ABSTRACT
Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of ß-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.
Subject(s)
Adipose Tissue, Brown/metabolism , Constitutive Androstane Receptor/metabolism , Lipolysis , Receptors, G-Protein-Coupled/metabolism , Thermogenesis , Adipocytes/metabolism , Animals , COS Cells , Cells, Cultured , Chlorocebus aethiops , Cold Temperature , Dietary Fats/pharmacology , Humans , Mice, Inbred C57BL , Phenotype , Receptors, G-Protein-Coupled/genetics , Signal Transduction , Sympathetic Nervous System/metabolism , Transcription, GeneticABSTRACT
Inorganic superionic conductors possess high ionic conductivity and excellent thermal stability but their poor interfacial compatibility with lithium metal electrodes precludes application in all-solid-state lithium metal batteries1,2. Here we report a LaCl3-based lithium superionic conductor possessing excellent interfacial compatibility with lithium metal electrodes. In contrast to a Li3MCl6 (M = Y, In, Sc and Ho) electrolyte lattice3-6, the UCl3-type LaCl3 lattice has large, one-dimensional channels for rapid Li+ conduction, interconnected by La vacancies via Ta doping and resulting in a three-dimensional Li+ migration network. The optimized Li0.388Ta0.238La0.475Cl3 electrolyte exhibits Li+ conductivity of 3.02 mS cm-1 at 30 °C and a low activation energy of 0.197 eV. It also generates a gradient interfacial passivation layer to stabilize the Li metal electrode for long-term cycling of a Li-Li symmetric cell (1 mAh cm-2) for more than 5,000 h. When directly coupled with an uncoated LiNi0.5Co0.2Mn0.3O2 cathode and bare Li metal anode, the Li0.388Ta0.238La0.475Cl3 electrolyte enables a solid battery to run for more than 100 cycles with a cutoff voltage of 4.35 V and areal capacity of more than 1 mAh cm-2. We also demonstrate rapid Li+ conduction in lanthanide metal chlorides (LnCl3; Ln = La, Ce, Nd, Sm and Gd), suggesting that the LnCl3 solid electrolyte system could provide further developments in conductivity and utility.
ABSTRACT
Aberrant expression of programmed death ligand-1 (PD-L1) in tumor cells promotes cancer progression by suppressing cancer immunity. The retinoblastoma protein RB is a tumor suppressor known to regulate the cell cycle, DNA damage response, and differentiation. Here, we demonstrate that RB interacts with nuclear factor κB (NF-κB) protein p65 and that their interaction is primarily dependent on CDK4/6-mediated serine-249/threonine-252 (S249/T252) phosphorylation of RB. RNA-seq analysis shows a subset of NF-κB pathway genes including PD-L1 are selectively upregulated by RB knockdown or CDK4/6 inhibitor. S249/T252-phosphorylated RB inversely correlates with PD-L1 expression in patient samples. Expression of a RB-derived S249/T252 phosphorylation-mimetic peptide suppresses radiotherapy-induced upregulation of PD-L1 and augments therapeutic efficacy of radiation in vivo. Our findings reveal a previously unrecognized tumor suppressor function of hyperphosphorylated RB in suppressing NF-κB activity and PD-L1 expression and suggest that the RB-NF-κB axis can be exploited to overcome cancer immune evasion triggered by conventional or targeted therapies.
Subject(s)
B7-H1 Antigen/metabolism , Prostatic Neoplasms/metabolism , Retinoblastoma Protein/metabolism , Transcription Factor RelA/metabolism , Tumor Escape , Animals , Antineoplastic Agents, Immunological/pharmacology , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , Chemoradiotherapy/methods , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/metabolism , Gene Expression Regulation, Neoplastic , HEK293 Cells , Humans , Male , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , PC-3 Cells , Phosphorylation , Prostatic Neoplasms/genetics , Prostatic Neoplasms/immunology , Prostatic Neoplasms/therapy , Protein Binding , Protein Interaction Domains and Motifs , Radiation Tolerance , Retinoblastoma Protein/genetics , Retinoblastoma Protein/immunology , Signal Transduction , Transcription Factor RelA/genetics , Transcription Factor RelA/immunology , Xenograft Model Antitumor AssaysABSTRACT
The conversion of CO2 into liquid fuels, using only sunlight and water, offers a promising path to carbon neutrality. An outstanding challenge is to achieve high efficiency and product selectivity. Here, we introduce a wireless photocatalytic architecture for conversion of CO2 and water into methanol and oxygen. The catalytic material consists of semiconducting nanowires decorated with core-shell nanoparticles, with a copper-rhodium core and a chromium oxide shell. The Rh/CrOOH interface provides a unidirectional channel for proton reduction, enabling hydrogen spillover at the core-shell interface. The vectorial transfer of protons, electrons, and hydrogen atoms allows for switching the mechanism of CO2 reduction from a proton-coupled electron transfer pathway in aqueous solution to hydrogenation of CO2 with a solar-to-methanol efficiency of 0.22%. The reported findings demonstrate a highly efficient, stable, and scalable wireless system for synthesis of methanol from CO2 that could provide a viable path toward carbon neutrality and environmental sustainability.
ABSTRACT
The bromodomain and extra-terminal domain (BET) protein BRD4 is emerging as a promising anticancer therapeutic target. However, resistance to BET inhibitors often occurs, and it has been linked to aberrant degradation of BRD4 protein in cancer. Here, we demonstrate that the deubiquitinase DUB3 binds to BRD4 and promotes its deubiquitination and stabilization. Expression of DUB3 is transcriptionally repressed by the NCOR2-HDAC10 complex. The NCOR2 gene is frequently deleted in castration-resistant prostate cancer patient specimens, and loss of NCOR2 induces elevation of DUB3 and BRD4 proteins in cancer cells. DUB3-proficient prostate cancer cells are resistant to the BET inhibitor JQ1 in vitro and in mice, but this effect is diminished by DUB3 inhibitory agents such as CDK4/6 inhibitor in a RB-independent manner. Our findings identify a previously unrecognized mechanism causing BRD4 upregulation and drug resistance, suggesting that DUB3 is a viable therapeutic target to overcome BET inhibitor resistance in cancer.
Subject(s)
Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 6/genetics , Endopeptidases/genetics , Gene Expression Regulation, Neoplastic , Nuclear Proteins/genetics , Prostatic Neoplasms, Castration-Resistant/genetics , Transcription Factors/genetics , Animals , Antineoplastic Agents/pharmacology , Azepines/pharmacology , Cell Cycle Proteins , Cell Line, Tumor , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/metabolism , Disease Progression , Drug Resistance, Neoplasm/genetics , Endopeptidases/metabolism , Histone Deacetylases/genetics , Histone Deacetylases/metabolism , Humans , Male , Mice , Nuclear Proteins/antagonists & inhibitors , Nuclear Proteins/metabolism , Nuclear Receptor Co-Repressor 2/deficiency , Nuclear Receptor Co-Repressor 2/genetics , Piperazines/pharmacology , Prostate/drug effects , Prostate/enzymology , Prostate/pathology , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/enzymology , Prostatic Neoplasms, Castration-Resistant/pathology , Protein Kinase Inhibitors/pharmacology , Proteolysis , Pyridines/pharmacology , Signal Transduction , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Transcription, Genetic , Triazoles/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
Molecular clocks in the periphery coordinate tissue-specific daily biorhythms by integrating input from the hypothalamic master clock and intracellular metabolic signals. One such key metabolic signal is the cellular concentration of NAD+, which oscillates along with its biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT). NAD+ levels feed back into the clock to influence rhythmicity of biological functions, yet whether this metabolic fine-tuning occurs ubiquitously across cell types and is a core clock feature is unknown. Here, we show that NAMPT-dependent control over the molecular clock varies substantially between tissues. Brown adipose tissue (BAT) requires NAMPT to sustain the amplitude of the core clock, whereas rhythmicity in white adipose tissue (WAT) is only moderately dependent on NAD+ biosynthesis, and the skeletal muscle clock is completely refractory to loss of NAMPT. In BAT and WAT, NAMPT differentially orchestrates oscillation of clock-controlled gene networks and the diurnality of metabolite levels. NAMPT coordinates the rhythmicity of TCA cycle intermediates in BAT, but not in WAT, and loss of NAD+ abolishes these oscillations similarly to high-fat diet-induced circadian disruption. Moreover, adipose NAMPT depletion improved the ability of animals to defend body temperature during cold stress but in a time-of-day-independent manner. Thus, our findings reveal that peripheral molecular clocks and metabolic biorhythms are shaped in a highly tissue-specific manner by NAMPT-dependent NAD+ synthesis.
Subject(s)
NAD , Nicotinamide Phosphoribosyltransferase , Animals , NAD/metabolism , Nicotinamide Phosphoribosyltransferase/genetics , Nicotinamide Phosphoribosyltransferase/metabolism , Circadian Rhythm/physiology , Adipose Tissue, Brown/metabolism , Obesity/metabolism , Cytokines/metabolismABSTRACT
L-type voltage-gated calcium (Ca2+) channels (L-VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown whether molecular mechanisms leading to disrupted L-VGCC across neurodegenerative disorders are conserved. Importantly, L-VGCC integrate synaptic signals to facilitate a plethora of cellular mechanisms; however, mechanisms that regulate L-VGCC channel density and subcellular compartmentalization are understudied. Herein, we report that in disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), deficits in dendritic L-VGCC activity are associated with increased expression of the RNA-binding protein (RBP) Parkinsonism-associated deglycase (DJ-1). DJ-1 binds the mRNA coding for the alpha and auxiliary Ca2+ channel subunits CaV1.2 and α2δ2, and represses their mRNA translation, only in the disease states, specifically preclinical models of tuberous sclerosis complex (TSC) and Alzheimer's disease (AD). In agreement, DJ-1-mediated repression of CaV1.2/α2δ2 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L-VGCC calcium activity. Finding of DJ-1-regulated L-VGCC activity in dendrites in TSC and AD provides a unique signaling pathway that can be targeted in clinical mTORopathies.
Subject(s)
Alzheimer Disease , Tuberous Sclerosis , Animals , Mice , Alzheimer Disease/genetics , Calcium/metabolism , Calcium Channels, L-Type/genetics , Calcium Channels, L-Type/metabolism , Dendrites/metabolism , Mammals/metabolism , Tuberous Sclerosis/geneticsABSTRACT
The gut microbiota and liver cancer have a complex interaction. However, the role of gut microbiome in liver tumor initiation remains unknown. Herein, liver cancer was induced using hydrodynamic transfection of oncogenes to explore liver tumorigenesis in mice. Gut microbiota depletion promoted liver tumorigenesis but not progression. Elevated sterol regulatory element-binding protein 2 (SREBP2) was observed in mice with gut flora disequilibrium. Pharmacological inhibition of SREBP2 or Srebf2 RNA interference attenuated mouse liver cancer initiation under gut flora disequilibrium. Furthermore, gut microbiota depletion impaired gut tryptophan metabolism to activate aryl hydrocarbon receptor (AhR). AhR agonist Ficz inhibited SREBP2 posttranslationally and reversed the tumorigenesis in mice. And, AhR knockout mice recapitulated the accelerated liver tumorigenesis. Supplementation with Lactobacillus reuteri, which produces tryptophan metabolites, inhibited SREBP2 expression and tumorigenesis in mice with gut flora disequilibrium. Thus, gut flora disequilibrium promotes liver cancer initiation by modulating tryptophan metabolism and up-regulating SREBP2.
Subject(s)
Dysbiosis , Gastrointestinal Microbiome , Liver Neoplasms , Sterol Regulatory Element Binding Protein 2 , Animals , Mice , Carcinogenesis , Liver Neoplasms/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Sterol Regulatory Element Binding Protein 2/metabolism , Tryptophan/metabolism , Dysbiosis/complicationsABSTRACT
The burgeoning prodrug strategy offers a promising avenue toward improving the efficacy and specificity of cytotoxic drugs. Elevated intracellular levels of glutathione (GSH) have been regarded as a hallmark of tumor cells and characteristic feature of the tumor microenvironment. Considering the pivotal involvement of elevated GSH in the tumorigenic process, a diverse repertoire of GSH-triggered prodrugs has been developed for cancer therapy, facilitating the attenuation of deleterious side effects associated with conventional chemotherapeutic agents and/or the attainment of more efficacious therapeutic outcomes. These prodrug formulations encompass a spectrum of architectures, spanning from small molecules to polymer-based and organic-inorganic nanomaterial constructs. Although the GSH-triggered prodrugs have been gaining increasing interests, a comprehensive review of the advancements made in the field is still lacking. To fill the existing lacuna, this review undertakes a retrospective analysis of noteworthy research endeavors, based on a categorization of these molecules by their diverse recognition units (i.e., disulfides, diselenides, Michael acceptors, and sulfonamides/sulfonates). This review also focuses on explaining the distinct benefits of employing various chemical architecture strategies in the design of these prodrug agents. Furthermore, we highlight the potential for synergistic functionality by incorporating multiple-targeting conjugates, theranostic entities, and combinational treatment modalities, all of which rely on the GSH-triggering. Overall, an extensive overview of the emerging field is presented in this review, highlighting the obstacles and opportunities that lie ahead. Our overarching goal is to furnish methodological guidance for the development of more efficacious GSH-triggered prodrugs in the future. By assessing the pros and cons of current GSH-triggered prodrugs, we expect that this review will be a handful reference for prodrug design, and would provide a guidance for improving the properties of prodrugs and discovering novel trigger scaffolds for constructing GSH-triggered prodrugs.
Subject(s)
Antineoplastic Agents , Prodrugs , Humans , Prodrugs/pharmacology , Prodrugs/chemistry , Retrospective Studies , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Glutathione/chemistry , Cell Line, TumorABSTRACT
The spleen is essential for lymphocyte proliferation, which is associated to sepsis prognosis. Adenosine 2A receptor (A2AR) blocking promotes lymphocyte proliferation in sepsis, however the mechanism is uncertain. Our sepsis cecum ligation perforation model showed that blocking A2AR increased survival and CD4+ cell numbers in a spleen-dependent mechanism. The sequencing of the transcriptome of the spleen indicated alterations in the expression of genes involved in the control of lymphocyte proliferation by inhibiting A2AR, including a reduction in the expression of PD-L1. Flow cytometry analysis of PD-L1 expression intensity in splenic cell subpopulations revealed that the Treg cell subpopulation was the strongest PD-L1-expressing cell population, and Treg PD-L1 expression decreased after blocking A2AR. In vitro activation of A2AR was able to upregulate PD-L1 expression of Treg and boost Treg capacity to limit lymphocyte proliferation, while blockage of PD-L1 partly reduced A2AR-activated Treg's ability to inhibit lymphocyte proliferation. In addition, blocking CREB phosphorylation significantly inhibited A2AR-induced PD-L1 expression. According to the findings of our research, inhibiting A2AR improves the prognosis of sepsis by lowering the level of PD-L1 expression by Treg in the spleen and reducing the inhibition of lymphocyte proliferation.
Subject(s)
Sepsis , Spleen , Humans , Spleen/metabolism , T-Lymphocytes, Regulatory/metabolism , Purinergic P1 Receptor Antagonists , B7-H1 Antigen/metabolism , Adenosine , Cell ProliferationABSTRACT
BACKGROUND: Intervertebral disc degeneration (IDD) is considered an important pathological basis for spinal degenerative diseases. Tissue engineering is a powerful therapeutic strategy that can effectively restore the normal biological properties of disc units. In this study, hydrogels loaded with growth/differentiation factor 5 (GDF5) and stem cells were combined to provide an effective strategy for nucleus pulposus regeneration. METHODS: Nucleus pulposus stem cells (NPSCs) were obtained by low-density inoculation and culture, and their stem cell characteristics were verified by flow cytometry and a tri-lineage-induced differentiation experiment. A decellularized nucleus pulposus matrix (DNPM) and chitosan hybrid hydrogel was prepared, and GDF5-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres were incorporated into the hydrogels to obtain a composite hydrogels with GDF5-loaded microspheres. Taking bone marrow mesenchymal stem cells (BMSCs) as a reference, the effect of composite hydrogels with GDF5-loaded microspheres on the chondrogenic differentiation of NPSCs was evaluated. A model of intervertebral disc degeneration induced by acupuncture on the tail of rats was constructed, and the repair effect of composite hydrogels with GDF5-loaded microspheres combined with NPSCs on IDD was observed. RESULTS: Stem cell phenotype identification, stemness gene expression and tri-lineage-induced differentiation confirmed that NPSCs had characteristics similar to those of BMSCs. The rat DNPM and chitosan hybrid hydrogels had good mechanical properties, and the GDF5-loaded microspheres sustainably released GDF5. NPSCs grew normally in the composite hydrogels and gradually expressed a chondrocyte phenotype. Animal experiments showed that the composite hydrogels with GDF5-loaded microspheres combined with NPSCs effectively promoted nucleus pulposus regeneration and that the effect of the hydrogels on the repair of IDD was significantly better than that of BMSCs. CONCLUSION: GDF5-loaded microspheres combined with DNPM/chitosan composite hydrogels can effectively promote the differentiation of NPSCs into nucleus pulposus-like cells and effectively preventIDD.
Subject(s)
Chitosan , Intervertebral Disc Degeneration , Nucleus Pulposus , Animals , Rats , Hydrogels , Intervertebral Disc Degeneration/therapy , Microspheres , Stem CellsABSTRACT
Protein tyrosine kinase-7 (PTK7) has been reported as a vital participant in the Wnt signaling pathway, influencing tumorigenesis and metastasis. However, their specific roles in the mechanisms underlying cancer development and progression remain elusive. Here, using direct stochastic optical reconstruction microscopy (dSTORM) with aptamer-probe labeling, we first revealed that a weakening clustering distribution of PTK7 on the basal membranes happened as cellular migration increased during cancer progression. This correspondence was further supported by a diminished aggregated state of PTK7 caused by direct enhancement of cell migration. By comparing the alterations in PTK7 distribution with activation or inhibition of specific Wnt signaling pathway, we speculated that PTK7 could modulate cell migration by participating in the interplay between canonical Wnt (in MCF7 cells) and noncanonical Wnt signals (in MDA-MB-231 cells). Furthermore, we discovered that the spatial distribution morphology of PTK7 was also subject to the hydrolysis ability and activation state of the related hydrolase Matrix metallopeptidase14 (MMP14). This function-related specific assembly of PTK7 reveals a clear relationship between PTK7 and cancer. Meanwhile, potential molecular interactions predicted by the apparent assembly morphology can promote a deep understanding of the functional mechanism of PTK7 in cancer progress.
Subject(s)
Receptor Protein-Tyrosine Kinases , Humans , Receptor Protein-Tyrosine Kinases/metabolism , Cell Movement , Cell Adhesion Molecules/metabolism , Wnt Signaling Pathway , Cell Line, Tumor , Neoplasms/metabolism , Neoplasms/pathology , Matrix Metalloproteinase 14/metabolismABSTRACT
On-site hydrogen production from liquid organic hydrogen carriers e.g., methanol provides an emerging strategy for the safe storage and transportation of hydrogen. Herein, a catalytic architecture consisting of nickel-cobalt nanoclusters dispersed on gallium nitride nanowires supported by silicon for light-driven hydrogen production from methanol is reported. By correlative microscopic, spectroscopic characterizations, and density functional theory calculations, it is revealed that NiCo nanoclusters work in synergy with GaN nanowires to enable the achievement of a significantly reduced activation energy of methanol dehydrogenation by switching the potential-limiting step from *CHO â *CO to *CH3O â *CH2O. In combination with the marked photothermal effect, a high hydrogen rate of 5.62 mol·gcat-1·h-1 with a prominent turnover frequency of 43,460 h-1 is achieved at 5 Wcm-2 without additional energy input. Remarkably, the synergy between Co and Ni, in combination with the unique surface of GaN, renders the architecture with outstanding resistance to sintering and coking. The architecture thereby exhibits a high turnover number of >16,310,000 over 600 h. Outdoor testing validates the viability of the architecture for active and robust hydrogen evolution under natural concentrated sunlight. Overall, this work presents a promising architecture for on-site hydrogen production from CH3OH by virtually unlimited solar energy.
ABSTRACT
Rwanda is known as the heart of Africa, reflecting the history of the world. Colonization and genocide have led to Rwanda's existing genetic structure. Herein, we used massively parallel sequencing to analyze 296 loci in 185 Rwandans and constructed a database for Rwandan forensic data for the first time. We found the following results: First, forensic parameters demonstrated that all loci were highly informative and could be used for forensic identification and paternity tests in Rwandans. Second, we found that the differences in genetic background between Rwandans and other African populations were similar but slight, as indicated by the massively parallel sequencing panel. Rwandans belonged to the African population and were inseparable from populations from neighboring countries. Also, Rwandans were closer to the European and American populations because of colonization, war, and other reasons. There was no scientific basis for racial classification established by colonization. Further research still needs to be carried out on more loci and larger Rwandan samples.
Subject(s)
Population Dynamics , Rwanda , Demography , AfricaABSTRACT
Murine Natural Killer cells were cultivated in vitro to isolate NK-derived exosomes. Subsequent quantification via qPCR confirmed enrichment of miR-1249-3p. Ana-1 murine macrophages were cultured in vitro and subsequently inoculated with Mycobacterium tuberculosis (MTB) strain H37Rv. NK-exo and NK-exo miR-1249-3p were separately applied to the infection model, followed by immunological assays conducted post-48-hour co-culture. Western blot analyses corroborated that NK-exo exhibited exosomal marker proteins Granzyme A (GzmA), Granzyme B (GzmB), and Perforin (PFN), alongside a notable enrichment of miR-1249-3p. Functionally, NK-exo augmented the expression levels of Caspase-9,-8, and -3, as well as PARP, while attenuating the expression of NLRP3, ASC, and Cleaved-Caspase-1. Furthermore, qPCR demonstrated an up-regulation of Caspase-9, -8, and -3, along with pro-apoptotic factors Bax and Bid, and a concomitant down-regulation of the anti-apoptotic factor Bcl-2. The expression levels of inflammatory markers ASC, NLRP3, Cleaved-Caspase-1, and IL-1ß were concomitantly decreased. ELISA findings indicated diminished levels of TNF-α and ROS secretion. NK-exo miR-1249-3p specifically targeted and attenuated the expression of SKOR-1, engendering up-regulation of apoptosis-associated proteins and down-regulation of inflammation-related proteins, consequently affecting cellular fate.Our empirical evidence substantiates that NK-exo induces macrophage apoptosis, thereby mitigating MTB survival. Furthermore, NK-exo miR-1249-3p directly targets and inhibits SKOR-1 expression, leading to macrophage apoptosis and consequently hampering the proliferation of MTB. The data implicate the potential therapeutic relevance of NK-exo and miR-1249-3p in managing drug-resistant tuberculosis.
Subject(s)
Exosomes , MicroRNAs , Mycobacterium tuberculosis , Animals , Mice , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Caspase 9/metabolism , Mycobacterium tuberculosis/metabolism , Exosomes/metabolism , Macrophages/metabolism , MicroRNAs/metabolismABSTRACT
Here we report B(C6F5)3/CPA-catalyzed enantioselective aza-Diels-Alder reaction of 3,3-difluoro-2-Aryl-3H-indoles with unactivated dienes to access chiral 10,10-difluoro-tetrahydropyrido[1,2-a]indoles. This protocol allows the formation of pyrazole-based C2-quaternary indolin-3-ones with high enantioselectivities and regioselectivities. Moreover, gram-scale synthesis of the 10,10-difluoro-tetrahydropyrido[1,2-a]indole skeleton was successfully achieved without any reduction in both yield and enantioselectivity.
ABSTRACT
BACKGROUND: The role of adjuvant transcatheter arterial chemoembolization (TACE) following repeated resection/ablation for recurrent hepatocellular carcinoma (HCC) remains uncertain. The aim of this study was to assess the effectiveness of adjuvant TACE following repeated resection or ablation in patients with early recurrent HCC. METHODS: Information for patients who underwent repeated surgery or radiofrequency ablation (RFA) for early recurrent HCCs (< 2 years) at our institution from January 2017 to December 2020 were collected. Patients were divided into adjuvant TACE and observation groups according to whether they received adjuvant TACE or not. The recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups before and after propensity score matching (PSM). RESULTS: Of the 225 patients enrolled, the median time of HCC recurrence was 11 months (IQR, 6-16 months). After repeated surgery or radiofrequency ablation (RFA) for recurrent tumors, 45 patients (20%) received adjuvant TACE while the remaining 180 (80%) didn't. There were no significant differences in RFS (P = 0.325) and OS (P = 0.072) between adjuvant TACE and observation groups before PSM. There were also no significant differences in RFS (P = 0.897) and OS (P = 0.090) between the two groups after PSM. Multivariable analysis suggested that multiple tumors, liver cirrhosis, and RFA were independent risk factors for the re-recurrence of HCC. CONCLUSION: Adjuvant TACE after repeated resection or ablation for early recurrent HCCs was not associated with a long-term survival benefit in this single-center cohort.
Subject(s)
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Hepatectomy , Liver Neoplasms , Neoplasm Recurrence, Local , Propensity Score , Humans , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/surgery , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/therapy , Liver Neoplasms/mortality , Liver Neoplasms/surgery , Liver Neoplasms/pathology , Chemoembolization, Therapeutic/methods , Male , Female , Middle Aged , Hepatectomy/methods , Aged , Radiofrequency Ablation/methods , Retrospective Studies , Combined Modality Therapy , Treatment Outcome , Chemotherapy, Adjuvant/methodsABSTRACT
Despite the economic, ecological, and scientific importance of the genera Salix L. (willows) and Populus L. (poplars, cottonwoods, and aspens) Salicaceae, we know little about the sources of differences in species diversity between the genera and of the phylogenetic conflict that often confounds estimating phylogenetic trees. Salix subgenera and sections, in particular, have been difficult to classify, with one recent attempt termed a "spectacular failure" due to a speculated radiation of the subgenera Vetrix and Chamaetia. Here, we use targeted sequence capture to understand the evolutionary history of this portion of the Salicaceae plant family. Our phylogenetic hypothesis was based on 787 gene regions and identified extensive phylogenetic conflict among genes. Our analysis supported some previously described subgeneric relationships and confirmed the polyphyly of others. Using an fbranch analysis, we identified several cases of hybridization in deep branches of the phylogeny, which likely contributed to discordance among gene trees. In addition, we identified a rapid increase in diversification rate near the origination of the Vetrix-Chamaetia clade in Salix. This region of the tree coincided with several nodes that lacked strong statistical support, indicating a possible increase in incomplete lineage sorting due to rapid diversification. The extraordinary level of both recent and ancient hybridization in both Salix and Populus have played important roles in the diversification and diversity in these two genera.
Subject(s)
Populus , Salix , Phylogeny , Salix/genetics , Populus/genetics , Biological Evolution , Hybridization, GeneticABSTRACT
Self-assemblies of two fluorenone-based derivatives (FE and FEC) consisting of a central 2,7-diphenyl-9-fluorenone polar moiety but differing in the flexible terminal groups were investigated by scanning tunneling microscopy (STM) at the 1-octanoic acid/HOPG interface under different concentrations and density functional theory calculation (DFT). STM results reveal a concentration-dependent polymorphic self-assembly behavior for FE, but without the presence of co-adsorbed solvents. As the concentration decreases, the dimer, bracket-like, and ribbon-like self-assembled structures were observed. On the contrary, FEC molecules assemble into only a type of oval-shaped morphology by the intermolecular N···H-O hydrogen bonds with the solvent molecules. Combined with DFT calculations, it can be deduced that the intermolecular van der Waals forces, dipole-dipole interactions, and hydrogen bonding are the main driving forces to stabilize the molecular packing of fluorenone-based polycatenars with strong polarity. Our work is of significance at the molecular level to further clarify the intermolecular interactions and conformational effects on the formation of molecular packing structures with liquid crystal property.
ABSTRACT
INTRODUCTION: The etiology and management of nonalcoholic fatty liver disease (NAFLD) after pancreaticoduodenectomy (PD) remain unclear. This study aimed to investigate the risk factors and outcomes of NAFLD after PD (PD-NAFLD). METHODS: Patients who underwent PD at our institution between June 2019 and September 2021 were enrolled in the study. The clinical manifestations and outcomes of the patients with PD-NAFLD were evaluated. Multivariable analysis was used to identify risk factors for PD-NAFLD. RESULTS: Of the 407 patients enrolled, PD-NAFLD was identified in 54 (13.2%). The median time of onset of PD-NAFLD was 72.5 (51.5-171.25) d postoperatively. Twenty-four patients (44.4%) recovered completely within 36 mo postoperatively. Adjuvant chemotherapy was administered in 147 malignant cases, and patients with PD-NAFLD encountered delay or discontinuation of chemotherapy more frequently than those without PD-NAFLD (55.9% versus 30.1%, P = 0.006). Multivariable analysis identified female sex, high body mass index, and neoadjuvant chemotherapy as independent risk factors for PD-NAFLD. CONCLUSIONS: PD-NAFLD is a common complication of PD. Female sex, high body mass index, and neoadjuvant chemotherapy may be associated with the development of PD-NAFLD. PD-NAFLD may interrupt the delivery of adjuvant chemotherapy in patients with malignant tumors.