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Cyclic GMP-AMP synthase (cGAS) binds pathogenic and other cytoplasmic double-stranded DNA (dsDNA) to catalyze the synthesis of cyclic GMP-AMP (cGAMP), which serves as the secondary messenger to activate the STING pathway and innate immune responses. Emerging evidence suggests that activation of the cGAS pathway is crucial for anti-tumor immunity; however, no effective intervention method targeting cGAS is currently available. Here we report that cGAS is palmitoylated by ZDHHC9 at cysteines 404/405, which promotes the dimerization and activation of cGAS. We further identified that lysophospholipase-like 1 (LYPLAL1) depalmitoylates cGAS to compromise its normal function. As such, inhibition of LYPLAL1 significantly enhances cGAS-mediated innate immune response, elevates PD-L1 expression, and enhances anti-tumor response to PD-1 blockade. Our results therefore reveal that targeting LYPLAL1-mediated cGAS depalmitoylation contributes to cGAS activation, providing a potential strategy to augment the efficacy of anti-tumor immunotherapy.
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Neoplasias , Nucleotidiltransferases , Humanos , Nucleotidiltransferases/metabolismo , Imunidade Inata/genética , Neoplasias/genética , Neoplasias/terapia , ImunoterapiaRESUMO
Topology1-3 and interactions are foundational concepts in the modern understanding of quantum matter. Their nexus yields three important research directions: (1) the competition between distinct interactions, as in several intertwined phases, (2) the interplay between interactions and topology that drives the phenomena in twisted layered materials and topological magnets, and (3) the coalescence of several topological orders to generate distinct novel phases. The first two examples have grown into major areas of research, although the last example remains mostly unexplored, mainly because of the lack of a material platform for experimental studies. Here, using tunnelling microscopy, photoemission spectroscopy and a theoretical analysis, we unveil a 'hybrid' topological phase of matter in the simple elemental-solid arsenic. Through a unique bulk-surface-edge correspondence, we uncover that arsenic features a conjoined strong and higher-order topology that stabilizes a hybrid topological phase. Although momentum-space spectroscopy measurements show signs of topological surface states, real-space microscopy measurements unravel a unique geometry of topologically induced step-edge conduction channels revealed on various natural nanostructures on the surface. Using theoretical models, we show that the existence of gapless step-edge states in arsenic relies on the simultaneous presence of both a non-trivial strong Z2 invariant and a non-trivial higher-order topological invariant, which provide experimental evidence for hybrid topology. Our study highlights pathways for exploring the interplay of different band topologies and harnessing the associated topological conduction channels in engineered quantum or nano-devices.
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G-protein coupled receptors (GPCRs), crucial in various diseases, are targeted of over 40% of approved drugs. However, the reliable acquisition of experimental GPCRs structures is hindered by their lipid-embedded conformations. Traditional protein-ligand interaction models falter in GPCR-drug interactions, caused by limited and low-quality structures. Generalized models, trained on soluble protein-ligand pairs, are also inadequate. To address these issues, we developed two models, DeepGPCR_BC for binary classification and DeepGPCR_RG for affinity prediction. These models use non-structural GPCR-ligand interaction data, leveraging graph convolutional networks and mol2vec techniques to represent binding pockets and ligands as graphs. This approach significantly speeds up predictions while preserving critical physical-chemical and spatial information. In independent tests, DeepGPCR_BC surpassed Autodock Vina and Schrödinger Dock with an area under the curve of 0.72, accuracy of 0.68 and true positive rate of 0.73, whereas DeepGPCR_RG demonstrated a Pearson correlation of 0.39 and root mean squared error of 1.34. We applied these models to screen drug candidates for GPR35 (Q9HC97), yielding promising results with three (F545-1970, K297-0698, S948-0241) out of eight candidates. Furthermore, we also successfully obtained six active inhibitors for GLP-1R. Our GPCR-specific models pave the way for efficient and accurate large-scale virtual screening, potentially revolutionizing drug discovery in the GPCR field.
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Descoberta de Drogas , Receptores Acoplados a Proteínas G , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Ligantes , Descoberta de Drogas/métodos , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Sítios de LigaçãoRESUMO
The mechanistic target of rapamycin complex 1 (mTORC1) is indispensable for preserving cellular and organismal homeostasis by balancing the anabolic and catabolic processes in response to various environmental cues, such as nutrients, growth factors, energy status, oxygen levels, and stress. Dysregulation of mTORC1 signaling is associated with the progression of many types of human disorders including cancer, age-related diseases, neurodegenerative disorders, and metabolic diseases. The way mTORC1 senses various upstream signals and converts them into specific downstream responses remains a crucial question with significant impacts for our perception of the related physiological and pathological process. In this review, we discuss the recent molecular and functional insights into the nutrient sensing of the mTORC1 signaling pathway, along with the emerging role of deregulating nutrient-mTORC1 signaling in cancer and age-related disorders.
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In this study, a really simple and efficient catalytic protocol for the construction of quinazolines from alcohol and diamine has been developed based on CuCoAl layered double hydroxide (CuCoAl-LDH). The developed CuCoAl-LDH catalyst could accelerate the cascade reactions without any additives and tolerate various alcohols with satisfactory yields. Cooperation between the Cu+ and Cu2+ species in CuCoAl-LDH was observed in the cascade reaction, and they are believed to be responsible for the oxidation of alcohol and dehydrogenation of the intermediate, respectively. The promoting effect of the substrate diamine was observed in the oxidation of alcohol, which simplifies the reaction system by eliminating the requirement for a base additive. The catalytic system exhibited highly practical potential for the synthesis of quinazolines, as demonstrated through recyclability investigations and scale-up experiments. A possible catalytic mechanism has been proposed based on a series of control experiments and EPR analysis.
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Histamine 4 receptor (H4R), the most recently identified subtype of histamine receptor, primarily induces inflammatory reactions upon activation. Several H4R antagonists have been developed for the treatment of inflammatory bowel disease (IBD) and atopic dermatitis (AD), but their use has been limited by adverse side effects, such as a short half-life and toxicity. Natural products, as an important source of anti-inflammatory agents, offer minimal side effects and reduced toxicity. This work aimed to identify novel H4R antagonists from natural products. An H4R target-pathway model deconvoluted downstream Gi and MAPK signaling pathways was established utilizing cellular label-free integrative pharmacology (CLIP), on which 148 natural products were screened. Cryptotanshinone was identified as selective H4R antagonist, with an IC50 value of 11.68 ± 1.30 µM, which was verified with Fluorescence Imaging Plate Reader (FLIPR) and Cellular Thermal Shift (CTS) assays. The kinetic binding profile revealed the noncompetitive antagonistic property of cryptotanshinone. Two allosteric binding sites of H4R were predicted using SiteMap, Fpocket and CavityPlus. Subsequent molecular docking and dynamics simulation indicated that cryptotanshinone interacts with H4R at a pocket formed by the outward interfaces between TM3/4/5, potentially representing a new allosteric binding site for H4R. Overall, this study introduced cryptotanshinone as a novel H4R antagonist, offering promise as a new hit for drug design of H4R antagonist. Additionally, this study provided a novel screening model for the discovery of H4R antagonists.
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Produtos Biológicos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Receptores Histamínicos H4 , Humanos , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Receptores Histamínicos H4/antagonistas & inibidores , Receptores Histamínicos H4/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Fenantrenos/farmacologia , Fenantrenos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/química , Simulação de Acoplamento Molecular , FenótipoRESUMO
MOTIVATION: Viruses, the most abundant biological entities on earth, are important components of microbial communities, and as major human pathogens, they are responsible for human mortality and morbidity. The identification of viral sequences from metagenomes is critical for viral analysis. As massive quantities of short sequences are generated by next-generation sequencing, most methods utilize discrete and sparse one-hot vectors to encode nucleotide sequences, which are usually ineffective in viral identification. RESULTS: In this article, Virtifier, a deep learning-based viral identifier for sequences from metagenomic data is proposed. It includes a meaningful nucleotide sequence encoding method named Seq2Vec and a variant viral sequence predictor with an attention-based long short-term memory (LSTM) network. By utilizing a fully trained embedding matrix to encode codons, Seq2Vec can efficiently extract the relationships among those codons in a nucleotide sequence. Combined with an attention layer, the LSTM neural network can further analyze the codon relationships and sift the parts that contribute to the final features. Experimental results of three datasets have shown that Virtifier can accurately identify short viral sequences (<500 bp) from metagenomes, surpassing three widely used methods, VirFinder, DeepVirFinder and PPR-Meta. Meanwhile, a comparable performance was achieved by Virtifier at longer lengths (>5000 bp). AVAILABILITY AND IMPLEMENTATION: A Python implementation of Virtifier and the Python code developed for this study have been provided on Github https://github.com/crazyinter/Seq2Vec. The RefSeq genomes in this article are available in VirFinder at https://dx.doi.org/10.1186/s40168-017-0283-5. The CAMI Challenge Dataset 3 CAMI_high dataset in this article is available in CAMI at https://data.cami-challenge.org/participate. The real human gut metagenomes in this article are available at https://dx.doi.org/10.1101/gr.142315.112. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Aprendizado Profundo , Microbiota , Humanos , Metagenoma , Software , Redes Neurais de ComputaçãoRESUMO
Proteins/peptides and saccharides are two kinds of bioactive substances in nature. Recently, increasing attention has been paid in understanding and utilizing covalent interactions between proteins/peptides and saccharides. The products obtained through covalent conjugation of proteins/peptides to saccharides are shown to have enhanced functional attributes, such as better gelling property, thermostability, and water-holding capacity. Additionally, food-derived protein/peptide-saccharide covalent conjugates (PSCCs) also have biological activities, such as antibacterial, antidiabetic, anti-osteoporosis, anti-inflammatory, anti-cancer, immune regulatory, and other activities that are widely used in the functional food industry. Moreover, PSCCs can be used as packaging or delivery materials to improve the bioavailability of bioactive substances, which expands the development of food-derived protein and saccharide resources. Thus, this review was aimed to first summarize the current status of sources, classification structures of natural PSCCs. Second, the methods of chemical synthesis, reaction conditions, characterization and reagent formulations that improve the desired functional characteristics of food-derived PSCCs were introduced. Third, functional properties such as emulsion, edible films/coatings, and delivery of active substance, bio-activities such as antioxidant, anti-osteoporosis, antidiabetic, antimicrobial of food-derived PSCCs were extensively discussed.
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Anti-Infecciosos , Carboidratos , Peptídeos , Antibacterianos , Proteínas , Anti-Infecciosos/químicaRESUMO
Osteoporosis is a public health concern and a cause of bone loss, increased risk of skeletal fracture, and a heavy economic burden. It is common in postmenopausal women and the elderly and is impacted by dietary factors, lifestyle and some secondary factors. Although many drugs are available for the treatment of osteoporosis, these therapies are accompanied by subsequent side effects. Hence, dietary interventions are highly important to prevent osteoporosis. This review was aimed to provide a comprehensive understanding of the roles of dietary nutrients derived from natural foods and of common dietary patterns in the regulation of osteoporosis. Nutrients from daily diets, such as unsaturated fatty acids, proteins, minerals, peptides, phytoestrogens, and prebiotics, can regulate bone metabolism and reverse bone loss. Meanwhile, these nutrients generally existed in food groups and certain dietary patterns also play critical roles in skeletal health. Appropriate dietary interventions (nutrients and dietary patterns) could be primary and effective strategies to prevent and treat osteoporosis across the lifespan for the consumers and food enterprises.
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Fraturas Ósseas , Osteoporose , Feminino , Humanos , Idoso , Densidade Óssea , Osteoporose/prevenção & controle , Osteoporose/tratamento farmacológico , Fraturas Ósseas/prevenção & controle , Fitoestrógenos , DietaRESUMO
The treatment of inflammatory bowel diseases (IBDs) has become a worldwide problem. Intestinal flora plays an important role in the development and progression of IBDs. Various risk factors (psychology, living habits, dietary patterns, environment) influence the structure and composition of the gut microbiota and contribute to the susceptibility to IBDs. This review aims to provide a comprehensive overview on risk factors regulating intestinal microenvironment which was contributed to IBDs. Five protective pathways related to intestinal flora were also discussed. We hope to provide systemic and comprehensive insights of IBDs treatment and to offer theoretical guidance for personalized patients with precision nutrition.
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Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100- < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.
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Neoplasias da Mama , Deficiência de Vitamina D , Humanos , Feminino , Estudos Prospectivos , Fatores de Risco , Vitamina D , Calcifediol , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologiaRESUMO
OBJECTIVE: We conducted a retrospective comparative cohort study to determine the phenotypic and real-world management differences in children with epilepsy and co-occurring autism as compared to those without autism. METHODS: Clinical variables, EEG, brain MRI, genetic results, medical and non-medical treatment were compared between 156 children with both epilepsy and autism, 156 randomly selected and 156 demographically matched children with epilepsy only. Logistic regression analyses were conducted to determine predictors of drug-resistant epilepsy (DRE). RESULTS: As compared to the'matched' cohort, more patients with autism had generalized motor seizures although not statistically significant after Benjamini-Hochberg correction (54.5%, vs 42.3%, p = .0314); they had a lower rate of electroclinical syndromes (12.8%, vs 30.1%, p = .0002). There were more incidental MRI findings but less positive MRI findings to explain their epilepsy in children with autism (26.3%, vs 13.8% and 14.3%, vs 34.2%, respectively; p = .0003). In addition, LEV, LTG, and VPA were the most common ASMs prescribed to children with autism, as opposed to LEV, OXC, and LTG in children without autism. No difference in the major EEG abnormalities was observed. Although the rates of DRE were similar (24.8%, vs 26.6%, p = .7203), we identified two clinical and five electrographic correlates with DRE in children with both epilepsy and autism and a final prediction modeling of DRE that included EEG ictal findings, focal onset seizures, generalized motor seizures, abnormal EEG background, age of epilepsy onset, and history of SE, which were distinct from those in children without autism. SIGNIFICANCE: Our study indicates that detailed seizure history and EEG findings are the most important evaluation and prediction tools for the development of DRE in children with epilepsy and co-occurring autism. Further studies of epilepsy in specific autism subgroups based on their etiology and clinical severity are warranted.
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Transtorno Autístico , Epilepsia Resistente a Medicamentos , Epilepsia Generalizada , Epilepsia , Criança , Humanos , Transtorno Autístico/complicações , Transtorno Autístico/diagnóstico por imagem , Estudos de Coortes , Epilepsia Resistente a Medicamentos/complicações , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Eletroencefalografia , Epilepsia/complicações , Epilepsia/diagnóstico por imagem , Epilepsia/tratamento farmacológico , Estudos Retrospectivos , Convulsões/tratamento farmacológicoRESUMO
ß-Ionone, the end ring analog of ß-carotenoids, has been proven to have an antitumor effect in a variety of cancers. In this study, we investigated the impact of ß-ionone on renal cell carcinoma (RCC) cell lines (786-O and ACHN) using colony formation assays, flow cytometry analysis, and western blot analysis. We found that ß-ionone effectively inhibited the proliferation of RCC cells in vitro, which was also confirmed in a xenograft model. Moreover, we found that ß-ionone could induce autophagy, as indicated by LC3 puncta in 786-O and ACHN cell lines and the expression of LC3 in ß-ionone-treated RCC cells. To further explore the underlying mechanism, we assessed liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) signaling pathway activity, and the results showed that ß-ionone inhibited the proliferation of RCC cells by inducing autophagy via the LKB1/AMPK signaling pathway. In summary, our findings provide a new therapeutic strategy of ß-ionone-induced autophagy in RCC.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias Renais/metabolismo , Autofagia , Proliferação de Células , Linhagem Celular TumoralRESUMO
Muscarine acetylcholine receptors (mAChRs) regulate a variety of central and peripheral physiological functions and emerge as important therapeutic targets for a number of diseases including chronic obstructive pulmonary disease (COPD). Inspired by two active natural products, we designed and synthesized a series of 2-(2,2-diarylethyl)-cyclamine derivatives for screening M3 mAChR antagonists. On this skeleton, the structural units including N heterocycle, aryl groups and its substituents on aryl were examined and resulted in a clear structure-activity relationships on the M3 mAChR. In general, these 2-(2,2-diarylethyl)-cyclamine derivatives exhibited good to excellent M3 antagonistic potency and receptor selectivity. The most active 5b-C1 had an IC50 value of 3 nM and the most of compound 6 displayed inactivity against histamine H1 receptor closely related to M3. In in vitro and in vivo evaluations of tracheo-relaxation function, some compounds even showed comparable activity to tiotropium bromide, a known blockbuster drug for COPD. Such excellent properties made these novel compounds potential candidates for COPD drug development.
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Antagonistas Muscarínicos , Doença Pulmonar Obstrutiva Crônica , Humanos , Antagonistas Muscarínicos/uso terapêutico , Derivados da Escopolamina/química , Derivados da Escopolamina/uso terapêutico , Receptor Muscarínico M3 , Brometo de Tiotrópio/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológicoRESUMO
Ten new indole alkaloids (1-10) as well as eleven known analogs (11-21) were isolated from the stems and hooks of Uncaria rhynchophylla. Their structure elucidation was based on extensive NMR studies, MS and ECD data, with the essential aid of DFT prediction of ECD spectra. Compound 1 was determined as a 17,19-seco-cadambine-type alkaloid, and compound 3 was confirmed to be a 3,4-seco-tricyclic monoterpene indole alkaloid, which are the first seco-alkaloids possessing such cleavage positions from U. rhynchophylla. All the isolated compounds were evaluated for their bioactivities on dopamine D2 and Mu opioid receptors for discovering natural therapeutic drugs targeting central nervous system (CNS) diseases. Compounds 1, 2, 4, 5, 20 and 21 showed antagonistic bioactivities on the D2 receptor (IC50 0.678-15.200 µM), and compounds 1, 3, 6, 9, 10, 13, 18, 19 and 21 exhibited antagonistic effects on the Mu receptor (IC50 2.243-32.200 µM). Among them, compounds 1 and 21 displayed dual-target activities. Compound 1 showed conspicuous antagonistic activity on D2 and Mu receptors with the IC50 values of 0.678 ± 0.182 µM and 13.520 ± 2.480 µM, respectively. Compound 21 displayed moderate antagonistic activity on the two receptors with the IC50 values at 15.200 ± 1.764 µM and 32.200 ± 5.695 µM, respectively.
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Antagonistas dos Receptores de Dopamina D2 , Alcaloides Indólicos , Uncaria , Alcaloides/química , Alcaloides/farmacologia , Dopamina/metabolismo , Alcaloides Indólicos/farmacologia , Alcaloides Indólicos/química , Receptores Opioides mu/antagonistas & inibidores , Uncaria/química , Antagonistas dos Receptores de Dopamina D2/química , Antagonistas dos Receptores de Dopamina D2/farmacologia , Antagonistas de Entorpecentes/química , Antagonistas de Entorpecentes/farmacologiaRESUMO
BACKGROUND: Sudden sensorineural hearing loss (SSNHL) is a multifactorial disease, and its etiology is still unknown. SSNHL may be caused by environmental factors and genetic changes. PCDH15 is associated with susceptibility to hearing loss. The relationship between PCDH15 and SSNHL remains unknown. METHODS: In this study, the potential association between PCDH15 polymorphism and SSNHL in Chinese population was evaluated. Two single nucleotide polymorphisms PCDH15-rs7095441 and rs11004085 in 195 SSNHL patients and 182 healthy controls were determined by TaqMan technology. RESULTS: In Chinese population, the TT genotype and T allele of rs7095441 are associated with increased susceptibility to SSNHL. The relationships between rs7095441 and the degree of hearing loss were analyzed, and TT genotype increased the risk of hearing loss. Among SSNHL patients, patients with TT genotype of rs7095441 have an increased risk of vertigo. CONCLUSION: This study found that the TT genotype of SNP rs7095441 can increase the risk of SSNHL in Chinese population.
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Surdez , Perda Auditiva Neurossensorial , Humanos , População do Leste Asiático , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/genética , Polimorfismo de Nucleotídeo Único/genética , ProtocaderinasRESUMO
Whole flaxseed (flour) as a good source of omega-3 fatty acid and phytochemicals with excellent nutritional and functional attributes has been used to enrich foods for health promotion and disease prevention. However, several limitations and contemporary challenges still impact the development of whole flaxseed (flour)-enriched products on the global market, such as naturally occurring antinutritional factors and entrapment of nutrients within food matrix. Whole flaxseed (flour) with different existing forms could variably alter the techno-functional performance of food matrix, and ultimately affect the edible qualities of fortified food products. The potential interaction mechanism between the subject and object components in fortified products has not been elucidated yet. Hence, in this paper, the physical structure and component changes of flaxseed (flour) by pretreatments coupled with their potential influences on the edible qualities of multiple fortified food products were summarized and analyzed. In addition, several typical food products, including baked, noodle, and dairy products were preferentially selected to investigate the potential influencing mechanisms of flaxseed (flour) on different substrate components. In particular, the altered balance between water absorption of flaxseed protein/gum polysaccharides and the interruption of gluten network, lipid lubrication, lipid-amylose complexes, syneresis, and so forth, were thoroughly elucidated. The overall impact of incorporating whole flaxseed (flour) on the quality and nutritional attributes of fortified food products, coupled with the possible solutions against negative influences are aimed. This paper could provide useful information for expanding the application of whole flaxseed (flour) based on the optimal edible and nutritional properties of fortified food products.
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Ácidos Graxos Ômega-3 , Linho , Linho/química , Proteínas , Farinha/análise , Ácidos Graxos Ômega-3/química , Controle de QualidadeRESUMO
The anisotropic van der Waals material α-MoO3 has recently attracted considerable attention because of the ability to support ellipse and hyperbolic phonon polaritons with extreme field confinement and long lifetimes, which can be used in topological transition and transformation polaritonics. However, the dispersion theory of some phonon polaritons in complex heterojunctions often requires tedious computation, which makes it difficult to simply judge and analyze the physical process of the photonic topological transition. Here we obtain the equivalent permittivity distribution of two-dimensional (2D) heterostructures by the effective medium theory and analyze the rotation-induced topological transitions and stack-dependent topological transitions of phonon polaritons. Unlike the previous discussion, we can predict the topological transition points by a parameter Éx/y(i.e., the permittivity ratio along the in-plane crystal axis of the equivalent medium) and design precisely the phonon polaritons in the stacked materials by controlling the equivalent permittivity after simple calculation. The feasibility of the effective medium theory is verified based on the 2D approximation model and the non-2D approximation model under the limit of an ultrathin slab. Meanwhile, we compare the field distributions and dispersions of the 2D heterostructures and the corresponding equivalent structure. The simulation suggests that the elliptic/hyperbolic responses of the stacked materials depend on the sign of Éx/y. The new, to the best of our knowledge, method not only provides an easier and clearer criterion for the study of photonic topological transition in anisotropic polaritons, but also shows great potential in designing some multilayer 2D heterostructures.
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A total of 33 structurally diverse isoquinoline alkaloids were isolated from the rhizomes of Menispermum dauricum, including seventeen benzylisoquinoline analogues (menisperdaurines A-Q, 1-17), five protoberberine analogues (menisperdaurines R-V, 18-22), a quaternary phenanthrene alkaloid (menisperdaurine W, 23) and ten known compounds (24-33). Compound structures, including absolute configurations, were determined by extensive spectroscopic methods, quantum chemical calculations of chemical shifts, and calculated and experimental electronic circular dichroism (ECD) data. Compounds 1-5 were glycosidic benzylisoquinolines with glucose moieties attached at the C-12 position. Compound 8 was the first example that was isolated from the rhizomes of Menispermum dauricum, benzylisoquinoline and an aromatic unit connected by a sugar bridge. Compounds were evaluated for their inhibitory effects on the dopamine D1 receptor. Compounds 1, 8, 21, 24 and 29 showed potent D1 antagonistic activities, with IC50 values ranging from 1.0 to 4.5 µM. Compound 1 exhibited the highest antagonistic activity with an IC50 value of 1.0 ± 0.2 µM.
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Alcaloides , Benzilisoquinolinas , Menispermum , Alcaloides/química , Alcaloides/farmacologia , Isoquinolinas/farmacologia , Menispermum/química , Estrutura Molecular , Receptores de Dopamina D1RESUMO
PURPOSE: The aim of the present study was to investigate the predictive value of the fibrinogen/albumin ratio index (FARI), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) on the prognosis of patients with operable head and neck squamous cell carcinoma (HNSCC). METHODS: A cohort of 155 operable HNSCC patients were enrolled. Laboratory and clinical data were extracted from the patients' electronic medical record. The optimal cut-off values were determined by receiver operating characteristic (ROC) curves analysis. Clinicopathological characteristics of patients were compared via Chi-square test. Survival curves were analyzed by Kaplan-Meier method. The prognostic factors were evaluated by univariate and multivariate analyses via the Cox hazards regression analysis. RESULTS: The median follow-up time was 31.7 months. An increased level of NLR was associated with later T stages, later N stages, and more advanced clinical stages(all P < 0.05). On univariate analyses, FARI, NLR, PLR, and N stage were correlated with progression-free survival (PFS) (all P < 0.05) as well as overall survival (OS) (all P < 0.05). And the clinical stage was only relevant to OS (P = 0.007). Multivariate Cox regression analysis revealed that FARI (HR 3.486, 95% CI 2.086-5.825, P < 0.001; HR 4.474, 95% CI 2.442-8.199, P < 0.001), NLR (HR 3.163, 95% CI 1.810-5.528, P < 0.001; HR 3.690, 95% CI 1.955-6.963, P < 0.001), and N stage (HR 1.718, 95% CI 1.058-2.789, P = 0.029; HR 1.777, 95% CI 1.024-3.084, P = 0.041) were independent prognostic factors for PFS and OS. CONCLUSION: Our findings indicate that FARI and NLR are effective and convenient markers for predicting prognosis in operable HNSCC patients.