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1.
Stat Med ; 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847215

RESUMO

Conventional pharmacokinetic (PK) bioequivalence (BE) studies aim to compare the rate and extent of drug absorption from a test (T) and reference (R) product using non-compartmental analysis (NCA) and the two one-sided test (TOST). Recently published regulatory guidance recommends alternative model-based (MB) approaches for BE assessment when NCA is challenging, as for long-acting injectables and products which require sparse PK sampling. However, our previous research on MB-TOST approaches showed that model misspecification can lead to inflated type I error. The objective of this research was to compare the performance of model selection (MS) on R product arm data and model averaging (MA) from a pool of candidate structural PK models in MBBE studies with sparse sampling. Our simulation study was inspired by a real case BE study using a two-way crossover design. PK data were simulated using three structural models under the null hypothesis and one model under the alternative hypothesis. MB-TOST was applied either using each of the five candidate models or following MS and MA with or without the simulated model in the pool. Assuming T and R have the same PK model, our simulation shows that following MS and MA, MB-TOST controls type I error rates at or below 0.05 and attains similar or even higher power than when using the simulated model. Thus, we propose to use MS prior to MB-TOST for BE studies with sparse PK sampling and to consider MA when candidate models have similar Akaike information criterion.

2.
Planta ; 260(1): 21, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847829

RESUMO

MAIN CONCLUSION: Petal developmental characteristics in Fumarioideae were similar at early stages, and the specialized nectar holder/pollen container formed by the outer/inner petals. The micro-morphology of these two structures, however, shows diversity in seven species. Elaborate petals have been modified to form different types, including petal lobes, ridges, protuberances, and spurs, each with specialized functions. Nectar holder and pollen container presumably have a function in plant-pollinator interactions. In Fumarioideae, four elaborate petals of the disymmetric/zygomorphic flower present architecture forming the "nectar holder" and "pollen container" structure at the bottom and top separately. In the present study, the petals of seven species in Fumarioideae were investigated by scanning electron microscopy, light microscope, and transmission electron microscopes. The results show that petal development could divided into six stages: initiation, enlargement, adaxial/abaxial differentiation, elaborate specializations (sacs, spurs, and lobes formed), extension, and maturation, while the specialized "nectar holder" and "pollen container" structures mainly formed in stage 4. "Nectar holder" is developed from the shallow sac/spur differentiated at the base of the outer petal, eventually forming a multi-organized complex structure, together with staminal nectaries (1-2) with individual sizes. A semi-closed ellipsoidal "pollen container" is developed from the apical part of the 3-lobed inner petals fused by middle lobes and attain different sizes. The adaxial epidermis cells are specialized, with more distinct punctate/dense columnar protrusions or wavy cuticles presented on obviously thickening cell walls. In addition, a large and well-developed cavity appears between the inner and outer epidermis of the petals. As an exception, Hypecoum erectum middle lobes present stamen mimicry. Elaborate petal structure is crucial for comprehending the petal diversity in Fumarioideae and provides more evidence for further exploration of the reproductive study in Papaveraceae.


Assuntos
Flores , Microscopia Eletrônica de Varredura , Néctar de Plantas , Pólen , Flores/anatomia & histologia , Flores/ultraestrutura , Flores/crescimento & desenvolvimento , Pólen/ultraestrutura , Microscopia Eletrônica de Transmissão , Polinização
3.
World J Urol ; 42(1): 370, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847900

RESUMO

PURPOSE: The objective was to evaluate the efficacy of transcutaneous electrical nerve stimulation (TENS) combined with mirabegron therapy compared with mirabegron monotherapy in the treatment of female patients with overactive bladder (OAB). METHODS: In this randomized controlled study, 100 female outpatients with OAB were screened. Among these patients, 86 who met the inclusion criteria were randomly divided into the TENS combined with mirabegron treatment group and mirabegron monotherapy treatment group, with 43 patients in each group. The voiding diary, Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire Symptom Bother Score (OAB-q SBS), total health-related quality of life (OAB-q HRQoL), and treatment satisfaction-visual analog scale (TS-VAS) score before and after treatment were recorded to evaluate the efficacy of OAB treatment. Seventy-nine of the 86 patients (40 in the TENS plus mirabegron group and 39 in the mirabegron monotherapy group) completed 12 weeks of treatment. RESULTS: TENS combined with mirabegron therapy was superior to mirabegron monotherapy in improving the primary endpoints, including the daily number of micturition episodes and the daily MVV/micturition and secondary endpoints, including the daily number of urgency episodes, the OABSS, the OAB-q SBS, the HRQoL score and TS-VAS score. There were no statistically significant differences in urgency urinary incontinence and nocturia between the groups. Some minor adverse effects were observed, including muscle pain, local paresthesia and constipation. CONCLUSIONS: The combination of TENS and mirabegron was more effective than mirabegron alone in the treatment of female patients with OAB. TRIAL REGISTRATION NUMBER: ChiCTR2400080528 (31.01.2024, retrospectively registered).


Assuntos
Acetanilidas , Tiazóis , Estimulação Elétrica Nervosa Transcutânea , Bexiga Urinária Hiperativa , Humanos , Bexiga Urinária Hiperativa/terapia , Bexiga Urinária Hiperativa/tratamento farmacológico , Feminino , Acetanilidas/uso terapêutico , Tiazóis/uso terapêutico , Estimulação Elétrica Nervosa Transcutânea/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Terapia Combinada , Idoso , Adulto , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Agentes Urológicos/uso terapêutico
4.
Cereb Cortex ; 34(6)2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38850218

RESUMO

Closed head injury is a prevalent form of traumatic brain injury with poorly understood effects on cortical neural circuits. Given the emotional and behavioral impairments linked to closed head injury, it is vital to uncover brain functional deficits and their driving mechanisms. In this study, we employed a robust viral tracing technique to identify the alteration of the neural pathway connecting the medial prefrontal cortex to the basolateral amygdala, and we observed the disruptions in neuronal projections between the medial prefrontal cortex and the basolateral amygdala following closed head injury. Remarkably, our results highlight that ZL006, an inhibitor targeting PSD-95/nNOS interaction, stands out for its ability to selectively reverse these aberrations. Specifically, ZL006 effectively mitigates the disruptions in neuronal projections from the medial prefrontal cortex to basolateral amygdala induced by closed head injury. Furthermore, using chemogenetic approaches, we elucidate that activating the medial prefrontal cortex projections to the basolateral amygdala circuit produces anxiolytic effects, aligning with the therapeutic potential of ZL006. Additionally, ZL006 administration effectively mitigates astrocyte activation, leading to the restoration of medial prefrontal cortex glutamatergic neuron activity. Moreover, in the context of attenuating anxiety-like behaviors through ZL006 treatment, we observe a reduction in closed head injury-induced astrocyte engulfment, which may correlate with the observed decrease in dendritic spine density of medial prefrontal cortex glutamatergic neurons.


Assuntos
Tonsila do Cerebelo , Ansiedade , Traumatismos Cranianos Fechados , Córtex Pré-Frontal , Animais , Córtex Pré-Frontal/efeitos dos fármacos , Masculino , Traumatismos Cranianos Fechados/complicações , Ansiedade/tratamento farmacológico , Tonsila do Cerebelo/efeitos dos fármacos , Camundongos , Vias Neurais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteína 4 Homóloga a Disks-Large/metabolismo
5.
J Anim Sci Biotechnol ; 15(1): 77, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38840220

RESUMO

BACKGROUND: Wooden breast (WB) myopathy is a common myopathy found in commercial broiler chickens worldwide. Histological examination has revealed that WB myopathy is accompanied by damage to the pectoralis major (PM) muscle. However, the underlying mechanisms responsible for the formation of WB in broilers have not been fully elucidated. This study aimed to investigate the potential role of hypoxia-mediated programmed cell death (PCD) in the formation of WB myopathy. RESULTS: Histological examination and biochemical analysis were performed on the PM muscle of the control (CON) and WB groups. A significantly increased thickness of the breast muscle in the top, middle, and bottom portions (P<0.01) was found along with pathological structure damage of myofibers in the WB group. The number of capillaries per fiber in PM muscle, and the levels of pO2 and sO2 in the blood, were significantly decreased (P < 0.01), while the levels of pCO2 and TCO2 in the blood were significantly increased (P < 0.05), suggesting hypoxic conditions in the PM muscle of the WB group. We further evaluated the PCD-related pathways including autophagy, apoptosis, and necroptosis to understand the consequence response to enhanced hypoxic conditions in the PM muscle of birds with WB. The ratio of LC3 II to LC3 I, and the autophagy-related factors HIF-1α, BNIP3, Beclin1, AMPKα, and ULK1 at the mRNA and protein levels, were all significantly upregulated (P < 0.05), showing that autophagy occurred in the PM muscle of the WB group. The apoptotic index, as well as the expressions of Bax, Cytc, caspase 9, and caspase 3, were significantly increased (P < 0.05), whereas Bcl-2 was significantly decreased (P < 0.05) in the WB-affected PM muscle, indicating the occurrence of apoptosis mediated by the mitochondrial pathway. Additionally, the expressions of necroptosis-related factors RIP1, RIP3, and MLKL, as well as NF-κB and the pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6, were all significantly enhanced (P < 0.05) in the WB-affected PM muscle. CONCLUSIONS: The WB myopathy reduces blood supply and induces hypoxia in the PM muscle, which is closely related to the occurrence of PCD including apoptosis, autophagy, and necroptosis within myofibers, and finally leads to abnormal muscle damage and the development of WB in broilers.

6.
Signal Transduct Target Ther ; 9(1): 142, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38825657

RESUMO

Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8+ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.


Assuntos
Inibidores de Checkpoint Imunológico , Animais , Camundongos , Inibidores de Checkpoint Imunológico/farmacologia , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Endopeptidases/genética , Células NIH 3T3 , Compostos Radiofarmacêuticos/uso terapêutico , Serina Endopeptidases/genética , Serina Endopeptidases/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Imunoterapia , Gelatinases/genética , Gelatinases/imunologia , Lutécio/farmacologia , Linhagem Celular Tumoral
7.
Cancer Med ; 13(11): e7356, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38850125

RESUMO

OBJECTIVE: Multiple myeloma (MM) is the leading indication of autologous hematopoietic stem cell transplantation. The aim of this study was to determine the incidence of mobilization failure and characterize the risk factors associated with poor mobilization (PM) of MM patients in novel therapies era. METHODS: We conducted a retrospective study of 211 MM patients who received their first peripheral blood stem cells (PBSC) mobilization at our single center. The following data were collected: age, gender, clinical stage, disease status, complete blood cell count, induction regimen, CD34+ cell count in peripheral blood (PB), and PBSC collections. RESULTS: In addition to conventional drugs, 22 (10.4%) patients received daratumumab containing induction, and 33 (15.6%) patients used plerixafor for poor mobilization (pre-apheresis PB CD34+ cells <20/µL). Failure of collection occurred in 24 (11.4%) patients and was correlated with low white blood cell (WBC), ≥3 cycles of lenalidomide treatment before mobilization, steady-state mobilization and nouse of plerixafor are associated with mobilization failure. Daratumumab-based induction treatment ≥2 courses, albumin >41 g/L before mobilization, and steady-state mobilization were risk factors for PM in subgroups of patients treated with lenalidomide for <3 courses. In addition, Hepatitis B virus infection at baseline, thalassemia and measurable residual disease positivity were recognized as predictive factors for PM in subset of chemo-mobilization patients. CONCLUSION: In addition to some well-recognized risk factors, baseline WBC count and daratumumab exposure ≥2 courses before mobilization were revealed as the predictive factors of mobilization failure, providing consultation for preemptive use of plerixafor.


Assuntos
Benzilaminas , Ciclamos , Mobilização de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mobilização de Células-Tronco Hematopoéticas/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Adulto , Ciclamos/uso terapêutico , Ciclamos/farmacologia , Benzilaminas/uso terapêutico , Células-Tronco de Sangue Periférico/metabolismo , Fatores de Risco , Anticorpos Monoclonais/uso terapêutico , Lenalidomida/uso terapêutico , Lenalidomida/administração & dosagem , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico/métodos , Transplante Autólogo
8.
J Opt Soc Am A Opt Image Sci Vis ; 41(6): 1027-1036, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38856410

RESUMO

The correlation and polarization singularities as the important parameters of a radially polarized Gaussian Schell-model vortex beam propagating in oceanic turbulence have been investigated in detail. On the one hand, the correlation singularity of the beam will first split, and then generate new correlation singularities, and finally vanish in pairs. The longer the propagating distance, the larger the rate of dissipation of mean-square temperature, and the lower initial correlation lengths reduce the stability of correlation singularities. On the other hand, polarization singularities also split during transmission. The different initial correlation lengths cause the uneven distribution of polarization singularities, and the high order topological charge leads to the generation of new polarization singularities at short distances. Our numerical findings may be of great significance for detection and imaging of the oceanic optical telecommunication links.

9.
CNS Neurosci Ther ; 30(6): e14792, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38867393

RESUMO

AIMS: Parkinson's disease (PD) patients experience improvement in motor symptoms after deep brain stimulation (DBS) and before initiating stimulation. This is called the microlesion effect. However, the mechanism remains unclear. The study aims to comprehensively explore the changes in functional connectivity (FC) patterns in movement-related brain regions in PD patients during the microlesion phase through seed-based FC analysis. METHODS: The study collected the resting functional magnetic resonance imaging data of 49 PD patients before and after DBS surgery (off stimulation). The cortical and subcortical areas related to motor function were selected for seed-based FC analysis. Meanwhile, their relationship with the motor scale was investigated. RESULTS: The motor-related brain regions were selected as the seed point, and we observed various FC declines within the motor network brain regions. These declines were primarily in the left middle temporal gyrus, bilateral middle frontal gyrus, right supplementary motor area, left precentral gyrus, left postcentral gyrus, left inferior frontal gyrus, and right superior frontal gyrus after DBS. CONCLUSION: The movement-related network was extensively reorganized during the microlesion period. The study provided new information on enhancing motor function from the network level post-DBS.


Assuntos
Estimulação Encefálica Profunda , Imageamento por Ressonância Magnética , Doença de Parkinson , Humanos , Estimulação Encefálica Profunda/métodos , Doença de Parkinson/terapia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/diagnóstico por imagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Córtex Motor/fisiopatologia , Córtex Motor/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia
10.
Front Microbiol ; 15: 1395340, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38855765

RESUMO

Background: Several studies have suggested a potential link between allergic rhinitis (AR) and gut microbiota. In response, we conducted a meta-analysis of Linkage Disequilibrium Score Regression (LDSC) and Mendelian randomization (MR) to detect their genetic associations. Methods: Summary statistics for 211 gut microbiota taxa were gathered from the MiBioGen study, while data for AR were sourced from the Pan-UKB, the FinnGen, and the Genetic Epidemiology Research on Aging (GERA). The genetic correlation between gut microbiota and AR was assessed using LDSC. The principal estimate of causality was determined using the Inverse-Variance Weighted (IVW) method. To assess the robustness of these findings, sensitivity analyses were conducted employing methods such as the weighted median, MR-Egger, and MR-PRESSO. The summary effect estimates of LDSC, forward MR and reverse MR were combined using meta-analysis for AR from different data resources. Results: Our study indicated a significant genetic correlation between genus Sellimonas (Rg = -0.64, p = 3.64 × 10-5, Adjust_P = 3.64 × 10-5) and AR, and a suggestive genetic correlation between seven bacterial taxa and AR. Moreover, the forward MR analysis identified genus Gordonibacter, genus Coprococcus2, genus LachnospiraceaeUCG010, genus Methanobrevibacter, and family Victivallaceae as being suggestively associated with an increased risk of AR. The reverse MR analysis indicated that AR was suggestively linked to an increased risk for genus Coprococcus2 and genus RuminococcaceaeUCG011. Conclusion: Our findings indicate a causal relationship between specific gut microbiomes and AR. This enhances our understanding of the gut microbiota's contribution to the pathophysiology of AR and lays the groundwork for innovative approaches and theoretical models for future prevention and treatment strategies in this patient population.

11.
Chem Commun (Camb) ; 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38869490

RESUMO

A Ce-based metal-organic tetrahedron was assembled for preserving the uncoordinated nature of 2,2'-bipyridyl groups to form a Cu-based photocatalyst, which protected CuI centers from intermolecular deactivation and showed high photocatalytic activity for the visible-light-mediated C(sp²)-S cross-coupling.

12.
Cell Mol Life Sci ; 81(1): 260, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38878096

RESUMO

The pathological advancement of osteoporosis is caused by the uneven development of bone marrow-derived mesenchymal stem cells (BMSCs) in terms of osteogenesis and adipogenesis. While the role of EEF1B2 in intellectual disability and tumorigenesis is well established, its function in the bone-fat switch of BMSCs is still largely unexplored. During the process of osteogenic differentiation, we observed an increase in the expression of EEF1B2, while a decrease in its expression was noted during adipogenesis. Suppression of EEF1B2 hindered the process of osteogenic differentiation and mineralization while promoting adipogenic differentiation. On the contrary, overexpression of EEF1B2 enhanced osteogenesis and strongly inhibited adipogenesis. Furthermore, the excessive expression of EEF1B2 in the tibias has the potential to mitigate bone loss and decrease marrow adiposity in mice with osteoporosis. In terms of mechanism, the suppression of ß-catenin activity occurred when EEF1B2 function was suppressed during osteogenesis. Our collective findings indicate that EEF1B2 functions as a regulator, influencing the differentiation of BMSCs and maintaining a balance between bone and fat. Our finding highlights its potential as a therapeutic target for diseases related to bone metabolism.


Assuntos
Adipogenia , Diferenciação Celular , Células-Tronco Mesenquimais , Osteogênese , Osteoporose , Via de Sinalização Wnt , beta Catenina , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Animais , Osteogênese/genética , Adipogenia/genética , Camundongos , Osteoporose/metabolismo , Osteoporose/patologia , beta Catenina/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Células da Medula Óssea/metabolismo , Células da Medula Óssea/citologia , Células Cultivadas
13.
J Pharm Sci ; 2024 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-38862090

RESUMO

Reformulation with addition of antioxidants is one potential mitigation strategy to prevent or reduce nitrosamine drug substance-related impurities (NDSRIs) in drug products. To explore whether there could be other approaches to demonstrate bioequivalence for a reformulated oral product, which typically needs in vivo bioequivalence studies to support the changes after approval, the effects of antioxidant on the in vitro permeability of BCS III model drug substances were investigated to see whether there could be any potential impact on drug absorption. Six antioxidants were screened and four (ascorbic acid, cysteine, α-tocopherol and propyl gallate) were selected based on their nitrosamine inhibition efficiencies. The study demonstrated that these four antioxidants, at the tested amounts, did not have observable impact on the in vitro permeability of the BCS III model drug substances across Caco-2 cell monolayers in the In Vitro Dissolution Absorption System (IDAS). An in vitro permeability study could be considered as part of one potential bioequivalence bridging approach for reformulated low-risk immediate release solid oral products and oral suspension products. Other factors such as the influence of antioxidants on intestinal transporter activities should be considered where appropriate.

14.
BMC Med Imaging ; 24(1): 129, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822274

RESUMO

BACKGROUND: Segmenting liver vessels from contrast-enhanced computed tomography images is essential for diagnosing liver diseases, planning surgeries and delivering radiotherapy. Nevertheless, identifying vessels is a challenging task due to the tiny cross-sectional areas occupied by vessels, which has posed great challenges for vessel segmentation, such as limited features to be learned and difficult to construct high-quality as well as large-volume data. METHODS: We present an approach that only requires a few labeled vessels but delivers significantly improved results. Our model starts with vessel enhancement by fading out liver intensity and generates candidate vessels by a classifier fed with a large number of image filters. Afterwards, the initial segmentation is refined using Markov random fields. RESULTS: In experiments on the well-known dataset 3D-IRCADb, the averaged Dice coefficient is lifted to 0.63, and the mean sensitivity is increased to 0.71. These results are significantly better than those obtained from existing machine-learning approaches and comparable to those generated from deep-learning models. CONCLUSION: Sophisticated integration of a large number of filters is able to pinpoint effective features from liver images that are sufficient to distinguish vessels from other liver tissues under a scarcity of large-volume labeled data. The study can shed light on medical image segmentation, especially for those without sufficient data.


Assuntos
Fígado , Tomografia Computadorizada por Raios X , Humanos , Tomografia Computadorizada por Raios X/métodos , Fígado/diagnóstico por imagem , Fígado/irrigação sanguínea , Meios de Contraste , Aprendizado de Máquina , Algoritmos , Aprendizado Profundo
15.
FASEB J ; 38(9): e23657, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38713087

RESUMO

The pathogenesis of osteoporosis (OP) is closely associated with the disrupted balance between osteogenesis and adipogenesis in bone marrow-derived mesenchymal stem cells (BMSCs). We analyzed published single-cell RNA sequencing (scRNA-seq) data to dissect the transcriptomic profiles of bone marrow-derived cells in OP, reviewing 56 377 cells across eight scRNA-seq datasets from femoral heads (osteoporosis or osteopenia n = 5, osteoarthritis n = 3). Seventeen genes, including carboxypeptidase M (CPM), were identified as key osteogenesis-adipogenesis regulators through comprehensive gene set enrichment, differential expression, regulon activity, and pseudotime analyses. In vitro, CPM knockdown reduced osteogenesis and promoted adipogenesis in BMSCs, while adenovirus-mediated CPM overexpression had the reverse effects. In vivo, intraosseous injection of CPM-overexpressing BMSCs mitigated bone loss in ovariectomized mice. Integrated scRNA-seq and bulk RNA sequencing analyses provided insight into the MAPK/ERK pathway's role in the CPM-mediated regulation of BMSC osteogenesis and adipogenesis; specifically, CPM overexpression enhanced MAPK/ERK signaling and osteogenesis. In contrast, the ERK1/2 inhibitor binimetinib negated the effects of CPM overexpression. Overall, our findings identify CPM as a pivotal regulator of BMSC differentiation, which provides new clues for the mechanistic study of OP.


Assuntos
Adipogenia , Carboxipeptidases , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais , Osteogênese , Análise de Célula Única , Animais , Feminino , Humanos , Camundongos , Carboxipeptidases/metabolismo , Carboxipeptidases/genética , Diferenciação Celular , Proteínas Ligadas por GPI , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Metaloendopeptidases , Camundongos Endogâmicos C57BL , Osteogênese/fisiologia , Osteogênese/genética , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Transcriptoma
16.
World J Microbiol Biotechnol ; 40(7): 199, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38727988

RESUMO

Glucagon-like peptide-1(GLP-1) is an incretin hormone secreted primarily from the intestinal L-cells in response to meals. GLP-1 is a key regulator of energy metabolism and food intake. It has been proven that P9 protein from A. muciniphila could increase GLP-1 release and improve glucose homeostasis in HFD-induced mice. To obtain an engineered Lactococcus lactis which produced P9 protein, mature polypeptide chain of P9 was codon-optimized, fused with N-terminal signal peptide Usp45, and expressed in L. lactis NZ9000. Heterologous secretion of P9 by recombinant L. lactis NZP9 were successfully detected by SDS-PAGE and western blotting. Notably, the supernatant of L. lactis NZP9 stimulated GLP-1 production of NCI-H716 cells. The relative expression level of GLP-1 biosynthesis gene GCG and PCSK1 were upregulated by 1.63 and 1.53 folds, respectively. To our knowledge, this is the first report on the secretory expression of carboxyl-terminal processing protease P9 from A. muciniphila in L. lactis. Our results suggest that genetically engineered L. lactis which expressed P9 may have therapeutic potential for the treatment of diabetes, obesity and other metabolic disorders.


Assuntos
Akkermansia , Peptídeo 1 Semelhante ao Glucagon , Lactococcus lactis , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/genética , Akkermansia/genética , Akkermansia/metabolismo , Lactococcus lactis/genética , Lactococcus lactis/metabolismo , Humanos , Células L , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Animais , Camundongos , Linhagem Celular , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
17.
J Hazard Mater ; 473: 134632, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38781852

RESUMO

Recent increases in organophosphate ester (OPE) application have led to their widespread presence, yet little is known about their temporal trends in food. This study collected milk samples from 13 countries across three continents during 2020-2023, finding detectable OPEs in all samples (range: 2.25-19.7; median: 7.06 ng/g ww). Although no statistical temporal differences were found for the total OPEs during the 4-year sampling campaign, it was interesting to observe significant variations in the decreasing trend for Cl-OPEs and concentration variations for aryl-OPEs and alkyl-OPEs (p < 0.05), indicating changing OPE use patterns. Packaged milk exhibited significant higher OPE levels than those found in directly collected raw unpackaged milk, and milk with longer shelf-life showed higher OPE levels, revealing packaging material as a contamination source. No significant geographical differences were observed in milk across countries (p > 0.05), but Shandong Province, a major OPE production site in China, showed relatively higher OPE concentrations. The Monte Carlo simulation of estimated daily intakes indicated no exposure risk from OPEs through milk consumption. The molecular docking method was used to assess human hormone binding affinity with OPEs, amongst which aryl-OPEs had the highest binding energies. The Toxicological-Priority-Index method which integrated chemical property, detection frequency, risk quotients, hazardous quotients and endocrine-disrupting effects was employed to prioritize OPEs. Aryl-OPEs showed the highest scores, deserving attention in the future.


Assuntos
Contaminação de Alimentos , Leite , Leite/química , Animais , Humanos , Contaminação de Alimentos/análise , Ésteres/análise , Organofosfatos/análise , Simulação de Acoplamento Molecular
18.
Oncol Rep ; 51(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38695244

RESUMO

Following the publication of the above article, a concerned reader drew to the Editor's attention that certain of the Transwell cell migration and invasion assay data featured in Figs. 5C and 6C were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had already been published elsewhere prior to the submission of this paper to Oncology Reports, or were submitted for consideration for publication at around the same time. In view of the fact that certain of these data had already apparently been published prior to the submission of this article for publication, the Editor of Oncology Reports has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 37: 2743­2750, 2017; DOI: 10.3892/or.2017.5555].

19.
Neural Netw ; 176: 106342, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38692188

RESUMO

Reinforcement Learning (RL) is a significant machine learning subfield that emphasizes learning actions based on environment to obtain optimal behavior policy. RL agents can make decisions at variable time scales in the form of temporal abstractions, also known as options. The issue of discovering options has seen a considerable research effort. Most notably, the Interest Option Critic (IOC) algorithm first extends the initial set to the interest function, providing a method for learning options specialized to certain state space regions. This approach offers a specific attention mechanism for action selection. Unfortunately, this method still suffers from the classic issues of poor data efficiency and lack of flexibility in RL when learning options end-to-end through backpropagation. This paper proposes a new approach called Salience Interest Option Critic (SIOC), which chooses subsets of existing initiation sets for RL. Specifically, these subsets are not learned by backpropagation, which is slow and tends to overfit, but through particle filters. This approach enables the rapid and flexible identification of critical subsets using only reward feedback. We conducted experiments in discrete and continuous domains, and our proposed method demonstrate higher efficiency and flexibility than other methods. The generated options are more valuable within a single task and exhibited greater interpretability and reusability in multi-task learning scenarios.


Assuntos
Algoritmos , Aprendizado de Máquina , Redes Neurais de Computação , Reforço Psicológico , Humanos , Recompensa , Tomada de Decisões/fisiologia , Fatores de Tempo
20.
Med ; 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38761802

RESUMO

BACKGROUND: Achieving universal health coverage (UHC) involves all individuals attaining accessible health interventions at an affordable cost. We examined current patterns and temporal trends of cancer mortality and UHC across sociodemographic index (SDI) settings, and quantified these association. METHODS: We used data from the Global Burden of Disease Study 2019 and Our World in Data. The UHC effective coverage index was obtained to assess the potential population health gains delivered by health systems. The estimated annual percentage change (EAPC) with a 95% confidence interval (CI) was calculated to quantify the trend of cancer age-standardized mortality rate (ASMR). A generalized linear model was applied to estimate the association between ASMR and UHC. FINDINGS: The high (EAPC = -0.9% [95% CI, -1.0%, -0.9%]) and high-middle (-0.9% [-1.0%, -0.8%]) SDI regions had the fastest decline in ASMR (per 100,000) for total cancers from 1990 to 2019. The overall UHC effective coverage index increased by 27.9% in the high-SDI quintile to 62.2% in the low-SDI quintile. A negative association was observed between ASMR for all-cancer (adjusted odds ratio [OR] = 0.87 [0.76, 0.99]), stomach (0.73 [0.56, 0.95]), breast (0.64 [0.52, 0.79]), cervical (0.42 [0.30, 0.60]), lip and oral cavity (0.55 [0.40, 0.75]), and nasopharynx (0.42 [0.26, 0.68]) cancers and high UHC level (the lowest as the reference). CONCLUSIONS: Our findings strengthen the evidence base for achieving UHC to improve cancer outcomes. FUNDING: This work is funded by the China National Natural Science Foundation and Chinese Academy of Medical Sciences Innovation Fund for Medical Science.

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