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1.
Artigo em Inglês | MEDLINE | ID: mdl-36674256

RESUMO

Promoting greener and sustainable development is one of the main goals of the most recent 14th Five-Year Plan (i.e., 2021-2025). Environmental regulation is seen as fundamental to green transformation and an important way for all of China to reach a high-quality and sustainable development mode. However, large spatial disparities exist across the different regions in China, so formulating region-oriented environmental regulatory policies to achieve regional high-quality and sustainable development is now a matter of great practical significance. In the present paper, we analyze this problem and begin by calculating the high development level measured through the Green Total Factor Productivity (GTFP) of 259 Chinese cities. Thereafter we construct a comprehensive index of environmental regulation through the linear weighted-sum method. Lastly, we investigate the spatiotemporal heterogeneity of the impact of environmental regulation on GTFP using a Geographically and Temporally Weighted Regression (GTWR) model. We find that: (1) From the spatial dimension perspective, the impact of environmental regulation of Chinese cities on GTFP is either linear (monotonically increasing or decreasing), non-linear (U-shaped or inverted U-shaped), or nonsignificant. Most cities have a U-shaped relationship, indicating that environmental regulation first inhibits GTFP at the early stage, but then promotes it. There are also significant differences among cities in the turning points of environmental regulation; (2) From the time dimension perspective, the number of cities is on the rise having monotonically decreasing impacts of environmental regulation on GTFP. Furthermore, even for the same city, the relationship between the two variables shows different characteristics in different years; (3) The impact of five control variables on GTFP may also vary from one city to another over the sample period, also presenting spatiotemporal heterogeneity effects. Consequently, the formulation and implementation of environmental regulatory policies should not only adapt to local conditions but also choose reasonable and effective measures to achieve high-quality development targets.


Assuntos
Eficiência , Desenvolvimento Sustentável , Cidades , China , Política Ambiental , Desenvolvimento Econômico
2.
BMC Public Health ; 23(1): 111, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647024

RESUMO

PURPOSE: The primary objective of this study was to evaluate knowledge and behavior of medication use among guardians of left-behind children (LBC) and non-left-behind children (NLBC). METHODS: A cross-sectional study was conducted in Chengdu, the major city of southwestern China from May 2020 to August 2020. A logistic regression model was conducted to assess medication-related knowledge and behavior of guardians between the LBC group and NLBC group, adjusted for confounders. Stratified analysis was further performed. RESULTS: The overall mean scores for knowledge and for behavior were 20.22 (standard deviation = 4.472) and 15.77 (standard deviation = 3.604), respectively. No significant difference was found in medication-related knowledge and behavior scores between LBC and NLBC guardians (P > 0.05). A significant difference was only observed after adjusting for past medical history and history of present illness (HPI). CONCLUSION: There was no significant difference in the awareness and behavior of medication use between guardians of LBC and NLBC in this study, having more contact with the doctor was an effective method of health education that could possibly improve their health literacy.


Assuntos
População Rural , Humanos , Criança , Estudos Transversais , China , Modelos Logísticos
3.
ACS Omega ; 8(1): 1534-1541, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36643470

RESUMO

Novel biocompatible palladium nanoparticles (Pd-NPs) have been prepared by microorganisms via Bacillus megaterium Y-4. It was demonstrated that ultrasonication treatment of biologically reduced Pd-NPs impart a much higher absorption in NIR regions and a better photothermal conversion efficiency to the material. The as-prepared material showed excellent biocompatibility and antibacterial activity under NIR irradiation. In less than 10 min, the disinfection efficiency for a low dosage of Pd-NPs (20 mg/L) was 99.99% toward both Staphylococcus aureus and Escherichia coli. The exclusive and even dispersed microbial Pd-NPs display a high efficiency of photothermal conversion under the irradiation of NIR, which endows them with excellent antibacterial activity in a low dosage.

4.
Sci China Life Sci ; 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36680676

RESUMO

The maintenance of proteostasis is essential for cellular and organism healthspan. How proteostasis collapse influences reproductive span remains largely unclear. In Caenorhabditis elegans, excess accumulation of vitellogenins, the major components in yolk proteins, is crucial for the development of the embryo and occurs throughout the whole body during the aging process. Here, we show that vitellogenin accumulation leads to reproduction cessation. Excess vitellogenin is accumulated in the intestine and transported into the germline, impairing lysosomal activity in these tissues. The lysosomal function in the germline is required for reproductive span by maintaining oocyte quality. In contrast, autophagy and sperm depletion are not involved in vitellogenin accumulation-induced reproductive aging. Our findings provide insights into how proteome imbalance has an impact on reproductive aging and imply that improvement of lysosomal function is an effective approach for mid-life intervention for maintaining reproductive health in mammals.

5.
J Mol Biol ; : 167968, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36681180

RESUMO

Type I interferons (IFN) are cytokines that bridge the innate and adaptive immune response, and thus play central roles in human health, including vaccine efficacy, immune response to cancer and pathogen infection, and autoimmune disorders. Post-translational protein modifications by the small ubiquitin-like modifiers (SUMO) have recently emerged as an important regulator of type I IFN expression as shown by studies using murine and cellular models and recent human clinical trials. However, the mechanism regarding how SUMOylation regulates type I IFN expression remains poorly understood. In this study, we show that SUMOylation inhibition does not activate IFNB1 gene promoter that is regulated by known canonical pathways including cytosolic DNA. Instead, we identified a binding site for the chromatin modification enzyme, the SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1), located between the IFNB1 promoter and a previously identified enhancer. We found that SETDB1 regulates IFNB1 expression and SUMOylation of SETDB1 is required for its binding and enhancing the H3K9me3 heterochromatin signal in this region. Heterochromatin, a tightly packed form of DNA, has been documented to suppress gene expression through suppressing enhancer function. Taken together, our study identified a novel mechanism of regulation of type I IFN expression, at least in part, through SUMOylation of a chromatin modification enzyme.

6.
Antioxidants (Basel) ; 12(1)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36671003

RESUMO

Adenosine triphosphate (ATP) released from dying cells with high concentrations is sensed as a danger signal by the P2X7 receptor. Sodium iodate (NaIO3) is an oxidative toxic agent, and its retinal toxicity has been used as the model of dry age-related macular degeneration (AMD). In this study, we used NaIO3-treated mice and cultured retinal cells, including BV-2 microglia, 661W photoreceptors, rMC1 Müller cells and ARPE-19 retinal epithelial cells, to understand the pathological action of P2X7 in retinal degeneration. We found that NaIO3 can significantly decrease the photoreceptor function by reducing a-wave and b-wave amplitudes in electroretinogram (ERG) analysis. Optical coherence tomography (OCT) analysis revealed the degeneration of retinal epithelium and ganglion cell layers. Interestingly, P2X7-/- mice were protected from the NaIO3-induced retinopathy and inflammatory NLRP3, IL-1ß and IL-6 gene expression in the retina. Hematoxylin and eosin staining indicated that the retinal epithelium was less deteriorated in P2X7-/- mice compared to the WT group. Although P2X7 was barely detected in 661W, rMC1 and ARPE-19 cells, its gene and protein levels can be increased after NaIO3 treatment, leading to a synergistic cytotoxicity of BzATP [2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate tri(triethyleneammonium)salt] and NaIO3 administration in ARPE-19 cells. In conclusion, the paracrine action of the ATP/P2X7 axis via cell-cell communication is involved in NaIO3-induced retinal injury. Our results show that P2X7 antagonist might be a potential therapy in inflammation-related retinal degeneration.

7.
Artigo em Inglês | MEDLINE | ID: mdl-36651967

RESUMO

BACKGROUND: Immune checkpoint inhibitors have transformed the treatment landscape of cancer treatment, but only a fraction of patients responds to treatment, leading to an increasing effort to repurpose clinically approved medications to augment ICI therapy. Metformin has been associated with improved survival outcomes in patients undergoing conventional chemotherapy. However, whether metformin provides survival benefits in patients receiving immune checkpoint inhibitors (ICIs) is unknown. METHODS: We performed a retrospective cohort study at two tertiary referral centers in Taiwan. All adult diabetes mellitus patients who were treated with ICIs between January 2015 and December 2021 were included. The primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS), respectively. RESULTS: In total, 878 patients were enrolled in our study, of which 86 patients used metformin and 78 patients used non-metformin diabetes medications. Compared with non-users, metformin users had a longer median OS (15.4 [IQR 5.6-not reached] vs. 6.1 [IQR, 0.8-21.0] months, P = 0.003) and PFS (5.1 [IQR 2.0-14.3] vs. 1.9 [IQR 0.7-8.6] months, P = 0.041). In a univariate Cox proportional hazard analysis, the use of metformin was associated with a reduction in the risk of mortality (HR: 0.53 [95% confidence interval: 0.35-0.81], P = 0.004) and disease progression (HR: 0.69 [95% CI 0.49-0.99], P = 0.042). The use of metformin remained associated with a lower risk of mortality after adjusting for baseline variables such as age, cancer stage, and underlying comorbidities (OS, HR: 0.55 [95% CI 0.34-0.87], P = 0.011). Similarly, the use of metformin was associated with a lower risk of disease progression. Importantly, the use of metformin before ICI initiation was not associated with a reduction in mortality (HR: 0.61 [95% CI 0.27-1.42], P = 0.25) or disease progression (HR: 0.69 [95% CI 0.33-1.43], P = 0.32). CONCLUSION: The use of metformin is associated with survival benefits in patients undergoing immunotherapy. Prospective clinical trials are warranted to define the role of metformin in augmenting immunotherapy.

8.
Lancet Glob Health ; 11(2): e218-e228, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36669806

RESUMO

BACKGROUND: Asthma is one of the most common non-communicable diseases globally. This study aimed to assess asthma medicine use, management plan availability, and disease control in childhood, adolescence, and adulthood across different country settings. METHODS: We used data from the Global Asthma Network Phase I cross-sectional epidemiological study (2015-20). A validated, written questionnaire was distributed via schools to three age groups (children, 6-7 years; adolescents, 13-14 years; and adults, ≥19 years). Eligible adults were the parents or guardians of children and adolescents included in the surveys. In individuals with asthma diagnosed by a doctor, we collated responses on past-year asthma medicines use (type of inhaled or oral medicine, and frequency of use). Questions on asthma symptoms and health visits were used to define past-year symptom severity and extent of asthma control. Income categories for countries based on gross national income per capita followed the 2020 World Bank classification. Proportions (and 95% CI clustered by centre) were used to describe results. Generalised structural equation multilevel models were used to assess factors associated with receiving medicines and having poorly controlled asthma in each age group. FINDINGS: Overall, 453 473 individuals from 63 centres in 25 countries were included, comprising 101 777 children (6445 [6·3%] with asthma diagnosed by a doctor), 157 784 adolescents (12 532 [7·9%]), and 193 912 adults (6677 [3·4%]). Use of asthma medicines varied by symptom severity and country income category. The most used medicines in the previous year were inhaled short-acting ß2 agonists (SABA; range across age groups, 29·3-85·3% participants) and inhaled corticosteroids (12·6-51·9%). The proportion of individuals with severe asthma symptoms not taking inhaled corticosteroids (inhaled corticosteroids alone or with long-acting ß2 agonists) was high in all age groups (934 [44·8%] of 2085 children, 2011 [60·1%] of 3345 adolescents, and 1142 [55·5%] of 2058 adults), and was significantly higher in middle-to-low-income countries. Oral SABA and theophylline were used across age groups and country income categories, contrary to current guidelines. Asthma management plans were used by 4049 (62·8%) children, 6694 (53·4%) adolescents, and 3168 (47·4%) adults; and 2840 (44·1%) children, 6942 (55·4%) adolescents, and 4081 (61·1%) adults had well controlled asthma. Independently of country income and asthma severity, having an asthma management plan was significantly associated with the use of any type of inhaled medicine (adjusted odds ratio [OR] 2·75 [95% CI 2·40-3·15] for children; 2·45 [2·25-2·67] for adolescents; and 2·75 [2·38-3·16] for adults) or any type of oral medicine (1·86 [1·63-2·12] for children; 1·53 [1·40-1·68] for adolescents; and 1·78 [1·55-2·04] for adults). Poor asthma control was associated with low country income (lower-middle-income and low-income countries vs high-income countries, adjusted OR 2·33 [95% CI 1·32-4·14] for children; 3·46 [1·83-6·54] for adolescents; and 4·86 [2·55-9·26] for adults). INTERPRETATION: Asthma management and control is frequently inadequate, particularly in low-resource settings. Strategies should be implemented to improve adherence to asthma treatment guidelines worldwide, with emphasis on access to affordable and quality-assured essential asthma medicines especially in low-income and middle-income countries. FUNDING: International Union Against Tuberculosis and Lung Disease, Boehringer Ingelheim New Zealand, AstraZeneca, UK National Institute for Health Research, UK Medical Research Council, European Research Council, the Spanish Instituto de Salud Carlos III. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.


Assuntos
Asma , Adulto , Criança , Humanos , Adolescente , Estudos Transversais , Administração por Inalação , Asma/tratamento farmacológico , Asma/epidemiologia , Corticosteroides/uso terapêutico , Quimioterapia Combinada
9.
J Affect Disord ; 324: 334-340, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36608848

RESUMO

The differential structural covariance of nucleus accumbens (NAcc), playing a vital role in etiology and treatment, remains unclear in depression. We aimed to investigate whether structural covariance of NAcc was altered and how it was modulated by illness duration and severity of symptom measured with Hamilton Depression scale (HAMD). T1-weighted anatomical images of never-treated first-episode patients with depression (n = 195) and matched healthy controls (HCs, n = 78) were acquired. Gray matter volumes were calculated using voxel-based morphometry analysis for each subject. Then, we explored abnormal structural covariance of NAcc and how the abnormality was modulated by illness duration and severity of symptom. Patients with depression exhibited altered structural covariance of NAcc connected to key brain regions in reward system including the medial orbitofrontal cortex, amygdala, insula, parahippocampa gyrus, precuneus, thalamus, hippocampus and cerebellum. In addition, the structural covariance of the NAcc was distinctly modulated by illness duration and the severity of symptom in patients with depression. What is more, the structural covariance of the NAcc connected to hippocampus was modulated by these two factors at the same time. These results elucidate altered structural covariance of the NAcc and its distinct modulation of illness duration and severity of symptom.


Assuntos
Depressão , Núcleo Accumbens , Humanos , Núcleo Accumbens/diagnóstico por imagem , Depressão/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Encéfalo , Substância Cinzenta/diagnóstico por imagem
10.
J Med Virol ; 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609855

RESUMO

The H10 subtypes of avian influenza viruses pose a continual threat to the poultry industry and human health. The sporadic spillover of H10 subtypes viruses from poultry to humans is represented by the H10N8 human cases in 2013 and the recent H10N3 human infection in 2021. However, the genesis and characteristics of the recent reassortment H10N3 viruses have not been systemically investigated. In this study, we characterized twenty H10N3 viruses isolated in live poultry markets during routine nationwide surveillance in China from 2014 to 2021. The viruses in the recent reassortant genotype acquired their hemagglutinin (HA) and neuraminidase (NA) genes from the duck H10 viruses and H7N3 viruses, respectively, whereas the internal genes were derived from chicken H9N2 viruses as early as 2019. Receptor-binding analysis indicated that two of the tested H10N3 viruses had a higher affinity for human-type receptors than for avian-type receptors, highlighting the potential risk of avian-to-human transmission. Animal studies showed that only viruses belonging to the recent reassortant genotype were pathogenic in mice; two tested viruses transmitted via direct contact and one virus transmitted by respiratory droplets in guinea pigs, though with limited efficiency. These findings emphasize the need for enhanced surveillance of H10N3 viruses. This article is protected by copyright. All rights reserved.

11.
Arch Virol ; 168(2): 54, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609927

RESUMO

Mangrove is among the most carbon-rich biomes on earth, and viruses are believed to play a significant role in modulating local and global carbon cycling. However, few viruses have been isolated from mangrove sediments to date. Here, we report the isolation of a novel Bacillus phage (named phage vB_BviS-A10Y) from mangrove sediments. Phage vB_BviS-A10Y has a hexameric head with a diameter of ~ 79.22 nm and a tail with a length of ~ 548.56 nm, which are typical features of siphophages. vB_BviS-A10Y initiated host lysis at 3.5 h postinfection with a burst size of 25 plaque-forming units (PFU)/cell. The genome of phage vB_BviS-A10Y is 162,435 bp long with 225 predicted genes, and the GC content is 34.03%. A comparison of the whole genome sequence of phage vB_BviS-A10Y with those of other phages from the NCBI viral genome database showed that phage vB_BviS-A10Y has the highest similarity (73.7% identity with 33% coverage) to Bacillus phage PBC2. Interestingly, abundant auxiliary metabolic genes (AMGs) were identified in the vB_BviS-A10Y genome. The presence of a ß-1,3-glucosyltransferase gene in the phage genome supported our previous hypothesis that mangrove viruses may manipulate carbon cycling directly through their encoded carbohydrate-active enzyme (CAZyme) genes. Therefore, our study will contribute to a better understanding of the diversity and potential roles of viruses in mangrove ecosystems.


Assuntos
Fagos Bacilares , Bacteriófagos , Vírus , Bacteriófagos/genética , Ecossistema , Genoma Viral/genética , Vírus/genética , Fagos Bacilares/genética , Genômica , Filogenia
12.
Cells ; 12(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36611972

RESUMO

Oral squamous cell carcinoma (OSCC) frequently carries high epidermal growth factor receptor (EGFR) expression. Erlotinib, a small molecule tyrosine kinase inhibitor (TKI), is an effective inhibitor of EGFR activity; however, resistance to this drug can occur, limiting therapeutic outcomes. Therefore, in the current study, we aimed to unveil key intracellular molecules and adjuvant reagents to overcome erlotinib resistance. First, two HSC-3-derived erlotinib-resistant cell lines, ERL-R5 and ERL-R10, were established; both exhibited relatively higher growth rates, glucose utilization, epithelial-mesenchymal transition (EMT), and invasiveness compared with parental cells. Cancer aggressiveness-related proteins, such as N-cadherin, Vimentin, Twist, MMP-2, MMP-9, and MMP-13, and the glycolytic enzymes PKM2 and GLUT1 were upregulated in ERL-R cells. Notably, ERL-R cells were sensitive to quercetin, a naturally-existing flavonol phytochemical with anti-cancer properties against various cancer cells. At a concentration of 5 µM, quercetin effectively arrested cell growth, reduced glucose utilization, and inhibited cellular invasiveness. An ERL-R5-derived xenograft mouse model confirmed the growth-inhibitory efficacy of quercetin. Additionally, knock-down of PKM2 by siRNA mimicked the effect of quercetin and re-sensitized ERL-R cells to erlotinib. Furthermore, adding quercetin blocked the development of erlotinib-mediated resistance by enhancing apoptosis. In conclusion, our data support the application of quercetin in anti-erlotinib-resistant OSCC and indicate that PKM2 is a determinant factor in erlotinib resistance and quercetin sensitivity.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Neoplasias Bucais , Humanos , Animais , Camundongos , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Quercetina/farmacologia , Quercetina/uso terapêutico , Piruvato Quinase , Neoplasias Pulmonares/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral , Neoplasias Bucais/tratamento farmacológico , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Glucose
13.
Artigo em Inglês | MEDLINE | ID: mdl-36639348

RESUMO

Prostate cancer (PCa) is one of the most common malignancies in men; recently, PCa-related mortality has increased worldwide. Although androgen deprivation therapy (ADT) is the standard treatment for PCa, patients often develop aggressive castration-resistant PCa (CRPC), indicating the presence of an alternative source of androgen. Clostridium scindens is a member of the gut microbiota and can convert cortisol to 11ß-hydroxyandrostenedione (11ß-OHA), which is a potent androgen precursor. However, the effect of C. scindens on PCa progression has not been determined. In this study, androgen-dependent PCa cells (LNCaP) were employed to investigate whether C. scindens-derived metabolites activate androgen receptor (AR), which is a pivotal step in the development of PCa. Results showed that cortisol metabolites derived from C. scindens-conditioned medium promoted proliferation and enhanced migration of PCa cells. Furthermore, cells treated with these metabolites presented activated AR and stimulated AR-regulated genes. These findings reveal that C. scindens has the potential to promote PCa progression via the activation of AR signaling. Further studies on the gut-prostate axis may help unravel an alternative source of androgen that triggers CRPC exacerbation.

14.
Biomed Pharmacother ; 159: 114252, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36641921

RESUMO

Diabetic nephropathy (DN) is one of the most severe complications of diabetes. However, due to its complex pathological mechanisms, no effective therapeutic methods (other than ACEIs and ARBs) have been applied, which have been used for many years in clinical practice. Recent studies have shown that emerging therapeutics, including novel target-based pharmacotherapy, cell therapies, and dietary regulation, are leading to new hopes for DN management. This review aims to shed new light on the treatment of DN by describing the important pathological mechanisms of DN and by analysing recent advances in clinical treatment, including drug therapy, cell therapy, and dietary regulation. In pathological mechanisms, RAAS activation, AGE accumulation, and EMT are involved in inflammation, cellular stress, apoptosis, pyroptosis, and autophagy. In pharmacotherapy, several new therapeutics, including SGLT2 inhibitors, GLP-1 agonists, and MRAs, are receiving public attention. In addition, stem cell therapies and dietary regulation are also being emphasized. Herein, we highlight the importance of combining therapy and dietary regulation in the treatment of DN and anticipate more basic research or clinical trials to verify novel strategies.

15.
Soft Matter ; 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36645088

RESUMO

Concentrated suspensions of particles at volume fractions (ϕ) ≥ 0.5 often exhibit complex rheological behavior, transitioning from shear thinning to shear thickening as the shear stress or shear rate is increased. These suspensions can be extruded to form 3D structures, with non-adsorbing polymers often added as rheology modifiers to improve printability. Understanding how non-adsorbing polymers affect the suspension rheology, particularly the onset of shear thickening, is critical to the design of particle inks that will extrude uniformly. In this work, we examine the rheology of concentrated aqueous suspensions of colloidal alumina particles and the effects of adding non-adsorbing polyvinylpyrrolidone (PVP). First, we show that suspensions with ϕalumina = 0.560-0.575 exhibited discontinuous shear thickening (DST), where the viscosity increased by up to two orders of magnitude above an onset stress (τmin). Increasing ϕalumina from 0.550 to 0.575 increased the viscosity and yield stress in the shear thinning regime and decreased τmin. Next, PVP was added at concentrations within the dilute and semi-dilute non-entangled regimes of polymer conformation (ϕPVP = 0.005-0.050) to suspensions with constant ϕalumina = 0.550. DST was observed in all cases and increasing ϕPVP increased the viscosity and yield stress. Interestingly, increasing ϕPVP also increased τmin. We posit that the free PVP chains act as lubricants between alumina particles, increasing the stress needed to induce thickening. Finally, we demonstrate through direct comparisons of suspensions with and without PVP how non-adsorbing polymer addition can extend the extrusion processing window due to the increase in τmin.

16.
Biopharm Drug Dispos ; 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36630933

RESUMO

Predicting the brain penetration of drugs has been notoriously difficult however recently, permeability-limited brain models have been constructed. Lead optimization for CNS compounds often focuses on compounds that have low transporter efflux, where passive permeability could be a main driver in determining CSF/brain concentrations. The main objective of this study was to evaluate the translatability of passive permeability data generated from different in vitro systems and its impact on the prediction of human CSF/brain concentrations using PBPK modeling. In vitro data were generated using gMDCK and PAMPA-BBB for comparison and predictions using a QSAR model were also evaluated. PBPK modeling was then performed for seven compounds with moderate-high permeability and a range of efflux in vitro, and the CSF/brain mass concentrations and Kpuu were reasonably predicted. This work provides the first step of a promising approach using bottom-up PBPK modeling for CSF/brain penetration prediction to support lead optimization and clinical candidate selection. This article is protected by copyright. All rights reserved.

17.
PeerJ ; 11: e14706, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36710872

RESUMO

Background: Identifying the cell types using unsupervised methods is essential for scRNA-seq research. However, conventional similarity measures introduce challenges to single-cell data clustering because of the high dimensional, high noise, and high dropout. Methods: We proposed a clustering method for small ScRNA-seq data based on Subspace and Weighted Distance (SSWD), which follows the assumption that the sets of gene subspace composed of similar density-distributing genes can better distinguish cell groups. To accurately capture the intrinsic relationship among cells or genes, a new distance metric that combines Euclidean and Pearson distance through a weighting strategy was proposed. The relative Calinski-Harabasz (CH) index was used to estimate the cluster numbers instead of the CH index because it is comparable across degrees of freedom. Results: We compared SSWD with seven prevailing methods on eight publicly scRNA-seq datasets. The experimental results show that the SSWD has better clustering accuracy and the partitioning ability of cell groups. SSWD can be downloaded at https://github.com/ningzilan/SSWD.

18.
CNS Neurosci Ther ; 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36708133

RESUMO

AIMS: N-methyl-D-aspartic acid (NMDA) receptors play subunit-specific role in central neuronal development. However, insights into the pharmacological modulation of NMDA receptors were mainly lack of subunit and synaptic selectivity. The purpose of the present study was to develop a novel strategy to rapidly recognize NMDA subunit 2A (NMDA-2A) ligands from natural products and provide subunit-selective drug candidates for Alzheimer's disease (AD). METHODS: The recombinant NMDA-2A containing a tag of epidermal growth factor receptor (EGFR) was expressed in Escherichia coli cells and immobilized on ibrutinib-modified microspheres based on the specific reaction between EGFR and its inhibitor ibrutinib. A novel affinity stationary phase was synthesized to screen NMDA-2A ligands from Gardenia jasminoides Ellis. RESULTS: The immobilized receptor column exhibited excellent receptor selectivity and ligand-binding activity. Crocetin was screened by using this method. In a cellular model of AD, the protein level of NMDA-2A was significantly decreased compared with the control group, while treatment with crocetin significantly increased NMDA-2A level in a concentration-dependent manner, confirming that crocetin could bind to NMDA-2A in vitro. CONCLUSION: In the present study, we developed a reliable method for the rapid identification of NMDA-2A ligands from natural products, which may be used as a platform for new drug discovery to generate high-quality drug candidates.

19.
World J Gastrointest Oncol ; 15(1): 195-204, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36684049

RESUMO

BACKGROUND: Intestinal natural killer/T-cell lymphoma (NKTCL) is a rare and aggressive non-Hodgkin's lymphoma, and its occurrence is closely related to Epstein-Barr virus infection. In addition, the clinical symptoms of NKTCL are not obvious, and the specific pathogenesis is still uncertain. While NKTCL may occur in any segment of the intestinal tract, its distinct location in the periampullary region, which leads clinicians to consider mimics of a pancreatic head mass, should also be addressed. Therefore, there remain huge challenges in the diagnosis and treatment of intestinal NKTCL. CASE SUMMARY: In this case, we introduce a male who presented to the clinic with edema of both lower limbs, accompanied by diarrhea, and abdominal pain. Endoscopic ultrasound (EUS) showed well-defined homogeneous hypoechoic lesions with abundant blood flow signals and compression signs in the head of the pancreas. Under the guidance of EUS- fine needle biopsy (FNB) with 19 gauge or 22 gauge needles, combined with multicolor flow cytometry immunophenotyping (MFCI) helped us diagnose NKTCL. During treatments, the patient was prescribed the steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide chemotherapy regimen. Unfortunately, he died of leukopenia and severe septic shock in a local hospital. CONCLUSION: Clinicians should enhance their understanding of NKTCL. Some key factors, including EUS characteristics, the right choice of FNB needle, and combination with MFCI, are crucial for improving the diagnostic rate and reducing the misdiagnosis rate.

20.
ISA Trans ; 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36697344

RESUMO

This paper addresses the redundancy resolution problem for underwater vehicle-manipulator systems (UVMSs). More specifically, a new redundancy resolution approach with motion coordination and dexterous manipulation is presented to guarantee the tracking accuracy of the end-effector while avoiding singular configurations of the manipulator. The task-priority redundancy resolution framework is adopted to achieve an effective coordinated motion of the vehicle and manipulator while exploiting the redundant degrees of freedom available. A dexterous manipulation task with low priority is proposed to reconfigure the UVMS into a more dexterous configuration by keeping the end-effector within the designed heuristic subset. An inequality-based singularity avoidance task is inserted into the redundancy resolution framework as a high-priority task to keep the measure of manipulability above a specified minimum value. Experimental results verify that the proposed approach significantly improves the dexterity and coordination of the UVMS.

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