The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes.

Blocking PD-1/PD-L1 signaling transforms cancer therapy and is assumed to unleash exhausted tumor-reactive CD8+ T cells in the tumor microenvironment (TME). However, recent studies have also indicated that the systemic tumor-reactive CD8+ T cells may respond to PD-1/PD-L1 immunotherapy. These discrepancies highlight the importance of further defining tumor-specific CD8+ T cell responders to PD-1/PD-L1 blockade. Here, using multiple preclinical tumor models, we revealed that a subset of tumor-specific CD8+ cells in the tumor draining lymph nodes (TdLNs) was not functionally exhausted but exhibited canonical memory characteristics. TdLN-derived tumor-specific memory (TTSM) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-TTSM cells exhibited superior anti-tumor therapeutic efficacy after adoptive transfer and were characterized as bona fide responders to PD-1/PD-L1 blockade. These findings highlight that TdLN-TTSM cells could be harnessed to potentiate anti-tumor immunotherapy.

Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma.

BACKGROUND AND AIMS: Molecular classification is a promising tool for prognosis prediction and optimizing precision therapy for HCC. Here, we aimed to develop a molecular classification of HCC based on the fatty acid degradation (FAD) pathway, fully characterize it, and evaluate its ability in guiding personalized therapy. APPROACH AND RESULTS: We performed RNA sequencing (RNA-seq), PCR-array, lipidomics, metabolomics, and proteomics analysis of 41 patients with HCC, in which 17 patients received anti-programmed cell death-1 (PD-1) therapy. Single-cell RNA sequencing (scRNA-seq) was performed to explore the tumor microenvironment. Nearly, 60 publicly available multiomics data sets were analyzed. The associations between FAD subtypes and response to sorafenib, transarterial chemoembolization (TACE), immune checkpoint inhibitor (ICI) were assessed in patient cohorts, patient-derived xenograft (PDX), and spontaneous mouse model ls. A novel molecular classification named F subtype (F1, F2, and F3) was identified based on the FAD pathway, distinguished by clinical, mutational, epigenetic, metabolic, and immunological characteristics. F1 subtypes exhibited high infiltration with immunosuppressive microenvironment. Subtype-specific therapeutic strategies were identified, in which F1 subtypes with the lowest FAD activities represent responders to compounds YM-155 and Alisertib, sorafenib, anti-PD1, anti-PD-L1, and atezolizumab plus bevacizumab (T + A) treatment, while F3 subtypes with the highest FAD activities are responders to TACE. F2 subtypes, the intermediate status between F1 and F3, are potential responders to T + A combinations. We provide preliminary evidence that the FAD subtypes can be diagnosed based on liquid biopsies. CONCLUSIONS: We identified 3 FAD subtypes with unique clinical and biological characteristics, which could optimize individual cancer patient therapy and help clinical decision-making.

Dual-Ligand Red Perovskite Ink for Electrohydrodynamic Printing Color Conversion Arrays over 2540 dpi in Near-Eye Micro-LED Display.

The lack of stability of red perovskite nanocrystals (PeNCs) remains the main problem that restricts their patterning application. In this work, the dual-ligand passivation strategy was introduced to stabilize PeNCs and inhibit their halogen ion migration during high-voltage electrohydrodynamic (EHD) inkjet printing. The as-printed red arrays exhibit the highest emisson intensity and least blue shift compared with samples with other passivation strategies under a high electric field during EHD inkjet printing. Combining with blue and green PeNC inks, single-color and tricolor color conversion layer arrays were successfully printed, with minimum pixel size of 5 µm and the highest spatial resolution of 2540 dpi. The color coordinate of CsPbBrI2 NCs arrays are located close to the red point, with a color gumat of 97.28% of Rec. 2020 standard. All of these show great potential in the application of color conversion layers in a near-eye micro-LED display.

Glutaryl-CoA dehydrogenase suppresses tumor progression and shapes an anti-tumor microenvironment in hepatocellular carcinoma.

BACKGROUND & AIMS: Crotonylation, a crotonyl-CoA-based non-enzymatic protein translational modification, affects diverse biological processes, such as spermatogenesis, tissue injury, inflammation, and neuropsychiatric diseases. Crotonylation shows decreased in hepatocellular carcinomas (HCCs), but the mechanism remains unknown. In this study, we aim to describe the role of glutaryl-CoA dehydrogenase (GCDH) in tumor suppression. METHODS: Three cohorts containing 40, 248 and 17 pairs of samples were used to evaluate the link between GCDH expression levels and the HCC clinical characteristics as well as anti-PD-1 response. Subcutaneous xenograft, orthotopic xenograft, Trp53Δhep/Δhep; MYC- as well as Ctnnboe; METoe- driven mouse models were adopted to validate GCDH effects on HCC suppression. RESULTS: GCDH depletion promoted HCC growth and metastasis, whereas its overexpression reversed these processes. As GCDH converts glutaryl-CoA to crotonyl-CoA to increase crotonylation levels, we performed lysine crotonylome analysis and identified the pentose phosphate pathway (PPP) and glycolysis-related proteins PGD, TKT, and ALDOC as GCDH-induced crotonylation targets. Crotonyl-bound targets showed allosteric effects that controlled their enzymatic activities, leading to decreases in ribose 5-phosphate and lactate production, further limiting the Warburg effect. PPP blockade also stimulated peroxidation, synergizing with senescent modulators to induce senescence in GCDHhigh cells. These cells induced the infiltration of immune cells by the senescence-associated secretory cell phenotype (SASP) to shape an anti-tumor immune microenvironment. Meanwhile, the GCDHlow population was sensitized to anti-programmed cell death protein 1 (PD-1) therapy. CONCLUSION: GCDH inhibits HCC progression via crotonylation-induced suppression of the PPP and glycolysis, resulting in HCC cell senescence. The senescent cell further shapes an anti-tumor microenvironment by SASP. The GCDHlow population is vulnerable to anti-PD-1 therapy because more PD-1+CD8+ T cells are exhibited in GCDHlow population. IMPACT AND IMPLICATIONS: GCDH is a favorable prognostic indicator in liver, lung, and renal cancers. In addition, most of GCDH depletion-induced toxic metabolites originate from the liver, accumulate locally, and cannot cross the blood-brain barrier. Therefore, studies on the correlation between GCDH and liver cancer would contribute to discovering the initiation and progression of hepatocellular carcinoma, of which over 70% of patients occupied >2-fold GCDH downregulation. Given that the GCDHlow and GCDHhigh HCC population can be distinguished based on serum glucose and ammonia levels, it will be worthwhile to evaluate the curative effects of pro-senescent and immune-therapeutic strategies based on the expression levels of GCDH.

Ileitis promotes MASLD progression via bile acid modulation and enhanced TGR5 signaling in ileal CD8+ T cells.

BACKGROUND & AIMS: Clinical evidence substantiates a link between inflammatory bowel disease, particularly Crohn's disease (CD), and metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to explore the underlying molecular mechanisms responsible for this association. METHODS: MASLD was induced by administering high-fat and western diets, while inflammatory bowel disease was induced using DSS (dextran sulfate sodium) and the Il10 knockout (KO) mouse model. The investigation into the role of secondary bile acids (SBAs) in ileitis involved employing metagenomic sequencing, conducting metabolomics detection, performing fecal microbiota transplantation, and constructing CD8+ T cell-specific gene knockout mice. RESULTS: In MASLD+DSS and Il10 KO MASLD mice, we observed ileitis characterized by T-cell infiltration and activation in the terminal ileum. This condition resulted in decreased bile acid levels in the portal vein and liver, inhibited hepatic farnesoid X receptor (FXR) activation, and exacerbated MASLD. Metagenomic and metabolomic analysis of ileal contents revealed increased Clostridium proliferation and elevated SBA levels in MASLD-associated ileitis. Experiments using germ-free mice and fecal microbiota transplantation suggested an association between SBA and MASLD-related ileitis. In vitro, SBAs promoted CD8+ T-cell activation via the TGR5, mTOR, and oxidative phosphorylation pathways. In vivo, TGR5 KO in CD8+ T cells effectively alleviated ileitis and reversed the MASLD phenotype. Clinical data further supported these findings, demonstrating a positive correlation between ileitis and MASLD. CONCLUSION: MASLD-induced changes in intestinal flora result in elevated levels of SBAs in the ileum. In the presence of a compromised intestinal barrier, this leads to severe CD8+ T cell-mediated ileitis through the TGR5/mTOR/oxidative phosphorylation signaling pathway. Ileitis-induced tissue damage impairs enterohepatic circulation, inhibits hepatic FXR activation, and exacerbates the MASLD phenotype. IMPACT AND IMPLICATIONS: Our study provides a comprehensive investigation of the interplay and underlying mechanisms connecting ileitis and metabolic dysfunction-associated steatotic liver disease (MASLD). Secondary bile acids produced by intestinal bacteria act as the critical link between MASLD and ileitis. Secondary bile acids exert their influence by disrupting liver lipid metabolism through the promotion of CD8+ T cell-mediated ileitis. In future endeavors to prevent and treat MASLD, it is essential to thoroughly account for the impact of the intestinal tract, especially the ileum, on liver function via the enterohepatic circulation.

Spatially resolved current density distribution in GaN-based flip-chip green mini-LEDs by microscopic hyperspectral imaging and modified two-level modeling.

A modified two-level model is proposed to study the spatially resolved current density distribution of GaN-based green miniaturized light-emitting diodes (mini-LEDs), combining with microscopic hyperspectral imaging. We found that the spatially resolved current density distribution reveals both the radiative and non-radiative recombination mappings, which can also be provided separately by this model. In addition, higher current density is not necessarily correlated with higher photon emission, especially for the regions around the electrode edges, where the high current density suggests current crowding and defect-related non-radiative recombination. The current density distribution of mini-LEDs is further verified by the laser-beam-induced current (LBIC) and the spatially resolved mappings of peak wavelength and FWHM. The modified two-level model also offers radiative/non-radiative mappings and is proved to be beneficial to determine the micro-zone current density distribution and to reveal the intrinsic radiative/non-radiative recombination mechanism of mini-LEDs.

Investigation of optical polarization characteristics of ultraviolet-C AlGaN multiple quantum wells by angle-resolved cathodoluminescence.

AlGaN-based ultraviolet-C (UV-C) light-emitting diodes (LEDs) face challenges related to their extremely low external quantum efficiency, which is predominantly attributed to the remarkably inadequate transverse magnetic (TM) light extraction efficiency (LEE). In this study, we employ angle-resolved cathodoluminescence (ARCL) spectroscopy to assess the optical polarization of (0001)-oriented AlGaN multiple quantum well (MQW) structures in UV-C LEDs, in conjunction with a focused ion beam and scanning electron microscopy (FIB/SEM) system to etch samples with various inclination angles (θ) of sidewall. This technique effectively distinguishes the spatial distribution of TM- and transverse electric (TE)-polarized photons contributing to the luminescence of the MQW structure. CL spectroscopy confirms that UV-C LEDs with a θ of 35° exhibit the highest CL signal compared to samples with other θ. Furthermore, we establish a model using finite difference time domain (FDTD) simulation to validate the mechanism of the outcomes. The complementary contribution of TM and TE photons at different specific angles are distinguished by ARCL and confirmed by simulation. At angles near the sidewall, the CL is dominated by the TM photons, which mainly contribute to the increased LEE and the decreased degree of polarization (DOP) to make the spatial distribution of CL more uniform. Additionally, this method allows us to analyze the polarization of light without the need for polarizers, enabling the differentiation of TE and TM modes. This distinction provides flexibility for selecting different emission mode based on various application requirements. The presented approach not only opens up new opportunities for enhanced UV-C light extraction but also provides valuable insights for future endeavors in device fabrication and epitaxial film growth.

Underground Mine Safety and Health: A Hybrid MEREC-CoCoSo System for the Selection of Best Sensor.

This research addresses the paramount issue of enhancing safety and health conditions in underground mines through the selection of optimal sensor technologies. A novel hybrid MEREC-CoCoSo system is proposed, integrating the strengths of the MEREC (Method for Eliciting Relative Weights) and Combined Compromise Solution (CoCoSo) methods. The study involves a three-stage framework: criteria and sensor discernment, criteria weight determination using MEREC, and sensor prioritization through the MEREC-CoCoSo framework. Fifteen criteria and ten sensors were identified, and a comprehensive analysis, including MEREC-based weight determination, led to the prioritization of "Ease of Installation" as the most critical criterion. Proximity sensors were identified as the optimal choice, followed by biometric sensors, gas sensors, and temperature and humidity sensors. To validate the effectiveness of the proposed MEREC-CoCoSo model, a rigorous comparison was conducted with established methods, including VIKOR, TOPSIS, TODIM, ELECTRE, COPRAS, EDAS, and TRUST. The comparison encompassed relevant metrics such as accuracy, sensitivity, and specificity, providing a comprehensive understanding of the proposed model's performance in relation to other established methodologies. The outcomes of this comparative analysis consistently demonstrated the superiority of the MEREC-CoCoSo model in accurately selecting the best sensor for ensuring safety and health in underground mining. Notably, the proposed model exhibited higher accuracy rates, increased sensitivity, and improved specificity compared to alternative methods. These results affirm the robustness and reliability of the MEREC-CoCoSo model, establishing it as a state-of-the-art decision-making framework for sensor selection in underground mine safety. The inclusion of these actual results enhances the clarity and credibility of our research, providing valuable insights into the superior performance of the proposed model compared to existing methodologies. The main objective of this research is to develop a robust decision-making framework for optimal sensor selection in underground mines, with a focus on enhancing safety and health conditions. The study seeks to identify and prioritize critical criteria for sensor selection in the context of underground mine safety. The research strives to contribute to the mining industry by offering a structured and effective approach to sensor selection, prioritizing safety and health in underground mining operations.

LED Junction Temperature Measurement: From Steady State to Transient State.

In this review, we meticulously analyze and consolidate various techniques used for measuring the junction temperature of light-emitting diodes (LEDs) by examining recent advancements in the field as reported in the literature. We initiate our exploration by delineating the evolution of LED technology and underscore the criticality of junction temperature detection. Subsequently, we delve into two key facets of LED junction temperature assessment: steady-state and transient measurements. Beginning with an examination of innovations in steady-state junction temperature detection, we cover a spectrum of approaches ranging from traditional one-dimensional methods to more advanced three-dimensional techniques. These include micro-thermocouple, liquid crystal thermography (LCT), temperature sensitive optical parameters (TSOPs), and infrared (IR) thermography methods. We provide a comprehensive summary of the contributions made by researchers in this domain, while also elucidating the merits and demerits of each method. Transitioning to transient detection, we offer a detailed overview of various techniques such as the improved T3ster method, an enhanced one-dimensional continuous rectangular wave method (CRWM), and thermal reflection imaging. Additionally, we introduce novel methods leveraging high-speed camera technology and reflected light intensity (h-SCRLI), as well as micro high-speed transient imaging based on reflected light (µ_HSTI). Finally, we provide a critical appraisal of the advantages and limitations inherent in several transient detection methods and offer prognostications on future developments in this burgeoning field.

Screening and anti-glioma activity of Chiloscyllium plagiosum anti-human IL-13Rα2 single-domain antibody.

Glioblastoma is a common and fatal malignant tumour of the central nervous system, with high invasiveness. Conventional treatments for this disease, including comprehensive treatment of surgical resection combined with chemoradiotherapy, are ineffective, with low survival rate and extremely poor prognosis. Targeted therapy is promising in overcoming the difficulties in brain tumour treatment and IL-13Rα2 is a widely watched target. The development of new therapies for glioma, however, is challenged by factors, such as the unique location and immune microenvironment of gliomas. The unique advantages of single-domain antibodies (sdAbs) may provide a novel potential treatment for brain tumours. In this study, Chiloscyllium plagiosum was immunized with recombinant IL-13Rα2 protein to produce sdAb and sdAb sequences were screened by multi-omics. The targeted sdAb genes obtained were efficiently expressed in the Escherichia coli prokaryotic expression system, showing a significant binding capacity to IL-13Rα2 in vitro. The cell proliferation and migration inhibitory effects of recombinant variable domain of the new antigen receptor (VNAR) on glioma cells were detected by CCK-8 and cell scratch assays. The sdAb obtained in this study showed high in vitro activity and favourable cell proliferation inhibitory effect on glioma cells, with potential clinical application value. The present study also provides a new direction and experimental basis for the development of targeted therapies for glioma.

The XOR-IDH3α axis controls macrophage polarization in hepatocellular carcinoma.

BACKGROUND & AIMS: Tumor-associated macrophages (TAMs) are indispensable in the hepatocellular carcinoma (HCC) tumor microenvironment. Xanthine oxidoreductase (XOR), also known as xanthine dehydrogenase (XDH), participates in purine metabolism, uric acid production, and macrophage polarization to a pro-inflammatory phenotype. However, the role of XOR in HCC-associated TAMs is unclear. METHODS: We evaluated the XOR level in macrophages isolated from HCC tissues and paired adjacent tissues. We established diethylnitrosamine/carbon tetrachloride (CCl4)-induced and orthotopically implanted HCC mouse models using mice with Xdh-specific depletion in the myeloid cell lineage (Xdhf/fLyz2cre) or Kupffer cells (Xdhf/fClec4fcre). We determined metabolic differences using specific methodologies, including metabolomics and metabolic flux. RESULTS: We found that XOR expression was downregulated in HCC TAMs and positively correlated with patient survival, which was strongly related to the characteristics of the tumor microenvironment, especially hypoxia. Using HCC-inflicted mice (Xdhf/fLyz2cre and Xdhf/fClec4fcre), we revealed that XOR loss in monocyte-derived TAMs rather than Kupffer cells promoted their M2 polarization and CD8+ T-cell exhaustion, which exacerbated HCC progression. In addition, the tricarboxylic acid cycle was disturbed, and the generation of α-ketoglutarate was enhanced within XOR-depleted macrophages. XOR inhibited α-ketoglutarate production by interacting with IDH3α catalytic sites (K142 and Q139). The increased IDH3α activity caused increased adenosine and kynurenic acid production in TAMs, which enhanced the immunosuppressive effects of TAMs and CD8+ T cells. CONCLUSIONS: The XOR-IDH3α axis mediates TAM polarization and HCC progression and may be a small-molecule therapeutic or immunotherapeutic target against suppressive HCC TAMs. IMPACT AND IMPLICATIONS: Immunotherapies have been widely applied to the treatment of hepatocellular carcinoma (HCC), but to date they have been associated with unsatisfactory efficacy. The tumor microenvironment of HCC is full of different infiltrating immune cells. Tumor-associated macrophages (TAMs) are vital components in the tumor microenvironment and are involved in HCC progression. Herein, we confirm the downregulation of XOR expression in TAMs isolated from human HCC. The loss of XOR in monocyte-derived macrophages increases IDH3 activity and results in an increase in α-ketoglutarate production, which can promote M2-like polarization. Additionally, XOR-null TAMs derived from monocytes promote CD8+ T-cell exhaustion via the upregulation of immunosuppressive metabolites, including adenosine and kynurenic acid. Given the prevalence and high rate of incidence of HCC and the need for improved therapeutic options for patients, our findings identify potential therapeutic targets that may be further studied to develop improved therapies.

Optical power degradation mechanisms in 271†nm AlGaN-based deep ultraviolet light-emitting diodes.

The degradation of AlGaN-based UVC LEDs under constant temperature and constant current stress for up to 500 hrs was analyzed in this work. During each degradation stage, the two-dimensional (2D) thermal distributions, I-V curves, optical powers, combining with focused ion beam and scanning electron microscope (FIB/SEM), were thoroughly tested and analyzed the properties and failure mechanisms of UVC LEDs. The results show that: 1) the opto-electrical characteristics measured before/during stress indicate that the increased leakage current and the generation of stress-induced defects increase the non-radiative recombination in the early stress stage, resulting in a decrease in optical power; 2) the increase of temperature caused by the deterioration of the Cr/Al layer of p-metal after 48 hrs of stress aggravates the optical power in UVC LEDs. The 2D thermal distribution in conjunction with FIB/SEM provide a fast and visual way to precisely locate and analyze the failure mechanisms of UVC LEDs.

Investigation on external quantum efficiency droops and inactivation efficiencies of AlGaN-based ultraviolet-c LEDs at 265-285 nm.

The temperature-dependent external quantum efficiency (EQE) droops of 265 nm, 275 nm, 280 nm, and 285 nm AlGaN-based ultraviolet-c light-emitting diodes (UVC-LEDs) differed in Al contents have been comprehensively investigated. The modifiedABCmodel (R = An+Bn2+Cn3) with the current-leakage related term,f(n)= Dn4, has been employed to analyze the recombination mechanisms in these UVC-LED samples. Experimental results reveal that, at relatively low electrical-current levels, the contribution of Shockley-Read-Hall (SRH) recombination exceeds those of the Auger recombination and carrier leakage. At relatively high electrical-current levels, the Auger recombination and carrier leakage jointly dominate the EQE droop phenomenon. Moreover, the inactivation efficiencies of 222 nm excimer lamp, 254 nm portable Mercury lamp, 265 nm, 280 nm, and 285 nm UVC-LED arrays in the inactivation ofEscherichia colihave been experimentally investigated, which could provide a technical reference for fighting against the new COVID-19.

Hollow Cuprous Oxide@Nitrogen-Doped Carbon Nanocapsules for Cascade Chemodynamic Therapy.

Cuprous-based nanozymes have demonstrated great potential for cascade chemodynamic therapy (CDT) due to their higher catalytic efficiency and simple reaction conditions. Here, hollow cuprous oxide@nitrogen-doped carbon (HCONC) dual-shell structures are designed as nanozymes for CDT oncotherapy. This HCONC with a size distribution of 130 nm is synthesized by a one-step hydrothermal method using cupric nitrate and dimethyl formamide as precursors. The thin-layer carbon (1.88 nm) of HCONC enhances the water-stability and reduces the systemic toxicity of cuprous oxide nanocrystals. The dissolved Cu+ of HCONC in acid solution induces a Fenton-like reaction and exhibits a fast reaction rate for catalyzing H2 O2 into highly toxic hydroxyl radicals (·OH). Meanwhile, the formed Cu+ consumes oversaturated glutathione (GSH) to avoid its destruction of ROS at the intracellular level. In general, both cellular and animal experiments show that HCONC demonstrates excellent antitumor ability without causing significant systemic toxicity, which may present tremendous potential for clinical cancer therapy.

Guanine Nucleotide-Binding Protein G(i) Subunit Alpha 2 Exacerbates NASH Progression by Regulating Peroxiredoxin 1-Related Inflammation and Lipophagy.

BACKGROUND AND AIMS: NASH is an advanced stage of liver disease accompanied by lipid accumulation, inflammation, and liver fibrosis. Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2) is a member of the "inhibitory" class of α-subunits, and recent studies showed that Gnai2 deficiency is known to cause reduced weight in mice. However, the role of GNAI2 in hepatocytes, particularly in the context of liver inflammation and lipid metabolism, remains to be elucidated. Herein, we aim to ascertain the function of GNAI2 in hepatocytes and its impact on the development of NASH. APPROACH AND RESULTS: Human liver tissues were obtained from NASH patients and healthy persons to evaluate the expression and clinical relevance of GNAI2. In addition, hepatocyte-specific Gnai2-deficient mice (Gnai2hep-/- ) were fed either a Western diet supplemented with fructose in drinking water (WDF) for 16 weeks or a methionine/choline-deficient diet (MCD) for 6 weeks to investigate the regulatory role and underlying mechanism of Gnai2 in NASH. GNAI2 was significantly up-regulated in liver tissues of patients with NASH. Following feeding with WDF or MCD diets, livers from Gnai2hep-/- mice had reduced steatohepatitis with suppression of markers of inflammation and an increase in lipophagy compared to Gnai2flox/flox mice. Toll-like receptor 4 signals through nuclear factor kappa B to trigger p65-dependent transcription of Gnai2. Intriguingly, immunoprecipitation, immunofluorescence, and mass spectrometry identified peroxiredoxin 1 (PRDX1) as a binding partner of GNAI2. Moreover, the function of PRDX1 in the suppression of TNF receptor-associated factor 6 ubiquitin-ligase activity and glycerophosphodiester phosphodiesterase domain-containing 5-related phosphatidylcholine metabolism was inhibited by GNAI2. Suppression of GNAI2 combined with overexpression of PRDX1 reversed the development of steatosis and fibrosis in vivo. CONCLUSIONS: GNAI2 is a major regulator that leads to the development of NASH. Thus, inhibition of GNAI2 could be an effective therapeutic target for the treatment of NASH.

Transient 2D Junction Temperature Distribution Measurement by Short Pulse Driving and Gated Integration with Ordinary CCD Camera.

The time resolution of the transient process is usually limited by the minimum exposure time of the high-speed camera. In this work, we proposed a method that can achieve nanosecond temporal resolution with an ordinary CCD camera by driving the LED under test with a periodic short-pulse signal and multiple-cycle superposition to obtain two-dimensional transient junction temperature distribution of the heating process. The temporal resolution is determined by the pulse width of the drive source. In the cooling process, the Boxcar gated integration principle is adopted to complete the two-dimensional transient junction temperature distribution with temporal resolution subject to the minimum exposure time of the CCD camera, i.e., 1 µs in this case. To demonstrate the validity of this method, we measured the two-dimensional transient junction temperature distribution of the blue LEDs according to the principle of thermoreflectance and compared it with the thermal imaging method.

Loss of Xanthine Oxidoreductase Potentiates Propagation of Hepatocellular Carcinoma Stem Cells.

BACKGROUND AND AIMS: Liver cancer stem cells (CSCs) exist in the tumor environment and are critically involved in the initiation and progression of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of self-renewal and maintenance of liver CSCs remain poorly understood. APPROACH AND RESULTS: We identified that xanthine oxidoreductase (XOR), which was expressed at low levels in human HCC samples and liver CSCs, restrained HCC formation and chemoresistance by attenuating liver CSC propagation. Mechanistically, XOR physically interacts with ubiquitin-specific peptidase 15 (USP15), thereby promoting deubiquitination of Kelch-like ECH associated protein 1 (KEAP1) to stabilize its expression, which leads to degradation of Nrf2 (nuclear factor erythroid 2-related factor 2) through ubiquitination and subsequently reactive oxygen species accumulation in liver CSCs. Finally, our data reveal that XOR promotes USP15-mediated Nrf2-KEAP1 signaling to block liver CSCs and tumor propagation. CONCLUSION: We identified that XOR may represent a potential therapeutic target for clinical intervention in HCC driven by liver CSCs.

On the exciton-assisted radiative recombination via impurity trap levels in AlGaN deep ultraviolet light-emitting diodes.

For decades, problems of parasitic emissions have been ubiquitously encountered in nearly all deep ultraviolet light-emitting diodes (DUV-LEDs). In this work, 450 nm parasitic peaks in 275 nm AlGaN DUV-LEDs have been studied in details. Upon careful comparisons and analyses on the electroluminescence and photoluminescence spectra at various injection levels and different temperatures, we have discovered a mechanism of exciton-assisted radiative recombination, namely, the reinforcement on radiative recombination via other impurity-trap levels (ITLs) by excitons that are generated in the midst of the band gap. For DUV-LED samples under investigation herein, a system of radiative ITLs within the band gap cannot be neglected. It includes two types of impurities located at two different energy levels, 3.80 eV and 2.75 eV, respectively. The former, establishing a sub-band edge, which behaves like an energy entrance to this system, contains a series of hydrogen-like excitons at a temperature lower than 100 K, which behaves like an energy entrance to this system. On the one hand, these excitons absorb carriers from band-edge and reduce the band-edge recombination. On the other hand they transfer the energy to lower impurity levels, enhancing the radiative recombination and giving rise to the 450 nm parasitic peak.

ARRB1 ameliorates liver ischaemia/reperfusion injury via antagonizing TRAF6-mediated Lysine 6-linked polyubiquitination of ASK1 in hepatocytes.

Hepatic ischaemia/reperfusion (I/R) injury is a major clinical problem during liver surgical procedures, which usually lead to early transplantation failure and higher organ rejection rate, and current effective therapeutic strategies are still limited. Therefore, in-depth exploring of the molecular mechanisms underlying liver I/R injury is key to the development of new therapeutic methods. ß-arrestins are multifunctional proteins serving as important signalling scaffolds in numerous physiopathological processes, including liver-specific diseases. However, the role and underlying mechanism of ß-arrestins in hepatic I/R injury remain largely unknown. Here, we showed that only ARRB1, but not ARRB2, was down-regulated during liver I/R injury. Hepatocyte-specific overexpression of ARRB1 significantly ameliorated liver damage, as demonstrated by decreases in serum aminotransferases, hepatocellular necrosis and apoptosis, infiltrating inflammatory cells and secretion of pro-inflammatory cytokines relative to control mice, whereas experiments with ARRB1 knockout mice gotten opposite effects. Mechanistically, ARRB1 directly interacts with ASK1 in hepatocytes and inhibits its TRAF6-mediated Lysine 6-linked polyubiquitination, which then prevents the activation of ASK1 and its downstream signalling pathway during hepatic I/R injury. In addition, inhibition of ASK1 remarkably abolished the disruptive effect result from ARRB1 deficiency in liver I/R injury in vivo, indicating that ASK1 was required for ARRB1 function in hepatic I/R injury. In conclusion, we proposed that ARRB1 is a novel protective regulator during liver I/R injury, and modulation of the regulatory axis between ARRB1 and ASK1 could be a novel therapeutic strategy to prevent this pathological process.

ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation. The causal mechanism underlying NASH is not fully elucidated. This study investigated the role of ß-Arrestin1 (ARRB1) in the progression of NASH. METHODS: Liver tissue from patients with NASH and controls were obtained to evaluate ARRB1 expression. NASH models were established in Arrb1-knockout and wild-type mice fed either a high-fat diet (HFD) for 26 weeks or a methionine/choline-deficient (MCD) diet for 6 weeks. RESULTS: ARRB1 expression was reduced in liver samples from patients with NASH. Reduced Arrb1 levels were also detected in murine NASH models. Arrb1 deficiency accelerated steatohepatitis development in HFD-/MCD-fed mice (accompanied by the upregulation of lipogenic genes and downregulation of ß-oxidative genes). Intriguingly, ARRB1 was found to interact with growth differentiation factor 15 (GDF15) and facilitated the transportation of GDF15 precursor (pro-GDF15) to the Golgi apparatus for cleavage and maturation. Treatment with recombinant GDF15 ablated the lipid accumulation in the presence of Arrb1 deletion both in vitro and in vivo. Re-expression of Arrb1 in the NASH models ameliorated the liver disease, and this effect was greater in the presence of pro-GDF15 overexpression. By contrast, the effect of pro-GDF15 overexpression alone was impaired in Arrb1-deficient mice. In addition, the severity of liver disease in patients with NASH was negatively correlated with ARRB1 expression. CONCLUSION: ARRB1 acts as a vital regulator in the development of NASH by facilitating the translocation of GDF15 to the Golgi apparatus and its subsequent maturation. Thus, ARRB1 is a potential therapeutic target for the treatment of NASH. LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is associated with the progressive dysfunction of lipid metabolism and a consequent inflammatory response. Decreased ARRB1 is observed in patients with NASH and murine NASH models. Re-expression of Arrb1 in the murine NASH model ameliorated liver disease, an effect which was more pronounced in the presence of pro-GDF15 overexpression, highlighting a promising strategy for NASH therapy.