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Metastasis constitutes the primary cause of cancer-related deaths, with the lung being a commonly affected organ. We found that activation of lung-resident group 2 innate lymphoid cells (ILC2s) orchestrated suppression of natural killer (NK) cell-mediated innate antitumor immunity, leading to increased lung metastases and mortality. Using multiple models of lung metastasis, we show that interleukin (IL)-33-dependent ILC2 activation in the lung is involved centrally in promoting tumor burden. ILC2-driven innate type 2 inflammation is accompanied by profound local suppression of interferon-γ production and cytotoxic function of lung NK cells. ILC2-dependent suppression of NK cells is elaborated via an innate regulatory mechanism, which is reliant on IL-5-induced lung eosinophilia, ultimately limiting the metabolic fitness of NK cells. Therapeutic targeting of IL-33 or IL-5 reversed NK cell suppression and alleviated cancer burden. Thus, we reveal an important function of IL-33 and ILC2s in promoting tumor metastasis via their capacity to suppress innate type 1 immunity.
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Eosinófilos/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Pulmão/imunologia , Linfócitos/imunologia , Animais , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Humanos , Tolerância Imunológica , Imunidade Inata , Interleucina-33/metabolismo , Interleucina-5/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Células Th2/imunologiaRESUMO
Californium (Cf) is currently the heaviest element accessible above microgram quantities. Cf isotopes impose severe experimental challenges due to their scarcity and radiological hazards. Consequently, chemical secrets ranging from the accessibility of 5f/6d valence orbitals to engage in bonding, the role of spin-orbit coupling in electronic structure, and reactivity patterns compared to other f elements, remain locked. Organometallic molecules were foundational in elucidating periodicity and bonding trends across the periodic table1-3, with a twenty-first-century renaissance of organometallic thorium (Th) through plutonium (Pu) chemistry4-12, and to a smaller extent americium (Am)13, transforming chemical understanding. Yet, analogous curium (Cm) to Cf chemistry has lain dormant since the 1970s. Here, we revive air-/moisture-sensitive Cf chemistry through the synthesis and characterization of [Cf(C5Me4H)2Cl2K(OEt2)]n from two milligrams of 249Cf. This bent metallocene motif, not previously structurally authenticated beyond uranium (U)14,15, contains the first crystallographically characterized Cf-C bond. Analysis suggests the Cf-C bond is largely ionic with a small covalent contribution. Lowered Cf 5f orbital energy versus dysprosium (Dy) 4f in the colourless, isoelectronic and isostructural [Dy(C5Me4H)2Cl2K(OEt2)]n results in an orange Cf compound, contrasting with the light-green colour typically associated with Cf compounds16-22.
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Recent advancements in spatial imaging technologies have revolutionized the acquisition of high-resolution multichannel images, gene expressions, and spatial locations at the single-cell level. Our study introduces xSiGra, an interpretable graph-based AI model, designed to elucidate interpretable features of identified spatial cell types, by harnessing multimodal features from spatial imaging technologies. By constructing a spatial cellular graph with immunohistology images and gene expression as node attributes, xSiGra employs hybrid graph transformer models to delineate spatial cell types. Additionally, xSiGra integrates a novel variant of gradient-weighted class activation mapping component to uncover interpretable features, including pivotal genes and cells for various cell types, thereby facilitating deeper biological insights from spatial data. Through rigorous benchmarking against existing methods, xSiGra demonstrates superior performance across diverse spatial imaging datasets. Application of xSiGra on a lung tumor slice unveils the importance score of cells, illustrating that cellular activity is not solely determined by itself but also impacted by neighboring cells. Moreover, leveraging the identified interpretable genes, xSiGra reveals endothelial cell subset interacting with tumor cells, indicating its heterogeneous underlying mechanisms within complex cellular interactions.
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Análise de Célula Única , Análise de Célula Única/métodos , Humanos , Algoritmos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Biologia Computacional/métodosRESUMO
Tumor metastasis involves cells migrating directionally in response to external chemical signals. Reactive oxygen species (ROS) in the form of H2O2 has been demonstrated as a chemoattractant for neutrophils but its spatial characteristics in tumor microenvironment and potential role in tumor cell dissemination remain unknown. Here we investigate the spatial ROS distribution in 3D tumor spheroids and identify a ROS concentration gradient in spheroid periphery, which projects into a H2O2 gradient in tumor microenvironment. We further reveal the role of H2O2 gradient to induce chemotaxis of tumor cells by activating Src and subsequently inhibiting RhoA. Finally, we observe that the absence of mitochondria cristae remodeling proteins including the mitochondria-localized actin motor Myosin 19 (Myo19) enhances ROS gradient and promotes tumor dissemination. Myo19 downregulation is seen in many tumors, and Myo19 expression is negatively associated with tumor metastasis in vivo. Together, our study reveals the chemoattractant role of tumor microenvironmental ROS and implies the potential impact of mitochondria cristae disorganization on tumor invasion and metastasis.
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Quimiotaxia , Peróxido de Hidrogênio , Espécies Reativas de Oxigênio , Miosinas/metabolismo , Fatores QuimiotáticosRESUMO
Cell-cell communications are vital for biological signalling and play important roles in complex diseases. Recent advances in single-cell spatial transcriptomics (SCST) technologies allow examining the spatial cell communication landscapes and hold the promise for disentangling the complex ligand-receptor (L-R) interactions across cells. However, due to frequent dropout events and noisy signals in SCST data, it is challenging and lack of effective and tailored methods to accurately infer cellular communications. Herein, to decipher the cell-to-cell communications from SCST profiles, we propose a novel adaptive graph model with attention mechanisms named spaCI. spaCI incorporates both spatial locations and gene expression profiles of cells to identify the active L-R signalling axis across neighbouring cells. Through benchmarking with currently available methods, spaCI shows superior performance on both simulation data and real SCST datasets. Furthermore, spaCI is able to identify the upstream transcriptional factors mediating the active L-R interactions. For biological insights, we have applied spaCI to the seqFISH+ data of mouse cortex and the NanoString CosMx Spatial Molecular Imager (SMI) data of non-small cell lung cancer samples. spaCI reveals the hidden L-R interactions from the sparse seqFISH+ data, meanwhile identifies the inconspicuous L-R interactions including THBS1-ITGB1 between fibroblast and tumours in NanoString CosMx SMI data. spaCI further reveals that SMAD3 plays an important role in regulating the crosstalk between fibroblasts and tumours, which contributes to the prognosis of lung cancer patients. Collectively, spaCI addresses the challenges in interrogating SCST data for gaining insights into the underlying cellular communications, thus facilitates the discoveries of disease mechanisms, effective biomarkers and therapeutic targets.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Perfilação da Expressão Gênica , Transcriptoma , Comunicação CelularRESUMO
Spatial cellular authors heterogeneity contributes to differential drug responses in a tumor lesion and potential therapeutic resistance. Recent emerging spatial technologies such as CosMx, MERSCOPE and Xenium delineate the spatial gene expression patterns at the single cell resolution. This provides unprecedented opportunities to identify spatially localized cellular resistance and to optimize the treatment for individual patients. In this work, we present a graph-based domain adaptation model, SpaRx, to reveal the heterogeneity of spatial cellular response to drugs. SpaRx transfers the knowledge from pharmacogenomics profiles to single-cell spatial transcriptomics data, through hybrid learning with dynamic adversarial adaption. Comprehensive benchmarking demonstrates the superior and robust performance of SpaRx at different dropout rates, noise levels and transcriptomics coverage. Further application of SpaRx to the state-of-the-art single-cell spatial transcriptomics data reveals that tumor cells in different locations of a tumor lesion present heterogenous sensitivity or resistance to drugs. Moreover, resistant tumor cells interact with themselves or the surrounding constituents to form an ecosystem for drug resistance. Collectively, SpaRx characterizes the spatial therapeutic variability, unveils the molecular mechanisms underpinning drug resistance and identifies personalized drug targets and effective drug combinations.
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Ecossistema , Medicina de Precisão , Humanos , Benchmarking , Sistemas de Liberação de Medicamentos , Perfilação da Expressão Gênica , TranscriptomaRESUMO
Malic acid is a major organic acid component of apples and a crucial determinant of fruit organoleptic quality. A candidate gene for malic acid content, designated MdMa1, was previously identified in the Ma locus, which is a major quantitative trait locus (QTL) for apple fruit acidity located on the linkage group 16. Region-based association mapping to detect candidate genes in the Ma locus identified MdMa1 and an additional MdMYB21 gene putatively associated with malic acid. MdMYB21 was significantly associated with fruit malic acid content, accounting for ~7.48% of the observed phenotypic variation in the apple germplasm collection. Analyses of transgenic apple calli, fruits and tomatoes demonstrated that MdMYB21 negatively regulated malic acid accumulation. The apple fruit acidity-related MdMa1 and its tomato ortholog, SlALMT9, exhibited lower expression profiles in apple calli, mature fruits and tomatoes in which MdMYB21 was overexpressed, compared with their corresponding wild-type variety. MdMYB21 directly binds to the MdMa1 promoter and represses its expression. Interestingly, a 2-bp variation in the MdMYB21 promoter region altered its expression and regulation of its target gene, MdMa1, expression. Our findings not only demonstrate the efficiency of integrating QTL and association mapping in the identification of candidate genes controlling complex traits in apples, but also provide insights into the complex regulatory mechanism of fruit malic acid accumulation.
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Malus , Malus/genética , Malus/metabolismo , Frutas/genética , Frutas/metabolismo , Malatos/metabolismo , Locos de Características Quantitativas/genética , Regulação da Expressão Gênica de Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
BACKGROUND: Sarcomas are diverse neoplasms with highly variable histological appearances in which diagnosis is often challenging and management options for metastatic/unresectable disease limited. Many sarcomas have distinctive molecular alterations, but the range of alterations is large, variable in type and rapidly increasing, meaning that testing by limited panels is unable to capture the broad spectrum of clinically pertinent genomic drivers required. Paired whole genome sequencing (WGS) in contrast allows comprehensive assessment of small variants, copy number and structural variants along with mutational signature analysis and germline testing. METHODS: Introduction of WGS as a diagnostic standard for all eligible patients with known or suspected soft tissue sarcoma over a 2-year period at a soft tissue sarcoma treatment centre. RESULTS: WGS resulted in a refinement in the diagnosis in 37% of cases, identification of a target for personalised therapy in 33% of cases, and a germline alteration in 4% of cases. CONCLUSION: Introduction of WGS poses logistical and training challenges, but offers significant benefits to this group of patients.
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Nanoarchitectonics of semiconductors shed light on efficient photocatalytic hydrogen evolution by precisely controlling the surface microenvironment of cocatalysts. Taking cadmium zinc sulfide (CZS) nanoparticles as a target, the spontaneous modifications are conducted by interactions between surface Cd2+/Zn2+ atoms and thiol groups in thioglycolic acid. The capping ligand impacts the semiconductor surface with a negative electronic environment, contributing to the full coverage of CZS by nickel-cobalt hydroxides (NiCo-LDHs) cocatalysts. The obtained core-shell CZS@NiCo-LDHs, possessing a shell thickness of ≈20 nm, exhibits a distinguished topology (SBET = 87.65m2 g-1), long surface carrier lifetime, and efficient charge-hole separation. Further photocatalytic hydrogen evaluation demonstrates an enhanced H2 evolution rate of 18.75 mmol g-1 h-1 with an apparent quantum efficiency of 16.3% at 420 nm. The recorded catalytic performance of the core-shell sample is 44.6 times higher than that of pure CZS nanospheres under visible light irradiation. Further density functional theory simulations indicate that sulfur atoms play the role of charge acceptor and surface Ni/Co atoms are electron donors, as well as a built-in electric field effect can be established. Altogether, this work takes advantage of strong S affinity from surface metal atoms, revealing the interfacial engineering toward improved visible-light-driven photocatalytic hydrogen evolution (PHE) activity.
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Fructokinase (FRK) activates fructose through phosphorylation, which sends the activated fructose into primary metabolism and regulates fructose signaling capabilities in plants. The apple (Malus × domestica) FRK gene MdFRK2 shows especially high affinity to fructose, and its overexpression decreases fructose levels in the leaves of young plants. However, in the current study of mature plants, fruits of transgenic apple trees overexpressing MdFRK2 accumulated a higher level of fructose than wild-type (WT) fruits (at both young and mature stages). Transgenic apple trees with high mRNA MdFRK2 expression showed no significant differences in MdFRK2 protein abundance or FRK enzyme activity compared to WT in mature leaves, young fruits, and mature fruits. Immunoprecipitation-mass spectrometry analysis identified an skp1, cullin, F-box (SCF) E3 ubiquitin ligase, calcyclin-binding protein (CacyBP), that interacted with MdFRK2. RNA-sequencing analysis provided evidence for ubiquitin-mediated post-transcriptional regulation of MdFRK2 protein for the maintenance of fructose homeostasis in mature leaves and fruits. Further analyses suggested an MdCacyBP-MdFRK2 regulatory module, in which MdCacyBP interacts with and ubiquitinates MdFRK2 to facilitate its degradation by the 26S proteasome, thus decreasing the FRK enzyme activity to elevate fructose concentration in transgenic apple trees. This result uncovered an important mechanism underlying plant fructose homeostasis in different organs through regulating the MdFRK2 protein level via ubiquitination and degradation. Our study provides usable data for the future improvement of apple flavor and expands our understanding of the molecular mechanisms underlying plant fructose content and signaling regulation.
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Malus , Malus/metabolismo , Proteína A6 Ligante de Cálcio S100/genética , Proteína A6 Ligante de Cálcio S100/metabolismo , Homeostase , Frutose , Açúcares/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismoRESUMO
High-power all-solid-state continuous-wave (CW) single-frequency laser with high linear polarization is a significant source for quantum optics and precision measurement. In this Letter, a high-power linearly polarized CW single-frequency laser based on the single-crystal fiber (SCF) master-oscillator power amplifier (MOPA) is presented, in which a homemade 140 W low-noise CW single-frequency laser and a Nd:YAG SCF are firstly employed as the seed laser and the medium of the MOPA, respectively. The mode-matching between the pump laser propagated with waveguide form and the freely propagated seed laser is optimized by considering the influence of the degradations of the polarization and the beam quality. Finally, when the incident powers of the pump and seed lasers are 262.6 W and 126.3 W, respectively, the seed waist radius is optimized to 200 µm. In this case, the output power of the linearly polarized laser reaches up to 208 W, which is the highest output power, to the best of our knowledge. The presented results provide a good reference for implementing a high power and high degree of the polarization and good beam quality laser based on the SCF MOPA.
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An all-solid-state single-frequency continuous-wave (CW) 355 nm ultraviolet (UV) laser based on a dispersion-compensated doubly resonant resonator is presented in this Letter that is achieved by employing homemade high-stability all-solid-state frequency-correlated dual-wavelength lasers at 1064 and 532 nm and a temperature-controlled type-I critical-phase-matching LiB3O5 (LBO) to act as the fundamental laser source and the nonlinear medium, respectively. The frequency-correlated dual-wavelength single-frequency CW laser supplies the fundamental frequency 1064 and 532 nm lasers with good frequency synchronization. And the temperature-controlled LBO acts as the dispersion-compensation element to realize double resonance of the 1064 and 532 nm laser. Finally, a 4.2 W high-stability 355 nm UV laser is experimentally obtained, and the corresponding total conversion efficiency is up to 20.5%. To the best of our knowledge, this is the highest power reported about single-frequency CW 355 nm UV laser. The presented method can pave a way to develop a compact single-frequency 355 nm UV laser with high output power.
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PURPOSE: Exercise-based cancer rehabilitation via digital technologies can provide a promising alternative to centre-based exercise training, but data for cancer patients and survivors are limited. We conducted a meta-analysis examining the effect of telehealth exercise-based cancer rehabilitation in cancer survivors on cardiorespiratory fitness, physical activity, muscle strength, health-related quality of life, and self-reported symptoms. METHODS: PubMed, Web of Science, and reference lists of articles related to the aim were searched up to March 2023. Randomized controlled clinical trials were included comparing the effect of telehealth exercise-based cancer rehabilitation with guideline-based usual care in adult cancer survivors. The primary result was cardiorespiratory fitness expressed by peak oxygen consumption. RESULTS: A total of 1510 participants were identified, and ten randomized controlled trials (n = 855) were included in the meta-analysis. The study sample was 85% female, and the mean age was 52.7 years. Meta-analysis indicated that telehealth exercise-based cancer rehabilitation significantly improved cardiorespiratory fitness (SMD = 0.34, 95% CI 0.20, 0.49, I2 = 42%, p < 0.001) and physical activity (SMD = 0.34, 95% CI, 0.17, 0.51, I2 = 71%, p < 0.001). It was uncertain whether telehealth exercise-based cancer rehabilitation, compared with guideline-based usual care, improved the quality of life (SMD = 0.23, 95%CI, -0.07, 0.52, I2 = 67%, p = 0.14) body mass index (MD = 0.46, 95% CI, -1.19, 2.12, I2 = 60%, p = 0.58) and muscle strength (SMD = 0.07, 95% CI, -0.14, 0.28, I2 = 37%, p = 0.51). CONCLUSION: This meta-analysis showed that telehealth exercise cancer rehabilitation could significantly increase cardiorespiratory fitness and physical activity levels and decrease fatigue. It is uncertain whether these interventions improve quality of life and muscle strength. High-quality and robust studies are needed to investigate specific home-based exercise regimens in different cancer subgroups to increase the certainty of the evidence.
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Aptidão Cardiorrespiratória , Terapia por Exercício , Força Muscular , Neoplasias , Qualidade de Vida , Humanos , Neoplasias/reabilitação , Terapia por Exercício/métodos , Feminino , Sobreviventes de Câncer , Ensaios Clínicos Controlados Aleatórios como Assunto , Telemedicina , Masculino , Exercício Físico , Pessoa de Meia-Idade , TelerreabilitaçãoRESUMO
Choroidal neovascularization (CNV) is the primary pathogenic process underlying wet age-related macular degeneration, leading to severe vision loss. Despite current anti-vascular endothelial growth factor (VEGF) therapies, several limitations persist. Crocetin, a major bioactive constituent of saffron, exhibits multiple pharmacological activities, yet its role and mechanism in CNV remain unclear. Here, we investigated the potential effects of crocetin on CNV using in vitro and in vivo models. In human umbilical vein endothelial cells, crocetin demonstrated inhibition of VEGF-induced cell proliferation, migration, and tube formation in vitro, as assessed by CCK-8 and EdU assays, transwell and scratch assays, and tube formation analysis. Additionally, crocetin suppressed choroidal sprouting in ex vivo experiments. In the human retinal pigment epithelium (RPE) cell line ARPE-19, crocetin attenuated cobalt chloride-induced hypoxic cell injury, as evidenced by CCK-8 assay. As evaluated by quantitative PCR and Western blot assay, it also reduced hypoxia-induced expression of VEGF and hypoxia-inducible factor 1α (HIF-1α), while enhancing zonula occludens-1 expression. In a laser-induced CNV mouse model, intravitreal administration of crocetin significantly reduced CNV size and suppressed elevated expressions of VEGF, HIF-1α, TNFα, IL-1ß, and IL-6. Moreover, crocetin treatment attenuated the elevation of phospho-S6 in laser-induced CNV and hypoxia-induced RPE cells, suggesting its potential anti-angiogenic effects through antagonizing the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Our findings indicate that crocetin may hold promise as an effective drug for the prevention and treatment of CNV.
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Neovascularização de Coroide , Células Endoteliais , Camundongos , Animais , Humanos , Células Endoteliais/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Sincalida/metabolismo , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/prevenção & controle , Neovascularização de Coroide/metabolismo , Hipóxia/metabolismo , Modelos Animais de Doenças , Epitélio Pigmentado da Retina/metabolismoRESUMO
Hexavalent chromium (Cr (VI)), one of the most detrimental pollutants, has been ubiquitously present in the environment and causes serious toxicity to humans, such as hepatotoxicity, nephrotoxicity, pulmonary toxicity, and cardiotoxicity. However, Cr (VI)-induced neurotoxicity in primary neuron level has not been well explored yet. Herein, potassium dichromate (K2Cr2O7) was employed to examine the neurotoxicity of Cr (VI) in rat primary hippocampal neurons. MTT test was used to examine the neural viability. Mitochondrial dysfunction was assessed by the JC-1 probe and Mito-Tracker probe. DCFH-DA and Mito-SOX Red were utilized to evaluate the oxidative status. Bcl-2 family and MAPKs expression were investigated using Western blotting. The results demonstrated that Cr (VI) treatment dose- and time-dependently inhibited neural viability. Mechanism investigation found that Cr (VI) treatment causes mitochondrial dysfunction by affecting Bcl-2 family expression. Moreover, Cr (VI) treatment also induces intracellular reactive oxygen species (ROS) generation, DNA damage, and MAPKs activation in neurons. However, inhibition of ROS by glutathione (GSH) effectually balanced Bcl-2 family expression, attenuated DNA damage and the MAPKs activation, and eventually improved neural viability neurons. Collectively, these above results above suggest that Cr (VI) causes significant neurotoxicity by triggering mitochondrial dysfunction, ROS-mediated oxidative damage and MAKPs activation.
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Doenças Mitocondriais , Estresse Oxidativo , Humanos , Ratos , Animais , Espécies Reativas de Oxigênio/metabolismo , Cromo/toxicidade , Glutationa/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
A Gram-stain-negative, aerobic, rod-shaped and halotolerant bacterium, designated as strain ASW11-75T, was isolated from intertidal sediments in Qingdao, PR China, and identified using a polyphasic taxonomic approach. Growth of strain ASW11-75T occurred at 10-45â°C (optimum, 37â°C), pH 6.5-9.0 (optimum, pH 8.0) and 0.5-18.0â% NaCl concentrations (optimum, 2.5â%). Phylogenetic analyses based on 16S rRNA gene sequences and 1179 single-copy orthologous clusters indicated that strain ASW11-75T is affiliated with the genus Marinobacter. Strain ASW11-75T showed highest 16S rRNA gene sequence similarity to 'Marinobacter arenosus' CAU 1620T (98.5â%). The digital DNA-DNA hybridization and average nucleotide identity values between strain ASW11-75T and its closely related strains (Marinobacter salarius R9SW1T, Marinobacter similis A3d10T, 'Marinobacter arenosus' CAU 1620T, Marinobacter sediminum R65T, Marinobacter salinus Hb8T, Marinobacter alexandrii LZ-8T and Marinobacter nauticus ATCC 49840T) were 19.8-24.5â% and 76.6-80.7â%, respectively. The predominant cellular fatty acids were C16â:â0, C18â:â1 ω9c and C16â:â0 N alcohol. The polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified aminophospholipid and two unidentified lipids. The major isoprenoid quinone was ubiquinone-9. The genomic DNA G+C content was 62.2âmol%. Based on genomic and gene function analysis, strain ASW11-75T had lower protein isoelectric points with higher ratios of acidic residues to basic residues and possessed genes related to ion transport and organic osmoprotectant uptake, implying its potential tolerance to salt. The results of polyphasic characterization indicated strain ASW11-75T represents a novel Marinobacter species, for which the name Marinobacter qingdaonensis sp. nov. with the type strain ASW11-75T is proposed. The type strain is ASW11-75T (=KCTC 82497T=MCCC 1K05587T).
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Ácidos Graxos , Marinobacter , Ácidos Graxos/química , Fosfolipídeos/química , Água do Mar/microbiologia , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Composição de Bases , DNA Bacteriano/genética , Técnicas de Tipagem BacterianaRESUMO
A Gram-negative, ellipsoidal to short-rod-shaped, motile bacterium was isolated from Beijing's urban air. The isolate exhibited the closest kinship with Noviherbaspirillum aerium 122213-3T, exhibiting 98.4â% 16S rRNA gene sequence similarity. Phylogenetic analyses based on 16S rRNA gene sequences and genomes showed that it clustered closely with N. aerium 122213-3T, thus forming a distinct phylogenetic lineage within the genus Noviherbaspirillum. The average nucleotide identity and digital DNA-DNA hybridization values between strain I16B-00201T and N. aerium 122213-3T were 84.6 and 29.4â%, respectively. The respiratory ubiquinone was ubiquinone 8. The major fatty acids (>10â%) were summed feature 3 (C16:1ω6c/C16:1ω7c, 43.3â%), summed feature 8 (C18:1ω7c/C18:1ω6c, 15.9â%) and C12:0 (11.0â%). The polyamine profile showed putrescine as the predominant compound. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, unknown lipids and unknown phosphatidylaminolipids. The phenotypic, phylogenetic and chemotaxonomic results consistently supported that strain I16B-00201T represented a novel species of the genus Noviherbaspirillum, for which the name Noviherbaspirillum album sp. nov. is proposed, with I16B-00201T (=CPCC 100848T=KCTC 52095T) designated as the type strain. Its DNA G+C content is 59.4 mol%. Pan-genome analysis indicated that some Noviherbaspirillum species possess diverse nitrogen and aromatic compound metabolism pathways, suggesting their potential value in pollutant treatment.
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Microbiologia do Ar , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano , Ácidos Graxos , Hibridização de Ácido Nucleico , Fosfolipídeos , Filogenia , RNA Ribossômico 16S , Análise de Sequência de DNA , Ubiquinona , RNA Ribossômico 16S/genética , Pequim , DNA Bacteriano/genética , Ácidos Graxos/análise , Fosfolipídeos/análiseRESUMO
AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Exenatida/efeitos adversos , Voluntários Saudáveis , Área Sob a Curva , Teste de Tolerância a Glucose , Método Duplo-Cego , Relação Dose-Resposta a DrogaRESUMO
Uranyl cation, as an emerging photocatalyst, has been successfully applied to synthetic chemistry in recent years and displayed remarkable catalytic ability under visible light. However, the molecular-level reaction mechanisms of uranyl photocatalysis are unclear. Here, we explore the mechanism of the stepwise benzylic C-H oxygenation of typical alkyl-substituted aromatics (i.e., toluene, ethylbenzene, and cumene) via uranyl photocatalysis using theoretical and experimental methods. Theoretical calculation results show that the most favorable reaction path for uranyl photocatalytic oxidation is as follows: first, hydrogen atom transfer (HAT) from the benzyl position to form a carbon radical ([Râ¢]), then oxygen addition ([Râ¢] + O2 â [ROOâ¢]), then radical-radical combination ([ROOâ¢] + [Râ¢] â [ROOR] â 2[ROâ¢]), and eventually [ROâ¢] reduction to produce alcohols, of which 2° alcohol would further be oxidized to ketones and 1° would be stepwise-oxygenated to acids. The results of the designed verification experiments and the capture of reactive intermediates were consistent with those of theoretical calculations and the previously reported research that the active benzylic C-H would be stepwise-oxygenated in the presence of uranyl. This work deepens our understanding of the HAT mechanism of uranyl photocatalysis and provides important theoretical support for the relevant application of uranyl photocatalysts in organic transformation.
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Alzheimer's disease (AD) is characterized by cognitive decline, often attributed to the deficiency of acetylcholine, which can undergo hydrolysis by acetylcholinesterase (AChE) within the biological milieu. Here, we report a supramolecular strategy that takes advantage of confinement effects to inhibit such a hydrolysis process, shedding some light on AD therapy. A water-soluble and bowl-shaped molecule, hexacarboxylated tribenzotriquinacene (TBTQ-C6), was employed to shield acetylcholine (G1) from enzymatic degradation through host-guest binding interactions. Our study revealed highly efficient host-guest interactions with a binding ratio of 1 : 3, resulting in a significant reduction in acetylcholine hydrolysis from 91.1% to 7.4% in the presence of AChE under otherwise identical conditions. Furthermore, TBTQ-C6 showed potential for attenuating the degradation of butyrylcholine (G2) by butyrylcholinesterase (BChE). The broader implications of this study extend to the potential use of molecular containers in various biochemical and pharmacological applications, opening new avenues for research in the field of neurodegenerative diseases.