Publisher Correction: The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells.

In the version of this article initially published, the institution name for affiliation 3 (Maryland Anderson Cancer Center) was incorrect. The correct institution is MD Anderson Cancer Center. The error has been corrected in the HTML and PDF versions of the article.

Corrigendum: The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells.

This corrects the article DOI: 10.1038/ni.3748.

The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells.

An imbalance in the lineages of immunosuppressive regulatory T cells (Treg cells) and the inflammatory TH17 subset of helper T cells leads to the development of autoimmune and/or inflammatory disease. Here we found that TAZ, a coactivator of TEAD transcription factors of Hippo signaling, was expressed under TH17 cell-inducing conditions and was required for TH17 differentiation and TH17 cell-mediated inflammatory diseases. TAZ was a critical co-activator of the TH17-defining transcription factor RORγt. In addition, TAZ attenuated Treg cell development by decreasing acetylation of the Treg cell master regulator Foxp3 mediated by the histone acetyltransferase Tip60, which targeted Foxp3 for proteasomal degradation. In contrast, under Treg cell-skewing conditions, TEAD1 expression and sequestration of TAZ from the transcription factors RORγt and Foxp3 promoted Treg cell differentiation. Furthermore, deficiency in TAZ or overexpression of TEAD1 induced Treg cell differentiation, whereas expression of a transgene encoding TAZ or activation of TAZ directed TH17 cell differentiation. Our results demonstrate a pivotal role for TAZ in regulating the differentiation of Treg cells and TH17 cells.

Remarkable heat conduction mediated by non-equilibrium phonon polaritons.

Surface waves can lead to intriguing transport phenomena. In particular, surface phonon polaritons (SPhPs), which result from coupling between infrared light and optical phonons, have been predicted to contribute to heat conduction along polar thin films and nanowires1. However, experimental efforts so far suggest only very limited SPhP contributions2-5. Through systematic measurements of thermal transport along the same 3C-SiC nanowires with and without a gold coating on the end(s) that serves to launch SPhPs, here we show that thermally excited SPhPs can substantially enhance the thermal conductivity of the uncoated portion of these wires. The extracted pre-decay SPhP thermal conductance is more than two orders of magnitude higher than the Landauer limit predicted on the basis of equilibrium Bose-Einstein distributions. We attribute the notable SPhP conductance to the efficient launching of non-equilibrium SPhPs from the gold-coated portion into the uncoated SiC nanowires, which is strongly supported by the observation that the SPhP-mediated thermal conductivity is proportional to the length of the gold coating(s). The reported discoveries open the door for modulating energy transport in solids by introducing SPhPs, which can effectively counteract the classical size effect in many technologically important films and improve the design of solid-state devices.

Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity.

Mitochondria need to be juxtaposed to phagosomes for the synergistic production of ample reactive oxygen species (ROS) in phagocytes to kill pathogens. However, how phagosomes transmit signals to recruit mitochondria has remained unclear. Here we found that the kinases Mst1 and Mst2 functioned to control ROS production by regulating mitochondrial trafficking and mitochondrion-phagosome juxtaposition. Mst1 and Mst2 activated the GTPase Rac to promote Toll-like receptor (TLR)-triggered assembly of the TRAF6-ECSIT complex that is required for the recruitment of mitochondria to phagosomes. Inactive forms of Rac, including the human Rac2(D57N) mutant, disrupted the TRAF6-ECSIT complex by sequestering TRAF6 and substantially diminished ROS production and enhanced susceptibility to bacterial infection. Our findings demonstrate that the TLR-Mst1-Mst2-Rac signaling axis is critical for effective phagosome-mitochondrion function and bactericidal activity.

On-device lead sequestration for perovskite solar cells.

Perovskite solar cells, as an emerging high-efficiency and low-cost photovoltaic technology1-6, face obstacles on their way towards commercialization. Substantial improvements have been made to device stability7-10, but potential issues with lead toxicity and leaching from devices remain relatively unexplored11-16. The potential for lead leakage could be perceived as an environmental and public health risk when using perovskite solar cells in building-integrated photovoltaics17-23. Here we present a chemical approach for on-device sequestration of more than 96 per cent of lead leakage caused by severe device damage. A coating of lead-absorbing material is applied to the front and back sides of the device stack. On the glass side of the front transparent conducting electrode, we use a transparent lead-absorbing molecular film containing phosphonic acid groups that bind strongly to lead. On the back (metal) electrode side, we place a polymer film blended with lead-chelating agents between the metal electrode and a standard photovoltaic packing film. The lead-absorbing films on both sides swell to absorb the lead, rather than dissolve, when subjected to water soaking, thus retaining structural integrity for easy collection of lead after damage.

Role of solute carrier transporters in regulating dendritic cell maturation and function.

Dendritic cells (DCs) are specialized antigen-presenting cells that initiate and regulate innate and adaptive immune responses. Solute carrier (SLC) transporters mediate diverse physiological functions and maintain cellular metabolite homeostasis. Recent studies have highlighted the significance of SLCs in immune processes. Notably, upon activation, immune cells undergo rapid and robust metabolic reprogramming, largely dependent on SLCs to modulate diverse immunological responses. In this review, we explore the central roles of SLC proteins and their transported substrates in shaping DC functions. We provide a comprehensive overview of recent studies on amino acid transporters, metal ion transporters, and glucose transporters, emphasizing their essential contributions to DC homeostasis under varying pathological conditions. Finally, we propose potential strategies for targeting SLCs in DCs to bolster immunotherapy for a spectrum of human diseases.

Diagnostic Prediction of portal vein thrombosis in chronic cirrhosis patients using data-driven precision medicine model.

BACKGROUND: Portal vein thrombosis (PVT) is a significant issue in cirrhotic patients, necessitating early detection. This study aims to develop a data-driven predictive model for PVT diagnosis in chronic hepatitis liver cirrhosis patients. METHODS: We employed data from a total of 816 chronic cirrhosis patients with PVT, divided into the Lanzhou cohort (n = 468) for training and the Jilin cohort (n = 348) for validation. This dataset encompassed a wide range of variables, including general characteristics, blood parameters, ultrasonography findings and cirrhosis grading. To build our predictive model, we employed a sophisticated stacking approach, which included Support Vector Machine (SVM), Naïve Bayes and Quadratic Discriminant Analysis (QDA). RESULTS: In the Lanzhou cohort, SVM and Naïve Bayes classifiers effectively classified PVT cases from non-PVT cases, among the top features of which seven were shared: Portal Velocity (PV), Prothrombin Time (PT), Portal Vein Diameter (PVD), Prothrombin Time Activity (PTA), Activated Partial Thromboplastin Time (APTT), age and Child-Pugh score (CPS). The QDA model, trained based on the seven shared features on the Lanzhou cohort and validated on the Jilin cohort, demonstrated significant differentiation between PVT and non-PVT cases (AUROC = 0.73 and AUROC = 0.86, respectively). Subsequently, comparative analysis showed that our QDA model outperformed several other machine learning methods. CONCLUSION: Our study presents a comprehensive data-driven model for PVT diagnosis in cirrhotic patients, enhancing clinical decision-making. The SVM-Naïve Bayes-QDA model offers a precise approach to managing PVT in this population.

Modulating PCGF4/BMI1 Stability Is an Efficient Metastasis-Regulatory Strategy Used by Distinct Subtypes of Cancer-Associated Fibroblasts in Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm prone to metastasis. Whether cancer-associated fibroblasts (CAFs) affect the metastasis of ICC is unclear. Herein, ICC patient-derived CAF lines and related cancerous cell lines were established and the effects of CAFs on the tumor progressive properties of the ICC cancerous cells were analyzed. CAFs could be classified into cancer-restraining or cancer-promoting categories based on distinct tumorigenic effects. The RNA-sequencing analyses of ICC cancerous cell lines identified polycomb group ring finger 4 (PCGF4; alias BMI1) as a potential metastasis regulator. The changes of PCGF4 levels in ICC cells mirrored the restraining or promoting effects of CAFs on ICC migration. Immunohistochemical analyses on the ICC tissue microarrays indicated that PCGF4 was negatively correlated with overall survival of ICC. The promoting effects of PCGF4 on cell migration, drug resistance activity, and stemness properties were confirmed. Mechanistically, cancer-restraining CAFs triggered the proteasome-dependent degradation of PCGF4, whereas cancer-promoting CAFs enhanced the stability of PCGF4 via activating the IL-6/phosphorylated STAT3 pathway. In summary, the current data identified the role of CAFs in ICC metastasis and revealed a new mechanism of the CAFs on ICC progression in which PCGF4 acted as the key effector by both categories of CAFs. These findings shed light on developing comprehensive therapeutic strategies for ICC.

Electrochemical Biosensors for Whole Blood Analysis: Recent Progress, Challenges, and Future Perspectives.

Whole blood, as one of the most significant biological fluids, provides critical information for health management and disease monitoring. Over the past 10 years, advances in nanotechnology, microfluidics, and biomarker research have spurred the development of powerful miniaturized diagnostic systems for whole blood testing toward the goal of disease monitoring and treatment. Among the techniques employed for whole-blood diagnostics, electrochemical biosensors, as known to be rapid, sensitive, capable of miniaturization, reagentless and washing free, become a class of emerging technology to achieve the target detection specifically and directly in complex media, e.g., whole blood or even in the living body. Here we are aiming to provide a comprehensive review to summarize advances over the past decade in the development of electrochemical sensors for whole blood analysis. Further, we address the remaining challenges and opportunities to integrate electrochemical sensing platforms.

Epigenetic regulation of DNA repair gene program by Hippo/YAP1-TET1 axis mediates sorafenib resistance in HCC.

Hepatocellular carcinoma (HCC) is a malignancy that occurs worldwide and is generally associated with poor prognosis. The development of resistance to targeted therapies such as sorafenib is a major challenge in clinical cancer treatment. In the present study, Ten-eleven translocation protein 1 (TET1) was found to be highly expressed in sorafenib-resistant HCC cells and knockdown of TET1 can substantially improve the therapeutic effect of sorafenib on HCC, indicating the potential important roles of TET1 in sorafenib resistance in HCC. Mechanistic studies determined that TET1 and Yes-associated protein 1 (YAP1) synergistically regulate the promoter methylation and gene expression of DNA repair-related genes in sorafenib-resistant HCC cells. RNA sequencing indicated the activation of DNA damage repair signaling was extensively suppressed by the TET1 inhibitor Bobcat339. We also identified TET1 as a direct transcriptional target of YAP1 by promoter analysis and chromatin-immunoprecipitation assays in sorafenib-resistant HCC cells. Furthermore, we showed that Bobcat339 can overcome sorafenib resistance and synergized with sorafenib to induce tumor eradication in HCC cells and mouse models. Finally, immunostaining showed a positive correlation between TET1 and YAP1 in clinical samples. Our findings have identified a previously unrecognized molecular pathway underlying HCC sorafenib resistance, thus revealing a promising strategy for cancer therapy.

Myocardial glycophagy flux dysregulation and glycogen accumulation characterize diabetic cardiomyopathy.

Diabetic heart disease morbidity and mortality is escalating. No specific therapeutics exist and mechanistic understanding of diabetic cardiomyopathy etiology is lacking. While lipid accumulation is a recognized cardiomyocyte phenotype of diabetes, less is known about glycolytic fuel handling and storage. Based on in vitro studies, we postulated the operation of an autophagy pathway in the myocardium specific for glycogen homeostasis - glycophagy. Here we visualize occurrence of cardiac glycophagy and show that the diabetic myocardium is characterized by marked glycogen elevation and altered cardiomyocyte glycogen localization. We establish that cardiac glycophagy flux is disturbed in diabetes. Glycophagy may represent a potential therapeutic target for alleviating the myocardial impacts of metabolic disruption in diabetic heart disease.

Tetrahedral Occupied V Ions Enabling Reversible Three-Electron Redox of Cr3+ /Cr6+ in Layered Cathode Materials for Potassium-Ion Batteries.

Reversible three-electron redox of Cr3+ /Cr6+ in layered cathode materials for rechargeable batteries is very attractive in layered cathode materials, which leads to high capacity and energy density for rechargeable batteries. However, the poor reversibility and Cr-ion migration make it very challenging. In this work, by introducing V ions into tetrahedral sites of layer-structured NaCrO2 , reversible three-electron redox of Cr3+ /Cr6+ is realized successfully in NaCr0.92 V0.05 O2 (NCV05) cathode for potassium-ion batteries with a cut-off voltage of 4.0 V. V ions can weaken the attraction of Cr to electrons, leading to enhanced valence change of Cr ions. On the other hand, V in tetrahedral sites can facilitate the reversible migration of Cr between octahedral and tetrahedral sites via coulombic repulsion to realize the reversible redox between Cr3+ and Cr6+ during charge and discharge processes. In addition, V ions can inhibit the phase transition from O3 phase to O'3 phase during the charge process by adjusting the crystal lattices. As a result, the NaCr0.92 V0.05 O2 cathode exhibits a high reversible capacity of 130 mAh g-1 with promising cycle stability and rate capability. The strategy opens new opportunity for developing high-capacity cathode materials for potassium-ion batteries.

Multiomics integration-based molecular characterizations of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly became a global health challenge, leading to unprecedented social and economic consequences. The mechanisms behind the pathogenesis of SARS-CoV-2 are both unique and complex. Omics-scale studies are emerging rapidly and offer a tremendous potential to unravel the puzzle of SARS-CoV-2 pathobiology, as well as moving forward with diagnostics, potential drug targets, risk stratification, therapeutic responses, vaccine development and therapeutic innovation. This review summarizes various aspects of understanding multiomics integration-based molecular characterizations of COVID-19, which to date include the integration of transcriptomics, proteomics, genomics, lipidomics, immunomics and metabolomics to explore virus targets and developing suitable therapeutic solutions through systems biology tools. Furthermore, this review also covers an abridgment of omics investigations related to disease pathogenesis and virulence, the role of host genetic variation and a broad array of immune and inflammatory phenotypes contributing to understanding COVID-19 traits. Insights into this review, which combines existing strategies and multiomics integration profiling, may help further advance our knowledge of COVID-19.

Electric manipulation on deformation of ionic ferrofluid sessile droplets.

Active electric-driven droplet manipulation in digital microfluidics constitutes a promising domain owing to the unique and programmable wettability inherent in sessile ionic droplets. The coupling between the electric field and flow field enables precise control over wetting characteristics and droplet morphology. This study delves into the deformation phenomena of ionic sessile ferrofluid droplets in ambient air induced by uniform electric fields. Under the assumption of a pinned mode throughout the process, the deformation is characterized by variations in droplet height and contact angle in response to the applied electric field intensity. A numerical model is formulated to simulate the deformation dynamics of ferrofluid droplets, employing the phase field method for tracking droplet deformation. The fidelity of the numerical outcomes is assessed through the validation process, involving a comparison of droplet geometric deformations with corresponding experimental results. The impact of the electric field on the deformation of dielectric droplets is modulated by parameters such as electric field strength and droplet size. Through meticulously designed experiments, the substantial influence of both field strength and droplet size is empirically verified, elucidating the behavior of ionic sessile droplets. Considering the interplay of electric force, viscous force, and interfacial tension, the heightened field intensity is observed to effectively reduce the contact angle, augment droplet height, and intensify internal droplet flow. Under varying electric field conditions, droplets assume diverse shapes, presenting a versatile approach for microfluidic operations. The outcomes of this research hold significant guiding implications for microfluidic manipulation, droplet handling, and sensing applications.

Development and validation of an early mortality risk model for pediatric hemophagocytic lymphohistiocytosis: a comparison with HScore, PELOD-2, P-MODS, and pSOFA.

There has been no severity evaluation model for pediatric patients with hemophagocytic lymphohistiocytosis (HLH) that uses readily available parameters. This study aimed to develop a novel model for predicting the early mortality risk in pediatric patients with HLH using easily obtained parameters whatever etiologic subtype. Patients from one center were divided into training and validation sets for model derivation. The developed model was validated using an independent validation cohort from the second center. The prediction model with nomogram was developed based on logistic regression. The model performance underwent internal and external evaluation and validation using the area under the receiver operating characteristic curve (AUC), calibration curve with 1000 bootstrap resampling, and decision curve analysis (DCA). Model performance was compared with the most prevalent severity evaluation scores, including the PELOD-2, P-MODS, and pSOFA scores. The prediction model included nine variables: glutamic-pyruvic transaminase, albumin, globulin, myohemoglobin, creatine kinase, serum potassium, procalcitonin, serum ferritin, and interval between onset and diagnosis. The AUC of the model for predicting the 28-day mortality was 0.933 and 0.932 in the training and validation sets, respectively. The AUC values of the HScore, PELOD-2, P-MODS and pSOFA were 0.815, 0.745, 0.659 and 0.788, respectively. The DCA of the 28-day mortality prediction exhibited a greater net benefit than the HScore, PELOD-2, P-MODS and pSOFA. Subgroup analyses demonstrated good model performance across HLH subtypes. The novel mortality prediction model in this study can contribute to the rapid assessment of early mortality risk after diagnosis with readily available parameters.

Effect of artificial intelligence on novice-performed colonoscopy: a multicenter randomized controlled tandem study.

BACKGROUND AND AIMS: The efficacy and safety of colonoscopy performed by artificial intelligence (AI)-assisted novices remain unknown. The aim of this study was to compare the lesion detection capability of novices, AI-assisted novices, and experts. METHODS: This multicenter, randomized, noninferiority tandem study was conducted across 3 hospitals in China from May 1, 2022, to November 11, 2022. Eligible patients were randomized into 1 of 3 groups: the CN group (control novice group, withdrawal performed by a novice independently), the AN group (AI-assisted novice group, withdrawal performed by a novice with AI assistance), or the CE group (control expert group, withdrawal performed by an expert independently). Participants underwent a repeat colonoscopy conducted by an AI-assisted expert to evaluate the lesion miss rate and ensure lesion detection. The primary outcome was the adenoma miss rate (AMR). RESULTS: A total of 685 eligible patients were analyzed: 229 in the CN group, 227 in the AN group, and 229 in the CE group. Both AMR and polyp miss rate were lower in the AN group than in the CN group (18.82% vs 43.69% [P < .001] and 21.23% vs 35.38% [P < .001], respectively). The noninferiority margin was met between the AN and CE groups of both AMR and polyp miss rate (18.82% vs 26.97% [P = .202] and 21.23% vs 24.10% [P < .249]). CONCLUSIONS: AI-assisted colonoscopy lowered the AMR of novices, making them noninferior to experts. The withdrawal technique of new endoscopists can be enhanced by AI-assisted colonoscopy. (Clinical trial registration number: NCT05323279.).

Peripheral 5-HT Mediates Gonadotropin-Inhibitory Hormone-Induced Feeding Behavior and Energy Metabolism Disorder in Chickens via the 5-HT2C Receptor.

INTRODUCTION: Since the discovery of gonadotropin-inhibitory hormone (GnIH), it has been found to play a critical role in reproduction in vertebrates. Recently, a regulatory role of GnIH in appetite and energy metabolism has emerged, although its precise physiological mechanisms remain unknown. METHODS: Thus, the present study evaluated the effects of a single or long-term intraperitoneal GnIH treatment on the food intake, weight, and glucolipid metabolism of chickens, as well as investigating the possible neuroendocrinology factors and mechanisms involved in GnIH-induced obesity and glucolipid metabolism disorder. RESULTS: Our results show that the intraperitoneal administration of GnIH to chickens resulted in a marked body mass increase, hyperlipidemia, hyperglycemia, and glucose intolerance. Subsequently, the results of metabolomics studies and the pharmacological inhibition of the 5-HT2C receptor revealed that blocking the 5-HT2C receptor reinforced the effects of GnIH on food intake, body weight, and blood glucose and lipid levels, resulting in even worse cases of GnIH-induced hyperglycemia, hyperlipidemia, and hepatic lipid deposition. This suggests that, via the 5-HT2C receptor, peripheral 5-HT may act as a negative feedback regulator to interplay with GnIH and jointly control energy balance homeostasis in chickens. DISCUSSION: Our present study provides evidence of cross-talk between GnIH and 5-HT in food intake and energy metabolism at the in vivo pharmacological level, and it proposes a molecular basis for these interactions, suggesting that functional interactions between GnIH and 5-HT may open new avenues for understanding the mechanism of the neuroendocrine network involved in appetite and energy metabolism, as well as providing a new therapeutic strategy to prevent obesity, diabetes, and metabolic disorders.

Domino Michael/Oxa-Michael Reactions of the Unsymmetric Double Michael Acceptor for Access to Bicyclic Furo[2,3-b]pyrrole.

By creating an unsymmetric double Michael acceptor 1, we were able to synthesize the nonaromatic-fused bicyclic furo[2,3-b]pyrrole nucleus using a domino Michael/oxa-Michael reaction. Adopting benzoyl acetonitrile 2d (CN as the electron-withdrawing group) as a substrate, we discovered a (DHQ)2AQN-catalyzed method for high diastereo- and enantioselectivity of those products. The reaction path has been determined by isolating the reaction intermediates, and density functional theory calculations support these findings. Beyond providing a synthetic approach, this work illustrated the compounds' possible use in antitumor activity.

Comparative analysis of dexmedetomidine, midazolam, and propofol impact on epilepsy-related mortality in the ICU: insights from the MIMIC-IV database.

BACKGROUND: Dexmedetomidine (Dex), midazolam, and propofol are three distinct sedatives characterized by varying pharmacological properties. Previous literature has indicated the positive impact of each of these sedatives on ICU patients. However, there is a scarcity of clinical evidence comparing the efficacy of Dex, midazolam, and propofol in reducing mortality among people with epilepsy (PWE). This study aimed to assess the impact of Dex, midazolam, and propofol on the survival of PWE. METHODS: The data were retrospectively retrieved from the Medical Information Mart for Intensive Care (MIMIC)-IV database (version 2.0). PWE were categorized into Dex, midazolam, and propofol groups based on the intravenously administered sedatives. PWE without standard drug therapy were included in the control group. Comparative analyses were performed on the data among the groups. RESULTS: The Dex group exhibited a significantly lower proportion of in-hospital deaths and a markedly higher in-hospital survival time compared to the midazolam and propofol groups (p < 0.01) after propensity score matching. Kaplan-Meier curves demonstrated a significant improvement in survival rates for the Dex group compared to the control group (p = 0.025). Analysis of Variance (ANOVA) revealed no significant differences in survival rates among the Dex, midazolam, and propofol groups (F = 1.949, p = 0.143). The nomogram indicated that compared to midazolam and propofol groups, Dex was more effective in improving the survival rate of PWE. CONCLUSION: Dex might improve the survival rate of PWE in the ICU compared to no standard drug intervention. However, Dex did not exhibit superiority in improving survival rates compared to midazolam and propofol.