Diaphragm Assessment by Multimodal Ultrasound Imaging in Healthy Subjects.

Background: In recent years, diaphragm ultrasound (DUS) has been used to identify diaphragm dysfunction in the intensive care unit (ICU). However, there are few studies on DUS parameters to evaluate function, normal ranges, and influencing factors in population. The aim of this study is to provide a methodological reference for clinical evaluation of diaphragm function by measuring different DUS parameters in a healthy population. Methods: A descriptive study was conducted 212 (105 males, 107 females) subjects with normal spirometry underwent ultrasound imaging in this study. The diaphragm contraction and motion related parameters and shear wave velocity (SWV) were measured in the supine position. The effects of gender, age, body mass index (BMI) and lifestyle on diaphragm ultrasound parameters were analyzed. Results: The diaphragm thickness at end-expiration (DT-exp) was 0.14 ±0.05 cm, the diaphragm thickness at end- inspiration (DT-insp) was 0.29±0.10 cm, with thickening fraction (TF) was 1.11±0.54. The diaphragm excursion (DE) was 1.68±0.37cm and diaphragm velocity was 1.45±0.41 cm/s during calm breathing. During deep breathing, the DE was 5.06±1.40cm and diaphragm velocity was 3.20±1.18 cm/s. The Diaphragm shear modulus-longitudinal view were Mean16.72±4.07kPa, Max25.04±5.58kPa, Min11.06±3.88kPa, SD2.56±0.98. The results of diaphragmatic measurement showed that the DT of males was significantly greater than that of females (P< 0.05), but there was no significant difference in TF. The DT-insp (r=0.155, P= 0.024) and the DT-exp (r=0.252, P=0.000) were positively correlated with age, and the DE during calm breathing was negatively correlated with age (r=-0.218, P= 0.001) and BMI (r=-00.280, P= 0.000). The DE (R=0.371, P=0.000) and velocity (R=0.368, P=0.000) during deep breathing were correlated with lifestyle. Conclusion: Our study provides normal reference values of the diaphragm and evaluates the influence of gender, age, body mass index and lifestyle on diaphragmatic morphology.

The Foxo1-YAP-Notch1 axis reprograms STING-mediated innate immunity in NASH progression.

Innate immune activation is critical for initiating hepatic inflammation during nonalcoholic steatohepatitis (NASH) progression. However, the mechanisms by which immunoregulatory molecules recognize lipogenic, fibrotic, and inflammatory signals remain unclear. Here, we show that high-fat diet (HFD)-induced oxidative stress activates Foxo1, YAP, and Notch1 signaling in hepatic macrophages. Macrophage Foxo1 deficiency (Foxo1M-KO) ameliorated hepatic inflammation, steatosis, and fibrosis, with reduced STING, TBK1, and NF-κB activation in HFD-challenged livers. However, Foxo1 and YAP double knockout (Foxo1/YAPM-DKO) or Foxo1 and Notch1 double knockout (Foxo1/Notch1M-DKO) promoted STING function and exacerbated HFD-induced liver injury. Interestingly, Foxo1M-KO strongly reduced TGF-ß1 release from palmitic acid (PA)- and oleic acid (OA)-stimulated Kupffer cells and decreased Col1α1, CCL2, and Timp1 expression but increased MMP1 expression in primary hepatic stellate cells (HSCs) after coculture with Kupffer cells. Notably, PA and OA challenge in Kupffer cells augmented LIMD1 and LATS1 colocalization and interaction, which induced YAP nuclear translocation. Foxo1M-KO activated PGC-1α and increased nuclear YAP activity, modulating mitochondrial biogenesis. Using chromatin immunoprecipitation (ChIP) coupled with massively parallel sequencing (ChIP-Seq) and in situ RNA hybridization, we found that NICD colocalizes with YAP and targets Mb21d1 (cGAS), while YAP functions as a novel coactivator of the NICD, which is crucial for reprogramming STING function in NASH progression. These findings highlight the importance of the macrophage Foxo1-YAP-Notch1 axis as a key molecular regulator that controls lipid metabolism, inflammation, and innate immunity in NASH.

Osteopontin Depletion in Non-haematopoietic Cells Improves Outcomes in Septic Mice by Enhancing Antimicrobial Peptide Production.

Osteopontin (Opn) depletion can improve septic outcomes, but the underlying mechanism remains unknown. In this study, we demonstrated that non-haematopoietic but not haematopoietic Opn depletion improved septic outcomes. Compared to wild-type (WT) mice, co-housed Opn-/- mice displayed enhanced production of antibacterial peptides (AMPs), decreased bacterial loads, and a distinct bacterial composition of gut microbiota. Fecal microbiota transplantation (FMT) and OPN neutralization assay showed that Opn depletion could reduce the bacterial loads and improve septic inflammation. By employing an intestinal organoid culture system, we proved that OPN neutralization in WT organoids could inactivate AKT and decrease FOXO3a phosphorylation, resulting in enhanced AMP production, whereas OPN treatment in OPN deficient organoids could activate AKT and increase FOXO3a phosphorylation, leading to reduced AMP production. Our findings identified OPN as a novel regulatory factor of AMP production to modulate bacterial loads and composition of gut microbiota, in turn affecting sepsis outcomes.

GPX4 transcriptionally promotes liver cancer metastasis via GRHL3/PTEN/PI3K/AKT axis.

Hepatocellular carcinoma (HCC) is among the most fatal types of malignancy, with a high prevalence of relapse and limited treatment options. As a critical regulator of ferroptosis and redox homeostasis, glutathione peroxidase 4 (GPX4) is commonly upregulated in HCC and is hypothesized to facilitate cancer metastasis, but this has not been fully explored in HCC. Here, we report that up-regulated GPX4 expression in HCC is strongly associated with tumor metastasis. FACS-based in vivo and in vitro analysis revealed that a cell subpopulation featuring lower cellular reactive oxygen species levels and ferroptosis resistance were involved in GPX4-mediated HCC metastasis. Mechanistically, GPX4 overexpressed in HCC tumor cells was enriched in the nucleus and transcriptionally silenced GRHL3 expression, thereby activating PTEN/PI3K/AKT signaling and promoting HCC metastasis. Functional studies demonstrated that GPX4 amino acids 110-145 are a binding site that interacts with the GRHL3 promoter. As AKT is a downstream target of GPX4, we combined the AKT inhibitor, AKT-IN3, with lenvatinib to effectively inhibit HCC tumor cell metastasis. Overall, these results indicate that the GPX4/GRHL3/PTEN/PI3K/AKT axis controls HCC cell metastasis and lenvatinib combined with AKT-IN3 represents a potential therapeutic strategy for patients with metastatic HCC.

Direct imaging of dynamic heterogeneous lithium-gold interaction at the electrochemical interface during the charging/discharging processes.

Lithium can smoothly plate on certain lithium alloys in theory, such as the Li-Au alloy, making the alloy/metal films promising current collectors for high energy density anode-free batteries. However, the actual performance of the batteries with alloy film electrodes often rapidly deteriorates. It remains challenging for current imaging approaches to provide sufficient details for fully understanding the process. Here, a "see-through" operando optical microscopic approach that allows direct imaging of Li-Au interaction with high spatiotemporal and chemical resolution has been developed. Through this approach, a two-step Li-Au alloying process that exhibits interesting complementary spatiotemporal evolution paths has been discovered. The alloying process regulates the nucleation of further Li deposition, while the Li nucleation sites generate pores on the electrode film. After several cycles, film rupture occurs due to the generation of an increased number of pores, thus explaining the previously unclear mechanism of poor cycling stability. We have also elucidated the deterioration mechanism of silver electrodes: the growth of defect pores in size, independent of the alloying process. Overall, this new imaging approach opens up an effective and simple way to monitor the dynamic heterogeneity of metal-metal interaction at the electrochemical interface, which could provide helpful insight for designing high-performance batteries.

Knowledge, attitudes and practices regarding spinal vascular malformations among doctors in China: a cross-sectional study.

OBJECTIVE: Knowledge, attitude and practice (KAP) models are essential tools for assessing healthcare professionals' understanding, beliefs and behaviours towards specific health issues. This study aimed to explore the KAP of Chinese doctors in diagnosing and treating spinal vascular malformations (SVM). DESIGN: A web-based cross-sectional survey. SETTING: This study was conducted between October and December 2022 through a self-administered questionnaire. PARTICIPANTS: Participants include full-time doctors who voluntarily participate. Doctors in advanced training, regular training or internships were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: The KAP scores of Chinese doctors in diagnosing and treating SVM measured by the questionnaire. RESULTS: A total of 517 doctors participated in the study, mostly in Shaanxi, China, working in SVM-relevant departments (n=396) or other departments (n=121). The doctors achieved an average knowledge score of 9.66±1.95 (range: 0-12), attitude score of 22.16±1.71 (range: 6-30) and practice scores of 46.13±5.35 for those in SVM-relevant departments (neurosurgery, orthopaedics and neurology) and 8.50±1.25 for those in other departments, respectively, revealing doctors have adequate knowledge, positive attitude and good practice, and those in SVM-relevant departments showing more adeptness compared with those in other departments. Moreover, multivariate logistic regression analysis showed that knowledge about SVM (OR=1.72, 95% CI 1.11 to 2.65, p=0.015), holding a master's degree (OR=1.85, 95% CI 1.14 to 3.00, p=0.013) and working in orthopaedics (OR=0.34, 95% CI 0.13 to 0.88, p=0.026) were independently associated with good attitude. CONCLUSION: Chinese doctors showed adequate knowledge, moderate attitudes and good practice regarding SVM. A continuing education programme may improve clinical practitioners' ability to manage SVM.

Efficient improvement in the electrochemical performance of petal-like lamellar NiMn-LDHs with affluent oxygen vacancies derived from Mn MOF-74.

Supercapacitors (SCs) as a kind of novel energy storage devices have emerged to meet the urgent requirement of environmentally friendly clean energy storage equipment. However, unsatisfactory energy density and low operating voltage tremendously restrict their practical application. Herein, petal-like lamellar NiMn-layered double hydroxide (NiMn-LDH) was successfully fabricated through a simple Ni(NO3)2 etching method with Mn MOF-74 as a sacrificial template. This NiMn-LDH 3/NF electrode exhibited an improved specific capacitance of 1410.2 F g-1 at a current density of 1 A g-1 (Mn MOF-74/NF: 172.2) owing to its high redox activity, compositional flexibility and intercalating capability. Importantly, NiMn-LDH was further optimized via a facile hydroperoxide treatment to harvest NiMn-LDH (O-LDH) with abundant oxygen vacancies, exhibiting remarkable improvement in specific capacitance (990%) compared to original MOF-74 before modification. The preparation of O-LDH enriches the electrode material engineering strategy and achieves improved electrochemical performance for application in new-generation SCs.

A Missing Traffic Data Imputation Method Based on a Diffusion Convolutional Neural Network-Generative Adversarial Network.

Traffic state data are key to the proper operation of intelligent transportation systems (ITS). However, traffic detectors often receive environmental factors that cause missing values in the collected traffic state data. Therefore, aiming at the above problem, a method for imputing missing traffic state data based on a Diffusion Convolutional Neural Network-Generative Adversarial Network (DCNN-GAN) is proposed in this paper. The proposed method uses a graph embedding algorithm to construct a road network structure based on spatial correlation instead of the original road network structure; through the use of a GAN for confrontation training, it is possible to generate missing traffic state data based on the known data of the road network. In the generator, the spatiotemporal features of the reconstructed road network are extracted by the DCNN to realize the imputation. Two real traffic datasets were used to verify the effectiveness of this method, with the results of the proposed model proving better than those of the other models used for comparison.

The macrophage STING-YAP axis controls hepatic steatosis by promoting the autophagic degradation of lipid droplets.

BACKGROUND AND AIMS: The hallmark of NAFLD or hepatic steatosis is characterized by lipid droplet (LD) accumulation in hepatocytes. Autophagy may have profound effects on lipid metabolism and innate immune response. However, how innate immune activation may regulate the autophagic degradation of intracellular LDs remains elusive. APPROACH AND RESULTS: A mouse model of a high-fat diet-induced NASH was used in the myeloid-specific stimulator of interferon genes (STING) knockout or STING/yes-associated protein (YAP) double knockout mice. Liver injury, lipid accumulation, lipid droplet proteins, autophagic genes, chromatin immunoprecipitation coupled with massively parallel sequencing, and RNA-Seq were assessed in vivo and in vitro . We found that high-fat diet-induced oxidative stress activates STING and YAP pathways in hepatic macrophages. The acrophage STING deficiency (myeloid-specific STING knockout) enhances nuclear YAP activity, reduces lipid accumulation, and increases autophagy-related proteins ATG5, ATG7, and light chain 3B but diminishes LD protein perilipin 2 expression. However, disruption of STING and YAP (myeloid STING and YAP double knockout) increases serum alanine aminotransferase and triglyceride levels and reduces ß-fatty acid oxidation gene expression but augments perilipin 2 levels, exacerbating high-fat diet-induced lipid deposition. Chromatin immunoprecipitation coupled with massively parallel sequencing reveals that macrophage YAP targets transmembrane protein 205 and activates AMP-activated protein kinase α, which interacts with hepatocyte mitofusin 2 and induces protein disulfide isomerase activation. Protein disulfide isomerase activates hypoxia-inducible factor-1α signaling, increases autophagosome colocalization with LDs, and promotes the degradation of perilipin 2 by interacting with chaperone-mediated autophagy chaperone HSC70. CONCLUSIONS: The macrophage STING-YAP axis controls hepatic steatosis by reprogramming lipid metabolism in a transmembrane protein 205/mitofusin 2/protein disulfide isomerase-dependent pathway. These findings highlight the regulatory mechanism of the macrophage STING-driven YAP activity on lipid control.

Macrophage RIPK3 triggers inflammation and cell death via the XBP1-Foxo1 axis in liver ischaemia-reperfusion injury.

Background & Aims: Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) is a central player in triggering necroptotic cell death. However, whether macrophage RIPK3 may regulate NOD1-dependent inflammation and calcineurin/transient receptor potential cation channel subfamily M member 7 (TRPM7)-induced hepatocyte death in oxidative stress-induced liver inflammatory injury remains elusive. Methods: A mouse model of hepatic ischaemia-reperfusion (IR) injury, the primary hepatocytes, and bone marrow-derived macrophages were used in the myeloid-specific RIPK3 knockout (RIPK3M-KO) and RIPK3-proficient (RIPK3FL/FL) mice. Results: RIPK3M-KO diminished IR stress-induced liver damage with reduced serum alanine aminotransferase/aspartate aminotransferase levels, macrophage/neutrophil infiltration, and pro-inflammatory mediators compared with the RIPK3FL/FL controls. IR stress activated RIPK3, inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α), x-box binding protein 1 (XBP1), nucleotide-binding oligomerisation domain-containing protein 1 (NOD1), NF-κB, forkhead box O1 (Foxo1), calcineurin A, and TRPM7 in ischaemic livers. Conversely, RIPK3M-KO depressed IRE1α, XBP1, NOD1, calcineurin A, and TRPM7 activation with reduced serum tumour necrosis factor α (TNF-α) levels. Moreover, Foxo1M-KO alleviated IR-induced liver injury with reduced NOD1 and TRPM7 expression. Interestingly, chromatin immunoprecipitation coupled with massively parallel sequencing revealed that macrophage Foxo1 colocalised with XBP1 and activated its target gene Zc3h15 (zinc finger CCCH domain-containing protein 15). Activating macrophage XBP1 enhanced Zc3h15, NOD1, and NF-κB activity. However, disruption of macrophage Zc3h15 inhibited NOD1 and hepatocyte calcineurin/TRPM7 activation, with reduced reactive oxygen species production and lactate dehydrogenase release after macrophage/hepatocyte coculture. Furthermore, adoptive transfer of Zc3h15-expressing macrophages in RIPK3M-KO mice augmented IR-triggered liver inflammation and cell death. Conclusions: Macrophage RIPK3 activates the IRE1α-XBP1 pathway and Foxo1 signalling in IR-stress livers. The XBP1-Foxo1 interaction is essential for modulating target gene Zc3h15 function, which is crucial for the control of NOD1 and calcineurin-mediated TRPM7 activation. XBP1 functions as a transcriptional coactivator of Foxo1 in regulating NOD1-driven liver inflammation and calcineurin/TRPM7-induced cell death. Our findings underscore a novel role of macrophage RIPK3 in stress-induced liver inflammation and cell death, implying the potential therapeutic targets in liver inflammatory diseases. Impact and implications: Macrophage RIPK3 promotes NOD1-dependent inflammation and calcineurin/TRPM7-induced cell death cascade by triggering the XBP1-Foxo1 axis and its target gene Zc3h15, which is crucial for activating NOD1 and calcineurin/TRPM7 function, implying the potential therapeutic targets in stress-induced liver inflammatory injury.

Hierarchical dandelion-like CoS2 hollow microspheres: self-assembly and controllable microwave absorption performance.

The emerging electromagnetic radiation and interference problems have promoted the rapid development of microwave absorption materials (MAMs). However, it remains a severe challenge to construct high-performance microwave absorption materials with broadband, lightweight and corrosion resistance within low filling contents. Herein, hierarchical dandelion-like CoS2 hollow microspheres were reasonably constructed via a solvothermal-hydrothermal etching-in situ vulcanization process. The structure morphology, composition and electromagnetic performance of all samples have been thoroughly tested. The research results demonstrated that the structure morphology of the prepared samples with a volume ratio of 1 : 1 between ethanol and H2O remained intact without serious damage. Notably, the as-obtained hierarchical dandelion-like CoS2 hollow microspheres (25 wt%) exhibited excellent microwave absorption capacity with a minimum reflection loss (RLmin) of -47.3 dB and the corresponding effective absorption bandwidth (EAB) of 8.4 GHz at 3.3 mm. Moreover, the broadest effective absorption bandwidth (EAB, RL < -10 dB) reached 9.0 GHz (9.0-18.0 GHz) at the matching thickness of 3.2 mm. The unparalleled multiple features including hierarchical hollow structure, tunable complex permittivity as well as the enhanced impedance matching endowed CoS2 great promise as high-performance microwave absorbers for solving the problem of electromagnetic pollution.

Thermal conductivity at finite temperature and electronic structure of the ultra-wide band gap fluorinated 2D GaN.

Passivation makes 2D hexagonal structure more stable than the planar variant. Surface fluorinated monolayer of GaN have been found to have ultra-wide band gap and have promising applications in optoelectronic conversion devices. In this work, using theoretical method, we have explored the thermal conductivity as well as the electronic structure of F-GaN. It has a low thermal conductivity of 7.67 W (mK)-1due to the low group velocity and short phonon lifetime. The calculated direct band gap value is 4.63 eV, which could be modulated by strain and biaxial strain is found to more effective. Attractively, direct band gap can be maintained under tensile strain. Breakdown of symmetry by uniaxial strain lifts the band degeneracy of the VBM, which will lead to polarized light emission. The in-depth analysis shows that Ga-F as well as N-F bonds are strongly ionic, which is responsible for its low thermal conductivity and ultra-wide band gap.

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

Opposite atom dependence of isotope engineering of thermal conductivity in bulk and 2D GaN.

Isotope engineering has been shown to be an effective means of regulating thermal conductivity. In this work, we studied the isotope engineering of thermal conductivity in bulk and 2D GaN, and diametrically opposite atom isotope dependence is found. That is, Ga isotope has a large effect (77%) on bulk GaN, while the effect of N isotope on the thermal conductivity is negligible. In 2D GaN, however, N isotope effect (20%) is more significant than that of Ga. Understanding of the different isotope dependence is achieved by deeper insight. Due to the relative magnitude of scattering rate, isotopic scattering influences the thermal conductivity of bulk and 2D GaN in different frequency regions, leading to the opposite atom dependence.

Formation characteristics of bacteria and fungi in sewers: In terms of signal molecule generation.

Bio-metabolism of diverse communities is the main reason of water quality variation in sewers, and the signal molecule generation of communities is dementated to be the key regulation procedure for community metabolism. To reveal the mechanism of pollutant biotransformation in complex sewer environment, this study explored the formation of bacteria and fungi and the signal molecule transduction characteristics in a pilot sewer. In this study, several kinds of signal molecules that produced by bacteria and fungi (C4-HSL, C6-HSL, C8-HSL, farnesol and tyrosol) were detected along the formation process of sewer biofilms. The results showed that, in the early stage, bacterial AHLs signaling molecules are beneficial to the synthesis of EPS, providing a good material basis for the growth of bacterial flora. In addition, tyrosol stimulates the formation of embryonic tubes in yeast cells, further promoting the growth of hyphae. At the later stage, AHLs signaling molecules and tyrosol jointly promoted the growth of biofilms. In conclusion, it is precisely because of the coexistence of bacteria and fungi in the sewer system that the generated signal molecules can jointly promote the synthesis and growth of biofilms through different pathways, and have positive feedback on the biodegradation of various pollutants. Based on the exploration, the ecological patterns of bacterial-fungal communities in urban sewer system were proposed and it could improve the understanding on the pollutant transformation behaviors in sewers.

Evaluation of Contrast-Enhanced Ultrasound in Diagnosis of Acute Kidney Injury of Patients in Intensive Care Unit.

Background: Ultrasound can assess renal perfusion, but its role in the evaluation of acute kidney injury (AKI) is still unclear. This prospective cohort study was to investigate the value of contrast-enhanced ultrasound (CEUS) in the evaluation of AKI in intensive care unit (ICU) patients. Methods: Fifty-eight patients were recruited from ICU between October 2019 and October 2020, and CEUS was used to monitor the renal microcirculation perfusion within 24h after admission. Parameters included rise time (RT), time to peak intensity (TTP), amplitude of peak intensity (PI), area under the curve (AUC), time from peak to one half (TP1/2) of renal cortex and medulla. Ultrasonographical findings, demographics, laboratory, etc were collected for further analysis. Results: There were 30 patients in the AKI group and 28 patients in the non-AKI group. The TTP, PI, TP1/2 of the cortex and the RT, TTP, TP1/2 of the medulla in the AKI group were significantly longer than in the non-AKI group (P < 0.05);. The TTP (OR = 1.261, 95% CI: 1.083-1.468, P = 0.003) (AUCs 0.733, Sen% 83.3, Spe%57.1), TP1/2 (OR = 1.079, 95% CI: 1.009-1.155, P = 0.027) (AUCs 0.658, Sen% 76.7, Spe%50.0) of the cortex and RT (OR = 1.453, 95% CI: 1.051-2.011, P = 0.024) (AUCs 0.686, Sen% 43.3, Spe%92.9) of the medulla were related to the AKI. Eight new-onset AKI cases occurred in the non-AKI group within 7 days, the RT, TTP, TP1/2 of the cortex and medulla were significantly longer in the new-onset AKI group than in the non-AKI group (P < 0.05), but serum creatinine and blood urea nitrogen were no differences between groups (P > 0.05). Conclusion: This study indicates CEUS can assess the renal perfusion in AKI. TTP and TP1/2 of the cortex and RT of the medulla can aid the diagnosis of AKI in ICU patients.

Elevated nuclear PIGL disrupts the cMyc/BRD4 axis and improves PD-1 blockade therapy by dampening tumor immune evasion.

To improve the efficacy of lenvatinib in combination with programmed death-1 (PD-1) blockade therapy for hepatocellular carcinoma (HCC), we screened the suppressive metabolic enzymes that sensitize HCC to lenvatinib and PD-1 blockade, thus impeding HCC progression. After analysis of the CRISPR‒Cas9 screen, phosphatidylinositol-glycan biosynthesis class L (PIGL) ranked first in the positive selection list. PIGL depletion had no effect on tumor cell growth in vitro but reprogrammed the tumor microenvironment (TME) in vivo to support tumor cell survival. Specifically, nuclear PIGL disrupted the interaction between cMyc/BRD4 on the distant promoter of target genes and thus decreased the expression of CCL2 and CCL20, which are involved in shaping the immunosuppressive TME by recruiting macrophages and regulatory T cells. PIGL phosphorylation at Y81 by FGFR2 abolished the interaction of PIGL with importin α/ß1, thus retaining PIGL in the cytosol and facilitating tumor evasion by releasing CCL2 and CCL20. Clinically, elevated nuclear PIGL predicts a better prognosis for HCC patients and presents a positive correlation with CD8 + T-cell enrichment in tumors. Clinically, our findings highlight that the nuclear PIGL intensity or the change in PIGL-Y81 phosphorylation should be used as a biomarker to guide lenvatinib with PD-1 blockade therapy.

Partial Unbalanced Feature Transport for Cross-Modality Cardiac Image Segmentation.

Deep learning based approaches have achieved great success on the automatic cardiac image segmentation task. However, the achieved segmentation performance remains limited due to the significant difference across image domains, which is referred to as domain shift. Unsupervised domain adaptation (UDA), as a promising method to mitigate this effect, trains a model to reduce the domain discrepancy between the source (with labels) and the target (without labels) domains in a common latent feature space. In this work, we propose a novel framework, named Partial Unbalanced Feature Transport (PUFT), for cross-modality cardiac image segmentation. Our model facilities UDA leveraging two Continuous Normalizing Flow-based Variational Auto-Encoders (CNF-VAE) and a Partial Unbalanced Optimal Transport (PUOT) strategy. Instead of directly using VAE for UDA in previous works where the latent features from both domains are approximated by a parameterized variational form, we introduce continuous normalizing flows (CNF) into the extended VAE to estimate the probabilistic posterior and alleviate the inference bias. To remove the remaining domain shift, PUOT exploits the label information in the source domain to constrain the OT plan and extracts structural information of both domains, which are often neglected in classical OT for UDA. We evaluate our proposed model on two cardiac datasets and an abdominal dataset. The experimental results demonstrate that PUFT achieves superior performance compared with state-of-the-art segmentation methods for most structural segmentation.

CT-based radiogenomic analysis dissects intratumor heterogeneity and predicts prognosis of colorectal cancer: a multi-institutional retrospective study.

BACKGROUND: This study aimed to develop a radiogenomic prognostic prediction model for colorectal cancer (CRC) by investigating the biological and clinical relevance of intratumoural heterogeneity. METHODS: This retrospective multi-cohort study was conducted in three steps. First, we identified genomic subclones using unsupervised deconvolution analysis. Second, we established radiogenomic signatures to link radiomic features with prognostic subclone compositions in an independent radiogenomic dataset containing matched imaging and gene expression data. Finally, the prognostic value of the identified radiogenomic signatures was validated using two testing datasets containing imaging and survival information collected from separate medical centres. RESULTS: This multi-institutional retrospective study included 1601 patients (714 females and 887 males; mean age, 65 years ± 14 [standard deviation]) with CRC from 5 datasets. Molecular heterogeneity was identified using unsupervised deconvolution analysis of gene expression data. The relative prevalence of the two subclones associated with cell cycle and extracellular matrix pathways identified patients with significantly different survival outcomes. A radiogenomic signature-based predictive model significantly stratified patients into high- and low-risk groups with disparate disease-free survival (HR = 1.74, P = 0.003). Radiogenomic signatures were revealed as an independent predictive factor for CRC by multivariable analysis (HR = 1.59, 95% CI:1.03-2.45, P = 0.034). Functional analysis demonstrated that the 11 radiogenomic signatures were predominantly associated with extracellular matrix and immune-related pathways. CONCLUSIONS: The identified radiogenomic signatures might be a surrogate for genomic signatures and could complement the current prognostic strategies.