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Interactions of water and chemical or bio-compound have a universal concern and have been extensively studied. For spectroscopic analysis, the complexity and the low resolution of the spectra make it difficult to obtain the spectral features showing the interactions. In this work, the structures and interactions in gaseous water and water-alcohol mixtures were studied using high-resolution infrared (HR-IR) spectroscopy. The spectral features of water clusters of different sizes, including dimer, trimer, tetramer and pentamer, were observed from the measured spectra of the samples in different volume concentrations, and the interactions of water and methanol/ethanol in the mixtures were obtained. In the analysis, a method based on principal component analysis was used to separate the overlapping spectra. In water-alcohol mixtures, when water is less, water molecules tend to interact with the OH groups on the exterior of the alcohol aggregate, and with the increase of water, a water cage forms around the aggregates. Furthermore, the ratio of the molecule number of methanol in the aggregate to that of water in the cage is around 1:2.3, and the ratio for ethanol is about 1:3.2.
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The applicability of cytosine base editors is hindered by their dependence on sequence context and by off-target effects. Here, by using AlphaFold2 to predict the three-dimensional structure of 1,483 cytidine deaminases and by experimentally characterizing representative deaminases (selected from each structural cluster after categorizing them via partitional clustering), we report the discovery of a few deaminases with high editing efficiencies, diverse editing windows and increased ratios of on-target to off-target effects. Specifically, several deaminases induced C-to-T conversions with comparable efficiency at AC/TC/CC/GC sites, the deaminases could introduce stop codons in single-copy and multi-copy genes in mammalian cells without double-strand breaks, and some residue conversions at predicted DNA-interacting sites reduced off-target effects. Structure-based generative machine learning could be further leveraged to expand the applicability of base editors in gene therapies.
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The demand for high-precision CRISPR/Cas9 systems in biomedicine is experiencing a notable upsurge. The editing system fdCas9 employs a dual-sgRNA strategy to enhance editing accuracy. However, the application of fdCas9 is constrained by the stringent requirement for two protospacer adjacent motifs (PAMs) of Cas9. Here, we devised an optimized editor, fRYdCas9, by merging FokI with the nearly PAM-less RYdCas9 variant, and two fRYdCas9 systems formed a dimer in a proper spacer length to accomplish DNA cleavage. In comparison to fdCas9, fRYdCas9 demonstrates a substantial increase in the number of editable genomic sites, approximately 330-fold, while maintaining a comparable level of editing efficiency. Through meticulous experimental validation, we determined that the optimal spacer length between two FokI guided by RYdCas9 is 16 base pairs. Moreover, fRYdCas9 exhibits a near PAM-less feature, along with no on-target motif preference via the library screening. Meanwhile, fRYdCas9 effectively addresses the potential risks of off-targets, as analyzed through whole genome sequencing (WGS). Mouse embryonic editing shows fRYdCas9 has robust editing capabilities. This study introduces a potentially beneficial alternative for accurate gene editing in therapeutic applications and fundamental research.
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INTRODUCTION: Polycystic ovary syndrome (PCOS) is associated with a wide range of unfavorable cardiometabolic risk factors, including obesity, hypertension, insulin resistance, impaired glucose metabolism, dyslipidemia, and metabolic syndrome. Compared with women with regular menstrual cycles, women with a history of irregular menstrual periods have an increased unfavorable cardiometabolic risk. Recently, the association between the severity of oligomenorrhea and hyperinsulinemia and insulin resistance has been demonstrated. However, evidence linking the severity of menstrual cyclicity with cardiometabolic risk in PCOS women is scarce. MATERIAL AND METHODS: This work was a prospective cross-sectional study. A total of 154 women diagnosed with PCOS by the Rotterdam criteria were recruited from July 2021 to September 2022. PCOS women with eumenorrheic (eumeno group), oligomenorrhea (oligo group), and amenorrhea (ameno group) underwent history and physical examination, gonadal steroid hormone measurement, lipid profile, oral glucose tolerance test, and homeostasis model assessment of insulin resistance. RESULTS: A trend toward an increase in unfavorable cardiometabolic risk markers including obesity, hypertension, prevalence of insulin resistance, prediabetes, dyslipidemia, and metabolic syndrome was observed in the ameno group (n = 57) as compared with the eumeno (n = 24) or oligo group (n = 73). A higher prevalence of insulin resistance (odds ratio [OR]: 3.02; 95% confidence interval [CI]: 1.03-8.81) and prediabetes (OR: 3.94; 95% CI: 1.01-15.40) was observed in the ameno group than in the eumeno group, and a higher proportion of dyslipidemia (OR: 2.44; 95% CI: 1.16-5.15) was observed in the ameno group than in the oligo group in the binary logistic regression analysis after adjusting for confounding factors. CONCLUSIONS: PCOS women with amenorrhea show a higher prevalence of insulin resistance, prediabetes, and dyslipidemia compared with those with oligomenorrhea or eumenorrhea. The severity of menstrual dysfunction could be used as a readily obtainable marker for the identification of PCOS women at greatest risk of cardiometabolic diseases.
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Factores de Riesgo Cardiometabólico , Trastornos de la Menstruación , Síndrome del Ovario Poliquístico , Humanos , Femenino , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/epidemiología , Adulto , Estudios Transversales , Estudios Prospectivos , Trastornos de la Menstruación/epidemiología , Resistencia a la Insulina , Síndrome Metabólico/epidemiología , Oligomenorrea/epidemiología , Índice de Severidad de la Enfermedad , Dislipidemias/epidemiología , Biomarcadores/sangre , Adulto Joven , Factores de RiesgoRESUMEN
The added value of candidate predictors for risk modeling is routinely evaluated by comparing the performance of models with or without including candidate predictors. Such comparison is most meaningful when the estimated risk by the two models are both unbiased in the target population. Very often data for candidate predictors are sourced from nonrepresentative convenience samples. Updating the base model using the study data without acknowledging the discrepancy between the underlying distribution of the study data and that in the target population can lead to biased risk estimates and therefore an unfair evaluation of candidate predictors. To address this issue assuming access to a well-calibrated base model, we propose a semiparametric method for model fitting that enforces good calibration. The central idea is to calibrate the fitted model against the base model by enforcing suitable constraints in maximizing the likelihood function. This approach enables unbiased assessment of model improvement offered by candidate predictors without requiring a representative sample from the target population, thus overcoming a significant practical challenge. We study theoretical properties for model parameter estimates, and demonstrate improvement in model calibration via extensive simulation studies. Finally, we apply the proposed method to data extracted from Penn Medicine Biobank to inform the added value of breast density for breast cancer risk assessment in the Caucasian woman population.
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Neoplasias de la Mama , Modelos Estadísticos , Humanos , Funciones de Verosimilitud , Femenino , Simulación por Computador , Medición de Riesgo/métodos , CalibraciónRESUMEN
INTRODUCTION: MicroRNAs (miRNAs) involve in destabilising messenger RNA or repressing translation of target molecules. Ginger-derived exosome-like nanoparticles (GELNs) play a crucial role in modulating intestinal inflammation. Moreover, GELNs contain highly heterogeneous miRNA. However, the role of miRNAs derived from GELNs in immunomodulation remains unclear. OBJECTIVES: This study aimed to elucidate the molecular basis of the unique biological effects mediated by miRNA derived from GELNs on macrophages. METHODS: GELNs were isolated using a combination of commercial exosome isolation kits and the differential centrifugation method, and the lipid composition of GELNs was determined using liquid chromatography-mass spectrometry. Subsequently, PKH26 labelled GELNs were taken up by macrophages. Furthermore, the modulation of inflammatory and immune responses by GELNs or osa-miR164d was assessed through the RNA-seq, RT-qPCR, online databases, and dual luciferase reporter assays to explore the underlying mechanisms of osa-miR164d. Biomimetic exosomes loaded with osa-miR164d were prepared using a microfluidic mixing device and systematically characterized. The therapeutic effects of osa-miR164d on relieving colitis were evaluated. RESULTS: We report for the first time that GELNs-derived osa-miR164d is a regulatory factor of reprogramming macrophage polarization, thereby inhibiting the intestinal inflammatory response. Mechanistically, osa-miR164d directly targets the 3'-UTRs of TAB1, which regulates macrophage polarization through the downregulation of NF-κB expression. In addition, We have designed a biomimetic exosome mimicking GELNs to deliver osa-miR164d (osa-miR164d-MGELNs). Notably, the osa-miR164d-MGELNs can efficiently reprogram macrophages to alleviate colitis-related symptoms. CONCLUSION: Our findings enhance the systematic understanding of how GELNs-derived osa-miR164d mediates cross-kingdom communication and provide an original engineering paradigm for mimicking GELNs to transfer miRNA.
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Broccoli contains an amount of biologically active substances, which bring beneficial effects on human health. Plant extracellular vesicles have been shown to be novel key factors in cancer diagnosis and tumor therapy. To date, the challenge of overcoming chemoresistance to 5-fluorouracil (5-FU) to facilitate the clinical management of colorectal cancer (CRC) has not been successful. Nevertheless, the functions of broccoli extracellular vesicles (BEVs) in the progression of CRC and 5-FU resistance are predominantly unclear. Herein, we showed that BEVs isolated from broccoli juice were effectively taken up by colorectal cancer HT-29 cells. The co-administration of BEVs and 5-FU significantly inhibited the proliferation and migration of colorectal cancer HT-29 cells, effectively blocking cell cycle progression. Furthermore, the co-administration of BEVs and 5-FU induced apoptosis by stimulating ROS production and disrupting mitochondrial function. Importantly, we found that BEVs reversed 5-FU resistance in HT-29 cells by suppressing the abnormal activation of the PI3K/Akt/mTOR signaling pathway. Collectively, our findings represent a novel strategy for utilizing BEVs to improve the efficacy of colorectal cancer treatment and enhance 5-FU chemosensitivity.
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Brassica , Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Neoplasias Colorrectales/metabolismo , Brassica/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Resistencia a Antineoplásicos , Neoplasias del Colon/tratamiento farmacológico , Apoptosis , Línea Celular Tumoral , Proliferación CelularRESUMEN
Heat sterilization enhances the safety and shelf-life of braised chicken, but its impact on protein digestibility and the release of metabolites remains unclear. Here, braised chicken was sterilized at 80⯰C (LS), 100⯰C (MS), and 121⯰C (HS) for 30â¯min. Protein digestibility was assessed by in vitro digestion, whereas the release of metabolites was analysed by UPLC-QTOF-MS spectroscopy. Results revealed that LS had higher gastrointestinal digestibility (88.86â¯%) than MS (81.79â¯%) and HS (78.13â¯%). Increased carbonyl content, turbidity, particle size, and hydrophobicity, along with decreased sulfhydryl content and solubility, indicated rising protein oxidation aggregation with higher sterilization temperatures, explaining reduced digestibility. 96 metabolites were identified. Compared to the control group, LS exhibited a statistically significant variation in the biosynthesis of unsaturated fatty acids, MS displayed a significant difference in purine metabolism, and HS showed a significant difference in primary bile acid biosynthesis. Thus, LS is a promising sterilization method.
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Pollos , Calor , Animales , Esterilización/métodos , Interacciones Hidrofóbicas e Hidrofílicas , DigestiónRESUMEN
BACKGROUND: Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dynamic role in the tumour cell cycle and corresponding effects leading to mitotic catastrophe and DNA damage have rarely been studied. RESULTS: In this paper, we found that the nucleoprotein SHCBP1 exhibits dynamic spatiotemporal expression during the tumour cell cycle, and SHCBP1 knockdown slowed cell cycle progression by inducing spindle disorder, as reflected by premature mitotic entry and multipolar spindle formation. This dysfunction was caused by G2/M checkpoint impairment mediated by downregulated WEE1 kinase and NEK7 (a member of the mammalian NIMA-related kinase family) expression and upregulated centromere/kinetochore protein Zeste White 10 (ZW10) expression. Moreover, both in vivo and in vitro experiments confirmed the significant inhibitory effects of SHCBP1 knockdown on tumour growth. Based on these findings, SHCBP1 knockdown in combination with low-dose DNA-damaging agents had synergistic tumouricidal effects on tumour cells. In response to this treatment, tumour cells were forced into the mitotic phase with considerable unrepaired DNA lesions, inducing mitotic catastrophe. These synergistic effects were attributed not only to the abrogation of the G2/M checkpoint and disrupted spindle function but also to the impairment of the DNA damage repair system, as demonstrated by mass spectrometry-based proteomic and western blotting analyses. Consistently, patients with low SHCBP1 expression in tumour tissue were more sensitive to radiotherapy. However, SHCBP1 knockdown combined with tubulin-toxic drugs weakened the killing effect of the drugs on tumour cells, which may guide the choice of chemotherapeutic agents in clinical practice. CONCLUSION: In summary, we elucidated the role of the nucleoprotein SHCBP1 in tumour cell cycle progression and described a novel mechanism by which SHCBP1 regulates tumour progression and through which targeting SHCBP1 increases sensitivity to DNA-damaging agent therapy, indicating its potential as a cancer treatment.
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Neoplasias , Proteómica , Animales , Humanos , Proliferación Celular/genética , Ciclo Celular/genética , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Mamíferos/metabolismo , Proteínas Adaptadoras de la Señalización Shc/genética , Proteínas Adaptadoras de la Señalización Shc/metabolismoRESUMEN
Adenine base editors (ABEs) and cytosine base editors (CBEs) enable the single nucleotide editing of targeted DNA sites avoiding generation of double strand breaks, however, the genomic features that influence the outcomes of base editing in vivo still remain to be characterized. High-throughput datasets from lentiviral integrated libraries were used to investigate the sequence features affecting base editing outcomes, but the effects of endogenous factors beyond the DNA sequences are still largely unknown. Here the base editing outcomes of ABE and CBE were evaluated in mammalian cells for 5012 endogenous genomic sites and 11,868 genome-integrated target sequences, with 4654 genomic sites sharing the same target sequences. The comparative analyses revealed that the editing outcomes of ABE and CBE at endogenous sites were substantially different from those obtained using genome-integrated sequences. We found that the base editing efficiency at endogenous target sites of both ABE and CBE was influenced by endogenous factors, including epigenetic modifications and transcriptional activity. A deep-learning algorithm referred as BE_Endo, was developed based on the endogenous factors and sequence information from our genomic datasets, and it yielded unprecedented accuracy in predicting the base editing outcomes. These findings along with the developed computational algorithms may facilitate future application of BEs for scientific research and clinical gene therapy.
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The FokI catalytic domain can be fused to various DNA binding architectures to improve the precision of genome editing tools. However, evaluation of off-target effects is essential for developing these tools. We use Genome-wide Off-target analysis by Two-cell embryo Injection (GOTI) to detect low-frequency off-target editing events in mouse embryos injected with FokI-based architectures. Specifically, we test FokI-heterodimers fused with TALENs, FokI homodimers fused with RYdCas9, or FokI catalytic domains alone resulting in no significant off-target effects. These FokI genome editing systems exhibit undetectable off-target effects in mouse embryos, supporting the further development of these systems for clinical applications.
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Edición Génica , Genoma , Animales , Ratones , Dominio Catalítico , Edición Génica/métodos , Sistemas CRISPR-CasRESUMEN
Disruption of pulmonary vascular homeostasis is a central feature of viral pneumonia, wherein endothelial cell (EC) death and subsequent angiogenic responses are critical determinants of the outcome of severe lung injury. A more granular understanding of the fundamental mechanisms driving reconstitution of lung endothelium is necessary to facilitate therapeutic vascular repair. Here, we demonstrated that TGF-ß signaling through TGF-ßR2 (transforming growth factor-ß receptor 2) is activated in pulmonary ECs upon influenza infection, and mice deficient in endothelial Tgfbr2 exhibited prolonged injury and diminished vascular repair. Loss of endothelial Tgfbr2 prevented autocrine Vegfa (vascular endothelial growth factor α) expression, reduced endothelial proliferation, and impaired renewal of aerocytes thought to be critical for alveolar gas exchange. Angiogenic responses through TGF-ßR2 were attributable to leucine-rich α-2-glycoprotein 1, a proangiogenic factor that counterbalances canonical angiostatic TGF-ß signaling. Further, we developed a lipid nanoparticle that targets the pulmonary endothelium, Lung-LNP (LuLNP). Delivery of Vegfa mRNA, a critical TGF-ßR2 downstream effector, by LuLNPs improved the impaired regeneration phenotype of EC Tgfbr2 deficiency during influenza injury. These studies defined a role for TGF-ßR2 in lung endothelial repair and demonstrated efficacy of an efficient and safe endothelial-targeted LNP capable of delivering therapeutic mRNA cargo for vascular repair in influenza infection.
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Gripe Humana , Humanos , Ratones , Animales , Receptor Tipo II de Factor de Crecimiento Transformador beta , Factor A de Crecimiento Endotelial Vascular , Pulmón/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , ARN MensajeroRESUMEN
Maternal secretion of recombinant proteins into chicken eggs may provide a viable approach for pharmaceutical production but remains limited by poor secretion efficiency through the membrane of oviduct cells, despite high expression levels. Here, we used site-specific integration of an EGFP fused to the OVAL gene by a rigid linker, (EAAAK)3, at the endogenous ovalbumin locus in chicken primordial germ cells to generate OVAL-E3-EGFP transgenic chickens, with transgenic chickens expressing CMV immediate enhancer/ß-actin-driven EGFP (CAG-EGFP) as a non-secreted control. In OVAL-E3-EGFP chickens, EGFP protein produced in maternal oviducts accumulates to high levels in eggs, but not in eggs of CAG-EGFP chickens. These results indicated that the secretion of foreign proteins can be substantially increased through fusion to the highly secreted endogenous ovalbumin. This study describes a basis for high yield recombinant protein expression in chicken eggs, enabling rapid and scalable production of numerous pharmaceutical proteins or metabolites.
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Human microorganisms, including bacteria, fungi, and viruses, play key roles in several physiological and pathological processes. Some studies discovered that tumour tissues once considered sterile actually host a variety of microorganisms, which have been confirmed to be closely related to oncogenesis. The concept of intratumoural microbiota was subsequently proposed. Microbiota could colonise tumour tissues through mucosal destruction, adjacent tissue migration, and hematogenic invasion and affect the biological behaviour of tumours as an important part of the tumour microenvironment. Mechanistic studies have demonstrated that intratumoural microbiota potentially promote the initiation and progression of tumours by inducing genomic instability and mutations, affecting epigenetic modifications, promoting inflammation response, avoiding immune destruction, regulating metabolism, and activating invasion and metastasis. Since more comprehensive and profound insights about intratumoral microbiota are continuously emerging, new methods for the early diagnosis and prognostic assessment of cancer patients have been under examination. In addition, interventions based on intratumoural microbiota show great potential to open a new chapter in antitumour therapy, especially immunotherapy, although there are some inevitable challenges. Here, we aim to provide an extensive review of the concept, development history, potential sources, heterogeneity, and carcinogenic mechanisms of intratumoural microorganisms, explore the potential role of microorganisms in tumour prognosis, and discuss current antitumour treatment regimens that target intratumoural microorganisms and the research prospects and limitations in this field.
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Microbiota , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Inmunoterapia , Carcinogénesis/genética , Transformación Celular Neoplásica , Microbiota/genética , Microambiente Tumoral/genéticaRESUMEN
INTRODUCTION: The continuous emergence and rapid spread of multidrug-resistant bacteria have accelerated the demand for the discovery of alternative antibiotics. Natural plants contain a variety of antibacterial components, which is an important source for the discovery of antimicrobial agents. OBJECTIVE: To explore the antimicrobial activities and related mechanisms of two lavandulylated flavonoids, sophoraflavanone G and kurarinone in Sophora flavescens against methicillin-resistant Staphylococcus aureus. METHODS: The effects of sophoraflavanone G and kurarinone on methicillin-resistant Staphylococcus aureus were comprehensively investigated by a combination of proteomics and metabolomics studies. Bacterial morphology was observed by scanning electron microscopy. Membrane fluidity, membrane potential, and membrane integrity were determined using the fluorescent probes Laurdan, DiSC3(5), and propidium iodide, respectively. Adenosine triphosphate and reactive oxygen species levels were determined using the adenosine triphosphate kit and reactive oxygen species kit, respectively. The affinity activity of sophoraflavanone G to the cell membrane was determined by isothermal titration calorimetry assays. RESULTS: Sophoraflavanone G and kurarinone showed significant antibacterial activity and anti-multidrug resistance properties. Mechanistic studies mainly showed that they could target the bacterial membrane and cause the destruction of the membrane integrity and biosynthesis. They could inhibit cell wall synthesis, induce hydrolysis and prevent bacteria from synthesizing biofilms. In addition, they can interfere with the energy metabolism of methicillin-resistant Staphylococcus aureus and disrupt the normal physiological activities of the bacteria. In vivo studies have shown that they can significantly improve wound infection and promote wound healing. CONCLUSION: Kurarinone and sophoraflavanone G showed promising antimicrobial properties against methicillin-resistant Staphylococcus aureus, suggesting that they may be potential candidates for the development of new antibiotic agents against multidrug-resistant bacteria.
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Antiinfecciosos , Staphylococcus aureus Resistente a Meticilina , Sophora , Sophora/química , Especies Reactivas de Oxígeno , Flavonoides/farmacología , Antibacterianos/farmacología , Antiinfecciosos/farmacología , Adenosina Trifosfato/farmacologíaRESUMEN
Antibacterial acetate grafted starch (AGS) was synthesized by isophorone diisocyanate (IPDI) coupling acetate esterified starch (AST) and the antimicrobial agent polyhexamethyleneguanidine hydrochloride (PHMG), and the antimicrobial properties of AGS were evaluated. The process parameters of AGS were: IPDI reacted with PHMG at 120 °C for 1 h, then, reacted with starch at 60 °C for 3 h. The grafting yield of PHMG and starch reached 28.43%. The Fourier transform infrared spectroscopy (FTIR) and Nuclear magnetic resonance (1H NMR) showed that the binding of IPDI to PHMG was successfully grafted on the AS. The antibacterial effect of AGS was investigated. AGS produced inhibition zones and confirmed its significant inhibitory effect on Escherichia coli and Staphylococcus aureus, as the grafting yield increased, the inhibition effect on bacteria became stronger. When the grafting yield was 28.43%, the inhibition rate of AGS was 90.24% for Escherichia coli. and 94.45% for Staphylococcus aureus. The experiments of water washing showed that after AGS was washed 10 times with water, the inhibition rate of AGS to E. coli. only reduced 3.04% and that of S. aureus 2.95%, indicating that the combination of PHMG and starch was stable and the inhibition effect was long-lasting, AGS has huge potential to be developed into antibacterial material.
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Escherichia coli , Almidón , Almidón/química , Staphylococcus aureus , Agua/química , Antibacterianos/farmacología , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
BACKGROUND: Previous studies have shown that insomnia affects human prefrontal function and that there are specific patterns of brain activation to counteract sleep and improve cognition. However, the effects of insomnia on the prefrontal cortex of MDD (major depressive disorder) patients and the patterns of activation to counteract sleep in MDD patients remain unclear. The aim of this study is to examine this using fNIRS (functional near-infrared spectroscopy). METHODS: Eighty depressed patients and 44 healthy controls were recruited for this study. fNIRS was used to assess changes in the concentration of oxygenated hemoglobin ([oxy-Hb]) in the prefrontal cortex of all participants during the VFT (verbal fluency test) and to record the number of words created to assess cognitive ability. The Pittsburgh Sleep Quality Index was used to assess sleep quality, and the Hamilton Rating Scale for Depression (24-item) and Hamilton Rating Scale for Anxiety (14-item) were used to assess the severity of depression and anxiety. RESULTS: When comparing patients, the healthy control group had significantly higher [oxy-Hb] values in the bilateral prefrontal cortex during VFT than the MDD group. In the MDD group, the [oxy-Hb] values in all brain regions except the right DLPFC were significantly higher in the group with insomnia than in the group without insomnia, but their VFT performance was significantly lower than in the group without insomnia and the healthy group. PSQI scores were positively correlated with [oxy-Hb] values in some left-brain regions, whereas HAMD and HAMA scores were not correlated with [oxy-Hb] values. CONCLUSION: The PFC was significantly less active during VFT in those with MDD than in healthy controls. All brain regions, except the right DLPFC, were significantly more active in MDD patients with insomnia than in those without insomnia, suggesting that sleep quality needs to be an important indicator in fNIRS screening. In addition, there was a positive correlation between the severity of insomnia in the left VLPFC and the level of activation, suggesting a role for the left brain region in the neurophysiology of overcoming sleepiness in MDD patients. these findings may provide new ideas for the treatment of MDD patients in the future. TRIAL REGISTRATION: Our experiment was registered in the China Clinical Trial Registry (registration number ChiCTR2200065622) on November 10.( The first patient was recruited in 10/11/2022.).
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Trastorno Depresivo Mayor , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Ansiedad , Depresión , Trastorno Depresivo Mayor/diagnóstico , Corteza Prefrontal/diagnóstico por imagen , Espectroscopía Infrarroja Corta/métodos , Trastornos del Inicio y del Mantenimiento del Sueño/complicacionesRESUMEN
The two-phase study design is a cost-efficient sampling strategy when certain data elements are expensive and, thus, can only be collected on a sub-sample of subjects. To date guidance on how best to allocate resources within the design has assumed that primary interest lies in estimating association parameters. When primary interest lies in the development and evaluation of a risk prediction tool, however, such guidance may, in fact, be detrimental. To resolve this, we propose a novel strategy for resource allocation based on oversampling cases and subjects who have more extreme risk estimates according to a preliminary model developed using fully observed predictors. Key to the proposed strategy is that it focuses on enhancing efficiency regarding estimation of measures of predictive accuracy, rather than on efficiency regarding association parameters which is the standard paradigm. Towards valid estimation and inference for accuracy measures using the resultant data, we extend an existing semiparametric maximum likelihood ethod for estimating odds ratio association parameters to accommodate the biased sampling scheme and data incompleteness. Motivated by our sampling design, we additionally propose a general post-stratification scheme for analyzing general two-phase data for estimating predictive accuracy measures. Through theoretical calculations and simulation studies, we show that the proposed sampling strategy and post-stratification scheme achieve the promised efficiency improvement. Finally, we apply the proposed methods to develop and evaluate a preliminary model for predicting the risk of hospital readmission after cardiac surgery using data from the Pennsylvania Health Care Cost Containment Council.
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Proyectos de Investigación , Humanos , Simulación por Computador , ProbabilidadRESUMEN
Probiotic-based therapy is a promising approach, which can positively modulate bacterial composition and maintain homeostasis. However, exogenous probiotics are easily destroyed by harsh conditions in vivo; thus, their application prospects have been severely limited. Specifically, oxytetracycline (OTC), a broad-spectrum antibiotic widely used in aquaculture, results in adverse intestinal environments, such as dysbacteriosis, oxidative damage, and gut dysmotility. Here, we describe a facile method to apply glycol chitosan/alginate as armor on the surface of probiotics to effectively protect them from the changed enteric environments induced by OTC. The results demonstrated that the coated Lacticaseibacillus rhamnosus GG (LGG) for only 2 h administration could significantly improve the colonization rate of LGG, and the relative abundance of Lacticaseibacillus can reach 80% in OTC-treated larvae intestines. We also explored the specific mechanisms of the coated LGG to diminish reactive oxygen species (ROS) generation and rescue gut dysmotility for OTC treatment, including enhancing the activity of antioxidative enzymes (CAT, SOD and GPx) and increasing 5-HT synthesis. The mitigation effect of the coated LGG for 2 h administration was comparable to that of uncoated LGG for 24 h administration. Encapsulation of LGG with polysaccharides provides a unique application example for generating useful bacterial therapeutics in harsh intestinal environments.
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Lacticaseibacillus rhamnosus , Oxitetraciclina , Probióticos , Alginatos , Animales , Antibacterianos , Quitosano , Larva , Estrés Oxidativo , Probióticos/farmacología , Especies Reactivas de Oxígeno , Serotonina , Superóxido Dismutasa , Pez CebraRESUMEN
The phenomenon of protein aggregation in food science is very common, but the formation mechanism is unclear. The formation of protein aggregates (PAs) is influenced by various factors, and aggregates with different sizes and shapes play an important role in food systems. Although there have been many reports on food PAs, many challenges still need to be addressed, and a systematic literature review is lacking. Thus, hypotheses about the PAs formation mechanism were summarized, and the fibrosis aggregates formation mechanism was described. The main findings of this paper indicate that the forces driving protein aggregation are covalent and non-covalent cross-linking interactions. The determination of PAs is mainly based on protein particle size combined with multispectral methods. PAs are not only associated with protein functional properties (such as emulsion and gel) but also related to harmful substances (such as advanced glycation end products, AGEs) formation. Finally, the applications of PAs in food science were summarized. Outlook and challenges were described from the perspectives of food processing conditions and parameters, food components and their interactions, food nutrition and health relationships, etc. This review will attract more food scientists to participate in related research on protein aggregation in the future.