Identification of prognostic biomarkers for cholangiocarcinoma by combined analysis of molecular characteristics of clinical MVI subtypes and molecular subtypes.

Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.

Proteomic Analysis Identifies GSN as a Noninvasive Circulating Serum Biomarker for Predicting Early Recurrence of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is susceptible to early recurrence, but it lacks effective predictive biomarkers. In this study, we retrospectively selected 179 individuals as a discovery cohort (126 HCC patients and 53 liver cirrhosis (LC) patients) for screening candidate serum biomarkers of early recurrence based on data independent acquisition-mass spectrometry strategy. And then, the candidate biomarkers were validated in an additional independent cohort with 192 individuals (142 HCC patients and 50 LC patients) using parallel reaction monitoring targeted quantitative techniques (PXD047852). Eventually, we validated that gelsolin (GSN) concentrations were significantly lower in HCC than in LC (p < 0.0001), patients with low GSN concentrations had a poor prognosis (p < 0.0001), and GSN concentrations were significantly lower in early recurrence HCC than in late recurrence HCC (p < 0.0001). These trends were also observed in alpha-fetoprotein (AFP)-negative HCC patients. The area under the curve of machine-learning-based predictive model (GSN and microvascular invasion) for predicting early recurrence risk reached 0.803 (95% confidence interval (CI): 0.786-0.820) and maintained the same efficacy in AFP-negative patients. In conclusion, GSN is a novel serum biomarker for early recurrence of HCC. The model could provide timely warning to HCC patients at high risk of recurrence.

Flavin Containing Monooxygenase 2 Prevents Cardiac Fibrosis via CYP2J3-SMURF2 Axis.

BACKGROUND: Cardiac fibrosis is a common pathological feature associated with adverse clinical outcome in postinjury remodeling and has no effective therapy. Using an unbiased transcriptome analysis, we identified FMO2 (flavin-containing monooxygenase 2) as a top-ranked gene dynamically expressed following myocardial infarction (MI) in hearts across different species including rodents, nonhuman primates, and human. However, the functional role of FMO2 in cardiac remodeling is largely unknown. METHODS: Single-nuclei transcriptome analysis was performed to identify FMO2 after MI; FMO2 ablation rats were generated both in genetic level using the CRISPR-cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) technology and lentivirus-mediated manner. Gain-of-function experiments were conducted using postn-promoter FMO2, miR1a/miR133a-FMO2 lentivirus, and enzymatic activity mutant FMO2 lentivirus after MI. RESULTS: A significant downregulation of FMO2 was consistently observed in hearts after MI in rodents, nonhuman primates, and patients. Single-nuclei transcriptome analysis showed cardiac expression of FMO2 was enriched in fibroblasts rather than myocytes. Elevated spontaneous tissue fibrosis was observed in the FMO2-null animals without external stress. In contrast, fibroblast-specific expression of FMO2 markedly reduced cardiac fibrosis following MI in rodents and nonhuman primates associated with diminished SMAD2/3 phosphorylation. Unexpectedly, the FMO2-mediated regulation in fibrosis and SMAD2/3 signaling was independent of its enzymatic activity. Rather, FMO2 was detected to interact with CYP2J3 (cytochrome p450 superfamily 2J3). Binding of FMO2 to CYP2J3 disrupted CYP2J3 interaction with SMURF2 (SMAD-specific E3 ubiquitin ligase 2) in cytosol, leading to increased cytoplasm to nuclear translocation of SMURF2 and consequent inhibition of SMAD2/3 signaling. CONCLUSIONS: Loss of FMO2 is a conserved molecular signature in postinjury hearts. FMO2 possesses a previously uncharacterized enzyme-independent antifibrosis activity via the CYP2J3-SMURF2 axis. Restoring FMO2 expression exerts potent ameliorative effect against fibrotic remodeling in postinjury hearts from rodents to nonhuman primates. Therefore, FMO2 is a potential therapeutic target for treating cardiac fibrosis following injury.

Circular RNA expression profile and functional analysis of circUvrag in light-induced photoreceptor degeneration.

BACKGROUND: Circular RNAs (circRNAs) are implicated in retinal pathophysiology; however, their expression profiles and functions in photoreceptor apoptosis are largely unknown. We explored circRNA-expression profiles and circUvrag (host gene: Uvrag, ultraviolet radiation resistance associated gene) function in light-induced photoreceptor apoptosis. METHODS: Sprague-Dawley rats and 661 W photoreceptor cells were exposed to blue light to establish light-induced photoreceptor degeneration. Differentially expressed circRNAs were identified using microarrays. Potential functions of dysregulated circRNAs were analysed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. CircUvrag expression and localization were evaluated using quantitative RT-PCR and fluorescence in situ hybridization, respectively. CircUvrag overexpression and knockdown were induced using a plasmid and a small interfering RNA, respectively, and retinal function and structure were assessed using scotopic electroretinography, haematoxylin-eosin staining, and TUNEL staining. Microglial migration was assessed using IBA1 immunostaining. The apoptosis ratio of photoreceptor cells in vitro was detected using flow cytometry. RESULTS: We identified 764 differentially expressed circRNAs, which were potentially related with the development of retinal structures, including neurons, dendrites, and synapses, and might participate in nervous-system pathophysiology. Light exposure enriched circUvrag in the cytoplasm of photoreceptors in the outer nuclear layer (ONL). CircUvrag knockdown decreased photoreceptor apoptosis and microglial migration to the ONL after light exposure, preserving ONL thickness and a-wave amplitude. In vitro, circUvrag knockdown inhibited photoreceptor apoptosis, although circUvrag overexpression slightly promoted photoreceptor apoptosis. CONCLUSIONS: CircUvrag knockdown attenuated light-induced photoreceptor apoptosis, and might be a potential target in retinal degeneration.

Extraction and Isolation of Two Polysaccharides from Chloranthus japonicus Sieb. and Evaluation of Their Anti-Gastric Cancer Activities.

Two unreported heteropolysaccharides, denoted as YCJP-1 and YCJP-2, were isolated from the herbs of Chloranthus japonicus. YCJP-1 was a heteropolysaccharide composed of glucose, galactose, arabinose, mannose, rhamnose, and a minor proportion of uronic acids, with the molecular weight mainly distributed in the 74,475-228,443 Da range. YCJP-2 was mainly composed of glucose, mannose, and galactose, with the molecular weights ranging from 848 to 5810 Da. To further evaluate the anti-gastric cancer effects of C. japonicus, the inhibitory effects of the crude polysaccharide (YCJP) and the purified polysaccharides (YCJP-1 and YCJP-2) were determined using a CCK-8 assay and colon-forming assay on MGC-803 and AGS gastric cancer cell lines. Our results showed that YCJP, YCJP-1, and YCJP-2 possess prominent inhibitory effects on the proliferation of MGC-803 and AGS cells, and the AGS cell was more sensitive to YCJP, YCJP-1, and YCJP-2. Moreover, YCJP-2 demonstrated superior anti-gastric cancer effects compared to YCJP-1. This could potentially be attributed to YCJP-2's higher glucose content and narrower molecular weight distribution.

[Efficacy and safety of rituximab in children and adolescents with mature B-cell non-Hodgkin's lymphoma: a Meta analysis]. / 利妥昔单抗治疗儿童及青少年成熟Bç»†èƒžéžéœå¥‡é‡‘æ·‹å·´ç˜¤ç–—æ•ˆåŠå®‰å ¨æ€§çš„Meta分析.

OBJECTIVES: To study the efficacy and safety of rituximab combined with chemotherapy in the treatment of children and adolescents with mature B-cell non-Hodgkin's lymphoma (B-NHL) through a Meta analysis. METHODS: The databases including PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, Web of Science, China National Knowledge Infrastructure, Wanfang Data, and Weipu were searched to obtain 10 articles on rituximab in the treatment of mature B-NHL in children and adolescents published up to June 2022, with 886 children in total. With 3-year event-free survival (EFS) rate, 3-year overall survival (OS) rate, complete remission rate, mortality rate, and incidence rate of adverse reactions as outcome measures, RevMan 5.4 software was used for Meta analysis, subgroup analysis, sensitivity analysis, and publication bias analysis. RESULTS: The rituximab+chemotherapy group showed significant increases in the 3-year EFS rate (HR=0.38, 95%CI: 0.25-0.59, P<0.001), 3-year OS rate (HR=0.29, 95%CI: 0.14-0.61, P=0.001), and complete remission rate (OR=3.72, 95%CI: 1.89-7.33, P<0.001) as well as a significant reduction in the mortality rate (OR=0.31, 95%CI: 0.17-0.57, P<0.001), as compared with the chemotherapy group without rituximab. There was no significant difference in the incidence rate of adverse reactions between the two groups (OR=1.28, 95%CI: 0.85-1.92, P=0.24). CONCLUSIONS: The addition of rituximab to the treatment regimen for children and adolescents with mature B-cell non-Hodgkin's lymphoma can bring significant survival benefits without increasing the incidence of adverse reactions.

Controllable Transformation of Metal-Organic Framework Nanosheets into Oxygen Vacancy NixCo3-xO4 Arrays for Ultrahigh-Capacitance Supercapacitors with Long Lifespan.

The amino-functionalized bimetal NH2-NiCo-MOF nanosheet array is first fabricated on Ni foam substrates and then controllably transformed into oxygen vacancy bimetal oxide arrays by simply thermal annealing in air. This NiCo-based oxide array (NixCo3-xO4/NF) achieves high capacitance (2484 F g-1 at 1 A g-1), excellent rate performance (91.4%), and long cycling life when assessed as promising electrode material for supercapacitors. Notably, the existing oxygen vacancy in NixCo3-xO4 promotes the electrochemical performance of NixCo3-xO4/NF due to the enhancement of electrical conductivity and capture capability for OH-. In addition, the assembled asymmetric supercapacitor (ASC) device exhibits an excellent energy density of 39.3 W h kg-1 at a power density of 800.2 W kg-1, which still remains 32.2 W h kg-1 even at a high power density of 7994.5 W kg-1. Furthermore, a light-emitting diode can be lightened for more than 6 min, demonstrating a great potential for practical application of ASC devices. This work knocks on the door of a feasible strategy for designing and synthesizing 2D metal oxide nanosheet arrays with excellent electrochemical properties.

Controllable In Situ Transformation of Layered Double Hydroxides into Ultrathin Metal-Organic Framework Nanosheet Arrays for Energy Storage.

Ultrathin two-dimensional metal-organic frameworks (MOFs) have convincing performances in energy storage, which can be put down to their accessible active sites with rapid charge transfer. Herein, NiCo-layered double hydroxide (LDH) nanosheet arrays are used as self-sacrificial templates to in situ fabricate ultrathin NiCo-MOF nanosheet arrays on Ni foam (NS/NF) by using organic ligands without adding metal sources. Two ultrathin MOF nanosheets with different ligands, terephthalate (BDC) and 2-aminoterephthalate (NH2-BDC), are synthesized, characterized, and discussed in detail. Specifically, NiCo-NH2-BDC-MOF NS/NF exhibits the best electrochemical performance as a battery-type electrode for supercapacitors, achieves an areal capacitance of 12.13 F cm-2 at a current density of 2 mA cm-2, and retains the original capacitance of 73.08 % after 5000 cycles at a current density of 50 mA cm-2. Furthermore, when NiCo-NH2-BDC-MOF NS/NF is assembled with activated carbon (AC) to form an asymmetric supercapacitor (ASC), an energy density of 0.81 mWh cm-2 can be provided at a power density of 1.60 mW cm-2. These results offer an effective and controllable synthetic strategy to in situ prepare ultrathin MOF nanosheet arrays with different ligands and metal ions from LDH precursors.

Structural and functional analysis of multiple subretinal fluid blebs after successful surgery for rhegmatogenous retinal detachment.

INTRODUCTION: This retrospective study investigated the clinical characteristics of multiple subretinal fluid blebs (MSFBs) after successful surgery for rhegmatogenous retinal detachment (RRD), and explored the association between MSFB with best-corrected visual acuity (BCVA) and metamorphopsia. METHODS: The study comprised 206 patients after successful surgery for RRD, with 58 and 148 eyes undergoing, respectively, scleral buckling (SB) and pars plana vitrectomy (PPV). The clinical characteristics of MSFBs were analyzed by optical coherence tomography (OCT). The choroidal vessels in some cases were evaluated with OCT angiography. M-charts were used to determine the metamorphopsia. RESULTS: MSFBs occurred in 17 (29.3%) and 8 (5.4%) eyes given SB and PPV, respectively. MSFBs appeared 5.6 ± 5.5 weeks after surgery and required 34.9 ± 13.8 weeks to disappear. Disrupted external limiting membrane and ellipsoid zone could still be seen in 83.3% and 66.7% of the patients 12 months after surgery; these rates were significantly higher than those of patients without MSFBs (P = 0.047, 0.022, respectively). Twelve months post-surgery, BCVA and metamorphopsia scores of the patients with MSFBs were statistically comparable to those of the controls. CONCLUSIONS: MSFBs occur more commonly after SB than PPV. MSFBs may delay the recovery of the outer retina structure, but do not affect postoperative BCVA and metamorphopsia.

Rice straw enhancing catalysis of Pseudomonas fluorescens lipase for synthesis of citronellyl acetate.

Citronellyl acetate as an important flavor, can be effectively synthesized by lipase catalysis in nonaqueous system. But lipases usually behave low catalytic activity due to aggregation and denaturation of them in organic phase. To enhance the nonaqueous catalysis, based on the mechanism of lipases activated at water/oil (organic phase) interface, the inexpensive race straw was processed into powder and filaments on which Pseudomonas fluorescens lipase was immobilized by physical adsorption, used for synthesis of citronellyl acetate via transesterification of citronellol and vinyl acetate. Results showed that the desired loading was 10 mg lipase immobilized on 30 mg rice straw filaments or 25 mg rice straw powder. When the two immobilized lipases were employed in the reaction system consisted of 1-mL citronellol and 2-mL vinyl acetate at 37 â„ƒ and 160 rpm, the conversions all reached 99.8% after 12 h. Under the reaction condition, the conversion catalyzed by 10 mg native lipase was 85.1%. Undergoing six times of 8-h reuses in the organic system, the filament and power immobilized lipases had weak activity attenuation rates 0.36 and 0.32% h-1, lower than 1.52% h-1 of native lipase. Even at the room temperature and the static state without shaking and stirring, the rice straw filaments immobilized lipase could brought conversion 62.9% after 10 h but the native lipase only gave 37.0%. Obviously, the rice straw, especially its filaments, is an inexpensive and available natural material to prepare immobilized lipase with desired catalysis in organic phase, meant significant potential in flavor industry.

[Clinical features and prognosis of children with Burkitt's lymphoma: an analysis of 62 cases]. / 儿童伯基特淋巴瘤62例临床特征及预后分析.

OBJECTIVES: To study the clinical features and chemotherapy response of Burkitt's lymphoma (BL) in children and the influence of rituximab on the prognosis of children with BL. METHODS: A retrospective analysis was performed for the medical data of 62 children with BL, including clinical features, therapeutic efficacy, and prognostic factors. The Cox regression model was used to identify the factors associated with poor prognosis in children with BL. According to whether rituximab was used, the children with advanced (stage III/IV) BL were divided into two groups: chemotherapy plus rituximab and chemotherapy alone. The prognosis was compared between the two groups. RESULTS: For these 62 children, the median age of onset was 5 years (range 1-14 years), and there were 58 boys (94%) and 4 girls (6%). The primary site was abdominal cavity in 41 children (66%), and head and neck in 16 children (26%). There were 1 child with stage I BL (2%), 8 with stage II BL (13%), 33 with stage III BL (53%), and 20 with stage IV BL (32%). The median follow-up time was 29 months, with progression/recurrence observed in 15 children (24%), and the 3-year overall survival (OS) rate and event-free survival (EFS) rate were 82.8%±5.2% and 77.3%±5.8%, respectively. For the children with stage III/IV BL, there was a significant difference in the 3-year the OS rate between the chemotherapy plus rituximab group (16 children) and the chemotherapy alone group (30 children) (93.3%±6.4% vs 65.6%±9.9%, P=0.042), while there was no significant difference in the 3-year EFS rate between the two groups (86.2%±9.1% vs 61.8%±10.1%, P>0.05). The Cox regression analysis showed that central nervous system involvement, lactate dehydrogenase >1 000 U/L, and early incomplete remission were the factors associated with poor prognosis (P<0.05). CONCLUSIONS: Chemotherapy combined with rituximab can improve the prognosis of children with stage III/IV BL. Central nervous system involvement, elevated lactate dehydrogenase level, and early incomplete remission may indicate a poor prognosis in children with BL.

[Risk factors for acute kidney injury after hematopoietic stem cell transplantation in children: a retrospective study]. / å„¿ç«¥é€ è¡€å¹²ç»†èƒžç§»æ¤åŽæ€¥æ€§è‚¾æŸä¼¤ç›¸å ³å±é™©å› ç´ çš„å›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To investigate the risk factors for acute kidney injury (AKI) after hematopoietic stem cell transplantation (HSCT) in children. METHODS: A retrospective analysis was performed on the medical data of 111 children who underwent HSCT from January 2018 to January 2020. A multivariate logistic regression analysis was used to identify the risk factors for AKI. The Kaplan-Meier survival analysis was used to compare the prognosis in children with different grades of AKI. RESULTS: Graft-versus-host disease (grade Ⅱ-Ⅳ) (OR=4.406, 95%CI: 1.501-12.933, P=0.007), hepatic veno-occlusive disease (OR=4.190, 95%CI: 1.191-14.740, P=0.026), and thrombotic microangiopathy (OR=10.441, 95%CI: 1.148-94.995, P=0.037) were closely associated with the development of AKI after HSCT. The children with stage Ⅲ AKI had a lower 1-year survival rate than those without AKI or with stage Ⅰ AKI or stage Ⅱ AKI (28.6%±12.1% vs 82.8%±5.2%/81.7%±7.4%/68.8%±11.6%; P<0.05). CONCLUSIONS: Children with stage Ⅲ AKI after HSCT have a higher mortality rate. Graft-versus-host disease, hepatic veno-occlusive disease, and thrombotic microangiopathy are closely associated with the development of AKI after HSCT.

Personalized neoantigen vaccine prevents postoperative recurrence in hepatocellular carcinoma patients with vascular invasion.

BACKGROUND: Clinically, prophylactic anti-recurrence treatments for hepatocellular carcinoma (HCC) patients after radical surgery are extremely limited. Neoantigen based vaccine can generate robust anti-tumor immune response in several solid tumors but whether it could induce anti-tumor immune response in HCC and serve as a safe and effective prophylactic strategy for preventing postoperative HCC recurrence still remain largely unclear. METHODS: Personalized neoantigen vaccine was designed and immunized for 10 HCC patients with high risk of postoperative recurrence in a prime-boost schedule. The safety and immune response were assessed through adverse events, tissue sequencing, ELISpot, TCR sequencing. The clinical response was evaluated by recurrence-free survival (RFS) and personalized circulating tumor DNA (ctDNA) sequencing. RESULTS: In the 10 enrolled patients, no obvious adverse events were observed during neoantigen vaccinations. Until the deadline of clinical trial, 8 of 10 patients were confirmed with clinical relapse by imaging, the other 2 patients remained relapse-free. From receiving first neoantigen vaccination, the median RFS of 10 patients were 7.4 months. Among 7 patients received all planned neoantigen vaccinations, 5 of them demonstrated neoantigen-induced T cell responses and have significantly longer RFS after radical surgery than other 5 patients without responsive neoantigens or only with prime vaccination and propensity scores matching control patients (p = 0.035). Moreover, tracking personalized neoantigen mutations in ctDNA could provide real-time evaluation of clinical response in HCC patients during neoantigen vaccination and follow up. CONCLUSION: Personalized neoantigen vaccine is proved as a safe, feasible and effective strategy for HCC anti-recurrence, and its progression could be sensitively monitored by corresponding neoantigen mutations in ctDNA, and thus provided solid information for individualized medicine in HCC. TRIAL REGISTRATION: This study was registered at Chinese Clinical Trial Registry; Registration number: ChiCTR1900020990 .

NF-κB-Interacting Long Noncoding RNA Regulates HIV-1 Replication and Latency by Repressing NF-κB Signaling.

NF-κB-interacting long noncoding RNA (NKILA) was recently identified as a negative regulator of NF-κB signaling and plays an important role in the development of various cancers. It is well known that NF-κB-mediated activation of human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)-driven gene expression is required for HIV-1 transcription and reactivation of latency. However, whether NKILA plays essential roles in HIV-1 replication and latency is unclear. Here, by ectopic expression and silencing experiments, we demonstrate that NKILA potently inhibits HIV-1 replication in an NF-κB-dependent manner by suppressing HIV-1 LTR promoter activity. Moreover, NKILA showed broad-spectrum inhibition on the replication of HIV-1 clones with different coreceptor tropisms as well as on LTR activity of various HIV-1 clinical subtypes. Chromatin immunoprecipitation (ChIP) assays revealed that NKILA expression abolishes the recruitment of p65 to the duplicated κB binding sites in the HIV-1 LTR. NKILA mutants disrupting NF-κB inhibition also lost the ability to inhibit HIV-1 replication. Notably, HIV-1 infection or reactivation significantly downregulated NKILA expression in T cells in order to facilitate viral replication. Downregulated NKILA was mainly due to reduced acetylation of histone K27 on the promoter of NKILA by HIV-1 infection, which blocks NKILA expression. Knockdown of NKILA promoted the reactivation of latent HIV-1 upon phorbol myristate acetate (PMA) stimulation, while ectopic NKILA suppressed the reactivation in a well-established clinical model of withdrawal of azidothymidine (AZT) in vitro These findings improve our understanding of the functional suppression of HIV-1 replication and latency by NKILA through NF-κB signaling.IMPORTANCE The NF-κB pathway plays key roles in HIV-1 replication and reactivation of HIV-1 latency. A regulator inhibiting NF-κB activation may be a promising therapeutic strategy against HIV-1. Recently, NF-κB-interacting long noncoding RNA (NKILA) was identified to suppress the development of different human cancers by inhibiting IκB kinase (IKK)-induced IκB phosphorylation and NF-κB pathway activation, whereas the relationship between NKILA and HIV-1 replication is still unknown. Here, our results show that NKILA inhibits HIV-1 replication and reactivation by suppressing HIV-1 long terminal repeat (LTR)-driven transcription initiation. Moreover, NKILA inhibited the replication of HIV-1 clones with different coreceptor tropisms. This project may reveal a target for the development of novel anti-HIV drugs.

LncRNA LncHrt preserves cardiac metabolic homeostasis and heart function by modulating the LKB1-AMPK signaling pathway.

Metabolic modulation is a promising therapeutic approach to prevent adverse remodeling of the ischemic heart. Because little is known about the involvement of long non-coding RNAs (lncRNAs) in regulating cardiac metabolism, we used unbiased transcriptome profiling in a mouse model of myocardial infarction (MI). We identified a novel cardiomyocyte-enriched lncRNA, called LncHrt, which regulates metabolism and the pathophysiological processes that lead to heart failure. AAV-based LncHrt overexpression protects the heart from MI as demonstrated by improved contractile function, preserved metabolic homeostasis, and attenuated maladaptive remodeling responses. RNA-pull down followed by mass spectrometry and RNA immunoprecipitation (RIP) identified SIRT2 as a LncHrt-interacting protein involved in cardiac metabolic regulation. Mechanistically, we established that LncHrt interacts with SIRT2 to preserve SIRT2 deacetylase activity by interfering with the CDK5 and SIRT2 interaction. This increases downstream LKB1-AMPK kinase signaling, which ameliorates functional and metabolic deficits. Importantly, we found the expression of the human homolog of mouse LncHrt was decreased in patients with dilated cardiomyopathy. Together, these studies identify LncHrt as a cardiac metabolic regulator that plays an essential role in preserving heart function by regulating downstream metabolic signaling pathways. Consequently, LncHrt is a potentially novel RNA-based therapeutic target for ischemic heart disease.

Rational design and chemical modification of TEAD coactivator peptides to target hippo signaling pathway against gastrointestinal cancers.

Human Hippo signaling pathway has been recognized as a new and promising therapeutic target of gastrointestinal cancers, which is regulated by the intermolecular recognition between the TEA domain (TEAD) transcription factor and its prime coactivators. The coactivator proteins adopt two hotspot sites, namely α-helix and Ω-loop, to interact with TEAD. Here, we demonstrate that both the α-helix and Ω-loop peptides cannot maintain in structured state when splitting from the full-length coactivator proteins; they exhibit a large intrinsic disorder in free state that prevents the coactivator peptide recognition by TEAD. Rational design is used to optimize the interfacial residues of coactivator α-helix peptides, which can effectively improve the favorable direct readout effect upon the peptide binding to TEAD. Chemical modification is employed to constrain the free α-helix peptide into native ordered conformation. The method introduces an all-hydrocarbon bridge across i and i + 4 residues to stabilize the helical structure of a free coactivator peptide, which can considerably reduce the unfavorable indirect readout effect upon the peptide binding to TEAD. The all-hydrocarbon bridge is designed to point out of the TEAD-peptide complex interface, which would not disrupt the direct intermolecular interaction between the TEAD and peptide. Therefore, the stapling only improves peptide affinity, but does not alter peptide specificity, to TEAD. Affinity assay confirms that the binding potency of coactivator α-helix peptides is improved substantially by >5-fold upon the rational design and chemical modification. Structural analysis reveals that the optimized/stapled peptides can form diverse nonbonded interactions such as hydrogen bonds and hydrophobic contacts with TEAD, thus conferring stability and specificity to the TEAD-peptide complex systems.

Relatively Independent Motion of a Continuous Nanocellulose Network in a Polymer Matrix.

Nanocellulose has been studied extensively in polymer composites as it can be employed as biobased reinforcement for synthetic polymers. However, the challenge to optimize the reinforcing component to consume applied energy as much as possible remains. This is related to the reacting force in the test sample and its extensibility. Prolonging the fracture strain of the material is one of the most effective strategies for such a purpose. The investigation on nanocellulose movement in a polymer matrix could shed light on the nanocellulose reinforcing mechanism's fundamental understanding. In this work, a continuous nanocellulose network was used to prepare nanocellulose/polymer composites. Different from using noncontinuous nanofillers, e.g., cellulose nanofibers and nanocrystal, the regenerated cellulose gel network used in this work could move together with the polymer under an axial signal force, serving as an excellent model advantageous in investigating the movement of nanocellulose in the polymer matrix. The deformation of the nanocellulose in the matrix was able to be evaluated by tracking the fracture strain of the materials. A series of chemical cross-linked nanoporous cellulose hydrogels (CCNCGs) were prepared, and their fracture strain increased first and then decreased as the molar ratio of epichlorohydrin (ECH) to the anhydroglucose unit (AGU) of cellulose increased. Two polymer matrices, polycaprolactone (PCL) and polyurethane (PU), were selected to be polymerized in CCNCGs in situ. The fracture strain of CCNCG/PCL and CCNCG/PU nanocomposites in the tensile test showed the same tendency as neat CCNCGs in the hydrated state, regardless of the surrounding environment. The relatively independent motion of the nanocellulose network in the polymer matrix was clearly demonstrated. Possible mechanisms of the nanocellulose's independent motion in the polymer matrix were discussed, implying the potential of independent deformation of the continuous nanocellulose network in the polymer matrix.

Moesin facilitates metastasis of hepatocellular carcinoma cells by improving invadopodia formation and activating ß-catenin/MMP9 axis.

Moesin has been proved to be implicated in invasiveness and metastasis in many other cancers, but unclear in HCC. Thus, this study was performed to investigate the clinical significance of moesin and its biological functions in HCC. The results showed that moesin was significantly up-regulated in HCC tissues and was an independent prognostic factor for predicting the recurrence of HCC patients, postoperatively. Furthermore, we also demonstrated that moesin promoted the migration and invasion of HCC cells in vitro and in vivo. And the mechanism studies indicated that moesin overexpression increased the formation of invadopodia and improved the activation of ß-catenin/MMP9 axis. Taken together, our findings revealed that moesin acted as an important onco-protein participating in the metastasis of HCC.

CD160 expression on CD8+ T cells is associated with active effector responses but limited activation potential in pancreatic cancer.

CD160 is an Ig-like glycoprotein expressed by the majority of circulating natural killer cells and γδ T cells. Whether CD160 could regulate CD8+ T-cell functions remains unknown. In this study, we investigated the effects of CD160 on CD8+ T cells in pancreatic cancer. First, we found that the frequency of PD-1+ cells was comparable between CD160+ and CD160-CD8+ T cells, with the former presenting significantly higher PD-1 expression level. In contrast, the frequency of TIM-3+ cells was higher among CD160+ cells but the expression level was comparable between CD160+ and CD160-CD8+ T cells. The IFN-γ and IL-2-expressing CD8+ T cells, directly ex vivo, were highly enriched in the CD160+ subset. However, when CD160+ and CD160-CD8+ T cells were stimulated, the proliferation levels of CD160+ and CD160- cells were initially comparable, but were significantly lower in CD160+CD8+ T cells than in CD160-CD8+ T cells later on. The IFN-γ and IL-2 transcription levels were initially higher in CD160+CD8+ T cells, but eventually reduced in CD160+CD8+ T cells compared to CD160-CD8+ T cells. Also, CD160+CD8+ T cells presented lower cytotoxic capacity than CD160-CD8+ T cells. Interestingly, we observed that tumor-infiltrating CD8+ T cells were significantly enriched with the CD160+ subset in pancreatic cancer patients. In addition, patients with higher frequencies of tumor CD160+CD8+ T cells presented lower survival. Overall, these data demonstrated that tumor-infiltrating CD8+ T cells were enriched with the CD160+ subset in pancreatic cancer, with active effector responses directly ex vivo but limited potential for further activation.

A Reactive Oxygen Species Scavenging and O2 Generating Injectable Hydrogel for Myocardial Infarction Treatment In vivo.

The excessive reactive oxygen species (ROS) and hypoxia deteriorate the inflammation-related diseases such as myocardial infarction (MI), and thereby deter the normal tissue repair and recovery and further lead to severe fibrosis and malfunction of tissues and organs. In particular, the MI has become one of the leading causes of death nowadays. In this study, a novel type of injectable hydrogel with dual functions of ROS scavenging and O2 generating is fabricated for MI treatment in vivo. The hydrogel is formed within 3 s from the synthetic ROS-cleavable hyperbranched polymers and methacrylate hyaluronic acid (HA-MA) under UV-irradiation. Addition of biocompatible and applicable catalase in vivo enables the further transition of H2 O2 , a major type of ROS, to O2 and H2 O. Results of rat MI model demonstrate that this hydrogel can significantly remove excessive ROS, inhibit cell apoptosis, increase M2/M1 macrophage ratio, promote angiogenesis, reduce infarcted area, and improve cardiac functions. With the appropriate degradation rate, simple structure and composition without cell seeding, and very excellent MI therapeutic effect, this ROS scavenging and O2 generating hydrogel has a great promise to be applied clinically.