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1.
Cell ; 187(18): 4905-4925.e24, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38971151

RESUMO

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.


Assuntos
Terapia Neoadjuvante , Neoplasias Ovarianas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Linfócitos T Reguladores , Microambiente Tumoral , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/imunologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Humanos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Camundongos , Terapia Neoadjuvante/métodos , Microambiente Tumoral/efeitos dos fármacos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Indazóis/uso terapêutico , Indazóis/farmacologia , Recombinação Homóloga , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral
2.
Small ; 20(28): e2311356, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38295058

RESUMO

The engineering of amorphous metal-organic frameworks (MOFs) offers potential opportunities for the construction of electrocatalysts for efficient oxygen evolution reaction (OER). Herein, highly efficient OER performance and durability in alkaline electrolyte are discovered for MOF-derived amorphous and porous electrocatalysts, which are synthesized in a brief procedure and can be facilely produced in scalable quantities. The structural inheritance of MOF amorphous catalysts is significant for the retention of catalytic sites and the diffusion of electrolytes, and the presence of Fe sites can change the electronic structure and effectively control the adsorption behavior of important intermediates, accelerating reaction kinetics. The obtained amorphous A-FeNi can be transformed from FeNi-MOF effortlessly and instantly, and it only needs low overpotentials of 152 and 232 mV at 10 and 100 mA cm-2 with a Tafel slope of 17 mV dec-1 in 1 m KOH for OER. Moreover, A-FeNi possesses high corrosion resistance and durability, therefore A-FeNi can work continually for at least 400 h at 100 mA cm-2. This work may pave a new avenue for the design of MOFs-related amorphous electrocatalyst.

3.
J Transl Med ; 22(1): 633, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38978106

RESUMO

BACKGROUND: Pancreatic cancer is one of the most lethal malignancies and the lack of treatment options makes it more deadly. Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has revolutionized cancer treatment and made great breakthroughs in treating hematological malignancies, however its success in treating solid cancers remains limited mainly due to the lack of tumor-specific antigens. On the other hand, the prolonged traditional manufacturing process poses challenges, taking 2 to 6 weeks and impacting patient outcomes. CD276 has recently emerged as a potential therapeutic target for anti-solid cancer therapy. Here, we investigated the efficacy of CD276 CAR-T and rapidly-manufactured CAR-T against pancreatic cancer. METHODS: In the present study, CD276 CAR-T was prepared by CAR structure carrying 376.96 scFv sequence, CD8 hinge and transmembrane domain, 4-1BB and CD3ζ intracellular domains. Additionally, CD276 rapidly-manufactured CAR-T (named CD276 Dash CAR-T) was innovatively developed by shortening the duration of ex vitro culture to reduce CAR-T manufacturing time. We evaluated the anti-tumor efficacy of CD276 CAR-T and further compared the functional assessment of Dash CAR-T and conventional CAR-T in vitro and in vivo by detecting the immunophenotypes, killing ability, expansion capacity and tumor-eradicating effect of CAR-T. RESULTS: We found that CD276 was strongly expressed in multiple solid cancer cell lines and that CD276 CAR-T could efficiently kill these solid cancer cells. Moreover, Dash CAR-T was successfully manufactured within 48-72 h and the functional validation was carried out subsequently. In vitro, CD276 Dash CAR-T possessed a less-differentiated phenotype and robust proliferative ability compared to conventional CAR-T. In vivo xenograft mouse model, CD276 Dash CAR-T showed enhanced anti-pancreatic cancer efficacy and T cell expansion. Besides, except for the high-dose group, the body weight of mice was maintained stable, and the state of mice was normal. CONCLUSIONS: In this study, we proved CD276 CAR-T exhibited powerful activity against pancreatic cancer cells in vitro and in vivo. More importantly, we demonstrated the manufacturing feasibility, acceptable safety and superior anti-tumor efficacy of CD276 Dash CAR-T generated with reduced time. The results of the above studies indicated that CD276 Dash CAR-T immunotherapy might be a novel and promising strategy for pancreatic cancer treatment.


Assuntos
Antígenos B7 , Imunoterapia Adotiva , Neoplasias Pancreáticas , Receptores de Antígenos Quiméricos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Humanos , Animais , Linhagem Celular Tumoral , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Imunoterapia Adotiva/métodos , Antígenos B7/metabolismo , Antígenos B7/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos , Proliferação de Células , Linfócitos T/imunologia
4.
Opt Express ; 32(10): 17481-17498, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38858931

RESUMO

As a vital constituent of water's optical properties, the absorption coefficients influence the distribution of underwater light field, consequently impacting the structures and functional patterns of riverine ecosystems. In this study, the light absorption of non-algal particulates (ad(λ), m-1), phytoplankton (aph(λ), m-1) and CDOM (ag(λ), m-1) of 380 water samples collected from 133 rivers in eight external river basins across China from 2013 to 2023 were examined to determine the optical absorption characteristics. Results showed significant differences in ad(λ), aph(λ) and ag(λ) across different basins. ① The water bodies of eight basins can be categorized into 5 dominant types of absorption coefficients. ② In eastern China, ag(440) exhibited a northeast-high and southwest-low spatial distribution pattern. The Songliao River Basin had the highest ag(440) than other basins. The higher slope S of ag(λ) in rivers compared to lakes and reservoirs confirm river water primarily derive CDOM from external sources, distinguishing them from lakes and reservoirs. ③ The Huaihe and Haihe River Basins had higher ad(440) and aph(440) values, primarily due to lower terrain and human activities, leading to the accumulation of suspended particles and nutrients. And soil erosion from the Loess Plateau caused significant differences in ad(440) between the upper and middle reaches of the Yellow River Basin. These findings hold significant implications for understanding the optical characteristics of rivers in China.

5.
Heredity (Edinb) ; 133(1): 11-20, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38822132

RESUMO

Genome-wide association study (GWAS) is a powerful tool to identify genomic loci underlying complex traits. However, the application in natural populations comes with challenges, especially power loss due to population stratification. Here, we introduce a bivariate analysis approach to a GWAS dataset of Arabidopsis thaliana. We demonstrate the efficiency of dual-phenotype analysis to uncover hidden genetic loci masked by population structure via a series of simulations. In real data analysis, a common allele, strongly confounded with population structure, is discovered to be associated with late flowering and slow maturation of the plant. The discovered genetic effect on flowering time is further replicated in independent datasets. Using Mendelian randomization analysis based on summary statistics from our GWAS and expression QTL scans, we predicted and replicated a candidate gene AT1G11560 that potentially causes this association. Further analysis indicates that this locus is co-selected with flowering-time-related genes. The discovered pleiotropic genotype-phenotype map provides new insights into understanding the genetic correlation of complex traits.


Assuntos
Arabidopsis , Flores , Estudo de Associação Genômica Ampla , Fenótipo , Locos de Características Quantitativas , Arabidopsis/genética , Estudo de Associação Genômica Ampla/métodos , Flores/genética , Polimorfismo de Nucleotídeo Único , Genótipo , Modelos Genéticos , Genética Populacional , Simulação por Computador , Alelos , Genoma de Planta , Análise da Randomização Mendeliana
6.
J Chem Inf Model ; 64(18): 7152-7162, 2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39259971

RESUMO

Combination therapy is increasingly favored by pharmaceutical companies and researchers as an effective way to quickly discover new drugs with excellent efficacy, especially in the treatment of complex diseases. Previously, we successfully developed a computational screening method to identify such combinations, although it fell short in elucidating their synergistic mechanisms. In this work, we have transitioned to a highest single agent (HSA) synergy model for network screening, which streamlines the discovery of promising combinations and facilitates the investigation of their synergistic effects. Through this refined approach, the trimebutine-methoxsalen combination emerged as a promising candidate for heart failure (HF) treatment, exhibiting significant in vitro cardioprotective effects and effectively mitigating isoproterenol (ISO)-induced structural remodeling in the mouse heart. Further mechanistic studies have demonstrated that trimebutine and methoxsalen could synergistically inhibit intracellular calcium overload in myocardial cells and reduce the production of ROS, thus exerting cardioprotective effects. Overall, this study introduces an advanced computational strategy that not only identifies a novel combination therapy against HF but also sheds light on its underlying synergistic mechanisms.


Assuntos
Insuficiência Cardíaca , Animais , Insuficiência Cardíaca/tratamento farmacológico , Camundongos , Sinergismo Farmacológico , Quimioterapia Combinada , Avaliação Pré-Clínica de Medicamentos , Cardiotônicos/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Isoproterenol/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Cálcio/metabolismo
7.
J Nat Prod ; 87(5): 1441-1453, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38722764

RESUMO

Herein, we report an extensive phytochemical study on the whole plant of Drymaria cordata, which led to the isolation of ten new orbitides, named drymariamides A-J (1-10). Compounds 2, 3, and 5 incorporate rare residues of noncanonical amino acids of kynurenine (Kyn) or 3a-hydroxypyrroloindoline (HPI). Their structures with absolute configurations were elucidated by a combination of spectroscopic analysis, advanced Marfey's method, X-ray diffraction, and electronic circular dichroism analysis. Compounds 1-10 exhibited antiadipogenic effects in 3T3-L1 adipocytes, and the most potent compound 7 showed an EC50 value of 1.17 ± 0.19 µM.


Assuntos
Células 3T3-L1 , Aminoácidos , Peptídeos Cíclicos , Animais , Camundongos , Aminoácidos/química , Estrutura Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Adipogenia/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo
8.
Heart Lung Circ ; 33(9): 1357-1364, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38925995

RESUMO

AIM: Admission systolic blood pressure is a significant predictor of in-hospital mortality in patients with acute type A aortic dissection (ATAAD). While previous studies have focussed on recording the highest blood pressure value from both arms, this study aimed to evaluate the associations between blood pressure in bilateral arms and in-hospital mortality. METHODS: Data were analysed from 262 patients with ATAAD treated at a single centre. The relationship between bilateral arm blood pressure upon admission and in-hospital mortality was assessed in a logistic regression model. To comprehensively evaluate potential non-linear relationships, the association between admission bilateral systolic blood pressure (SBP) and the risk of in-hospital mortality was analysed using restricted cubic splines on a continuous scale. RESULTS: Mean age was 53.6±12.5 years and 194 (74.0%) were male. Baseline and operative data showed that ages, body mass index, smoking, left-arm SBP, left-arm diastolic blood pressure (DBP), right-arm SBP, right-arm DBP, syncope, cerebral/cardiac ischaemia, retrograde brain perfusion, Bentall procedure, coronary artery bypass grafting, and aortic valve replacement significantly differed among the left-arm SBP tertiles. In-hospital mortality was 17.6% (46 of 262). Restricted cubic splines demonstrated that the relationship between presenting left-arm SBP and in-hospital mortality followed a U-shaped curve, whereas non-linearity was not detected in the right arm. CONCLUSION: This study found a U-shaped association between admission left-arm SBP and in-hospital mortality in ATAAD surgery patients, whereas a non-linearity relationship was not detected for right-arm SBP. Low left-arm SBP independently correlated with increased in-hospital mortality, underscoring the significance of bilateral blood pressure differences in ATAAD prognosis.


Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Pressão Sanguínea , Mortalidade Hospitalar , Humanos , Masculino , Mortalidade Hospitalar/tendências , Dissecção Aórtica/cirurgia , Dissecção Aórtica/mortalidade , Dissecção Aórtica/fisiopatologia , Feminino , Pessoa de Meia-Idade , Pressão Sanguínea/fisiologia , Aneurisma da Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/mortalidade , Aneurisma da Aorta Torácica/fisiopatologia , Estudos Retrospectivos , Doença Aguda , Sístole , Fatores de Risco , Seguimentos , Taxa de Sobrevida/tendências , Idoso
9.
Angew Chem Int Ed Engl ; 63(15): e202400281, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38339811

RESUMO

The development of highly efficient electrocatalysts for complete oxidation of ethylene glycol (EG) in direct EG fuel cells is of decisive importance to hold higher energy efficiency. Despite some achievements, their progress, especially electrocatalytic selectivity to complete oxidated C1 products, is remarkably slower than expected. In this work, we developed a facile aqueous synthesis of Ir-doped CuPd single-crystalline mesoporous nanotetrahedrons (Ir-CuPd SMTs) as high-performance electrocatalyst for promoting oxidation cleavage of C-C bond in alkaline EG oxidation reaction (EGOR) electrocatalysis. The synthesis relied on precise reduction/co-nucleation and epitaxial growth of Ir, Cu and Pd precursors with cetyltrimethylammonium chloride as the mesopore-forming surfactant and extra Br- as the facet-selective agent under ambient conditions. The products featured concave nanotetrahedron morphology enclosed by well-defined (111) facets, single-crystalline and mesoporous structure radiated from the center, and uniform elemental composition without any phase separation. Ir-CuPd SMTs disclosed remarkably enhanced electrocatalytic activity and excellent stability as well as superior selectivity of C1 products for alkaline EGOR electrocatalysis. Detailed mechanism studies demonstrated that performance improvement came from structural and compositional synergies, which kinetically accelerated transports of electrons/reactants within active sites of penetrated mesopores and facilitated oxidation cleavage of high-energy-barrier C-C bond of EG for desired C1 products. More interestingly, Ir-CuPd SMTs performed well in coupled electrocatalysis of anode EGOR and cathode nitrate reduction, highlighting its high potential as bifunctional electrocatalyst in various applications.

10.
Small ; 19(24): e2208212, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36916691

RESUMO

137 Cs and 90 Sr are hazardous to ecological environment and human health due to their strong radioactivity, long half-life, and high mobility. However, effective adsorption and separation of Cs+ and Sr2+ from acidic radioactive wastewater is challenging due to stability issues of material and the strong competition of protons. Herein, a K+ -activated niobium germanate (K-NGH-1) presents efficient Cs+ /Sr2+ coadsorption and highly selective Cs+ /Sr2+ separation, respectively, under different acidity conditions. In neutral solution, K-NGH-1 exhibits ultrafast adsorption kinetics and high adsorption capacity for both Cs+ and Sr2+ (qm Cs  = 182.91 mg g-1 ; qm Sr  = 41.62 mg g-1 ). In 1 M HNO3 solution, K-NGH-1 still possesses qm Cs of 91.40 mg g-1 for Cs+ but almost no adsorption for Sr2+ . Moreover, K-NGH-1 can effectively separate Cs+ from 1 M HNO3 solutions with excess competing Sr2+ and Mn + (Mn +  = Na+ , Ca2+ , Mg2+ ) ions. Thus, efficient separation of Cs+ and Sr2+ is realized under acidic conditions. Besides, K-NGH-1 shows excellent acid and radiation resistance and recyclability. All the merits above endow K-NGH-1 with the first example of niobium germanates for radionuclides remediation. This work highlights the facile pH control approach towards bifunctional ion exchangers for efficient Cs+ /Sr2+ coadsorption and selective separation.

11.
Opt Express ; 31(10): 15682-15696, 2023 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-37157663

RESUMO

Mueller matrix microscopy is capable of polarization characterization of pathological samples and polarization imaging based digital pathology. In recent years, hospitals are replacing glass coverslips with plastic coverslips for automatic preparations of dry and clean pathological slides with less slide-sticking and air bubbles. However, plastic coverslips are usually birefringent and introduce polarization artifacts in Mueller matrix imaging. In this study, a spatial frequency based calibration method (SFCM) is used to remove such polarization artifacts. The polarization information of the plastic coverslips and the pathological tissues are separated by the spatial frequency analysis, then the Mueller matrix images of pathological tissues are restored by matrix inversions. By cutting two adjacent lung cancer tissue slides, we prepare paired samples of very similar pathological structures but one with a glass coverslip and the other with a plastic coverslip. Comparisons between Mueller matrix images of the paired samples show that SFCM can effectively remove the artifacts due to plastic coverslip.


Assuntos
Microscopia , Birrefringência , Calibragem
12.
Opt Lett ; 48(21): 5711-5714, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37910740

RESUMO

Monitoring microvascular structure and function is of great significance for the diagnosis of many diseases. In this study, we demonstrate the feasibility of OR-PAM to nailbed microcirculation detection as a new, to the best of our knowledge, application scenario in humans. We propose a dual-wavelength optical-resolution photoacoustic microscopy (OR-PAM) with improved local-flexible coupling to image human nailbed microvasculature. Microchip lasers with 532 nm wavelength are employed as the pump sources. The 558 nm laser is generated from the 532 nm laser through the stimulated Raman scattering effect. The flowing water, circulated by a peristaltic pump, maintains the acoustic coupling between the ultrasonic transducer and the sample. These designs improve the sensitivity, practicality, and stability of the OR-PAM system for human in vivo experiments. The imaging of the mouse ear demonstrates the ability of our system to acquire structural and functional information. Then, the system is applied to image human nailbed microvasculature. The imaging results reveal that the superficial capillaries are arranged in a straight sagittal pattern, approximately parallel to the long axis of the finger. The arterial and venular limbs are distinguished according to their oxygen saturation differences. Additionally, the images successfully discover the capillary loops with single or multiple twists, the oxygen release at the end of the capillary loop, and the changes when the nailbed is abnormal.


Assuntos
Microscopia , Técnicas Fotoacústicas , Animais , Camundongos , Humanos , Microscopia/métodos , Microvasos/diagnóstico por imagem , Lasers , Capilares , Análise Espectral , Técnicas Fotoacústicas/métodos
13.
Chemistry ; 29(16): e202203142, 2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36565275

RESUMO

Enhancing catalytic performance as well as reducing catalyst cost are the eternal pursuit for the catalysis community. Herein, a simple and effective palladium-doped cobalt (Pd/Co) catalyst with high Pd atom utilization efficiency was synthesized via galvanic replacement reaction for the selective hydrogenation of nitrobenzene with H2 at room temperature, delivering >99 % yield of aniline with up to 158 times higher catalytic activity than commercial palladium powder. Detailed characterizations and DFT calculations revealed that Co-Pd interaction leads to a decrease in electron density of Pd and the distance between Pd atoms that results in the enhanced catalytic performance. Further experiments indicated that the Pd/Co catalyst serves as a highly efficient, selective, and recyclable catalyst for a range of nitroarene substrates. This work might provide a green and sustainable methodology to design and synthesize highly active catalysts with high utilization efficiency of the noble metals in fundamental and applied research.

14.
J Org Chem ; 88(1): 455-461, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36516399

RESUMO

Baccaramiones A-D (1-4), four highly oxygenated and rearranged trinorditerpenoids, were isolated from Baccaurea ramiflora. Compound 1 is a 1(10 → 5)-abeo-15,16,17-trinor-ent-abietane featuring a unique 5/6/6 spirocyclic scaffold, and 2-4 are the first example of a novel 20(10 → 5)-abeo-15,16,17-trinor-ent-abietane skeleton. Their structures were established by spectroscopic analysis, X-ray crystallography, and electronic circular dichroism calculations. A plausible biosynthetic pathway for 1-4 was proposed. Interestingly, compounds 3 and 4 exhibited significant immunosuppressive activities against concanavalin A-induced T cell proliferation and lipopolysaccharide-induced B cell proliferation in vitro.


Assuntos
Abietanos , Imunossupressores , Abietanos/química , Dicroísmo Circular , Estrutura Molecular
15.
J Nat Prod ; 86(10): 2315-2325, 2023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37728995

RESUMO

Eleven densely functionalized new dihydro-ß-agarofuran sesquiterpenoid derivatives, named maytenoids A-K (1-11), as well as one known analog, were isolated and characterized from Maytenus austroyunnanensis. Their structures were assigned based on analysis of spectroscopic data and X-ray crystallography. Compounds 1-9 are macrocyclic sesquiterpene pyridine alkaloids generated by the respective acylation of the hydroxy groups at C-3 and C-13 of dihydro-ß-agarofuran sesquiterpenoids via diverse pyridine dicarboxylic acids. Compounds 1, 2, 5-10, and 12 exhibited significant inhibitory effects on NO production at 10 µM in lipopolysaccharide (LPS)-stimulated BV2 cells.


Assuntos
Alcaloides , Maytenus , Sesquiterpenos , Maytenus/química , Estrutura Molecular , Alcaloides/farmacologia , Alcaloides/química , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Piridinas/química
16.
Mol Ther ; 30(4): 1706-1720, 2022 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-35114391

RESUMO

Endometrial decidualization is a prerequisite for implantation, and impaired decidualization is associated with recurrent implantation failure (RIF). Coding genes of the HOX family have been clarified as critical regulators in endometrial decidualization, but the role of long non-coding RNAs (lncRNAs) in the HOX gene family has yet to be determined. The aim of this study was to clarify the possible roles of lncRNAs in the HOX gene family in decidualization. In this study, we identified that HOXA11-AS was the most reduced lncRNA in the HOX family in the human endometrium during the window of implantation, and it was elevated in RIF patients. Mechanistically, HOXA11-AS negatively regulated decidualization through competitive interaction with PTBP1, an RNA-binding protein. Binding of PTBP1 to HOXA11-AS limited PTBP1 availability to regulate PKM1/2 alternative splicing, resulting in enhanced PKM1 and diminished PKM2 expression, thus attenuating decidualization. The pattern of high HOXA11-AS expression and impaired PKM2 splicing was consistently observed in RIF patients. Collectively, our study indicates that the increase of HOXA11-AS is detrimental to endometrial decidualization, likely contributing to RIF. Our study may shed light on the pathogenesis and treatment of RIF.


Assuntos
Implantação do Embrião , Endométrio , Genes Homeobox , RNA Longo não Codificante , Implantação do Embrião/genética , Endométrio/metabolismo , Feminino , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Células Estromais/metabolismo , Fatores de Transcrição/genética
17.
Mar Drugs ; 22(1)2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-38276647

RESUMO

Glycosaminoglycans (GAGs) with unique structures from marine animals show intriguing pharmacological activities and negligible biological risks, providing more options for us to explore safer agents. The swim bladder is a tonic food and folk medicine, and its GAGs show good anticoagulant activity. In this study, two GAGs, CMG-1.0 and GMG-1.0, were extracted and isolated from the swim bladder of Cynoscion microlepidotus and Gadus morhua. The physicochemical properties, precise structural characteristics, and anticoagulant activities of these GAGs were determined for the first time. The analysis results of the CMG-1.0 and GMG-1.0 showed that they were chondroitin sulfate (CS)/dermatan sulfate (DS) hybrid chains with molecular weights of 109.3 kDa and 123.1 kDa, respectively. They were mainly composed of the repeating disaccharide unit of -{IdoA-α1,3-GalNAc4S-ß1,4-}- (DS-A). The DS-B disaccharide unit of -{IdoA2S-α1,3-GalNAc4S-ß1,4-}- also existed in both CMG-1.0 and GMG-1.0. CMG-1.0 had a higher proportion of CS-O disaccharide unit -{-GlcA-ß1,3-GalNAc-ß1,4-}- but a lower proportion of CS-E disaccharide unit -{-GlcA-ß1,3-GalNAc4S6S-ß1,4-}- than GMG-1.0. The disaccharide compositions of the GAGs varied in a species-specific manner. Anticoagulant activity assay revealed that both CMG-1.0 and GMG-1.0 had potent anticoagulant activity, which can significantly prolong activated partial thromboplastin time. GMG-1.0 also can prolong the thrombin time. CMG-1.0 showed no intrinsic tenase inhibition activity, while GMG-1.0 can obviously inhibit intrinsic tenase with EC50 of 58 nM. Their significantly different anticoagulant activities may be due to their different disaccharide structural units and proportions. These findings suggested that swim bladder by-products of fish processing of these two marine organisms may be used as a source of anticoagulants.


Assuntos
Sulfatos de Condroitina , Dermatan Sulfato , Animais , Sulfatos de Condroitina/farmacologia , Sulfatos de Condroitina/química , Dermatan Sulfato/farmacologia , Dermatan Sulfato/análise , Dermatan Sulfato/química , Bexiga Urinária/química , Glicosaminoglicanos/química , Anticoagulantes/farmacologia , Dissacarídeos
18.
Mar Drugs ; 21(3)2023 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-36976197

RESUMO

Echinoderms have been attracting increasing attention for their polysaccharides, with unique chemical structure and enormous potential for preparing drugs to treat diseases. In this study, a glucan (TPG) was obtained from the brittle star Trichaster palmiferus. Its structure was elucidated by physicochemical analysis and by analyzing its low-molecular-weight products as degraded by mild acid hydrolysis. The TPG sulfate (TPGS) was prepared, and its anticoagulant activity was investigated for potential development of anticoagulants. Results showed that TPG consisted of a consecutive α1,4-linked D-glucopyranose (D-Glcp) backbone together with a α1,4-linked D-Glcp disaccharide side chain linked through C-1 to C-6 of the main chain. The TPGS was successfully prepared with a degree of sulfation of 1.57. Anticoagulant activity results showed that TPGS significantly prolonged activated partial thromboplastin time, thrombin time, and prothrombin time. Furthermore, TPGS obviously inhibited intrinsic tenase, with an EC50 value of 77.15 ng/mL, which was comparable with that of low-molecular-weight heparin (LMWH) (69.82 ng/mL). TPGS showed no AT-dependent anti-FIIa and anti-FXa activities. These results suggest that the sulfate group and sulfated disaccharide side chains play a crucial role in the anticoagulant activity of TPGS. These findings may provide some information for the development and utilization of brittle star resources.


Assuntos
Anticoagulantes , Glucanos , Animais , Anticoagulantes/farmacologia , Anticoagulantes/química , Sulfatos/química , Heparina de Baixo Peso Molecular , Equinodermos , Polissacarídeos/farmacologia , Tempo de Tromboplastina Parcial
19.
Sensors (Basel) ; 23(20)2023 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-37896668

RESUMO

To improve communication stability, more wireless devices transmit multi-modal signals while operating. The term 'modal' refers to signal waveforms or signal types. This poses challenges to traditional specific emitter identification (SEI) systems, e.g., unknown modal signals require extra open-set mode identification; different modes require different radio frequency fingerprint (RFF) extractors and SEI classifiers; and it is hard to collect and label all signals. To address these issues, we propose an enhanced SEI system consisting of a universal RFF extractor, denoted as multiple synchrosqueezed wavelet transformation of energy unified (MSWTEu), and a new generative adversarial network for feature transferring (FTGAN). MSWTEu extracts uniform RFF features for different modal signals, FTGAN transfers different modal features to a recognized distribution in an unsupervised manner, and a novel training strategy is proposed to achieve emitter identification across multi-modal signals using a single clustering method. To evaluate the system, we built a hybrid dataset, which consists of multi-modal signals transmitted by various emitters, and built a complete civil air traffic control radar beacon system (ATCRBS) dataset for airplanes. The experiments show that our enhanced SEI system can resolve the SEI problems associated with crossing signal modes. It directly achieves 86% accuracy in cross-modal emitter identification using an unsupervised classifier, and simultaneously obtains 99% accuracy in open-set recognition of signal mode.

20.
J Environ Manage ; 342: 118318, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37315460

RESUMO

Groundwater is an important resource to maintain the sustainable development of urban wetlands. The Jixi National Wetland Park (JNWP) was studied to realize the refined prevention and control of groundwater. The self-organizing map-K-means algorithm (SOM-KM), improved water quality index (IWQI), health risk assessment model and forward model were used comprehensively to evaluate the groundwater status and solute sources in different periods. The results showed that the groundwater chemical type in most areas was the HCO3-Ca type. Groundwater chemistry data from different periods were clustered into five groups. Groups 1 and 5 are affected by agricultural and industrial activities, respectively. The IWQI value in the normal period was higher in most areas due to the influence of spring ploughing. The east side of the JNWP was disturbed by human activities, and the quality of drinking water continued to deteriorate from the wet period to the dry period. 64.29% of the monitoring points showed good irrigation suitability. The health risk assessment model showed that the health risk was the largest in the dry period and the smallest in the wet period. The main factors causing health risks in the wet period and other periods were NO3- and F-, respectively. The overall cancer risk was within acceptable limits. The forward model and ion ratio analysis showed that the weathering of carbonate rocks was the main factor affecting the evolution of groundwater chemistry, accounting for 67.16%. The high-risk areas of pollution were mainly concentrated in the east of the JNWP. K+ and Cl- were the key monitoring ions in the risk-free zone and potential risk zone, respectively. The research can be used to help decision-makers carry out fine zoning control of groundwater.


Assuntos
Água Subterrânea , Poluentes Químicos da Água , Humanos , Monitoramento Ambiental/métodos , Áreas Alagadas , Poluentes Químicos da Água/análise , Água Subterrânea/análise , Qualidade da Água
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