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1.
Chem Sci ; 15(18): 6800-6815, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38725508

RESUMO

A CoII-porphyrin complex (1) with an appended aza-crown ether for Lewis acid (LA) binding was synthesized and characterized. NMR spectroscopy and electrochemistry show that cationic group I and II LAs (i.e., Li+, Na+, K+, Ca2+, Sr2+, and Ba2+) bind to the aza-crown ether group of 1. The binding constant for Li+ is comparable to that observed for a free aza-crown ether. LA binding causes an anodic shift in the CoII/CoI couple of between 10 and 40 mV and also impacts the CoIII/CoII couple. The magnitude of the anodic shift of the CoII/CoI couple varies linearly with the strength of the LA as determined by the pKa of the corresponding metal-aqua complex, with dications giving larger shifts than monocations. The extent of the anodic shift of the CoII/CoI couple also increases as the ionic strength of the solution decreases. This is consistent with electric field effects being responsible for the changes in the redox properties of 1 upon LA binding and provides a novel method to tune the reduction potential. Density functional theory calculations indicate that the bound LA is 5.6 to 6.8 Å away from the CoII ion, demonstrating that long-range electrostatic effects, which do not involve changes to the primary coordination sphere, are responsible for the variations in redox chemistry. Compound 1 was investigated as a CO2 reduction electrocatalyst and shows high activity but rapid decomposition.

2.
bioRxiv ; 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38746461

RESUMO

Inspired by the power of transcriptional synthetic receptors and hoping to complement them to expand the toolbox for cell engineering, we establish LIDAR (Ligand-Induced Dimerization Activating RNA editing), a modular post-transcriptional synthetic receptor platform that harnesses RNA editing by ADAR. LIDAR is compatible with various receptor architectures in different cellular contexts, and enables the sensing of diverse ligands and the production of functional outputs. Furthermore, LIDAR can sense orthogonal signals in the same cell and produce synthetic spatial patterns, potentially enabling the programming of complex multicellular behaviors. Finally, LIDAR is compatible with compact encoding and can be delivered by synthetic mRNA. Thus, LIDAR expands the family of synthetic receptors, holding the promise to empower basic research and therapeutic applications.

3.
J Med Chem ; 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722757

RESUMO

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against Plasmodium spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure-activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.

4.
Chin Med J (Engl) ; 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38716704

RESUMO

BACKGROUND: This systematic review aimed to examine whether dual-task (DT) training was superior to single-task (ST) training in improving DT walking, balance and cognitive function for individuals with Parkinson's disease (PD). METHODS: Literature search was performed in the following electronic databases: PubMed, the Cochrane Library, Web of Science, and Metstr covering inception to May 10, 2023. And in order to facilitate comparison across trials, we calculated the effect size (Hedges' g) of gait, balance, cognitive, and other parameters under both ST and DT conditions, using the mean change score and standard deviation (SD) of change score of the experimental and control groups. Randomized controlled trials that examined the effects of DT motor and cognitive training in individuals with Parkinson's disease were included for this systematic review. RESULTS: A total of 335 participants recruited from six articles (five studies) were involved in this review. In terms of walking function, only double support time and stride time variability showed significant between-group difference (Hedges' g = 0.34, 0.18, respectively). Compared to ST training group, DT training group had a more improvement effect in laboratory balance measurement (Hedges' g = 0.18, 0.25), but no significant improvement in clinical balance measurement. No significant between-group differences were observed, thus its training effect on cognitive function was inconclusive. CONCLUSIONS: The DT training failed to achieve promising results better than ST training in improving DT walking and balance functions for individuals with PD. Any firm conclusion cannot be drawn at present, due to the limited number of eligible publications. Larger sample size and high-quality studies are needed to investigate the effectiveness of DT training in individuals with PD.

5.
Heliyon ; 10(9): e30536, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38737229

RESUMO

Objective: To investigate and compare the differences between the incidence of falls, balance and living environment among older persons in urban villages and other types of residential areas. Methods: We surveyed 580 older adults living in different types of residential areas in Shantou, China, surveying basic information, fall incidence, balance ability testing of older persons, home environment safety assessment. Results: The incidence of falls among older people in urban villages (19.54 %) was between urban areas(26.63 %) and rural areas(16.91 %). The influencing factors of falls in different residential types were different. Near-fall, abnormal bowel movement, and impaired balance ability were the risk factors of falls among older persons in urban villages. Divorce/single, fair and poor hearing loss and near-fall were the risk factors of falls in urban older adults. Frailty and impaired balance ability were the risk factors of falls in rural older people. Conclusions: Risk factors for falls in older people vary according to the characteristics of their living areas and relevant interventions should be targeted according to the characteristics of falls occurring in different residential areas.

6.
Mar Pollut Bull ; 202: 116307, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38564820

RESUMO

This study utilizes ultraviolet and fluorescence spectroscopic indices of dissolved organic matter (DOM) from sediments, combined with machine learning (ML) models, to develop an optimized predictive model for estimating sediment total organic carbon (TOC) and identifying adjacent land-use types in coastal sediments from the Yellow and Bohai Seas. Our results indicate that ML models surpass traditional regression techniques in estimating TOC and classifying land-use types. Penalized Least Squares Regression (PLR) and Cubist models show exceptional TOC estimation capabilities, with PLR exhibiting the lowest training error and Cubist achieving a correlation coefficient 0.79. In land-use classification, Support Vector Machines achieved 85.6 % accuracy in training and 92.2 % in testing. Maximum fluorescence intensity and ultraviolet absorbance at 254 nm were crucial factors influencing TOC variations in coastal sediments. This study underscores the efficacy of ML models utilizing DOM optical indices for near real-time estimation of marine sediment TOC and land-use classification.


Assuntos
Carbono , Monitoramento Ambiental , Sedimentos Geológicos , Aprendizado de Máquina , Sedimentos Geológicos/química , Carbono/análise , Monitoramento Ambiental/métodos
7.
Nutr J ; 23(1): 45, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38644466

RESUMO

BACKGROUND: Breast cancer is the most common malignancy in women worldwide. The relationship between remnant cholesterol (RC) and the prognosis of patients with breast cancer has not been clearly reported. This study investigated the prognostic value of RC in predicting mortality in patients with breast cancer. METHODS: This study prospectively analysed 709 women patients with breast cancer from the Investigation on Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) project. Restricted cubic splines were used to analyse the dose-response relationship between RC and breast cancer mortality. The Kaplan-Meier method was used to evaluate the overall survival of patients with breast cancer. A Cox regression analyses was performed to assess the independent association between RC and breast cancer mortality. Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce confounding. Sensitivity analysis was performed after excluding patients with underlying diseases and survival times shorter than one year. RESULTS: A linear dose-response relationship was identified between RC and the risk of all-cause mortality in patients with breast cancer (p = 0.036). Kaplan-Meier survival analysis and log-rank test showed that patients with high RC levels had poorer survival than those with low RC levels (p = 0.007). Univariate and multivariate Cox regression analyses showed that RC was an independent risk factor for mortality in women patients with breast cancer. IPTW-adjusted analyses and sensitivity analyses showed that CR remained a prognostic factor. CONCLUSIONS: RC is an independent risk factor for the prognosis of patients with breast cancer, and patients with higher RC levels have poorer survival.


Assuntos
Neoplasias da Mama , Colesterol , Lipoproteínas , Humanos , Feminino , Neoplasias da Mama/mortalidade , Colesterol/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Prognóstico , Adulto , Estimativa de Kaplan-Meier , Fatores de Risco , Modelos de Riscos Proporcionais , Biomarcadores/sangue , Triglicerídeos/sangue , Idoso
8.
BMC Plant Biol ; 24(1): 289, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38627624

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) play a crucial role in regulating gene expression vital for the growth and development of plants. Despite this, the role of lncRNAs in Chinese cabbage (Brassica rapa L. ssp. pekinensis) pollen development and male fertility remains poorly understood. RESULTS: In this study, we characterized a recessive genic male sterile mutant (366-2 S), where the delayed degradation of tapetum and the failure of tetrad separation primarily led to the inability to form single microspores, resulting in male sterility. To analyze the role of lncRNAs in pollen development, we conducted a comparative lncRNA sequencing using anthers from the male sterile mutant line (366-2 S) and the wild-type male fertile line (366-2 F). We identified 385 differentially expressed lncRNAs between the 366-2 F and 366-2 S lines, with 172 of them potentially associated with target genes. To further understand the alterations in mRNA expression and explore potential lncRNA-target genes (mRNAs), we performed comparative mRNA transcriptome analysis in the anthers of 366-2 S and 366-2 F at two stages. We identified 1,176 differentially expressed mRNAs. Remarkably, GO analysis revealed significant enrichment in five GO terms, most notably involving mRNAs annotated as pectinesterase and polygalacturonase, which play roles in cell wall degradation. The considerable downregulation of these genes might contribute to the delayed degradation of tapetum in 366-2 S. Furthermore, we identified 15 lncRNA-mRNA modules through Venn diagram analysis. Among them, MSTRG.9997-BraA04g004630.3 C (ß-1,3-glucanase) is associated with callose degradation and tetrad separation. Additionally, MSTRG.5212-BraA02g040020.3 C (pectinesterase) and MSTRG.13,532-BraA05g030320.3 C (pectinesterase) are associated with cell wall degradation of the tapetum, indicating that these three candidate lncRNA-mRNA modules potentially regulate pollen development. CONCLUSION: This study lays the foundation for understanding the roles of lncRNAs in pollen development and for elucidating their molecular mechanisms in regulating male sterility in Chinese cabbage.


Assuntos
Brassica rapa , Brassica , Infertilidade Masculina , RNA Longo não Codificante , Masculino , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Brassica/genética , Perfilação da Expressão Gênica/métodos , Transcriptoma , Fertilidade , Regulação da Expressão Gênica de Plantas , Infertilidade das Plantas/genética
9.
Phys Rev Lett ; 132(14): 146401, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38640385

RESUMO

A series of recent experimental works on twisted MoTe_{2} homobilayers have unveiled an abundance of exotic states in this system. Valley-polarized quantum anomalous Hall states have been identified at hole doping of ν=-1, and the fractional quantum anomalous Hall effect is observed at ν=-2/3 and ν=-3/5. In this Letter, we investigate the electronic properties of AA-stacked twisted bilayer MoTe_{2} at ν=-2 by k-space Hartree-Fock calculations. We identify a series of phases, among which a noteworthy phase is the antiferromagnetic Chern insulator, stabilized by an external electric field. We attribute the existence of this Chern insulator to an antiferromagnetic instability at a topological phase transition between the quantum spin hall phase and a band insulator phase. Our research proposes the potential of realizing a Chern insulator beyond ν=-1, and contributes fresh perspectives on the interplay between band topology and electron-electron correlations in moiré superlattices.

10.
Zhongguo Zhong Yao Za Zhi ; 49(5): 1249-1254, 2024 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-38621971

RESUMO

The chemical constituents of Draconis Sanguis were preliminarily studied by macroporous resin, silica gel, dextran gel, and high-performance liquid chromatography. One retro-dihydrochalcone, four flavonoids, and one stilbene were isolated. Their chemical structures were identified as 4-hydroxy-2,6-dimethoxy-3-methyldihydrochalcone(1), 4'-hydroxy-5,7-dimethoxy-8-methylflavan(2), 7-hydroxy-4',5-dimethoxyflavan(3),(2S)-7-hydroxy-5-methoxy-6-methylflavan(4),(2S)-7-hydroxy-5-methoxyflavan(5), and pterostilbene(6) by modern spectroscopy, physicochemical properties, and literature comparison. Compound 1 was a new compound. Compounds 2 and 6 were first found in the Arecaceae family. Compound 5 had the potential to prevent and treat diabetic kidney disease.


Assuntos
Arecaceae , Diabetes Mellitus , Nefropatias Diabéticas , Medicamentos de Ervas Chinesas , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Flavonoides/análise , Medicamentos de Ervas Chinesas/química , Cromatografia Líquida de Alta Pressão/métodos
11.
Adv Sci (Weinh) ; : e2308390, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38626374

RESUMO

The smart materials with multi-color and stimuli-responsive luminescence are very promising for next generation of optical information encryption and anti-counterfeiting, but these materials are still scarce. Herein, a multi-level information encryption strategy is developed based on the polychromatic emission of Sb-doped double perovskite powders (SDPPs). Cs2NaInCl6:Sb, Cs2KInCl6:Sb, and Cs2AgInCl6:Sb synthesized through coprecipitation methods exhibit broadband emissions with bright blue, cyan, and orange colors, respectively. The information transmitted by specific SDPP is encrypted when different SDPPs are mixed. The confidential information can be decrypted by selecting the corresponding narrowband filter. Then, an encrypted quick response (QR) code with improved security is demonstrated based on this multi-channel selection strategy. Moreover, the three types of SDPPs exhibit three different water-triggered luminescence switching behaviors. The confidential information represented by Cs2NaInCl6:Sb can be erased/recovered through a simple water spray/drying. Whereas, the information collected from the green channel is permanently erased by moisture, which fundamentally avoids information leakage. Therefore, different encryption schemes can be designed to meet a variety of encryption requirements. The multicolor and stimuli-responsive luminescence greatly enrich the flexibility of optical information encryption, which leaps the level of security and confidentiality.

12.
Front Bioeng Biotechnol ; 12: 1365514, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38572356

RESUMO

Valorization of food processing effluent (FPE) by microalgae cultivation for astaxanthin production is regarded as a potential strategy to solve the environmental pollution of food processing industry and promote the development of eco-friendly agriculture. In this review paper, microalgal species which have the potential to be employed for astaxanthin in FPE were identified. Additionally, in terms of CO2 emission, the performances of microalgae cultivation and traditional methods for FPE remediation were compared. Thirdly, an in-depth discussion of some innovative technologies, which may be employed to lower the total cost, improve the nutrient profile of FPE, and enhance the astaxanthin synthesis, was provided. Finally, specific effects of dietary supplementation of algal astaxanthin on the growth rate, immune response, and pigmentation of animals were discussed. Based on the discussion of this work, the cultivation of microalgae in FPE for astaxanthin production is a value-adding process which can bring environmental benefits and ecological benefits to the food processing industry and agriculture. Particularly, technological innovations in recent years are promoting the shift of this new idea from academic research to practical application. In the coming future, with the reduction of the total cost of algal astaxanthin, policy support from the governments, and further improvement of the innovative technologies, the concept of growing microalgae in FPE for astaxanthin will be more applicable in the industry.

13.
Compr Rev Food Sci Food Saf ; 23(3): e13355, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38685870

RESUMO

Resistant starch type 3 (RS3), often found in cooked starchy food, has various health benefits due to its indigestible properties and physiological functions such as promoting the abundance of gut beneficial microbial flora and inhibiting the growth of intestinal pathogenic bacteria. However, it is challenging to develop starchy food with high RS3 content. This review aims to provide a detailed overview of current advancements to enhance RS3 content in starchy food and its effects of RS3 on gut microbiota. These approaches include breeding high-amylose cereals through gene editing techniques, processing, enzyme treatments, storage, formation of RS3 nanoparticles, and the incorporation of bioactive compounds. The mechanisms, specific conditions, advantages, and disadvantages associated with each approach and the potential effects of RS3 prepared by different methods on gut microbiota are summarized. In conclusion, this review contains important information that aims to provide guidelines for developing an efficient RS3 preparation process and promote the consumption of RS3-enriched starchy foods to improve overall health outcomes.


Assuntos
Microbioma Gastrointestinal , Amido , Amido/química , Humanos , Amido Resistente , Grão Comestível/química , Animais
14.
Int J Environ Health Res ; : 1-12, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38576314

RESUMO

Limited studies in China have explored the association between gravidae exposure to PM2.5 and small for gestational age infants (SGA), yielding inconsistent results. This study in Wuhan utilized daily excessive concentration hours (DECH) as a novel measure to assess PM2.5's impact on SGA. Data on air pollutants and pregnant women were collected from the Wuhan Municipal Ecology and Environmental Bureau and Wuhan Children's Hospital, respectively. Logistic regression models were employed to evaluate the contribution of PM2.5-DECH and PM2.5-mean to SGA. Significant correlations were observed between PM2.5-mean and SGA during the second trimester [OR = 1.23 (95% CI: 1.14-1.32)] and the entire pregnancy [OR = 1.15 (95% CI: 1.07-1.24)]. Similar correlations were found between PM2.5-DECH and SGA. These findings suggest that increased PM2.5 exposure is associated with a higher risk of SGA, and DECH may be used as a prospective substitute indicator for daily average concentration in similar studies.

15.
Artigo em Inglês | MEDLINE | ID: mdl-38577938

RESUMO

The aim of this study is to evaluate the developments in the treatment and prevalence of hypertension by demographic subgroups in least developed area of China in 2012 and 2022. This population-based cross-sectional study was conducted in 2012 and 2022, we applied stratified multistage random sampling to investigate residents aged 18 years or older in Gansu, the least developed province in the northwest of China. Questionnaires and anthropometric measurements were given to all respondents. The standardized prevalence of hypertension in adults in Gansu increased from 26.1% in 2012 to 28.8% in 2022. Compared with 2012, the control rate remains decreased despite the significantly improved awareness and treatment rates of hypertension in 2022. Apart from the reversal of the control rate, the trend of higher prevalence in men and higher awareness and treatment rates in women has not changed. There was an obviously increase in the proportion of participants who had received health education and hypertension management services from medical workers. The treatment was still primarily monotherapy, and there was no significant improvement in the prescription of medication. The prevalence of hypertension has increased mildly in the least developed region of China over the past decade, and the challenge of hypertension management has shifted from increasing awareness and treatment rates to increasing control rates. The onset and control of hypertension are affected by education methods, BMI, local economic conditions and other factors, and targeted strategies can be adopted to strengthen the management of hypertension in economically underdeveloped areas of China.

16.
Perfusion ; : 2676591241245876, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38587932

RESUMO

PURPOSE: Exercise-based cardiac rehabilitation (EBCR) improves functional capacity in heart failure (HF). However, data on the effect of EBCR in patients with advanced HF and left ventricular assist devices (LVADs) are limited. This meta-analysis aimed to evaluate the impact of EBCR on the functional ability of LVAD patients by comparing the corresponding outcome indicators between the EBCR and ST groups. METHODS: PubMed, Embase, Clinical Trials, and Cochrane Library databases were searched for studies assessing and comparing the effects of EBCR and standard therapy (ST) in patients following LVAD implantation. Using pre-defined criteria, appropriate studies were identified and selected. Data from selected studies were extracted in a standardized fashion, and a meta-analysis was performed using a fixed-effects model. The protocol was registered on INPLASY (202340073). RESULTS: In total, 12 trials involving 477 patients were identified. The mean age of the participants was 52.9 years, and 78.6% were male. The initiation of EBCR varied from LVAD implantation during the index hospitalization to 11 months post-LVAD implantation. The median rehabilitation period ranged from 2 weeks to 18 months. EBCR was associated with improved peak oxygen uptake (VO2) in all trials. Quantitative analysis was performed in six randomized studies involving 214 patients (EBCR: n = 130, ST: n = 84). EBCR was associated with a significantly high peak VO2 (weighted mean difference [WMD] = 1.64 mL/kg/min; 95% confidence interval [CI], 0.20-3.08; p = .03). Similarly, 6-min walk distance (6MWD) showed significantly greater improvement in the EBCR group than in the ST group (WMD = 34.54 m; 95% CI, 12.47-56.42; p = .002) in 266 patients (EBCR, n = 140; ST, n = 126). Heterogeneity was low among the included trials. None of the included studies reported serious adverse events related to EBCR, indicating the safety of EBCR after LVAD implantation. CONCLUSION: This study demonstrated that EBCR following LVAD implantation is associated with greater improvement in functional capacity compared with ST as reflected by the improved peak VO2 and 6MWD values. Considering the small number of patients in this analysis, further research on the clinical impact of EBCR in LVAD patients is warranted.

17.
Acta Pharm Sin B ; 14(3): 1204-1221, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38486987

RESUMO

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor cells. The pro-death effect of Nur77 can be regulated by its interaction with Bcl-2, resulting in conversion of Bcl-2 from a survival to killer. As Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy, targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer therapeutics. Here, we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 pathway. In vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer (TNBC) and MCF-7/LCC2 tamoxifen-resistant breast cancer (TAMR) in a Nur77-dependent manner. Mechanistic studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria, resulting in mitochondria-related apoptosis. Interestingly, XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 condensates. Together, our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

20.
Foods ; 13(6)2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38540877

RESUMO

Food-derived peptides have been extensively studied for their benefits in humans. Hen eggs, characterized by high protein and digestibility, are an excellent source of food-derived bioactive peptides. This review summarizes the preparation methods, purification, and identification of hen egg-derived peptides (HEPs). The preparation methods mainly include enzymatic hydrolysis, microbial fermentation, and chemical synthesis. Genetic engineering is an emerging trend of HEP preparation. Then, we summarize the biological activities of HEPs, such as antioxidant activities, enzyme inhibitory activity, and antibacterial activity, of which the enzyme inhibitory activity is comprehensively summarized for the first time. The structure-activity relationship and underlying mechanism of the HEPs are further elucidated. Finally, the applications, future challenges, and opportunities of HEPs were mainly discussed in the food and non-food sectors. We focus on the potential applications of HEPs in intestinal health and assembly delivery and provide a reference for the further utilization and commercial development of HEPs.

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