Layer Hall effect in a 2D topological axion antiferromagnet.

Whereas ferromagnets have been known and used for millennia, antiferromagnets were only discovered in the 1930s1. At large scale, because of the absence of global magnetization, antiferromagnets may seem to behave like any non-magnetic material. At the microscopic level, however, the opposite alignment of spins forms a rich internal structure. In topological antiferromagnets, this internal structure leads to the possibility that the property known as the Berry phase can acquire distinct spatial textures2,3. Here we study this possibility in an antiferromagnetic axion insulator-even-layered, two-dimensional MnBi2Te4-in which spatial degrees of freedom correspond to different layers. We observe a type of Hall effect-the layer Hall effect-in which electrons from the top and bottom layers spontaneously deflect in opposite directions. Specifically, under zero electric field, even-layered MnBi2Te4 shows no anomalous Hall effect. However, applying an electric field leads to the emergence of a large, layer-polarized anomalous Hall effect of about 0.5e2/h (where e is the electron charge and h is Planck's constant). This layer Hall effect uncovers an unusual layer-locked Berry curvature, which serves to characterize the axion insulator state. Moreover, we find that the layer-locked Berry curvature can be manipulated by the axion field formed from the dot product of the electric and magnetic field vectors. Our results offer new pathways to detect and manipulate the internal spatial structure of fully compensated topological antiferromagnets4-9. The layer-locked Berry curvature represents a first step towards spatial engineering of the Berry phase through effects such as layer-specific moiré potential.

Endothelial YAP Mediates Hyperglycemia-Induced Platelet Hyperactivity and Arterial Thrombosis.

BACKGROUND: Hyperglycemia-a symptom that characterizes diabetes-is highly associated with atherothrombotic complications. However, the underlying mechanism by which hyperglycemia fuels platelet activation and arterial thrombus formation is still not fully understood. METHODS: The profiles of polyunsaturated fatty acid metabolites in the plasma of patients with diabetes and healthy controls were determined with targeted metabolomics. FeCl3-induced carotid injury model was used to assess arterial thrombus formation in mice with endothelial cell (EC)-specific YAP (yes-associated protein) deletion or overexpression. Flow cytometry and clot retraction assay were used to evaluate platelet activation. RNA sequencing and multiple biochemical analyses were conducted to unravel the underlying mechanism. RESULTS: The plasma PGE2 (prostaglandin E2) concentration was elevated in patients with diabetes with thrombotic complications and positively correlated with platelet activation. The PGE2 synthetases COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E synthase-1) were found to be highly expressed in ECs but not in other type of vessel cells in arteries from both patients with diabetes and hyperglycemic mice, compared with nondiabetic individuals and control mice, respectively. A combination of RNA sequencing and ingenuity pathway analyses indicated the involvement of YAP signaling. EC-specific deletion of YAP limited platelet activation and arterial thrombosis in hyperglycemic mice, whereas EC-specific overexpression of YAP in mice mimicked the prothrombotic state of diabetes, without affecting hemostasis. Mechanistically, we found that hyperglycemia/high glucose-induced endothelial YAP nuclear translocation and subsequently transcriptional expression of COX-2 and mPGES-1 contributed to the elevation of PGE2 and platelet activation. Blockade of EP3 (prostaglandin E receptor 3) activation by oral administration of DG-041 reversed the hyperactivity of platelets and delayed thrombus formation in both EC-specific YAP-overexpressing and hyperglycemic mice. CONCLUSIONS: Collectively, our data suggest that hyperglycemia-induced endothelial YAP activation aggravates platelet activation and arterial thrombus formation via PGE2/EP3 signaling. Targeting EP3 with DG-041 might be therapeutic for diabetes-related thrombosis.

The application of three-dimensional custom-made prostheses in chest wall reconstruction after oncologic sternal resection.

BACKGROUND AND OBJECTIVES: As one of the cutting-edge advances in the field of reconstruction, three-dimensional (3D) printing technology has been constantly being attempted to assist in the reconstruction of complicated large chest wall defects. However, there is little literature assessing the treatment outcomes of 3D printed prostheses for chest wall reconstruction. This study aimed to analyze the surgical outcomes of 3D custom-made prostheses for the reconstruction of oncologic sternal defects and to share our experience in the surgical management of these rare and complex cases. METHODS: We summarized the clinical features of the sternal tumor in our center, described the surgical techniques of the application of 3D customized prosthesis for chest wall reconstruction, and analyzed the perioperative characteristics, complications, overall survival (OS), and recurrence-free survival of patients. RESULTS: Thirty-two patients with the sternal tumor who underwent chest wall resection were identified, among which 13 patients used 3D custom-made titanium implants and 13 patients used titanium mesh for sternal reconstruction. 22 cases were malignant, and chondrosarcoma is the most common type. The mean age was 46.9 years, and 53% (17/32) of the patients were male. The average size of tumor was 6.4 cm, and the mean defect area was 76.4 cm2. 97% (31/32) patients received R0 resection. Complications were observed in 29% (9/32) of patients, of which wound infection (22%, 7/32) was the most common. The OS of the patients was 72% at 5 years. CONCLUSION: We demonstrated that with careful preoperative assessment, 3D customized prostheses could be a viable alternative for complex sternal reconstruction.

Single-cell Mayo Map (scMayoMap): an easy-to-use tool for cell type annotation in single-cell RNA-sequencing data analysis.

BACKGROUND: Single-cell RNA-sequencing (scRNA-seq) has become a widely used tool for both basic and translational biomedical research. In scRNA-seq data analysis, cell type annotation is an essential but challenging step. In the past few years, several annotation tools have been developed. These methods require either labeled training/reference datasets, which are not always available, or a list of predefined cell subset markers, which are subject to biases. Thus, a user-friendly and precise annotation tool is still critically needed. RESULTS: We curated a comprehensive cell marker database named scMayoMapDatabase and developed a companion R package scMayoMap, an easy-to-use single-cell annotation tool, to provide fast and accurate cell type annotation. The effectiveness of scMayoMap was demonstrated in 48 independent scRNA-seq datasets across different platforms and tissues. Additionally, the scMayoMapDatabase can be integrated with other tools and further improve their performance. CONCLUSIONS: scMayoMap and scMayoMapDatabase will help investigators to define the cell types in their scRNA-seq data in a streamlined and user-friendly way.

Targeting BCAA metabolism to potentiate metformin's therapeutic efficacy in the treatment of diabetes in mice.

AIMS/HYPOTHESIS: An increasing body of evidence has shown that the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine and valine) is impaired in obese animals and humans, contributing to the development of insulin resistance and type 2 diabetes. Promoting BCAA catabolism benefits glycaemic control. It remains unclear whether BCAA catabolism plays a role in the therapeutic efficacy of currently used glucose-lowering drugs such as metformin. METHODS: Mice were treated with vehicle or metformin (250 mg/kg per day) for more than 4 weeks to investigate the effects of metformin in vivo. In vitro, primary mouse hepatocytes and HepG2 cells were treated with 2 mmol/l metformin. The therapeutic efficacy of metformin in the treatment of type 2 diabetes was assessed in genetically obese (ob/ob) mice and high-fat-diet-induced obese (DIO) mice. Enhancing BCAA catabolism was achieved with a pharmacological agent, 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2). The ob/ob mice were treated with a low-BCAA diet or intermittent protein restriction (IPR) to reduce BCAA nutritional intake. RESULTS: Metformin unexpectedly inhibited the catabolism of BCAAs in obese mice, resulting in an elevation of BCAA abundance. AMP-activated protein kinase (AMPK) mediated the impact of metformin on BCAA catabolism in hepatocytes. Importantly, enhancing BCAA catabolism via a pharmacological agent BT2 significantly potentiated the glucose-lowering effect of metformin while decreasing circulating BCAA levels in ob/ob and DIO mice. Similar outcomes were achieved by a nutritional approach of reducing BCAA intake. IPR also effectively reduced the circulating BCAA abundance and enhanced metformin's glucose-lowering effect in ob/ob mice. BT2 and IPR treatments reduced the expression of fructose-1,6-bisphosphatase 1, a rate-limiting enzyme in gluconeogenesis, in the kidney but not liver, indicating the involvement of renal gluconeogenesis. CONCLUSIONS/INTERPRETATION: Metformin self-limits its therapeutic efficacy in the treatment of type 2 diabetes by triggering the suppression of BCAA catabolism. Enhancing BCAA catabolism pharmacologically or reducing BCAA intake nutritionally potentiates the glucose-lowering effect of metformin. These data highlight the nutritional impact of protein on metformin's therapeutic efficacy and provide new strategies targeting BCAA metabolism to improve metformin's effects on the clinical outcome in diabetes.

Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice.

Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy.

Edge-Cloud Collaborative Defense against Backdoor Attacks in Federated Learning.

Federated learning has a distributed collaborative training mode, widely used in IoT scenarios of edge computing intelligent services. However, federated learning is vulnerable to malicious attacks, mainly backdoor attacks. Once an edge node implements a backdoor attack, the embedded backdoor mode will rapidly expand to all relevant edge nodes, which poses a considerable challenge to security-sensitive edge computing intelligent services. In the traditional edge collaborative backdoor defense method, only the cloud server is trusted by default. However, edge computing intelligent services have limited bandwidth and unstable network connections, which make it impossible for edge devices to retrain their models or update the global model. Therefore, it is crucial to detect whether the data of edge nodes are polluted in time. This paper proposes a layered defense framework for edge-computing intelligent services. At the edge, we combine the gradient rising strategy and attention self-distillation mechanism to maximize the correlation between edge device data and edge object categories and train a clean model as much as possible. On the server side, we first implement a two-layer backdoor detection mechanism to eliminate backdoor updates and use the attention self-distillation mechanism to restore the model performance. Our results show that the two-stage defense mode is more suitable for the security protection of edge computing intelligent services. It can not only weaken the effectiveness of the backdoor at the edge end but also conduct this defense at the server end, making the model more secure. The precision of our model on the main task is almost the same as that of the clean model.

Hydrothermal treatment enhances energy recovery from pig manure digestate and improves the properties of residues.

Energy recovery from biowaste is of high significance for a sustainable society. Herein, hydrothermal treatment (HT) was applied to valorize pig manure digestate. The effects of hydrothermal operational parameters, including temperature (130-250 °C), residence time (15-90 min), and total solid (TS) concentration (10%-20%), on reducing sugar yield were investigated in this study. Among them, hydrothermal temperature was identified as the most important factor influencing reducing sugar yield, followed by the TS concentration and time. The optimal hydrothermal conditions for the pig manure digestate were 175.6 °C, 35.4 min and a TS concentration of 10% with a reduced sugar yield of 9.81 mg gTS-1. The addition of hydrolysate could enhance methane production by 21.6-50.4% from the anaerobic digestion of pig manure than that without the hydrolysate addition. After HT, the hygienic quality, including fecal coliform number and ascaris egg mortality, was improved in the residual digestate. Antibiotics such as sulfamonomethoxine, oxytetracycline, doxycycline and sulfaclodazine in the pig manure digestate were decomposed during HT and decreased environmental risk. These findings indicated that the hydrothermal process might be an effective technique to recover energy from the digestate of livestock and poultry manure and to improve the residual digestate for subsequent utilization.

Environmental pollutant exposure associated with altered early-life gut microbiome: Results from a birth cohort study.

Emerging evidence shows that the gut microbiota interacts with environmental pollutants, but the effect of early exposure on the neonatal microbiome remains unknown. We investigated the association between maternal exposure to environmental pollutants and changes in early-life gut microbiome development. We surveyed 16S rRNA gene on meconium and fecal samples (at 1, 3, and 6 months) from the Brazilian birth cohort, and associated with levels of metals, perfluoroalkyl chemicals (PFAS), and pesticides in maternal and umbilical cord blood. The results indicate that the magnitude of the microbiome changes associated with increasing pollutant exposure was bigger in cesarean-section (CS) born and CS-born-preterm babies, in relation to vaginally (VG) delivered infants. Breastfeeding was associated with a stronger pollutant-associated effect on the infant feces, suggesting that the exposure source could be maternal milk. Differences in microbiome effects associated with maternal or cord blood pollutant concentrations suggest that fetal exposure time - intrauterine or perinatal - may matter. Finally, despite the high developmental microbiota variability, specific microbionts were consistently affected across all pollutants, with taxa clusters found in samples from infants exposed to the highest toxicant exposure. The results evidence that perinatal exposure to environmental pollutants is associated with alterations in gut microbiome development which may have health significance.

Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets.

BACKGROUND: Branched-chain amino acids (BCAAs), essential nutrients including leucine, isoleucine, and valine, serve as a resource for energy production and the regulator of important nutrient and metabolic signals. Recent studies have suggested that dysfunction of BCAA catabolism is associated with the risk of cardiovascular disease. Platelets play an important role in cardiovascular disease, but the functions of BCAA catabolism in platelets remain unknown. METHODS: The activity of human platelets from healthy subjects before and after ingestion of BCAAs was measured. Protein phosphatase 2Cm specifically dephosphorylates branched-chain α-keto acid dehydrogenase and thereby activates BCAA catabolism. Protein phosphatase 2Cm-deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation. RESULTS: We found that ingestion of BCAAs significantly promoted human platelet activity (n=5; P<0.001) and arterial thrombosis formation in mice (n=9; P<0.05). We also found that the valine catabolite α-ketoisovaleric acid and the ultimate oxidation product propionyl-coenzyme A showed the strongest promotion effects on platelet activation, suggesting that the valine/α-ketoisovaleric acid catabolic pathway plays a major role in BCAA-facilitated platelet activation. Protein phosphatase 2Cm deficiency significantly suppresses the activity of platelets in response to agonists (n=5; P<0.05). Our results also suggested that BCAA metabolic pathways may be involved in the integrin αIIbß3-mediated bidirectional signaling pathway that regulates platelet activation. Mass spectrometry identification and immunoblotting revealed that BCAAs enhanced propionylation of tropomodulin-3 at K255 in platelets or Chinese hamster ovary cells expressing integrin αIIbß3. The tropomodulin-3 K255A mutation abolished propionylation and attenuated the promotion effects of BCAAs on integrin-mediated cell spreading, suggesting that K255 propionylation of tropomodulin-3 is an important mechanism underlying integrin αIIbß3-mediated BCAA-facilitated platelet activation and thrombosis formation. In addition, the increased levels of BCAAs and the expression of positive regulators of BCAA catabolism in platelets from patients with type 2 diabetes mellitus are significantly correlated with platelet hyperreactivity. Lowering dietary BCAA intake significantly reduced platelet activity in ob/ob mice (n=4; P<0.05). CONCLUSIONS: BCAA catabolism is an important regulator of platelet activation and is associated with arterial thrombosis risk. Targeting the BCAA catabolism pathway or lowering dietary BCAA intake may serve as a novel therapeutic strategy for metabolic syndrome-associated thrombophilia.

miR-182-5p Promotes Growth in Oral Squamous Cell Carcinoma by Inhibiting CAMK2N1.

BACKGROUND/AIMS: Emerging evidence suggests that the propagation of oral squamous cell carcinoma (OSCC) is influenced by the abnormal expression of microRNAs (miRNAs). This study aimed to characterize the involvement of miR-182-5p in OSCC by targeting the calcium/ calmodulin-dependent protein kinase II inhibitor CAMK2N1. METHODS: miR-182-5p expression was quantified in OSCC tissues and cell lines with reverse transcription polymerase chain reaction (RT-PCR). Cell colony formation, Cell Counting Kit-8 (CCK-8), Ki-67, and nude mouse xenograft assays were used to characterize the role of miR-182-5p in the proliferation of OSCC. A miR-182-5p target gene was identified with western blotting, RT-PCR, and luciferase activity assays. OSCC patient survival based on CAMK2N1 expression was also analyzed. RESULTS: miR-182-5p was up-regulated in in vitro cell lines and in vivo clinical OSCC samples. CCK-8, colony formation, and Ki-67 assays revealed that miR-182-5p promoted the growth and proliferation of OSCC cells. miR-182-5p directly targeted CAMK2N1, as evidenced by luciferase assays and target prediction algorithms. CAMK2N1 operated as a tumor suppressor gene in patients with OSCC. Down-regulating miR-182-5p expression in the CAL-27 cell line restored CAMK2N1-mediated OSCC cell proliferation. miR-182-5p expression inhibited the activation of AKT, ERK1/2, and NF-κB. Mice injected with CAL-27 cells transfected with miR-182-5p-inhibitor demonstrated a significant increase in tumor size and weight and increased CAMK2N1 mRNA and protein expression compared with the miR-negative control group. CONCLUSION: The miR-182-5p-CAMK2N1 pathway can be potentially targeted to regulate the proliferation of OSCC cells.

Branched chain amino acid metabolic reprogramming in heart failure.

Metabolic remodeling is a hall-mark of cardiac maturation and pathology. The switch of substrate utilization from glucose to fatty acid is observed during post-natal maturation period in developing heart, but the process is reversed from fatty acids to glucose in the failing hearts across different clinic and experimental models. Majority of the current investigations have been focusing on the regulatory mechanism and functional impact of this metabolic reprogramming involving fatty acids and carbohydrates. Recent progress in metabolomics and transcriptomic analysis, however, revealed another significant remodeled metabolic branch associated with cardiac development and disease, i.e. Branched-Chain Amino Acid (BCAA) catabolism. These findings have established BCAA catabolic deficiency as a novel metabolic feature in failing hearts with potentially significant impact on the progression of pathological remodeling and dysfunction. In this review, we will evaluate the current evidence and potential implication of these discoveries in the context of heart diseases and novel therapies. This article is part of a Special Issue entitled: The role of post-translational protein modifications on heart and vascular metabolism edited by Jason R.B. Dyck & Jan F.C. Glatz.

Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.

BACKGROUND: Although metabolic reprogramming is critical in the pathogenesis of heart failure, studies to date have focused principally on fatty acid and glucose metabolism. Contribution of amino acid metabolic regulation in the disease remains understudied. METHODS AND RESULTS: Transcriptomic and metabolomic analyses were performed in mouse failing heart induced by pressure overload. Suppression of branched-chain amino acid (BCAA) catabolic gene expression along with concomitant tissue accumulation of branched-chain α-keto acids was identified as a significant signature of metabolic reprogramming in mouse failing hearts and validated to be shared in human cardiomyopathy hearts. Molecular and genetic evidence identified the transcription factor Krüppel-like factor 15 as a key upstream regulator of the BCAA catabolic regulation in the heart. Studies using a genetic mouse model revealed that BCAA catabolic defect promoted heart failure associated with induced oxidative stress and metabolic disturbance in response to mechanical overload. Mechanistically, elevated branched-chain α-keto acids directly suppressed respiration and induced superoxide production in isolated mitochondria. Finally, pharmacological enhancement of branched-chain α-keto acid dehydrogenase activity significantly blunted cardiac dysfunction after pressure overload. CONCLUSIONS: BCAA catabolic defect is a metabolic hallmark of failing heart resulting from Krüppel-like factor 15-mediated transcriptional reprogramming. BCAA catabolic defect imposes a previously unappreciated significant contribution to heart failure.

AI-2 quorum sensing negatively regulates rbf expression and biofilm formation in Staphylococcus aureus.

Staphylococcus aureus is an important pathogen that is capable of forming biofilms on biomaterial surfaces to cause biofilm-associated infections. Autoinducer 2 (AI-2), a universal language for interspecies communication, is involved in a variety of physiological activities, although its exact role in Gram-positive bacteria, especially in S. aureus, is not yet thoroughly characterized. Herein we demonstrate that inactivation of luxS, which encodes AI-2 synthase, resulted in increased biofilm formation and higher polysaccharide intercellular adhesion (PIA) production compared with the wild-type strain in S. aureus NCTC8325. The transcript level of rbf, a positive regulator of biofilm formation, was significantly increased in the luxS mutant. All of the parental phenotypes could be restored by genetic complementation and chemically synthesized 4,5-dihydroxy-2,3-pentanedione, the AI-2 precursor molecule, suggesting that AI-2 has a signaling function to regulate rbf transcription and biofilm formation in S. aureus. Phenotypic analysis revealed that the luxS rbf double mutant produced approximately the same amount of biofilms and PIA as the rbf mutant. In addition, real-time quantitative reverse transcription-PCR analysis showed that the icaA transcript level of the rbf mutant was similar to that of the luxS rbf double mutant. These findings demonstrate that the LuxS/AI-2 system regulates PIA-dependent biofilm formation via repression of rbf expression in S. aureus. Furthermore, we demonstrated that Rbf could bind to the sarX and rbf promoters to upregulate their expression.

3D Quantum Hall Effect of Fermi Arcs in Topological Semimetals.

The quantum Hall effect is usually observed in 2D systems. We show that the Fermi arcs can give rise to a distinctive 3D quantum Hall effect in topological semimetals. Because of the topological constraint, the Fermi arc at a single surface has an open Fermi surface, which cannot host the quantum Hall effect. Via a "wormhole" tunneling assisted by the Weyl nodes, the Fermi arcs at opposite surfaces can form a complete Fermi loop and support the quantum Hall effect. The edge states of the Fermi arcs show a unique 3D distribution, giving an example of (d-2)-dimensional boundary states. This is distinctly different from the surface-state quantum Hall effect from a single surface of topological insulator. As the Fermi energy sweeps through the Weyl nodes, the sheet Hall conductivity evolves from the 1/B dependence to quantized plateaus at the Weyl nodes. This behavior can be realized by tuning gate voltages in a slab of topological semimetal, such as the TaAs family, Cd_{3}As_{2}, or Na_{3}Bi. This work will be instructive not only for searching transport signatures of the Fermi arcs but also for exploring novel electron gases in other topological phases of matter.

MiR-150 Inhibits Cell Growth In Vitro and In Vivo by Restraining the RAB11A/WNT/ß-Catenin Pathway in Thyroid Cancer.

BACKGROUND Emerging evidence has shown that downregulation or upregulation of microRNAs (miRNAs) plays an important role in the development and progression of thyroid cancer (TC). However, the potential role of miR-150 and its biological function in TC remains largely unclear. MATERIAL AND METHODS Real-time polymerase chain reaction (RT-qPCR) was employed to detect the expression level of miR-150 and RAB11A in human TC tissue and human normal thyroid tissue. MTT assay, colony formation assay, flow cytometry cell cycle, and apoptosis assay were used to investigate the role of miR-150 and RAB11A on the malignant phenotypes in vitro. Nude mouse xenograft assay and western blot assay was used to verify the function of miR-150 in vivo. Western blot assay and immunofluorescence assay were used to detect the activation of WNT/ß-catenin pathway mediated by miR-150 and RAB11A. EGFP reporter assay, RT-qPCR assay, and western blot assay were used to validate the regulation relationship. RESULTS This study demonstrated that miR-150 expression in human TC tissues was markedly downregulated. Moreover, overexpression of miR-150 markedly inhibited cell proliferation via inducing the cell cycle arrest and promoting cell apoptosis by directly targeting RAB11A in vitro and suppressing tumor growth in vivo. However, overexpression of RAB11A promoted cell malignant phenotypes. In addition, miR-150 restrained the RAB11A mediated WNT/ß-catenin activation in TC cells. CONCLUSIONS miR-150 may function as a suppressor gene in TC cells by inhibiting the RAB11A/WNT/ß-catenin pathway.

Keto acid metabolites of branched-chain amino acids inhibit oxidative stress-induced necrosis and attenuate myocardial ischemia-reperfusion injury.

Branched chain α-keto acids (BCKAs) are endogenous metabolites of branched-chain amino acids (BCAAs). BCAA and BCKA are significantly elevated in pathologically stressed heart and contribute to chronic pathological remodeling and dysfunction. However, their direct impact on acute cardiac injury is unknown. Here, we demonstrated that elevated BCKAs significantly attenuated ischemia-reperfusion (I/R) injury and preserved post I/R function in isolated mouse hearts. BCKAs protected cardiomyocytes from oxidative stress-induced cell death in vitro. Mechanistically, BCKA protected oxidative stress induced cell death by inhibiting necrosis without affecting apoptosis or autophagy. Furthermore, BCKAs, but not BCAAs, protected mitochondria and energy production from oxidative injury. Finally, administration of BCKAs during reperfusion was sufficient to significantly attenuate cardiac I/R injury. These findings uncover an unexpected role of BCAA metabolites in cardioprotection against acute ischemia/reperfusion injury, and demonstrate the potential use of BCKA treatment to preserve ischemic tissue during reperfusion.

Involvement of the Hippo pathway in regeneration and fibrogenesis after ischaemic acute kidney injury: YAP is the key effector.

Renal tubule cells can recover after they undergo AKI (acute kidney injury). An incomplete repair of renal tubules can result in progressive fibrotic CKD (chronic kidney disease). Studies have revealed the relationship between tubular epithelial cells and kidney fibrogenesis. However, the underlying mechanism remains unclear. Hippo pathway components were evaluated in complete/incomplete repair of I/R (ischaemia/reperfusion) AKI rat models, HK-2 cells and AKI human renal biopsy samples. We found that the expression levels of the Hippo pathway components changed dynamically during kidney regeneration and fibrogenesis in rat models of I/R-induced AKI and human renal biopsy samples. The transcription cofactor YAP (Yes-associated protein) might be a key effector of renal regeneration and fibrogenesis. Our results showed further that YAP might elicit both beneficial and detrimental effects on I/R AKI. After I/R injury occurred, YAP could promote the repair of the injured epithelia. The constant YAP increase and activation might be related to interstitial fibrosis and abnormal renal tubule differentiation. These results indicate that the proper modulation of the Hippo pathway, specifically the transcription cofactor YAP, during repair might be a potent therapeutic target in AKI-CKD transition after I/R injury.

Regulatory mechanism of the three-component system HptRSA in glucose-6-phosphate uptake in Staphylococcus aureus.

Glucose-6-phosphate (G6P) is a common alternative carbon source for various bacteria, and its uptake usually relies on the hexose phosphate antiporter UhpT. In the human pathogenic bacterium Staphylococcus aureus, the ability to utilize different nutrients, particularly alternative carbon source uptake in glucose-limiting conditions, is essential for its fitness in the host environment during the infectious process. It has been reported that G6P uptake in S. aureus is regulated by the three-component system HptRSA. When G6P is provided as the only carbon source, HptRSA could sense extracellular G6P and activate uhpT expression to facilitate G6P utilization. However, the regulatory mechanism of HptRSA is still unclear. In this study, we further investigated the HptRSA system in S. aureus. First, we confirmed that HptRSA is necessary for the normal growth of this pathogen in chemically defined medium with G6P supplementation, and we discovered that HptRSA could exclusively sense extracellular G6P compared to the other organophosphates we tested. Next, using isothermal titration calorimetry, we found that HptA could bind to G6P, suggesting that it may be the G6P sensor. After that experiment, using an electrophoresis mobility shift assay, we verified that the response regulator HptR could directly bind to the uhpT promoter and identified a putative binding site from -67 to -96-bp. Subsequently, we created different point mutations in the putative binding site and revealed that the entire 30-bp sequence is essential for HptR regulation. In summary, we unveiled the regulatory mechanism of the HptRSA system in S. aureus, HptA most likely functions as the G6P sensor, and HptR could implement its regulatory function by directly binding to a conserved, approximately 30-bp sequence in the uhpT promoter.

Differential Regulation of Bcl-xL Gene Expression by Corticosterone, Progesterone, and Retinoic Acid.

Corticosterone (CT), progesterone (PG), and retinoic acid (RA) are capable of inhibiting Doxorubicin (Dox) from inducing apoptosis in rat cardiomyocytes. Mechanistically, CT, PG, and RA induce increases of Bcl-xL protein and mRNA, and activate a 3.2 kb bcl-x gene promoter. CT and RA, but not PG, induced the activity of a 0.9 kb bcl-x promoter, containing sequences for AP-1 and NF-kB binding. RA, but not CT or PG, induced NF-kB activation. CT, but not PG or RA, induced AP-1 activation, and induction of the 0.9 kb bcl-x reporter by CT was inhibited by dominant negative c-Jun TAM-67 or removal of AP-1 binding site. Therefore, although CT, PG, and RA all induce Bcl-xL mRNA and protein, three independent mechanisms are in operation: while CT induces Bcl-xL via AP-1 transcription factor, and RA induces NF-kB activation and bcl-x promoter activity, PG induces Bcl-xL via a mechanism independent of NF-kB or AP-1.