RESUMEN
Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.
Asunto(s)
Linfocitos T CD8-positivos , Serotonina , Linfocitos T CD8-positivos/metabolismo , Serotonina/metabolismo , Serotonina/farmacología , Procesamiento Proteico-Postraduccional , Transducción de SeñalRESUMEN
Anxiety is a remarkably common condition among patients with pharyngitis, but the relationship between these disorders has received little research attention, and the underlying neural mechanisms remain unknown. Here, we show that the densely innervated pharynx transmits signals induced by pharyngeal inflammation to glossopharyngeal and vagal sensory neurons of the nodose/jugular/petrosal (NJP) superganglia in mice. Specifically, the NJP superganglia project to norepinephrinergic neurons in the nucleus of the solitary tract (NTSNE). These NTSNE neurons project to the ventral bed nucleus of the stria terminalis (vBNST) that induces anxiety-like behaviors in a murine model of pharyngeal inflammation. Inhibiting this pharynxâNJPâNTSNEâvBNST circuit can alleviate anxiety-like behaviors associated with pharyngeal inflammation. This study thus defines a pharynx-to-brain axis that mechanistically links pharyngeal inflammation and emotional response.
Asunto(s)
Faringitis , Faringe , Humanos , Animales , Ratones , Ansiedad , Encéfalo , Células Receptoras Sensoriales , InflamaciónRESUMEN
MOTIVATION: It is difficult to generate new molecules with desirable bioactivity through ligand-based de novo drug design, and receptor-based de novo drug design is constrained by disease target information availability. The combination of artificial intelligence and phenotype-based de novo drug design can generate new bioactive molecules, independent from disease target information. Gene expression profiles can be used to characterize biological phenotypes. The Transformer model can be utilized to capture the associations between gene expression profiles and molecular structures due to its remarkable ability in processing contextual information. RESULTS: We propose TransGEM (Transformer-based model from gene expression to molecules), which is a phenotype-based de novo drug design model. A specialized gene expression encoder is used to embed gene expression difference values between diseased cell lines and their corresponding normal tissue cells into TransGEM model. The results demonstrate that the TransGEM model can generate molecules with desirable evaluation metrics and property distributions. Case studies illustrate that TransGEM model can generate structurally novel molecules with good binding affinity to disease target proteins. The majority of genes with high attention scores obtained from TransGEM model are associated with the onset of the disease, indicating the potential of these genes as disease targets. Therefore, this study provides a new paradigm for de novo drug design, and it will promote phenotype-based drug discovery. AVAILABILITY AND IMPLEMENTATION: The code is available at https://github.com/hzauzqy/TransGEM.
Asunto(s)
Diseño de Fármacos , Humanos , Fenotipo , Perfilación de la Expresión Génica/métodos , Inteligencia Artificial , Algoritmos , Expresión Génica , LigandosRESUMEN
BACKGROUND: Osteoarthritis (OA), the most common joint disease, is linked with chondrocyte apoptosis and extracellular matrix (ECM) degradation. Charged multivesicular body protein 5 (CHMP5), a member of the multivesicular body, has been reported to serve as an anti-apoptotic protein to participate in leukemia development. However, the effects of CHMP5 on apoptosis and ECM degradation in OA remain unclear. METHODS: In this study, quantitative proteomics was performed to analyze differential proteins between normal and OA patient articular cartilages. The OA mouse model was constructed by the destabilization of the medial meniscus (DMM). In vitro, interleukin-1 beta (IL-1ß) was used to induce OA in human chondrocytes. CHMP5 overexpression and silencing vectors were created using an adenovirus system. The effects of CHMP5 on IL-1ß-induced chondrocyte apoptosis were investigated by CCK-8, flow cytometry, and western blot. The effects on ECM degradation were examined by western blot and immunofluorescence. The potential mechanism was explored by western blot and Co-IP assays. RESULTS: Downregulated CHMP5 was identified by proteomics in OA patient cartilages, which was verified in human and mouse articular cartilages. CHMP5 overexpression repressed cell apoptosis and ECM degradation in OA chondrocytes. However, silencing CHMP5 exacerbated OA chondrocyte apoptosis and ECM degradation. Furthermore, we found that the protective effect of CHMP5 against OA was involved in nuclear factor kappa B (NF-κB) signaling pathway. CONCLUSIONS: This study demonstrated that CHMP5 repressed IL-1ß-induced chondrocyte apoptosis and ECM degradation and blocked NF-κB activation. It was shown that CHMP5 might be a novel potential therapeutic target for OA in the future.
Asunto(s)
Apoptosis , Condrocitos , Matriz Extracelular , Hialuronoglucosaminidasa , FN-kappa B , Osteoartritis , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Cartílago Articular/metabolismo , Cartílago Articular/patología , Condrocitos/metabolismo , Condrocitos/patología , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Interleucina-1beta/metabolismo , FN-kappa B/metabolismo , Osteoartritis/metabolismo , Osteoartritis/patología , Osteoartritis/genética , Proteómica/métodosRESUMEN
The electrocatalytic conversion of nitrate (NO3 -) to NH3 (NO3RR) at ambient conditions offers a promising alternative to the Haber-Bosch process. The pivotal factors in optimizing the proficient conversion of NO3 - into NH3 include enhancing the adsorption capabilities of the intermediates on the catalyst surface and expediting the hydrogenation steps. Herein, the Cu/Cu2O/Pi NWs catalyst is designed based on the directed-evolution strategy to achieve an efficient reduction of NO3â¾. Benefiting from the synergistic effect of the OV-enriched Cu2O phase developed during the directed-evolution process and the pristine Cu phase, the catalyst exhibits improved adsorption performance for diverse NO3RR intermediates. Additionally, the phosphate group anchored on the catalyst's surface during the directed-evolution process facilitates water electrolysis, thereby generating Hads on the catalyst surface and promoting the hydrogenation step of NO3RR. As a result, the Cu/Cu2O/Pi NWs catalyst shows an excellent FE for NH3 (96.6%) and super-high NH3 yield rate of 1.2 mol h-1 gcat. -1 in 1 m KOH and 0.1 m KNO3 solution at -0.5 V versus RHE. Moreover, the catalyst's stability is enhanced by the stabilizing influence of the phosphate group on the Cu2O phase. This work highlights the promise of a directed-evolution approach in designing catalysts for NO3RR.
RESUMEN
Precursor supply plays a significant role in the production of secondary metabolites. In Streptomyces bacteria, propionyl-, malonyl-, and methylmalonyl-CoA are the most common precursors used for polyketide biosynthesis. Although propionyl-CoA synthetases participate in the propionate assimilation pathway and directly convert propionate into propionyl-CoA, malonyl- and methylmalonyl-CoA cannot be formed using common acyl-CoA synthetases. Therefore, both acetyl- and propionyl-CoA carboxylation, catalyzed by acyl-CoA carboxylases, should be considered when engineering a microorganism chassis to increase polyketide production. In this study, we identified a transcriptional regulator of the TetR family, BkdR, in Streptomyces albus B4, which binds directly to the promoter region of the neighboring pccAB operon. This operon encodes acetyl/propionyl-CoA carboxylase and negatively regulates its transcription. In addition to acetate and propionate, the binding of BkdR to pccAB is disrupted by acetyl- and propionyl-CoA ligands. We identified a 16-nucleotide palindromic BkdR-binding motif (GTTAg/CGGTCg/TTAAC) in the intergenic region between pccAB and bkdR. When bkdR was deleted, we found an enhanced supply of malonyl- and methylmalonyl-CoA precursors in S. albus B4. In this study, spinosad production was detected in the recombinant strain after introducing the entire artificial biosynthesized gene cluster into S. albus B4. When supplemented with propionate to provide propionyl-CoA, the novel bkdR-deleted strain produced 29.4% more spinosad than the initial strain in trypticase soy broth (TSB) medium. IMPORTANCE: In this study, we describe a pccAB operon involved in short-chain acyl-CoA carboxylation in S. albus B4 chassis. The TetR family regulator, BkdR, represses this operon. Our results show that BkdR regulates the precursor supply needed for heterologous spinosad biosynthesis by controlling acetyl- and propionyl-CoA assimilation. The deletion of the BkdR-encoding gene exerts an increase in heterologous spinosad yield. Our research reveals a regulatory mechanism in short-chain acyl-CoA metabolism and suggests new possibilities for S. albus chassis engineering to enhance heterologous polyketide yield.
Asunto(s)
Proteínas Bacterianas , Combinación de Medicamentos , Macrólidos , Streptomyces , Macrólidos/metabolismo , Streptomyces/genética , Streptomyces/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Regulación Bacteriana de la Expresión Génica , Ingeniería Metabólica , Operón , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Acilcoenzima A/metabolismoRESUMEN
The dry tropics occupy ~40% of the tropical land surface and play a dominant role in the trend and interannual variability of the global carbon cycle. Previous studies have reported considerable changes in the dry tropical precipitation seasonality due to climate change, however, the accompanied changes in the length of the vegetation growing season (LGS)-the key period of carbon sequestration-have not been examined. Here, we used long-term satellite observations along with in-situ flux measurements to investigate phenological changes in the dry tropics over the past 40 years. We found that only ~18% of the dry tropics show a significant (p ≤ .1) increasing trend in LGS, while ~13% show a significant decreasing trend. The direction of the LGS change depended not only on the direction of precipitation seasonality change but also on the vegetation water use strategy (i.e. isohydricity) as an adaptation to the long-term average precipitation seasonality (i.e. whether the most of LGS is in the wet season or dry season). Meanwhile, we found that the rate of LGS change was on average ~23% slower than that of precipitation seasonality, caused by a buffering effect from soil moisture. This study uncovers potential mechanisms driving phenological changes in the dry tropics, offering guidance for regional vegetation and carbon cycle studies.
Asunto(s)
Cambio Climático , Ecosistema , Estaciones del Año , Ciclo del Carbono , Secuestro de CarbonoRESUMEN
Quantum theory allows information to flow through a single device in a coherent superposition of two opposite directions, resulting into situations where the input-output direction is indefinite. Here we introduce a theoretical method to witness input-output indefiniteness in a single quantum device, and we experimentally demonstrate it by constructing a photonic setup that exhibits input-output indefiniteness with a statistical significance exceeding 69 standard deviations. Our results provide a way to characterize input-output indefiniteness as a resource for quantum information and photonic quantum technologies and enable tabletop simulations of hypothetical scenarios exhibiting quantum indefiniteness in the direction of time.
RESUMEN
A novel bacterial strain, designated WL0086T, was isolated from a marine sediment sample collected in Lianyungang city, Jiangsu province, PR China. This strain showed the highest 16S rRNA gene sequence similarity to Geminisphaera colitermitum TAV2T (92.7â%) of the family Opitutaceae, and all the unclassified cultured and uncultured isolates with similarities >95â% were from marine environments. Cells were Gram-stain-negative, aerobic, non-motile cocci with a size of 0.6-0.8 µm in diameter. Strain WL0086T was positive for both oxidase and catalase, and grew at 20-37â°C (optimum, 28â°C), with 1.5-11.0â% NaCl (w/v; optimum, 2.5-4.0â%) and at pH 5.0-9.0 (optimum, pH 7.0). The major polar lipid profile of strain WL0086T consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, and phosphatidylcholine. The major isoprenoid quinone was menaquinone-7 and the predominant fatty acids were iso-C14â:â0, anteiso-C15â:â0, C16â:â0 and C16â:â1 ω9c. The complete genome consisted of a chromosome with 6â109â182 bp. The G+C content of genomic DNA was 64.0%. Results of phylogenomic analysis based on the 16S rRNA gene sequence and the whole genome suggested that strain WL0086T formed a distinct clade closely neighbouring the members of the family Opitutaceae. On the basis of phylogenetic, phenotypic, and chemotaxonomic evidences, strain WL0086T should represent a novel genus of the family Opitutaceae, for which the name Actomonas aquatica gen. nov., sp. nov. is proposed. The type strain is WL0086T (=MCCC 1K05844T=JCM 34677T=GDMCC 1.2411T).
Asunto(s)
Carbono , Fijación del Nitrógeno , Composición de Base , Ácidos Grasos/química , Filogenia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , ADN Bacteriano/genética , Técnicas de Tipificación BacterianaRESUMEN
OBJECTIVES: To investigate the feasibility of non-contrast-enhanced MR angiography (NCE-MRA) in evaluating the morphology and blood supply of left gastric vein (LGV) in patients with gastroesophageal varices. METHODS: Between March 2021 and October 2022, patients with gastroesophageal varices and who underwent NCE-MRA were retrospectively reviewed. In order to evaluate the blood supply of LGV, superior mesenteric vein (SMV) and splenic vein (SV) were visualized separately by using inflow-sensitive inversion recovery sequence. Two radiologists independently assessed the image quality, determined the origination and the blood supply of LGV, and measured the diameter of LGV. The origination and diameter of LGV were compared between NCE-MRA and contrast-enhanced CT. Differences in blood supply were compared between LGVs with different originations. RESULTS: A total of 53 patients were enrolled in this study and the image quality was categorized as good or excellent in 52 patients. No significant differences were observed in visualizing the origination and the diameter of LGV between NCE-MRA and contrast-enhanced CT (p > .05). The blood supply of LGV was related to its origination (p < .001). Most LGVs with SV origination were supplied by SV. If LGV was originated from the portal vein (PV), about 70% of them were supplied by both SV and SMV. Compared with LGVs with SV origination, LGVs with PV origination showed more chance to receive blood from SMV (p < .001). CONCLUSION: Non-contrast-enhanced MR angiography appears to be a reliable technique in evaluating the morphology and blood supply of LGV in patients with gastroesophageal varices. CLINICAL RELEVANCE STATEMENT: Non-contrast-enhanced MR angiography provides valuable information for the management of gastroesophageal varices. Especially, it benefits patients with renal insufficiency. KEY POINTS: ⢠Non-contrast-enhanced MR angiography using inflow-sensitive inversion recovery technique can be used for evaluating not only morphology as CT but also blood supply of left gastric vein. ⢠The blood supply of left gastric vein is related to its origination and left gastric vein with portal vein origination shows more chance to receive blood from superior mesenteric vein.
Asunto(s)
Várices Esofágicas y Gástricas , Estudios de Factibilidad , Angiografía por Resonancia Magnética , Humanos , Masculino , Femenino , Persona de Mediana Edad , Várices Esofágicas y Gástricas/diagnóstico por imagen , Estudios Retrospectivos , Angiografía por Resonancia Magnética/métodos , Anciano , Adulto , Estómago/irrigación sanguínea , Estómago/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Vena Esplénica/diagnóstico por imagen , Venas Mesentéricas/diagnóstico por imagen , Medios de ContrasteRESUMEN
Currently, most conventional methods to achieve imidazo[1,5-a]pyridines have limitations for the synthesis of 3-acyl imidazo[1,5-a]pyridines. Herein, a novel and efficient Cu(I)-catalyzed three-component annulation method for the synthesis of valuable 3-acyl imidazo[1,5-a]pyridines by the reaction of 2-pyridinyl-substituted p-QMs, terminal alkynes, and TsN3 in the presence of O2 under mild conditions have successfully been developed. The investigation indicated that molecular oxygen (O2) and TsN3, respectively, serving as oxygen and nitrogen sources, were essential for the successful completion of the reaction system.
RESUMEN
The through-space charge transfer thermally activated delayed fluorescence (TSCT-TADF) properties of a series of molecules were characterized and tested theoretically by density functional theory and time-dependent density functional theory. By analyzing the weak interaction of the molecules at the ground state and calculating the transition contribution ratio of the donor, acceptor, and bridge in the excited state, we verified the through-space charge transfer characteristic of these molecules. We designed new molecules on the basis of the reported molecules (non-TADF molecule 1 and TADF molecule 2) to improve the performance. Smaller singlet-triplet energy gaps and larger spin-orbit coupling were obtained in the designed molecules, which is beneficial to obtain higher intersystem crossing and reverse intersystem crossing rates (kRISC). In addition, we calculated the radiation rate and the singlet-triplet reorganization energy, which is used to characterize the nonradiation rate. The comprehensive evaluation of both radiative and nonradiative processes shows that molecules 4 and 6 have the potential to be highly efficient TSCT-TADF materials.
RESUMEN
Low dimensional organic inorganic metal halide materials have shown broadband emission and large Stokes shift, making them widely used in various fields and a promising candidate material. Here, the zero-dimensional lead-free bromide single crystals (C6H14N)3Bi2Br9·H2O (1) and (C6H14N)3Sb3Br12 (2) were synthesized. They crystallized in the monoclinic crystal system with the space group of P21 and P21/n, respectively. Through ultraviolet-visible-near-infrared (UV-vis-NIR) absorption analysis, the band gaps of (C6H14N)3Bi2Br9·H2O and (C6H14N)3Sb3Br12 are found to be 2.75 and 2.83 eV, respectively. Upon photoexcitation, (C6H14N)3Bi2Br9·H2O exhibit broad-band red emission peaking at 640 nm with a large Stokes shift of 180 nm and a lifetime of 2.94 ns, and the emission spectrum of (C6H14N)3Sb3Br12 are similar to those of (C6H14N)3Bi2Br9·H2O. This exclusive red emission is ascribed to the self-trapping exciton transition caused by lattice distortion, which is confirmed through both experiments and first-principles calculations. In addition, due to the polar space group structure and the large spin-orbit coupling (SOC) associated with the heavy elements of Bi and Br of crystal 1, an obvious Rashba effect was observed. The discovery of organic inorganic metal bromide material provides a critical foundation for uncovering the connection between 0D metal halide materials' structures and properties.
RESUMEN
An efficient and metal-free method for the synthesis of 3-aryl pyrido[1,2-a]indoles from aryne intermediates and 2-pyridinyl-substituted p-QMs was successfully developed under ambient conditions. The reaction offered a novel and practical protocol to access some diverse functional molecules in good to excellent yields. The proposed mechanism indicated that the reaction proceeded via a formal [3 + 2] cycloaddition step.
RESUMEN
BACKGROUND: Chondrocyte oxidative stress and apoptosis are critical factors contributing to the pathogenesis of osteoarthritis (OA). Methionine sulfoxide reductase B2 (MSRB2) is a mitochondrial protein that protects cells from oxidative stress and is involved in apoptosis. This study aimed to investigated the expression of MSRB2 in articular cartilage tissues and elucidated its effect on H2O2-stimulated chondrocytes. METHODS: Human chondrocytes were cultured in Dulbecco's modified Eagle's medium (DMEM)/F12. MSRB2 overexpression in chondrocytes was achieved by transfecting with an MSRB2 overexpression plasmid. Western blot, quantitative RT-PCR, Immunofluorescence staining, and TUNEL assay were employed in this study. RESULTS: MSRB2 expression was found to be reduced in OA patients. Furthermore, overexpression of MSRB2 in H2O2-induced chondrocytes mitigated apoptosis and enhanced cell viability. Elevated MSRB2 expression diminished chondrocyte ROS contents, decreased cytochrome C (Cyc) in the cytoplasm, and regulated mitochondrial membrane potential to maintain mitochondrial homeostasis. Interestingly, knockdown of charged multivesicular body protein 5 (CHMP5) led to a decreased inMSRB2 expression in chondrocytes. Additionally, protein levels of CHMP5 and MSRB2 were reduced in H2O2-stimulated chondrocytes, and silencing CHMP5 reduced MSRB2 expression. Knockdown of CHMP5 increased cleaved caspase-3 expression in H2O2-induced chondrocytes and elevated TUNEL-positive chondrocytes. CONCLUSION: MSRB2 decreased in OA, and overexpression of MSRB2 alleviated oxidative stress and apoptosis of chondrocyte.
RESUMEN
The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global public health crisis. The causative agent, the SARS-CoV-2 virus, enters host cells via molecular interactions between the viral spike protein and the host cell ACE2 surface protein. The SARS-CoV-2 spike protein is extensively decorated with up to 66 N-linked glycans. Glycosylation of viral proteins is known to function in immune evasion strategies but may also function in the molecular events of viral entry into host cells. Here, we show that N-glycosylation at Asn331 and Asn343 of SARS-CoV-2 spike protein is required for it to bind to ACE2 and for the entry of pseudovirus harboring the SARS-CoV-2 spike protein into cells. Interestingly, high-content glycan binding screening data have shown that N-glycosylation of Asn331 and Asn343 of the RBD is important for binding to the specific glycan molecule G4GN (Galß-1,4 GlcNAc), which is critical for spike-RBD-ACE2 binding. Furthermore, IL-6 was identified through antibody array analysis of conditioned media of the corresponding pseudovirus assay. Mutation of N-glycosylation of Asn331 and Asn343 sites of the spike receptor-binding domain (RBD) significantly reduced the transcriptional upregulation of pro-inflammatory signaling molecule IL-6. In addition, IL-6 levels correlated with spike protein levels in COVID-19 patients' serum. These findings establish the importance of RBD glycosylation in SARS-CoV-2 pathogenesis, which can be exploited for the development of novel therapeutics for COVID-19.
Asunto(s)
Enzima Convertidora de Angiotensina 2 , COVID-19 , Interleucina-6 , Unión Proteica , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Internalización del Virus , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Humanos , Glicosilación , Enzima Convertidora de Angiotensina 2/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiología , Interleucina-6/metabolismo , COVID-19/virología , COVID-19/metabolismo , Células HEK293 , Asparagina/metabolismo , Polisacáridos/metabolismoRESUMEN
Previous studies about anhedonia symptoms in bipolar depression (BD) ignored the unique role of gender on brain function. This study aims to explore the regional brain neuroimaging features of BD with anhedonia and the sex differences in these patients. The resting-fMRI by applying fractional amplitude of low-frequency fluctuation (fALFF) method was estimated in 263 patients with BD (174 high anhedonia [HA], 89 low anhedonia [LA]) and 213 healthy controls. The effects of two different factors in patients with BD were analyzed using a 3 (group: HA, LA, HC) × 2 (sex: male, female) ANOVA. The fALFF values were higher in the HA group than in the LA group in the right medial cingulate gyrus and supplementary motor area. For the sex-by-group interaction, the fALFF values of the right hippocampus, left medial occipital gyrus, right insula, and bilateral medial cingulate gyrus were significantly higher in HA males than in LA males but not females. These results suggested that the pattern of high activation could be a marker of anhedonia symptoms in BD males, and the sex differences should be considered in future studies of BD with anhedonia symptoms.
RESUMEN
Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.
RESUMEN
Climate change due to increased greenhouse gas emissions (GHG) in the atmosphere has been consistently observed since the mid-20th century. The profound influence of global climate change on greenhouse gas (GHG) emissions, encompassing carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O), has established a vital feedback loop that contributes to further climate change. This intricate relationship necessitates a comprehensive understanding of the underlying feedback mechanisms. By examining the interactions between global climate change, soil, and GHG emissions, we can elucidate the complexities of CO2, CH4, and N2O dynamics and their implications. In this study, we evaluate the global climate change relationship with GHG globally in 246 countries. We find a robust positive association between climate and GHG emissions. By 2100, GHG emissions will increase in all G7 countries and China while decreasing in the United Kingdom based on current economic growth policies, resulting in a net global increase, suggesting that climate-driven increase in GHG and climate variations impact crop production loss due to soil impacts and not provide climate adaptation. The study highlights the diverse strategies employed by G7 countries in reducing GHG emissions, with France leveraging nuclear power, Germany focusing on renewables, and Italy targeting its industrial and transportation sectors. The UK and Japan are making significant progress in emission reduction through renewable energy, while the US and Canada face challenges due to their industrial activities and reliance on fossil fuels.
Asunto(s)
Gases de Efecto Invernadero , Gases de Efecto Invernadero/análisis , Dióxido de Carbono/análisis , Agricultura , Suelo , Producción de Cultivos , Metano/análisis , Óxido Nitroso , Efecto InvernaderoRESUMEN
OBJECTIVE: Vascular aberrancy of superior mesenteric artery (SMA) may contribute to the occurrence of SMA dissection. However, there is no direct evidence to support this hypothesis. Etiology, natural history, classification, and treatment options of ISMAD are still in controversial at some degree. We also review the current understanding of ISMAD based on our results. METHODS: Out of 57 patients, 2 cases of isolated superior mesenteric artery dissection (ISMAD) which concomitant with replaced common hepatic artery with SMA origin, are first reported. RESULTS: Two patients have no any typical etiological factors, such as atherosclerosis, hypertension, long-term smoking, and connective tissue disease. The contrast-enhanced computed tomography and (or) angiography showed concomitant SMA aberrancy. They have 81.2°, 132.7° SMA angle, respectively. After conservative treatment of 4, 6 days, respectively, these 2 patients were discharged smoothly. CONCLUSION: Vascular aberrancy may be a new identified risk factor for ISMAD. Even in ISMAD cases with vascular aberrancy, conservative treatment still can be used as first line therapy.