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1.
J Hazard Mater ; 422: 126942, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34449343

RESUMO

The abuse of antibiotics on animals could induce the development of antibiotic resistant genes (ARGs) and antibiotic resistant bacteria (ARB), and acesulfame potassium (ACE) is the widely used artificial sweetener in animal feed. Generally speaking, ACE and ARB often coexist in livestock wastewater, however, the impact of the co-occurrence of ACE and ARB on the transmission of ARGs is still unknown. In this study, the effects of ACE on vertical gene transfer (VGT) and horizontal gene transfer (HGT) were both evaluated. For VGT, ACE may hinder the spread of sul gene in Pseudomonas HLS-6 by blocking ARB growth. As for HGT (from Escherichia coli DH5α to Pseudomonas HLS-6), environmentally relevant ACE concentration could facilitate the conjugative transfer. The underlying mechanisms of HGT were characterized by enhanced cell membrane permeability, reactive oxygen species overproduction, SOS response, energy supply, which were all further verified by the changes in transcription levels of related genes. Interestingly, intracellular Mg2+ in donor strain was found for the first time as an indicator for the conjugation occurrence in ACE treated mating system. This study may provide new insights into the role of ACE on ARGs proliferation and highlight its potential environmental impacts.

2.
Appl Ergon ; 99: 103638, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34768226

RESUMO

Advanced driver assistance systems (ADAS) can enhance road safety by sending warning signals to drivers. Multimodal signals are gaining attention in ADAS warning design because they offer redundant information that facilitates human-system communication. However, no consensus has been reached on which multimodal design offers optimal benefit to road safety. Icons iconically map the real world and are associated with fast recognition and response time. Therefore, this study aims to investigate whether visual and auditory icons will benefit the effectiveness of audiovisual multimodal warnings. Thirty-two participants (16 females) experienced four types of unimodal warnings (high and low mapping visual warnings and high and low mapping auditory warnings) and four types of audiovisual warnings (high mapping visual + high mapping auditory warning, low mapping visual + low mapping auditory warning, high mapping visual + low mapping auditory warning, and low mapping visual + high mapping auditory warning) in simulated driving conditions. Visual warnings are presented in a head-up display. Results showed that multimodal warnings outperformed unimodal warnings (i.e., modality effect). We found mapping effect in audiovisual warnings, but only high mapping auditory constituents benefited warning effectiveness. Eye movement results revealed that the high mapping constituents might distract drivers from the road. This study adds evidence that multimodal warnings can offer extra benefits to drivers and high mapping auditory signals should be included in multimodal warning design to achieve better driving performance.


Assuntos
Acidentes de Trânsito , Condução de Veículo , Atenção , Simulação por Computador , Movimentos Oculares , Feminino , Humanos , Tempo de Reação
3.
J Hazard Mater ; 423(Pt A): 126866, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34482079

RESUMO

Antibiotic resistant bacteria (ARB) and the antibiotic resistance genes (ARGs) dissemination via plasmid-mediated conjugation have attracted considerable attentions. In this research, sulfidated nanoscale zerovalent iron (S-nZVI)/peroxymonosulfate (PMS) and S-nZVI/peroxydisulfate (PDS) process were investigated to inactivate ARB (Escherichia coli DH5α with RP4 plasmid, Pseudomonas. HLS-6 contains sul1 and intI1 on genome DNA sequence). S-nZVI/PMS system showed higher efficiency than S-nZVI/PDS on ARB inactivation. Thus, the optimal condition 28 mg/L S-nZVI coupled with 153.7 mg/L (0.5 mM) PMS was applied to remove both intracellular ARGs (iARGs) and ARB. The oxidative damage of ARB cell was systemically studied by cell viability, intracellular Mg2+ levels, the changes of extracellular and internal structure, integrity of cell walls and membranes and enzymatic activities. S-nZVI/PMS effectively inactivated ARB (~7.32 log) within 15 min. These effects were greatly higher than those achieved individually. Moreover, removal efficiencies of iARGs sul1, intI1 and tetA were 1.52, 1.79 and 1.56 log, respectively. These results revealed that S-nZVI and PMS have a synergistic effect against ARB and iARGs. The regrowth assays illustrated that the ARB were effectively inactivated. By verifying the inhibitory impacts of S-nZVI/PMS treatment on conjugation transfer, this work highlights a promising alternative technique for inhibiting the horizontal gene transfer.

4.
Sci Total Environ ; : 151599, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34774958

RESUMO

The intergeneric conjugative transfer of antibiotic resistance genes (ARGs) is recognized as an important way to the dissemination of antibiotic resistance. However, it is unknown whether the extensive use of chloroxylenol (para-chloro-meta-xylenol, PCMX) in many pharmaceutical personal care products will lead to the spread of ARGs. In this study, the abilities and mechanisms of PCMX to accelerate the intergeneric conjugative transfer were investigated. Results showed that exposure of bacteria to environmental concentrations of PCMX (0.20-1.00 mg/L) can significantly stimulate the increase of conjugative transfer by 8.45-9.51 fold. The phenotypic experiments and genome-wide RNA sequencing revealed that 0.02-5.00 mg/L PCMX exposure could increase the content of alkaline phosphatase and malondialdehyde, which are characteristic products of cell wall and membrane damage. In addition, PCMX could lead to excessive production of reactive oxygen species (ROS) by 1.26-2.00 times, the superoxide dismutase and catalase produced by bacteria in response to oxidative stress were not enough to neutralize the damage of ROS, thus promoting the conjugative transfer. Gene Ontology enrichment analysis indicated that cell membrane permeability, pili, some chemical compounds transport and energy metabolism affected conjugative transfer. This study deepened the understanding of PCMX in promoting propagation of ARGs, and provided new perspectives for use and treatment of personal care products.

5.
Transl Vis Sci Technol ; 10(13): 12, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34751742

RESUMO

Purpose: The purpose of this study was to analyze the choroidal sublayer morphologic features in emmetropic and myopic children using an automatic segmentation model, and to explore the relationship between choroidal sublayers and spherical equivalent refraction (SER). Methods: We collected data on 92 healthy children (92 eyes) from the Ophthalmology Department of Peking University First Hospital. The data were allocated to three groups: emmetropia (+0.50 diopters [D] to -0.50 D), low myopia (-0.75 D to -3.00 D), and moderate myopia (-3.25 D to -5.75 D). We performed standardized optical coherence tomography (OCT) and developed a new segmentation technique to measure choroidal thickness (CT), large-vessel choroidal layer (LVCL), medium-vessel choroidal layer (MVCL), and small-vessel choroidal layer thickness (SVCL), and evaluated the choroidal vascular system (choroidal vascular volume [VV], choroidal vascular index [CVI], and choroidal vascular density [CVD]). Results: All choroidal sublayers (LVCL, MVCL, and SVCL) were significantly thinner in myopic than in emmetropic eyes (P < 0.05), the thinnest choroidal region being the nasal outer subfield (P < 0.05). In all choroidal regions of SVCL, a positive correlation was found between SER and thickness ratio (P < 0.001). In most subfields of MVCL, a similar correlation was found (P < 0.050), the exceptions being the two nasal subfields (0.050 < P < 0.300). In contrast, the thickness ratio of LVCL decreased in all subfields (P < 0.050). VV correlated with SER negatively in LVCL in all subfields (all P < 0.001) and most subfields in MVCL except for two temporal subfields (0.050 < P < 0.200). However, no significant correlations were found between CVI and SER in LVCL (P > 0.050) and MVCL (with the exception being the temporal inner subfield, P = 0.011). Conclusions: Thickness of choroidal sublayers was reduced with higher myopic SER, whereas changes in thickness ratio varied between sublayers. No significant correlations between CVI and SER suggested that both choroidal stromal and vascular volume decreases proportionately. Translational Relevance: Automatic segmentation model will be helpful for future clinical trials to quantify choroidal sublayer morphologic features in myopia.

6.
Curr Pharm Teach Learn ; 13(11): 1393-1397, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34799050

RESUMO

INTRODUCTION: Team-based learning (TBL) is a small group active learning andragogy promoting the development of critical thinking, communication, and teamwork skills. Across higher education, the adoption of educational technology is often driven by many purported benefits, features, and conveniences, including learning from anywhere, easy access to materials and assessment, task automation, performance tracking, engagement monitoring, and higher fidelity for simulated experiences. Institutions may also choose to adopt technology to boost program reputation and visibility. However, unexpected effects following the adoption of new technology may interfere with active learning, trust, and cohesion between learner-learner or learner-instructor. PERSPECTIVE: In many cases, the potential long-term impact of technology on teaching and learning is overlooked. This commentary calls awareness to and discusses the potential impact of adopting technology on active teaching and learning processes in the context of TBL. IMPLICATIONS: A systematic process for programs to explore the influence of technology on the essential elements of teaching and learning, to support decision making, and to focus on quality educational processes is proposed. Programs should systematically consider influences on quality, access, independent work, peer interactions, and contextual approach when adopting technology.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34724039

RESUMO

Nesfatin-1 is a neuropeptide produced in the hypothalamus. It is known that Nesfatin-1 is involved in food uptake, fat storage, and other metabolic regulation. We hypothesized that Nesfatin-1 may play a role in cardiovascular tissue. Free fatty acids (FFAs) are known to be the risk factor for cardiovascular diseases. FFAs mediated endothelial dysfunction is the critical mechanism of many cardiovascular disorders. The present study explores the protective effects of Nesfatin-1 on FFAs-induced endothelial inflammation and the underlying mechanism. We found that significantly increased lactate dehydrogenase (LDH) release and production of inflammatory factors were observed in FFAs treated human aortic endothelial cells (HAECs), accompanied by the enhanced attachment of U937 monocytes to HAECs and upregulated cell adhesion molecule vascular cell adhesion molecule-1 (VCAM-1), which were dramatically reversed by the treatment with Nesfatin-1. In addition, the promoted level of nuclear regulator NF-κB p65 and transcriptional function of NF-κB in FFAs treated HAECs were greatly suppressed by HAECs. Growth Factor Independent 1 Transcriptional Repressor 1 (Gfi1), an important negative regulator of NF-κB activity, was significantly downregulated in HAECs by FFAs and was upregulated by Nesfatin-1. Lastly, the inhibitory effects of Nesfatin-1 against FFAs-induced NF-κB activation and adhesion of U937 monocytes to HAECs were abolished by the knockdown of Gfi1. In conclusion, our data reveal that Nesfatin-1 inhibited FFAs-induced endothelial inflammation mediated by the Gfi1/NF-κB signaling pathway.

8.
J Couns Psychol ; 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34647766

RESUMO

Psychotherapy has been shown to be effective on a broad level (e.g., Wampold & Imel, 2015); however, a growing body of literature has revealed that some therapists have outcome inequities within their caseloads. These inequities have been observed on the basis of social identities including race (see Imel et al., 2011, for example) and gender measured on the binary (Owen et al., 2009). However, despite the great need for further research on sexual minority populations in psychotherapy, this phenomenon has yet to be explored on the basis of sexual orientation (i.e., if a disparity exists within-therapist caseloads between queer-identified and heterosexual clients). The present study was comprised of a sample of 1,725 clients treated by 50 therapists at a university counseling center (17.7% of the sample endorsed a sexual minority status). Multilevel modeling was used to analyze data from the Behavioral Health Measure-20 (BHM-20; Kopta & Lowry, 2002). The results indicated that clients' sexual orientation status was not significantly associated with any of the BHM-20 subscales or with the Global Mental Health Scale (GMH). Of interest was that therapists varied in the extent to which their clients' symptoms and GMH improved and how that improvement varied by client sexual orientation status. Thus, attention must be paid not only to which therapists are more and less effective overall, but also to the specifics of which clients (and the social identities those clients hold) are improving while under their care. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

9.
Comput Struct Biotechnol J ; 19: 5455-5465, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603638

RESUMO

The key step for SARS-CoV-2 to infect human cells is the membrane fusion triggered by the binding of the viral extracellular Spike protein to the human extracellular receptor, the angiotensin-converting enzyme 2 (ACE2). Although the Cryo-electron microscopy (Cryo-EM) uncovered the static atomic details of ACE2 homodimers, there is still a lack of research on the kinetic and thermodynamic properties of these full-length structures. This information is helpful to understand and interpret the role of ACE2 in the cell entry of SARS-CoV-2. In order to obtain this information, we performed microsecond-scale conventional and accelerated molecular dynamics (MD) simulations of full-length all-atomic systems of the RBD-ACE2 complex, the normal and torsional conformations of the apo-ACE2 homodimer. The comparative analysis of these systems showed that there were differences in their allosteric signal pathways and motion trends. These results may be helpful to further explore the cell entry mechanism of SARS-CoV-2. Moreover, the binding free energy and hydrogen bond distribution analysis of RBD-ACE2 binding interface provided the binding motifs that may be critical to allosteric signal transmission and RBD binding. These multi-conformational binding motifs can be used as targets or templates for the inhibitor design of the cell entry of SARS-CoV-2.

10.
Oxid Med Cell Longev ; 2021: 7807046, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34707780

RESUMO

In this study, a chemical investigation on the fruits of Livistona chinensis (FLC) led to the isolation and identification of 45 polyphenols and 5 alkaloids, including two new compounds (Livischinol (1) and Livischinine A (46)), an undescribed compound (47) and 47 known compounds. FLC was predicted with novel potential antidiabetic function by collecting and analyzing the potential targets of the ingredients. Compound 32 exhibited significant α-glucosidase inhibitory activity (IC50 = 5.71 µM) and 1, 6, and 44 showed the PTP1B inhibitory activity with IC50 values of 9.41-22.19 µM, while that of oleanolic acid was 28.58 µM. The competitive inhibitors of PTP1B (compounds 1 and 44) formed strong binding affinity, with catalytic active sites, proved by kinetic analysis, fluorescence spectra measurements, and computational simulations, and stimulated glucose uptake in the insulin-resistant HepG2 cells at the dose of 50 µM. In addition, FLC was rich in antioxidant and anti-inflammatory bioactive compounds so that they could be developed as nutraceuticals against diabetes.

11.
Aging (Albany NY) ; 13(20): 23442-23458, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34714255

RESUMO

OBJECTIVE: Hyperamylasemia was found in a group of patients with COVID-19 during hospitalization. However, the evolution and the clinical significance of hyperamylasemia in COVID-19, is not well characterized. DESIGN: In this retrospective cohort study, the epidemiological, demographic, laboratory, treatment and outcome information of 1,515 COVID-19 patients with available longitudinal amylase records collected from electronic medical system were analyzed to assess the prevalence and clinical significance of hyperamylasemia in this infection. Associated variables with hyperamylasemia in COVID-19 were also analyzed. RESULTS: Of 1,515 patients, 196 (12.9%) developed hyperamylasemia, among whom 19 (1.3%) greater than 3 times upper limit of normal (ULN) and no clinical acute pancreatitis was seen. Multivariable ordered logistic regression implied older age, male, chronic kidney disease, several medications (immunoglobin, systemic corticosteroids, and antifungals), increased creatinine might be associated with hyperamylasemia during hospitalization. Restricted cubic spline analysis indicated hyperamylasemia had a J-shaped association with all-cause mortality and the estimated hazard ratio per standard deviation was 2.85 (2.03-4.00) above ULN. Based on the multivariable mixed-effect cox or logistic regression model taking hospital sites as random effects, elevated serum amylase during hospitalization was identified as an independent risk factor associated with in-hospital death and intensive complications, including sepsis, cardiac injury, acute respiratory distress syndrome, and acute kidney injury. CONCLUSIONS: Elevated serum amylase was independently associated with adverse clinical outcomes in COVID-19 patients. Since early intervention might change the outcome, serum amylase should be monitored dynamically during hospitalization.


Assuntos
Amilases/sangue , COVID-19/diagnóstico , Mortalidade Hospitalar , Hiperamilassemia/complicações , SARS-CoV-2/isolamento & purificação , Doença Aguda , Idoso , COVID-19/sangue , COVID-19/mortalidade , COVID-19/terapia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Hiperamilassemia/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2/genética
12.
Rev Sci Instrum ; 92(8): 084705, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470427

RESUMO

In order to meet the application needs of gyromagnetic nonlinear transmission lines, a pulsed power generator is required to output short duration pulses with a fast rising edge in high repetitive-rate mode. In this paper, a low-impedance high-power pulsed generator based on the forming line with a built-in Tesla transformer is explored and developed. The generator includes a 14 Ω coaxial forming line, a SF6/N2 gas switch, and a resistive dummy load, which can steadily operate in 100 Hz mode and suits the needs above. The pulsed forming line adopts transformer oil as the insulation medium and has a large shell radius and short length to reduce impedance. It has been verified by CST simulation that a relatively high coupling coefficient (0.93) can be achieved when the length-radius ratio is 3.2. The maximum forming line charging voltage is -600 kV in single-shot mode, while the charging voltage is -520 kV in repetitive-rate mode. The output pulse duration is 13 ns with a 4 ns rising edge, and its amplitude for a 10 Ω load is -220 kV at a repetition rate of 100 Hz. The experimental results showed the feasibility of the low-impedance nanosecond periodically pulsed generator based on an oil forming line charged from the high-coupling Tesla transformer. These efforts expand the technical route of the pulse forming line with a built-in Tesla transformer and set a good foundation for its application in the future.

13.
Int J Ophthalmol ; 14(9): 1334-1344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34540608

RESUMO

AIM: To illustrate the underlying mechanism how prominin-1 (also known as Prom1) mutation contribute to progressive photoreceptor degeneration. METHODS: A CRISPR-mediated Prom1 knockout (Prom1-KO) mice model in the C57BL/6 was generated and the photoreceptor degeneration phenotypes by means of structural and functional tests were demonstrated. Immunohistochemistry and immunoblot analysis were performed to reveal the localization and quantity of related outer segment (OS) proteins. RESULTS: The Prom1-KO mice developed the photoreceptor degeneration phenotype including the decreased outer nuclear layer (ONL) thickness and compromised electroretinogram amplitude. Immunohistochemistry analysis revealed impaired trafficking of photoreceptor OS proteins. Immunoblot data demonstrated decreased photoreceptor OS proteins. CONCLUSION: Prom1 deprivation causes progressive photoreceptor degeneration. Prom1 is essential for maintaining normal trafficking and normal quantity of photoreceptor OS proteins. The new light is shed on the pathogenic mechanism underlying photoreceptor degeneration caused by Prom1 mutation.

14.
ACS Appl Mater Interfaces ; 13(38): 45201-45213, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34525803

RESUMO

Overproduction of reactive oxygen species (ROS) within tumors can cause oxidative stress on tumor cells to induce death, which has motivated us to develop ROS-mediated tumor therapies, such as typical photodynamic therapy (PDT) and Fenton reaction-mediated chemodynamic therapy (CDT). However, these therapeutic modalities suffer from compromised treatment efficacy owing to their limited generation of highly reactive ROS in a tumor microenvironment (TME). In this work, a nanoscale iron-based metal-organic framework, MIL-101(Fe), is synthesized as a Fenton nanocatalyst to perform the catalytic conversion of hydroxyl radicals (·OH) from hydrogen peroxide (H2O2) under the acidic environment and as a biocompatible and biodegradable nanocarrier to deliver a 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) photosensitizer for light-activated singlet oxygen (1O2) generation. By coupling such chemodynamic/photodynamic effects, the photosensitizer-integrated nanoagents (MIL-101(Fe)@TCPP) could enable more ROS production within tumors to induce amplified oxidative damage for tumor-specific synergistic therapy. In vitro results show that MIL-101(Fe)@TCPP nanoagents achieve the acid-responsive CDT and effective PDT, and synergistic CDT/PDT provides an enhanced therapeutic effect. Ultimately, based on such synergistic therapy, MIL-101(Fe)@TCPP nanoagents cause a significant tumor growth inhibition in vivo without severe side effects, showing great potential for anti-tumor application.

15.
J Agric Food Chem ; 69(37): 10920-10931, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34491753

RESUMO

Thrombin is a crucial regulatory serine protease in hemostasis and thrombosis and has been a therapeutic target of thrombotic events. A novel oyster-derived thrombin inhibitory dodecapeptide (IEELEELEAER, P-2-CG) was identified and characterized. P-2-CG prolonged thrombin time from 9.6 s to 23.3 s at 5 mg/mL in vitro. P-2-CG bound to thrombin Exosite-I domain spontaneously. The occupied Exosite-I blocked fibrinogen binding, which prolonged fibrinogen clotting time to 28 s from 18.5 s. Molecule dynamics demonstrated the interaction of P-2-CG and thrombin Exosite-I involved in eight hydrogen bonds and lots of electrostatic forces. The residue Tyr76 at thrombin Exosite-I is one critical amino acid for fibrinogen binding. The Glu11 in P-2-CG was bound with Tyr76 through strong hydrogen bonds and hydrophobic action. P-2-CG also significantly reduced the mortality of mice that suffered an acute pulmonary embolism induced by thrombin and inhibited mice tail thrombosis induced by κ-carrageenan. The thrombin inhibitory efficiency in vitro and antithrombosis in vivo of P-2-CG provided insight for further applications to serve as an antithrombotic agent.


Assuntos
Trombina , Trombose , Animais , Anticoagulantes , Sítios de Ligação , Fibrinogênio , Camundongos , Ligação Proteica , Trombose/tratamento farmacológico , Trombose/prevenção & controle
16.
Mikrochim Acta ; 188(8): 285, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34347172

RESUMO

Early diagnosis of hepatitis C virus (HCV) infection is essential to prevent disease from spreading and progression. Herein, a novel electrochemical biosensor was developed for ultrasensitive detection of HCV core antigen (HCVcAg) based on terminal deoxynucleotidyl transferase (TdT) amplification and DNA nanowires (DNW). After sandwich-type antibody-antigen recognition, the antibody-conjugated DNA was pulled to the electrode surface and further extended into a long DNA sequence by robust TdT reaction. Then, large numbers of methylene blue-loaded DNW (MB@DNW) as signal labels are linked to the extended DNA sequence. This results in an amplified electrochemical signal for HCVcAg determination, typically measured at around -0.25 V (Ag/AgCl). Under the optimum conditions, the proposed biosensor achieved a wide linear range for HCVcAg from 0.1 to 312.5 pg/mL with a low limit of detection of 32 fg/mL. The good practicality of the biosensor was demonstrated by recovery experiment (recoveries from 98 to 104% with RSD of 2.5-4.4%) and comparison with enzyme-linked immunosorbent assay (ELISA). Given the highlighted performance, the biosensor is expected to act as a reliable sensing tool for HCVcAg determination in clinics. Schematic representation of the ultrasensitive electrochemical biosensor based on terminal deoxynucleotidyl transferase (TdT) amplification linked with methylene blue-loaded DNA nanowires (MB@DNW), which can be applied to the determination of hepatitis C virus core antigen (HCVcAg) in clinical samples. dTTPs, 2'-deoxythymidine 5'-triphosphate.

17.
Mol Psychiatry ; 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385597

RESUMO

Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks.

18.
J Gerontol Soc Work ; : 1-15, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34379578

RESUMO

This study examines the experience of grandparents providing regular childcare to their young grandchildren in China. Due to unique cultural and social factors, regular childcare provided by grandparents is becoming increasingly common in China. Unfortunately, published research on this topic does not provide a sufficient understanding of the experiences of grandparents who provide the regular care and the impact this has on their life. A qualitative, cross-sectional study was conducted in an urban village setting in Changsha China, where participants (N = 11) were recruited using purposive sampling. Data were collected between April 2019 and June 2019 and thematically analyzed using a seven-step modified procedure established by Colaizzi. Three key themes were identified: (1) Dominant factors motivating grandparenting; (2) Sweet burden of grandparenting; and, (3) Unmet needs. Study findings showed that while the Chinese grandparents perceived value and benefits to providing regular childcare, there are also significant challenges that need to be addressed. Interventions at a household and community level can be implemented to improve their childcare role.

19.
Mol Pharm ; 18(9): 3638-3648, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34424706

RESUMO

Targeting metastatic esophageal squamous cell carcinoma (ESCC) has been a challenge in clinical practice. Emerging evidence demonstrates that C-X-C chemokine receptor 4 (CXCR4) highly expresses in ESCC and plays a pivotal role in the process of tumor metastasis. We developed a copper-64 (t1/2 = 12.7 h, 19% beta+) labeling route of NOTA-CP01 derived from LY2510924, a cyclopeptide-based CXCR4 potent antagonist, in an attempt to noninvasively visualize CXCR4 expression in metastatic ESCC. Precursor NOTA-CP01 was designed by modifying the C-terminus of LY2510925 with bis-t-butyl NOTA via a butane-1,4-diamine linker. The radiolabeling process was finished within 15 min with high radiochemical yield (>95%), radiochemical purity (>99%), and specific activity (10.5-21 GBq/µmol) (non-decay-corrected). The in vitro solubility and stability tests revealed that [64Cu]NOTA-CP01 had a high water solubility (log P = -3.44 ± 0.12, n = 5) and high stability in saline and fetal bovine serum. [64Cu]NOTA-CP01 exhibited CXCR4-specific binding with a nanomolar affinity (IC50 = 1.61 ± 0.96 nM, Kd = 0.272 ± 0.14 nM) similar to that of the parental LY2510924. The in vitro cell uptake assay indicated that the [64Cu]NOTA-CP01-selective accumulation in EC109 cells was CXCR4-specific. Molecular docking of the CXCR4/NOTA-CP01 complex suggested that the Lys, Arg, and NOTA of this ligand have a strong polar interaction with the key residues of CXCR4, which explains the tight affinity of [64Cu]NOTA-CP01 for CXCR4. To test the target engagement in vivo, prolonged-time positron emission computed tomography (PET) imaging was performed at 0.5, 4, 6, 8, 12, 16, and 24 h postinjection of [64Cu]NOTA-CP01 to the EC109 tumor-bearing mice. The EC109 tumors were most visible with high contrast to the contralateral background at 6 h postinjection. The tracer revealed receptor-specific tumor accumulation, which was illustrated by effective blocking via coinjection with a blocking dose of LY2510924. Quantification analysis of the prolonged-time images showed that there was obvious radioactivity accumulation in the tumor (1.27 ± 0.19%ID/g) with the best tumor-to-blood ratio (4.79 ± 0.06) and tumor-to-muscle ratio (15.44 ± 2.94) at 6 h postinjection of the probe. The immunofluorescence and immunohistochemistry confirmed the positive expression of CXCR4 in the EC109 tumor and ESCC and metastatic lymph nodes of patients, respectively. We concluded that [64Cu]NOTA-CP01 possessed a very high target engagement for CXCR4-positive ESCC and could be a potential candidate in the clinical detection of metastatic ESCC.

20.
Eur J Pharmacol ; 909: 174405, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34384755

RESUMO

Cornus Officinalis (Cornus), the dried pulp of mature Cornus, is used to treat liver diseases. However, the pharmacological mechanism of Cornus in the treatment of hepatocellular carcinoma (HCC) has not been systematically studied. The chemical compounds and the bioactive chemical compounds of Cornus were screened through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Gene Cards database was used to explore the targets in liver cancer pathogenesis. The disease-drug Venn diagram was constructed using the VENN 2.1 and the STRING database was used to analyze protein-protein Interaction Network (PPI). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed using the R package. Molecular docking was performed using Discovery Studio were assessed using Pymol and Discovery Studio 2016. Cell survival of BEL-7404 cells treated by Hydroxygenkwanin (HGK) were valued through CCK-8 assay. Expressions of caspase-3 and cleaved PARP was detected through Western blot. Pharmacological network diagrams of the Cornus compound-target network and HCC-related target network were successfully constructed. A total of 20 active compounds, 1841 predicted biological targets of Cornus, and 7100 HCC-related targets were identified. 37 target genes between Cornus and HCC were screened trough the network pharmacology. Molecular docking studies suggested that HGK has the highest affinity with caspase-3. HGK could induce apoptosis of HCC cells and significantly activate the caspase-3 protease activity in BEL-7404. This study systematically elaborated the mechanism of Cornus in the treatment of HCC and provided a new perspective to exploit Antineoplastic from Cornus.

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