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COP9 signalosome catalytic subunit CSN5 plays a key role in tumorigenesis and tumor immunity, showing potential as an anticancer target. Currently, only a few CSN5 inhibitors have been reported, at least partially, due to the challenges in establishing assays for CSN5 deubiquitinase activity. Here, we present the establishment and validation of a simple and reliable non-catalytic activity assay platform for identifying CSN5 inhibitors utilizing a new fluorescent probe, CFP-1, that exhibits enhanced fluorescence and fluorescence polarization features upon binding to CSN5. By using this platform, we identified 2-aminothiazole-4-carboxylic acids as new CSN5 inhibitors, which inhibited CSN5 but slightly downregulated PD-L1 in cancer cells. Furthermore, through the integration of deep learning-enabled virtual screening, we discovered that shikonins are nanomolar CSN5 inhibitors, which can upregulate PD-L1 in HCT116 cells. The binding modes of these structurally distinct inhibitors with CSN5 were explored by using microsecond-scale molecular dynamics simulations and tryptophan quenching assays.
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Objective: To study the effectiveness of liver transplantation (LT) in treating mitochondrial DNA depletion syndrome (MDS) caused by the MPV17 gene variant. Case presentation: A boy aged 2.8 years presented with edema of the lower limbs and abdomen, which persisted for over 10 days and was of unknown origin; this was accompanied by abnormal liver function, intractable hypoglycemia, and hyperlactatemia. During the second week of onset, he developed acute-on-chronic liver failure and was diagnosed with MDS due to homozygous variant c.293C>T in the MPV17 gene. Subsequently, he underwent LT from a cadaveric donor. At follow-up after 15 months, his liver function was found to be normal, without any symptoms. Additionally, a literature review was performed that included MDS patients with the MPV17 variant who underwent LT. The results demonstrated that the survival rates for MDS patients who underwent LT were 69.5%, 38.6%, 38.6%, and 38.6% at 1-year, 5-year, 10-year, and 20-year intervals, respectively. Sub-group analyses revealed the survival rate of MDS patients with isolated liver disease (83.33%, 5/6) was higher than that of hepatocerebral MDS patients (44.44%, 8/18). Fifteen variants were identified in the MPV17 gene, and patients with the c.293C>T (p.P98l) variant exhibited the highest survival rate. Conclusion: Hepatocerebral MDS patients without neurological symptoms may benefit from LT.
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Efficient coupling in broad wavelength range is desirable for wide-spectrum infrared light detection, yet this is a challenge for intersubband transition in semiconductor quantum wells (QWs). High-Q cavities mostly intensify the absorption at peak wavelengths but with shrinking bandwidth. Here, we propose a novel approach to expand the operating spectral range of the Quantum Well Infrared Photodetectors (QWIPs). By processing the QWs into asymmetric micro-pillar array structure, the device demonstrates a substantial enhancement in spectral response across the wavelength from 7.1 µm to 12.3 µm with guided mode resonance (GMR) effects. The blackbody responsivity is then increased by 3 times compared to that of the 45° polished edge-coupled counterpart. Meanwhile, the dark current density remains unchanged after the deep etching process, which will benefit the electrical performance of the detector with reduced volume duty ratio. In contrast to the symmetric micro-pillar array that contains simple resonance mode, the detectivity of QWIP in asymmetric pillar structure is found to be improved by 2-4 times within the range of 9.5 µm to 15 µm.
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Engineering Yarrowia lipolytica to produce astaxanthin provides a promising route. Here, Y. lipolytica M2 producing a titer of 181 mg/L astaxanthin was isolated by iterative atmospheric and room-temperature plasma mutagenesis and diphenylamine-mediated screening. Interestingly, a negative correlation was observed between cell biomass and astaxanthin production. To reveal the underlying mechanism, RNA-seq analysis of transcriptional changes was performed in high producer M2 and reference strain M1, and a total of 1379 differentially expressed genes were obtained. Data analysis revealed that carbon flux was elevated through lipid metabolism, acetyl-CoA and mevalonate supply, but restrained through central carbon metabolism in strain M2. Moreover, upregulation of other pathways such as ATP-binding cassette transporter and thiamine pyrophosphate possibly provided more cofactors for carotenoid hydroxylase and relieved cell membrane stress caused by astaxanthin insertion. These results suggest that balancing cell growth and astaxanthin production may be important to promote efficient biosynthesis of astaxanthin in Y. lipolytica.
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Perfilação da Expressão Gênica , Xantofilas , Yarrowia , Yarrowia/genética , Yarrowia/metabolismo , Xantofilas/metabolismo , Engenharia Metabólica , Transcriptoma , Regulação Fúngica da Expressão Gênica , Redes e Vias Metabólicas/genética , Análise do Fluxo Metabólico , Metabolismo dos Lipídeos , BiomassaRESUMO
BACKGROUND: The objective was to provide international recommendations on anti-aging dermocosmetics for clinical practice starting with essential ingredients for protection and repair before working up to advanced products for specific concerns. Methods: Seven international experts reviewed 8 hypothetical case scenarios covering different ages, skin issues (eg, sensitivity, acne, melasma), and exposure to exposome factors for both sexes and all Fitzpatrick skin types (FST). The RAND/UCLA appropriateness method was used to obtain consensus. Seventeen key ingredients were rated on a scale from 1 (totally inappropriate) to 9 (totally appropriate). Statistical analysis, 2 meetings, and email discussions refined the recommendations. RESULTS: High-factor broad-spectrum sunscreen (ie, protects against ultraviolet [UV] A and B rays), niacinamide, and other topical antioxidants were recommended for all scenarios. Further discussions were required for other ingredients. Tinted sunscreen/iron oxide were recommended for all FST, although compliance may be sub-optimal for darker skin phototypes (IV-VI), if not cosmetically acceptable. Combining a facial foundation with broad-spectrum sunscreen was recommended for darker phototypes to obtain visible light protection closely matching diverse color tones. Retinols were not recommended as a first-line treatment for sensitive skin, especially FST V and VI, due to the risk of irritation. After ablative laser treatment, alpha hydroxy acids should be avoided or used with caution in FST IV to VI due to the risk of post-inflammatory hyperpigmentation. CONCLUSION: We describe a simple, practical tool for use in daily dermatology consultations for providing recommendations on anti-aging dermocosmetics to cover diverse and inclusive populations of patients, addressing all skin types and international needs. J Drugs Dermatol. 2024;23(1):1337-1343. doi:10.36849/JDD.7798.
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Higiene da Pele , Protetores Solares , Feminino , Masculino , Humanos , Consenso , Pele , EnvelhecimentoRESUMO
In this study, a response surface methodology (RSM) was used to determine the best combination for acid degradation parameters to reduce the viscosity of Plantago ovata Forssk seed polysaccharide (POFP). Then, the two major homogeneous polysaccharides (AH-POFP1 and AH-POFP3) were obtained by DEAE-650 M and Sephadex G-100 column chromatography. The apparent structure of the main fraction AH-POFP1 was characterized by SEM, TG and XRD, and the linkage of AH-POFP1 was determined by a combination of partial acidolysis, Smith's degradation, methylation analysis and 2D NMR analysis. Structural analysis showed that AH-POFP1 was mainly composed of xylose, with a molecular weight of 618.1 kDa, and had a backbone of 1 â 4-linked Xylp, as well as branches of T-linked Xylp, 1 â 4-linked Xylp attached to the O-2 position. The antioxidant activity assays showed that the both AH-POFP1 and AH-POFP3 possess strong scavenging radical ability. Moreover, AH-POFP1 inhibits the secretion of pro-inflammatory factors, and promotes the secretion of anti-inflammatory factors, thereby exerting anti-inflammatory effects. These findings may help to guide future applications of Plantago ovata Forssk in the fields of food, health care, and pharmacy.
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Plantago , Plantago/química , Polissacarídeos/química , Antioxidantes/farmacologia , Antioxidantes/análise , Sementes/química , Anti-Inflamatórios/farmacologiaRESUMO
BACKGROUND: In this article, we review and discuss the photoprotection behavior of Asians based on the literature, along with a subanalysis of an original online survey, and make recommendations to optimize photoprotection for Asian populations to prevent photoaging and pigmentary disorders. METHODS: An international panel of eight dermatologists from Asia (China, Korea, Japan, Singapore, Indonesia, and Vietnam) met to discuss sunscreen photoprotection for Asian patients. Additionally, a subanalysis of an online survey by 3000 respondents from three Asian countries (China, Indonesia, and Japan) investigated general public awareness and attitudes to sun exposure. RESULTS: A pre-meeting survey of the eight experts from Asia showed key concerns of Asian patients consulting dermatologists are pigmentary disorders, especially actinic/senile lentigo, post-inflammatory hyperpigmentation, melasma, vitiligo, and Hori's nevus. The survey subanalysis of participants from China, Indonesia, and Japan with predominantly Fitzpatrick skin types (FST) II to IV revealed that they are particularly concerned about sun exposure causing photoaging and pigmentary disorders. Most of the respondents indicated they have limited knowledge on sunlight radiation and appropriate sunscreen protection factors. Only 22%, 13%, and 3% for China, Indonesia, and Japan, respectively, systematically use multiple protective measures (using sunscreen, avoiding midday sun, staying in the shade, wearing a hat, protective clothing, and sunglasses) when exposed to the sun. CONCLUSIONS: Further education is needed for Asian populations on the importance of comprehensive daily photoprotection, including broad-spectrum sunscreen, with high UVA and visible light protection, to reduce and prevent photoaging and pigmentary disorders.
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Lentigo , Transtornos de Fotossensibilidade , Neoplasias Cutâneas , Humanos , Protetores Solares/uso terapêutico , Neoplasias Cutâneas/prevenção & controle , Luz Solar/efeitos adversos , Transtornos de Fotossensibilidade/tratamento farmacológico , Inquéritos e Questionários , ÁsiaRESUMO
OBJECTIVE: To evaluate the effects of Sanren Tang (SRT, ) on a high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in mice and to investigate the hepatic transcriptome regulated by SRT. METHODS: The primary SRT components were identified using ultra-high-performance liquid chromatography-high-resolution accurate mass spectrometry. The SRT-induced pharmacological effects on HFD-induced NAFLD were evaluated in mice for 16 weeks. Obeticholic acid was used as a control drug. Body weight, food intake, and homeostatic model assessment for insulin resistance (HOMA-IR) index were analysed. Hepatic histological changes were observed in haematoxylin and eosin-stained sections and quantified using the NAFLD activity score (NAS). Serum alanine aminotransferase (ALT) and hepatic triglyceride (TG) levels were measured. Lipids in hepatocytes were visualised by Oil red staining. RNA-sequencing was performed to determine the transcriptome profile of the liver tissue. The differentially expressed genes were validated using real-time polymerase chain reaction and Western blotting. RESULTS: Four principal compounds were identified in the SRT: adenosine, amygdalin, luteoloside, and magnolol. SRT ameliorated hepatic histology and lipid deposition in the NAFLD mice, and decreased HOMA-IR, NAS and ALT, and hepatic TG levels. Hepatic transcriptome analysis revealed 232 HFD-regulated genes that were reversed by SRT simultaneously. Retinol metabolism, cytokine-cytokine receptor interaction, and peroxisome proliferator-activated receptor (PPAR) γ signalling were the top three SRT-regulated pathways in NAFLD. CONCLUSIONS: SRT significantly ameliorated HFD-induced NAFLD, which was correlated with the regulation of genes enriched in the retinol metabolism, cytokine-cytokine receptor interaction, and PPARγ signalling pathways.
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Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Transcriptoma , Dieta Hiperlipídica/efeitos adversos , Vitamina A/metabolismo , Vitamina A/farmacologia , Fígado , Metabolismo dos Lipídeos , Citocinas/metabolismo , Receptores de Citocinas/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Metallo-ß-lactamases (MBLs) are zinc-dependent enzymes capable of hydrolyzing all bicyclic ß-lactam antibiotics, posing a great threat to public health. However, there are currently no clinically approved MBL inhibitors. Despite variations in their active sites, MBLs share a common catalytic mechanism with carbapenems, forming similar reaction species and hydrolysates. We here report the development of 2-aminothiazole-4-carboxylic acids (AtCs) as broad-spectrum MBL inhibitors by mimicking the anchor pharmacophore features of carbapenem hydrolysate binding. Several AtCs manifested potent activity against B1, B2, and B3 MBLs. Crystallographic analyses revealed a common binding mode of AtCs with B1, B2, and B3 MBLs, resembling binding observed in the MBL-carbapenem product complexes. AtCs restored Meropenem activity against MBL-producing isolates. In the murine sepsis model, AtCs exhibited favorable synergistic efficacy with Meropenem, along with acceptable pharmacokinetics and safety profiles. This work offers promising lead compounds and a structural basis for the development of potential drug candidates to combat MBL-mediated antimicrobial resistance.
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Carbapenêmicos , Inibidores de beta-Lactamases , Animais , Camundongos , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/química , Carbapenêmicos/farmacologia , Meropeném/farmacologia , Ácidos Carboxílicos , beta-Lactamases/metabolismo , Antibacterianos/farmacologia , Antibacterianos/químicaRESUMO
Reference intervals (RIs) of laboratory testing play a fundamental role in medical activities. RIs vary greatly for populations in different areas This study aimed to evaluate the age- and sex-specific reference intervals for a healthy population in a typical city of northern China. A cross-sectional study was performed in 4 tertiary care centers of Shijiazhuang of China, biochemical analytes were analyzed using a Beckman Coulter AU5800 (Beckman Coulter Inc., Brea, CA). A total of 42,979 healthy individuals were involved in this study. Grouped by age- and sex-specific, reference intervals of all the measures have been established. We found that different age groups of males and females have significant differences (all P < .001) in levels of various biochemical analytes. We provided a comprehensive age- and sex-specific RIs for biochemical analytes, which showed dynamic changes with both age and sex. For the local population, the reference intervals established here can be adopted in other clinical laboratories after appropriate validation.
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Serviços de Laboratório Clínico , Masculino , Feminino , Humanos , Adulto , Estudos Transversais , Valores de Referência , Padrões de Referência , ChinaRESUMO
Yiyi Fuzi Baijiang Powder(YFBP), originating from Synopsis of the Golden Chamber, is a classic prescription composed of Coicis Semen, Aconiti Lateralis Radix Praeparata, and Patriniae Herba for the treatment of abscesses and pus discharge. This article presented a systematic analysis of the clinical application of YFBP, including the indicated diseases, the number of cases, efficacy, dosage, administration methods, and compatibility with other drugs. The analysis reveals that YFBP has a wide range of clinical applications. It is commonly used, often with modifications or in combination with western medicine, for diseases in the fields of gastroente-rology, gynecology, urology, dermatology, and others. And most of the Traditional Chinese Medicine(TCM) evidence involved in these diseases are damp-heat evudence. The prescription shows rich variations in clinical administration methods, and most of which are the treatment of aqueous decoction of it. The therapeutic effect is also significant, and the total effective rate of clinical treatment is re-latively high. Additionally, this article summarized the pharmacological research on YFBP and found that it possessed various pharmacological effects, including anti-inflammatory, antioxidant, anticancer, and immune-modulating properties. Finally, correlation analysis was conducted on the main diseases, TCM types, prescription doses, pharmacological effects and action targets of YFBP, which to show the relationship between these five aspects in a visual form, reflecting the relationship between its clinical application and modern pharmacological effects. These findings provide a reference basis for further development and research on YFBP.
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Aconitum , Diterpenos , Medicamentos de Ervas Chinesas , Pós , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional ChinesaRESUMO
A retrospective analysis was performed from May 2003 to October 2021 at our hospital. One hundred and eleven neonates diagnosed with gastric perforation were categorized into non-survivor and survivor groups based on prognosis. The mortality rate was 23.42%. Logistic regression was used to analyze the factors influencing the early neonatal death. The non-survivor groups showed more abdominal distension, vomiting, hypoxia, acidosis, hyperkalemia, and coagulation abnormalities. Serum potassium concentration (odds ratio [OR] 2.148, P = .043) was an independent risk factor; however, arterial partial pressure of oxygen (OR 0.977, P = .024), bicarbonate (OR 0.779, P = .023), and platelet count (OR 0.986, P = .014) had protective effects on neonatal death. Based on this, a visualized nomogram prediction model was constructed, patients who had a nomogram score of more than 163.787 was considered to have high risks of mortality, the area under the curve of this was up to 0.828 (95% confidence interval [0.733, 0.923]), the sensitivity was 80.0%, and the specificity was 76.9%.
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BACKGROUND: Panax ginseng cultivated under the forest is popular because its shape and effective ingredients are similar to wild ginseng. The growth of P. ginseng in the larch forest is generally better than in the broad-leaved forest, and the incidence rate of diseases is low. Therefore, the selection of forest species is one of the basic factors in the successful cropping of P. ginseng. METHODS: Illumina HiSeq high-throughput sequencing was used to analyze the 16S rRNA/ITS gene sequence of P. ginseng rhizosphere soil under larch forest to study the rhizosphere microbiome's diversity and community composition structure. RESULTS: The species classification and richness of rhizosphere bacterial and fungal communities in the same-aged P. ginseng were similar. Consistent with the soil system of commonly cultivated crops, Proteobacteria, Actinobacteriota, Acidobacteriota, Verrucomicrobiota, Chloroflexi, and Basidiomycota, Ascomycota were the dominant phylum of bacteria and fungi, respectively. Compared with the soil without planting P. ginseng, the diversity of microorganisms and community structure of continuous planting for 2 years, 5 years, and 18 years of P. ginseng rhizosphere soil had little change. The accumulation levels of Ilyonectria, Fusarium, Gibberella, and Cylindrocarpon were not significantly increased with planting P. ginseng and the increased age of cropping P. ginseng. CONCLUSIONS: The results of this study showed that the soil function of the larch forest was good, which provided a theoretical basis for the land selection and soil improvement of cultivating P. ginseng under the larch forest.
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Fusarium , Hypocreales , Larix , Microbiota , Panax , RNA Ribossômico 16S/genética , Rizosfera , Microbiota/genética , FlorestasRESUMO
Anterior cervical spine surgery is a common type of neck surgery in orthopaedics. Swallowing disorder is one of the most common complications after surgery. It is characterized by food entering the esophagus from the mouth through the pharynx. The process of reaching the stomach is hampered and leads to increases in a range of risk factors that affect the health of the patient. This article reviews relevant literature reports from recent years retrieved from various national and international medical databases, aiming to find more economical, effective, and simple perioperative nursing strategies for patients with cervical anterior surgery through evidence-based thinking and methods, with the aim of developing a personalized care model that is easy to implement and has a long-lasting effect and a wide range of rehabilitation benefits to better serve patients.
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Vértebras Cervicais , Transtornos de Deglutição , Procedimentos Ortopédicos , Humanos , Vértebras Cervicais/cirurgia , Transtornos de Deglutição/etiologia , Procedimentos Ortopédicos/efeitos adversos , Complicações Pós-Operatórias/etiologiaRESUMO
OBJECTIVE: To examine the efficacy of early intervention (4 weeks before pollen dispersal) with sphenopalatine ganglion (Xinwu acupoint) stimulation in patients with allergies after the onset of seasonal allergic rhinitis (SAR). METHODS: This is a prospective, randomized and unblinded half-open study. Forty-one SAR volunteers were randomly assigned to either the sphenopalatine ganglion (SPG) acupuncture plus supplementary acupuncture (SPG group) or the sham-SPG acupuncture plus supplementary acupuncture (SA group) stimulation 4 weeks before the onset of allergy season. The changes of the total nasal symptom score (TNSS) and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores were measured on the first week in the onset of allergy season. RESULTS: Four patients dropped out due to local hematoma and pain in the SPG and SA groups. The remaining 37 patients continued through to the end of the trial. After early intervention 4 weeks before the onset of allergy season, the sneezing, nasal congestion and itchiness scores in the first week of onset time were significantly lower in the SPG group than in the SA group patients ( 0.001). The RQLQ score obtained at the onset of symptoms indicated that symptoms were more significantly ameliorated in the SPG group than in the SA group (0.001). CONCLUSIONS: The results of this study confirmed that early intervention by sphenopalatine ganglion (Xinwu acupoint) stimulation can effectively improve the symptoms and the quality of SAR patients' daily lives.
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Terapia por Acupuntura , Rinite Alérgica Sazonal , Rinite Alérgica , Humanos , Rinite Alérgica Sazonal/tratamento farmacológico , Pontos de Acupuntura , Qualidade de Vida , Estudos Prospectivos , Terapia por Acupuntura/métodos , Rinite Alérgica/tratamento farmacológico , Resultado do TratamentoRESUMO
In additive manufacturing (AM), the mechanical properties of manufactured parts are often insufficient due to complex defects and residual stresses, limiting their use in high-value or mission-critical applications. Therefore, the research and application of nondestructive testing (NDT) technologies to identify defects in AM are becoming increasingly urgent. This article reviews the recent progress in online detection technologies in AM, a special introduction to the high-speed synchrotron X-ray technology for real-time in situ observation, and analysis of defect formation processes in the past 5 years, and also discusses the latest research efforts involving process monitoring and feedback control algorithms. The formation mechanism of different defects and the influence of process parameters on defect formation, important parameters such as defect spatial resolution, detection speed, and scope of application of common NDT methods, and the defect types, advantages, and disadvantages associated with current online detection methods for monitoring three-dimensional printing processes are summarized. In response to the development requirements of AM technology, the most promising trends in online detection are also prospected. This review aims to serve as a reference and guidance for the work to identify/select the most suitable measurement methods and corresponding control strategy for online detection.
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BACKGROUND: Most studies on the association of maternal pregnancy weight with offspring weight trajectory have a short follow-up time. This study aimed to explore the associations of maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) with childhood weight trajectories in a 7-year birth cohort. METHODS: A total of 946 mother-child pairs (467 boys and 479 girls) from a longitudinal birth cohort in Tianjin City, China, were included in this study, ranging from pregnancy to offspring at 7 years. The outcome variable was defined as overweight or not overweight in offspring at the last round. A group-based trajectory model was applied to identify childhood BMI trajectory groups. RESULTS: Five discrete BMI trajectory groups were identified and characterized as constant underweight (25.2%), constant normal weight (42.8%), and high or increasing trajectory [at risk of overweight (16.9%), progressive overweight (11.0%) and progressive obesity (4.1%)]. Maternal prepregnancy overweight was associated with 1.72 (95% CI 1.14-2.60, P = 0.01) to 4.02 (95% CI 1.94-8.36, P < 0.001) times the risk of all high or increasing trajectory groups, and excessive GWG was related to groups at risk of overweight [relative risk ratio (RRR) 2.09, 95% CI 1.27-3.46, P = 0.004] and progressive obesity (RRR 3.33, 95% CI 1.13-9.79, P = 0.029). Children in all high or increasing trajectory groups were associated with greater overweight risk at the last round [risk ratios (RRs) ranged from 3.54 (95% CI 2.53-4.95, P < 0.001) to 6.18 (95% CI 4.05-9.42, P < 0.001)]. CONCLUSION: Maternal prepregnancy overweight and excessive gestational weight gain were associated with increasing or high-level childhood body mass index trajectories as well as a greater risk of overweight at 7 years.
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Propionic acid (PA) is a water-soluble substance that has been shown to be beneficial for improving colon-related diseases. However, its appliance as a nutraceutical ingredient is hampered by its volatility, irritating odor, and easy absorption in the stomach and small intestine. A chitosan solution containing propionic acid was dispersed in a palm oil/corn oil mixture with polyglycerol polyricinoleate (PGPR) to form PA-loaded water-in-oil (W/O) emulsions. The stability of the emulsions was improved by the inclusion of both chitosan and palm oil, where the chitosan reduced the emulsion particle size and palm oil increased the viscosity. The thermal volatility and storage stability of the encapsulated propionic acid were significantly improved due to the stability of emulsion structure and hydrogen bonding between chitosan and propionic acid. Around 56% of propionic acid remained within the aqueous phase after the simulated gastrointestinal digestion. Our results indicate that W/O emulsions might be candidates as colon-targeted delivery systems for propionic acid, which could be beneficial for maintaining colon health.