8+ Resident-Memory T Cells in Autoimmune Hepatitis.

BACKGROUND AND AIMS: The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic. APPROACH AND RESULTS: We report herein that CD69+ CD103+ CD8+ tissue-resident memory T cells (TRM ) are significantly increased in the liver of patients with AIH compared to chronic hepatitis B, NAFLD, and healthy control tissues. In addition, there was a significant statistical correlation between elevation of CD8+ TRM cells and AIH disease severity. Indeed, in patients with successful responses to immunosuppression, the frequencies of such hepatic CD8+ TRM cells decreased significantly. CD69+ CD8+ and CD69+ CD103+ CD8+ T cells, also known as CD8+ TRM cells, reflect tissue residency and are well known to provide intense immune antigenic responses. Hence, it was particularly interesting that patients with AIH also manifest an elevated expression of IL-15 and TGF-ß on inflammatory cells, and extensive hepatic expression of E-cadherin; these factors likely contribute to the development and localization of CD8+ TRM cells. Based on these data and, in particular, the relationships between disease severity and CD8+ TRM cells, we studied the mechanisms involved with glucocorticoid (GC) modulation of CD8+ TRM cell expansion. Our data reflect that GCs in vitro inhibit the expansion of CD8+ TRM cells induced by IL-15 and TGF-ß and with direct down-regulation of the nuclear factor Blimp1 of CD8+ TRM cells. CONCLUSIONS: Our data suggest that CD8+ TRM cells play a critical role in the pathogenesis of AIH, and GCs attenuate hepatic inflammation through direct inhibition of CD8+ TRM cell expansion.

3D Reconstruction with Single-Shot Structured Light RGB Line Pattern.

Single-shot 3D reconstruction technique is very important for measuring moving and deforming objects. After many decades of study, a great number of interesting single-shot techniques have been proposed, yet the problem remains open. In this paper, a new approach is proposed to reconstruct deforming and moving objects with the structured light RGB line pattern. The structured light RGB line pattern is coded using parallel red, green, and blue lines with equal intervals to facilitate line segmentation and line indexing. A slope difference distribution (SDD)-based image segmentation method is proposed to segment the lines robustly in the HSV color space. A method of exclusion is proposed to index the red lines, the green lines, and the blue lines respectively and robustly. The indexed lines in different colors are fused to obtain a phase map for 3D depth calculation. The quantitative accuracies of measuring a calibration grid and a ball achieved by the proposed approach are 0.46 and 0.24 mm, respectively, which are significantly lower than those achieved by the compared state-of-the-art single-shot techniques.

Alterations of gut microbiome in autoimmune hepatitis.

OBJECTIVE: The significance of the liver-microbiome axis has been increasingly recognised as a major modulator of autoimmunity. The aim of this study was to take advantage of a large well-defined corticosteroids treatment-naïve group of patients with autoimmune hepatitis (AIH) to rigorously characterise gut dysbiosis compared with healthy controls. DESIGN: We performed a cross-sectional study of individuals with AIH (n=91) and matched healthy controls (n=98) by 16S rRNA gene sequencing. An independent cohort of 28 patients and 34 controls was analysed to validate the results. All the patients were collected before corticosteroids therapy. RESULTS: The gut microbiome of steroid treatment-naïve AIH was characterised with lower alpha-diversity (Shannon and observed operational taxonomic units, both p<0.01) and distinct overall microbial composition compared with healthy controls (p=0.002). Depletion of obligate anaerobes and expansion of potential pathobionts including Veillonella were associated with disease status. Of note, Veillonella dispar, the most strongly disease-associated taxa (p=8.85E-8), positively correlated with serum level of aspartate aminotransferase and liver inflammation. Furthermore, the combination of four patients with AIH-associated genera distinguished AIH from controls with an area under curves of approximately 0.8 in both exploration and validation cohorts. In addition, multiple predicted functional modules were altered in the AIH gut microbiome, including lipopolysaccharide biosynthesis as well as metabolism of amino acids that can be processed by bacteria to produce immunomodulatory metabolites. CONCLUSION: Our study establishes compositional and functional alterations of gut microbiome in AIH and suggests the potential for using gut microbiota as non-invasive biomarkers to assess disease activity.

Alpine grassland plants grow earlier and faster but biomass remains unchanged over 35 years of climate change.

Satellite data indicate significant advancement in alpine spring phenology over decades of climate warming, but corresponding field evidence is scarce. It is also unknown whether this advancement results from an earlier shift of phenological events, or enhancement of plant growth under unchanged phenological pattern. By analyzing a 35-year dataset of seasonal biomass dynamics of a Tibetan alpine grassland, we show that climate change promoted both earlier phenology and faster growth, without changing annual biomass production. Biomass production increased in spring due to a warming-induced earlier onset of plant growth, but decreased in autumn due mainly to increased water stress. Plants grew faster but the fast-growing period shortened during the mid-growing season. These findings provide the first in situ evidence of long-term changes in growth patterns in alpine grassland plant communities, and suggest that earlier phenology and faster growth will jointly contribute to plant growth in a warming climate.

Epigenetics of Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with non-suppurative destruction of the intrahepatic bile ducts. The interplay of genetics and environmental triggers contributes to the onset of the disease and subsequently results in cholestasis and progressive fibrosis. Recently, genome-wide association studies (GWAS) have identified multiple genes influencing the susceptibility to PBC in HLA and non-HLA loci. However, it is estimated that the known risk variants merely account for no more than 20% of the heritability of PBC and causes of the remaining heritability remain uncertain. Increasing evidence suggests that the presence of epigenetic abnormalities may explain the "missing heritability" that cannot be captured by GWAS. Among these epigenetic mechanisms, DNA methylation, histone modification, and noncoding RNAs (i.e. miRNA and lncRNA) are involved in the pathogenesis of PBC. Additionally, telomere dysregulation in biliary epithelial cells (BECs) may play a role in disease onset, whereas a deficiency in sex chromosome and skewed gene expression in the X chromosome may to some extent explain the female dominance in PBC.

Cytotoxic KLRG1 expressing lymphocytes invade portal tracts in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease with an immunopathogenesis that includes highly differentiated cytotoxic T cell infiltration in portal areas. We have taken advantage of a large and well-defined cohort of patients with PBC, AIH, chronic hepatitis virus, and healthy controls to study for the presence of highly differentiated T cells which express the killer cell lectin-like receptor G1 (KLRG1). Such studies were performed using both liver and peripheral blood mononuclear cells. In particular, gene expression data (GSE79850) from 16 PBC patients stratified according to future risk of liver transplantation were analyzed for markers of highly differentiated cytotoxic T cells. Liver biopsy samples from 44 PBC patients were studied by immunohistochemistry and a separate cohort of PBC blood samples were studied by flow cytometry. Gene expression data demonstrated correlation of increased KLRG1 and cytotoxic lymphocyte molecules, such as granzyme B (GZMB) and perforin (PRF1), to disease severity as measured by future risk of liver transplantation. Immunohistochemistry demonstrated abundant infiltration of KLRG1+ cells into liver portal areas (mean of 45% of infiltrating cells, range 25-75%) positively correlated with hepatic inflammatory (r = 0.47, p = 0.001) and hepatic fibrosis (r = 0.34, p = 0.021) scores. KLRG1+ lymphocyte liver portal area infiltration was positively correlated with serum alkaline phosphatase (r = 0.45, p = 0.005) and GGT (r = 0.40, p = 0.014), and AST (r = 0.35, p = 0.033) levels. Mononuclear blood flow cytometry studies showed KLRG1+ lymphocytes had greater levels of cytotoxic molecules (granzyme B and perforin), inflammatory cytokines (IFN-γ and TNF-α) and inflammatory chemokine receptors (CCR5 and CX3CR1) than KLRG1-counterparts. However, clearly the most significant data was that found in liver with the intense portal infiltrates that are unique to PBC. Conclusion: Highly cytotoxic KLRG1+ lymphocytes have invaded PBC liver portal areas. Liver KLRG1 gene expression and the abundance of KLRG1+ lymphocytes are positively correlated with disease biomarkers used as clinical trial outcome measures (liver transplantation and serum alkaline phosphatase), suggesting the targeting of KLRG1+ lymphocytes as a rational approach for PBC therapeutic drug development.

Histologically proven AMA positive primary biliary cholangitis but normal serum alkaline phosphatase: Is alkaline phosphatase truly a surrogate marker?

BACKGROUND AND AIMS: The most highly directed and specific autoantibody in human immunopathology is the serologic hallmark of primary biliary cholangitis (PBC), antimitochondrial antibodies (AMAs). However the clinical significance of finding a positive AMA, with normal alkaline phosphatase (ALP) remains enigmatic. METHODS: We took advantage of 169 consecutive outpatients who were identified as having a positive AMA, but normal ALP levels between January 2012 and January 2018. A liver biopsy was performed on 67/169 of these AMA positive normal ALP patients. RESULTS: In all 169 patients we reconfirmed the AMA and also performed anti-gp210 and anti-sp100, liver stiffness (LSM) assessed by vibration-controlled transient elastography (VCTE), an abdominal computed tomography (CT) scan, and either a magnetic resonance imaging (MRI) or ultrasound. The liver biopsies were reviewed by two unbiased observers. 87.6% of the 169 patients were females with a mean age of 46; the median AMA titer 1:320; an elevated serum IgM was found in 53.3%. Importantly, in patients with a liver biopsy, 55（82.1%）out of 67 had varying degrees of cholangitis activity, diagnostic of PBC. CONCLUSION: In patients who were AMA-positive but had normal ALP levels, more than 80% were associated with histological classic PBC. These data emphasize the importance of a positive AMA, even with a normal ALP and also question the role of ALP as a sole surrogate marker of cholangitis.

How drivers perform under different scenarios: Ability-related driving style extraction for large-scale dataset.

The extraction and analysis of driving style are essential for a comprehensive understanding of human driving behaviours. Most existing studies rely on subjective questionnaires and specific experiments, posing challenges in accurately capturing authentic characteristics of group drivers in naturalistic driving scenarios. As scenario-oriented naturalistic driving data collected by advanced sensors becomes increasingly available, the application of data-driven methods allows for a exhaustive analysis of driving styles across multiple drivers. Following a theoretical differentiation of driving ability, driving performance, and driving style with essential clarifications, this paper proposes a quantitative determination method grounded in large-scale naturalistic driving data. Initially, this paper defines and derives driving ability and driving performance through trajectory optimisation modelling considering various cost indicators. Subsequently, this paper proposes an objective driving style extraction method grounded in the Gaussian mixture model. In the experimental phase, this study employs the proposed framework to extract both driving abilities and performances from the Waymo motion dataset, subsequently determining driving styles. This determination is accomplished through the establishment of quantifiable statistical distributions designed to mirror data characteristics. Furthermore, the paper investigates the distinctions between driving styles in different scenarios, utilising the Jensen-Shannon divergence and the Wilcoxon rank-sum test. The empirical findings substantiate correlations between driving styles and specific scenarios, encompassing both congestion and non-congestion as well as intersection and non-intersection scenarios.

Benchmarking clustering, alignment, and integration methods for spatial transcriptomics.

BACKGROUND: Spatial transcriptomics (ST) is advancing our understanding of complex tissues and organisms. However, building a robust clustering algorithm to define spatially coherent regions in a single tissue slice and aligning or integrating multiple tissue slices originating from diverse sources for essential downstream analyses remains challenging. Numerous clustering, alignment, and integration methods have been specifically designed for ST data by leveraging its spatial information. The absence of comprehensive benchmark studies complicates the selection of methods and future method development. RESULTS: In this study, we systematically benchmark a variety of state-of-the-art algorithms with a wide range of real and simulated datasets of varying sizes, technologies, species, and complexity. We analyze the strengths and weaknesses of each method using diverse quantitative and qualitative metrics and analyses, including eight metrics for spatial clustering accuracy and contiguity, uniform manifold approximation and projection visualization, layer-wise and spot-to-spot alignment accuracy, and 3D reconstruction, which are designed to assess method performance as well as data quality. The code used for evaluation is available on our GitHub. Additionally, we provide online notebook tutorials and documentation to facilitate the reproduction of all benchmarking results and to support the study of new methods and new datasets. CONCLUSIONS: Our analyses lead to comprehensive recommendations that cover multiple aspects, helping users to select optimal tools for their specific needs and guide future method development.

A zinc oxide resonant nano-accelerometer with ultra-high sensitivity.

Nanoelectromechanical system accelerometers have the potential to be utilized in next-generation consumer electronics, inertial navigation, and seismology due to their low cost, small size, and low power consumption. There is an urgent need to develop resonant accelerometer with high sensitivity, precision and robustness. Here, a zinc oxide resonant nano-accelerometer with high sensitivity has been designed and prototyped using zinc oxide nanowires. Within a device two nanowires were symmetrically placed close to a notched flexure to evaluate acceleration based on differential resonant frequencies. Additionally, microleverages were integrated in the accelerometer to enhance its sensitivity by amplifying the inertial force. High performance of the accelerometer has been demonstrated by the measured absolute sensitivity (16.818 kHz/g), bias instability (13.13 µg at 1.2 s integration time) and bandwidth (from 4.78 to 29.64 kHz), respectively. These results suggest that zinc oxide nanowires could be a candidate to develop future nanoelectromechanical resonant accelerometer potentially used for inertial navigation, tilt measurement, and geophysical measurements.

A novel automatic segmentation method directly based on magnetic resonance imaging K-space data for auxiliary diagnosis of glioma.

Background: The use of segmentation architectures in medical imaging, particularly for glioma diagnosis, marks a significant advancement in the field. Traditional methods often rely on post-processed images; however, key details can be lost during the fast Fourier transformation (FFT) process. Given the limitations of these techniques, there is a growing interest in exploring more direct approaches. The adaption of segmentation architectures originally designed for road extraction for medical imaging represents an innovative step in this direction. By employing K-space data as the modal input, this method completely eliminates the information loss inherent in FFT, thereby potentially enhancing the precision and effectiveness of glioma diagnosis. Methods: In the study, a novel architecture based on a deep-residual U-net was developed to accomplish the challenging task of automatically segmenting brain tumors from K-space data. Brain tumors from K-space data with different under-sampling rates were also segmented to verify the clinical application of our method. Results: Compared to the benchmarks set in the 2018 Brain Tumor Segmentation (BraTS) Challenge, our proposed architecture had superior performance, achieving Dice scores of 0.8573, 0.8789, and 0.7765 for the whole tumor (WT), tumor core (TC), and enhanced tumor (ET) regions, respectively. The corresponding Hausdorff distances were 2.5649, 1.6146, and 2.7187 for the WT, TC, and ET regions, respectively. Notably, compared to traditional image-based approaches, the architecture also exhibited an improvement of approximately 10% in segmentation accuracy on the K-space data at different under-sampling rates. Conclusions: These results show the superiority of our method compared to previous methods. The direct performance of lesion segmentation based on K-space data eliminates the time-consuming and tedious image reconstruction process, thus enabling the segmentation task to be accomplished more efficiently.

Gut microbiome pattern impacts treatment response in primary biliary cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is a progressive autoimmune liver disease. An inadequate response to ursodeoxycholic acid (UDCA) poses a high risk of progression toward end-stage liver disease. Gut dysbiosis has been implicated in PBC. Here, we aimed to investigate microbial signatures that permit risk stratification and provide mechanistic insights into novel therapies for PBC. METHODS: We prospectively recruited UDCA treatment-naive patients with PBC and performed metagenomic sequencing and metabolomic profiling using stool and serum samples obtained before (n = 132) and after (n = 59) treatment. PBC microbiome subtypes were identified using unsupervised machine learning methods and validated in two independent cohorts. FINDINGS: PBC baseline metagenomes clustered into two community subtypes characterized by varying abundances of Clostridia taxa. Compared with Clostridialow microbiomes, Clostridiahigh microbiomes were more similar to healthy controls. Notably, patients in the Clostridialow subtype exhibited a 2-fold higher UDCA non-response rate compared to those in the Clostridiahigh subtype (41% vs. 20%, p = 0.015). Integrative analysis of metagenomic and metabolomic data revealed divergent functional modules and metabolic activities between the two metacommunities. In particular, anaerobic fermentation and the production of bioactive metabolites, including tryptophan derivatives and secondary bile acids, crucial for immune regulation and gut barrier maintenance, were markedly diminished in the Clostridialow subtype. Moreover, UDCA administration reconfigured the fecal microbial and metabolic profiles only in the Clostridiahigh group. Importantly, the microbiome subtypes and their associations with UDCA response were reproducible in two independent treatment-naive PBC cohorts. CONCLUSIONS: Characterizing baseline microbiota patterns may enable the prediction of treatment outcomes in PBC and facilitate personalized treatment strategies. FUNDING: This research was mainly supported by the National Natural Science Foundation of China.

A spatiotemporal atlas of cholestatic injury and repair in mice.

Cholestatic liver injuries, characterized by regional damage around the bile ductular region, lack curative therapies and cause considerable mortality. Here we generated a high-definition spatiotemporal atlas of gene expression during cholestatic injury and repair in mice by integrating spatial enhanced resolution omics sequencing and single-cell transcriptomics. Spatiotemporal analyses revealed a key role of cholangiocyte-driven signaling correlating with the periportal damage-repair response. Cholangiocytes express genes related to recruitment and differentiation of lipid-associated macrophages, which generate feedback signals enhancing ductular reaction. Moreover, cholangiocytes express high TGFß in association with the conversion of liver progenitor-like cells into cholangiocytes during injury and the dampened proliferation of periportal hepatocytes during recovery. Notably, Atoh8 restricts hepatocyte proliferation during 3,5-diethoxycarbonyl-1,4-dihydro-collidin damage and is quickly downregulated after injury withdrawal, allowing hepatocytes to respond to growth signals. Our findings lay a keystone for in-depth studies of cellular dynamics and molecular mechanisms of cholestatic injuries, which may further develop into therapies for cholangiopathies.

Health education in the management of chronic diseases among the elderly in the community with the assistance of a Mask R-CNN model.

OBJECTIVE: To analyze the role of health education in the management of chronic diseases in older people in the community and the countermeasures. METHODS: After establishing a community health management model for chronic diseases of the elderly based on references, a prospective study was conducted on 120 elderly patients with chronic diseases registered in Xinyang Zhongxing Community Health Service Center, Xixiangtang District, Nanning City from January 2019 to June 2020. The lottery method was used to divide all patients into observation and control groups. Patients in the control group received conventional chronic disease health management, while the observation group received an additional community-based chronic disease health education model for the elderly on the basis of care given to the control group. The change in chronic disease prevention knowledge mastering, medical compliance behavior score, anxiety and depression score, and quality of life score before and after the intervention were compared. RESULTS: After intervention, the awareness rates of patients in the observation group on the clinical manifestations, diagnostic criteria, high-risk behaviors, susceptible population and preventive measures of chronic diseases were significantly higher than that in the control group (all P<0.05), the scores of diet, exercise and lifestyle were significantly higher than those in the control group (all P<0.05), and the scores of depression and anxiety were significantly lower than those in the control group (all P<0.05). The scores of mental function, physical function and social function were significantly higher than those of control group (all P<0.05). CONCLUSION: Health education intervention play an important role in community management of chronic diseases in elderly patients. It effectively improves patients' understanding of the disease and enhances their compliance to medical advice, while reducing patients' anxiety, depression mood and improving their quality of life.