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1.
Neural Regen Res ; 17(3): 601-607, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34380900

RESUMO

Epidural stimulation of the spinal cord is a promising technique for the recovery of motor function after spinal cord injury. The key challenges within the reconstruction of motor function for paralyzed limbs are the precise control of sites and parameters of stimulation. To activate lower-limb muscles precisely by epidural spinal cord stimulation, we proposed a high-density, flexible electrode array. We determined the regions of motor function that were activated upon epidural stimulation of the spinal cord in a rat model with complete spinal cord, which was established by a transection method. For evaluating the effect of stimulation, the evoked potentials were recorded from bilateral lower-limb muscles, including the vastus lateralis, semitendinosus, tibialis anterior, and medial gastrocnemius. To determine the appropriate stimulation sites and parameters of the lower muscles, the stimulation characteristics were studied within the regions in which motor function was activated upon spinal cord stimulation. In the vastus lateralis and medial gastrocnemius, these regions were symmetrically located at the lateral site of L1 and the medial site of L2 vertebrae segment, respectively. The tibialis anterior and semitendinosus only responded to stimulation simultaneously with other muscles. The minimum and maximum stimulation threshold currents of the vastus lateralis were higher than those of the medial gastrocnemius. Our results demonstrate the ability to identify specific stimulation sites of lower muscles using a high-density and flexible array. They also provide a reference for selecting the appropriate conditions for implantable stimulation for animal models of spinal cord injury. This study was approved by the Animal Research Committee of Southeast University, China (approval No. 20190720001) on July 20, 2019.

2.
Mol Biol Rep ; 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725747

RESUMO

BACKGROUND: Oncomelania hupensis hupensis is the only intermediate host of Schistosoma japonicum, the causative agent of schistosomiasis in China and is therefore of significant medical and veterinary health importance. Although tremendous progress has been achieved, there remains an understudied area of approximately 2.06 billion m2 of potential snail habitats. This area could be further increased by annual flooding. Therefore, an understanding of population genetics of snails in these areas may be useful for future monitoring and control activities. METHODS AND RESULTS: We sampled snails from Hexian (HX), Zongyang (ZY) and Shitai (ST) in Anhui (schistosomiasis transmission control), and from Hengtang (HT), Taicang (TC), Dongsan (DS) and Xisan (XS) in Jiangsu (schistosomiasis transmission interrupted), downstream of Anhui. ST, DS and XS are classified as hilly and mountainous areas, and HX, ZY, TC and HT as lake and marshland areas. The mitochondrial cytochrome c oxidase subunit I gene were sequenced. Out of 115 snails analyzed, 29 haplotypes were identified. We observed 56 (8.72%) polymorphic sites consisting of 51 transitions, four transversions and one multiple mutational change. The overall haplotype and nucleotide diversity were 0.899 and 0.01569, respectively. Snail populations in Anhui had higher genetic diversity than in Jiangsu. 73.32% of total variation was distributed among sites and 26.68% within sites. Snails were significantly separated according to eco-epidemiological settings in both network and phylogenetic analyses. CONCLUSION: Our results could provide important guidance towards assessing coevolutionary interactions of snails with S. japonicum, as well as for future molluscan host monitoring and control activities.

3.
Medicine (Baltimore) ; 100(39): e27306, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596128

RESUMO

BACKGROUND: The purpose of this study was to compare the hemodynamic parameters of symptomatic and asymptomatic abdominal aortic aneurysms (AAAs) to explore the risk factors for AAA rupture. METHODS: We conducted a retrospective analysis of 26 patients with symptomatic small AAAs and 60 patients with asymptomatic small AAAs. Computational fluid dynamics methods were used to compare hemodynamic characteristics between the symptomatic and asymptomatic groups and to evaluate risk factors for the occurrence of symptomatic AAAs. RESULTS: The maximum diameters in the symptomatic and asymptomatic groups were 49.7 ±â€Š4.94 mm and 48.4 ±â€Š4.55 mm, respectively. Wall shear stress values at turbulent flow regions in the symptomatic and asymptomatic groups were 0.0098 ±â€Š0.0084 Pa versus 0.0174 ±â€Š0.0068 Pa, respectively. Shear stress values at the site with maximal blood flow impact force in the symptomatic and asymptomatic groups were 1.13 ±â€Š0.466 Pa and 2.04 ±â€Š0.42 Pa, respectively. The areas of the intra-luminal thrombus in the section with the maximum diameter in the symptomatic and asymptomatic groups were 952.19 ±â€Š413.53 mm2 versus 646.63 ±â€Š296.88 mm2, respectively. CONCLUSION: The wall shear stress in the symptomatic group was lower than that in the asymptomatic group.


Assuntos
Aneurisma da Aorta Abdominal/fisiopatologia , Hemodinâmica/fisiologia , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Comorbidade , Feminino , Humanos , Hidrodinâmica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
4.
Chin Med J (Engl) ; 134(17): 2025-2036, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34517376

RESUMO

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characteristic of small airway inflammation, obstruction, and emphysema. It is well known that spirometry alone cannot differentiate each separate component. Computed tomography (CT) is widely used to determine the extent of emphysema and small airway involvement in COPD. Compared with the pulmonary function test, small airway CT phenotypes can accurately reflect disease severity in patients with COPD, which is conducive to improving the prognosis of this disease. CT measurement of central airway morphology has been applied in clinical, epidemiologic, and genetic investigations as an inference of the presence and severity of small airway disease. This review will focus on presenting the current knowledge and methodologies in chest CT that aid in identifying discrete COPD phenotypes.


Assuntos
Obstrução das Vias Respiratórias , Doença Pulmonar Obstrutiva Crônica , Enfisema Pulmonar , Humanos , Fenótipo , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Enfisema Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X
5.
Front Cell Dev Biol ; 9: 719192, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497808

RESUMO

Oxaliplatin (OXA) resistance in the treatment of different types of cancer is an important and complex problem. The culture of tumor organoids derived from gastric cancer can help us to provide a deeper understanding of the underlying mechanisms that lead to OXA resistance. In this study, our purpose was to understand the mechanisms that lead to OXA resistance, and to provide survival benefits to patients with OXA through targeted combination therapies. Using sequence analysis of OXA-resistant and non-OXA-resistant organoids, we found that PARP1 is an important gene that mediates OXA resistance. Through the patients' follow-up data, it was observed that the expression level of PARP1 was significantly correlated with OXA resistance. This was confirmed by genetic manipulation of PARP1 expression in OXA-resistant organoids used in subcutaneous tumor formation. Results further showed that PARP1 mediated OXA resistance by inhibiting the base excision repair pathway. OXA also inhibited homologous recombination by CDK1 activity and importantly made cancers with normal BRCA1 function sensitive to PARP inhibition. As a result, combination of OXA and Olaparib (PARP-1/2/3 inhibitor), inhibited in vivo and in vitro OXA resistant organoid growth and viability.

6.
Sci Rep ; 11(1): 19122, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580375

RESUMO

68Ga-radiolabeled small molecules that specifically target prostate-specific membrane antigen (PSMA) have been extensively investigated, and some of these tracers have been used in the diagnosis of prostate cancer via 68Ga-positron emission tomography (68Ga-PET). Nevertheless, current 68Ga-labeled radiotracers show only fair detection rates for metastatic prostate cancer lesions, especially those with lower levels of prostate specific antigen (PSA), which often occurs in the biochemical recurrence of prostate cancer. The goal of this study was to design and synthesize a new PSMA-targeted radiotracer, 68Ga-SC691, with high affinity for prostate cancer cells and excellent pharmacokinetics. To this end, structural optimization was carried out on the bifunctional group, target motif, and linker while the high affinity targeting scaffold remained. To explore its potential in the clinic, a comparative study was further performed in vitro and in vivo between 68Ga-SC691 and 68Ga-PSMA-11, a clinically approved tracer for PSMA-positive prostate cancer. SC691 was radiolabeled to provide 68Ga-SC691 in 99% radiolabeling yield under mild conditions. High uptake and a high internalization ratio into LNCaP cells were observed in in vitro studies. In vivo studies showed that 68Ga-SC691 had favorable biodistribution properties and could specifically accumulate on PSMA-positive LNCaP xenografts visualized by micro-PET/CT. This radiotracer showed excellent PET imaging quality and comparable, if not higher, uptake in LNCaP xenografts than 68Ga-PSMA-11.

7.
Chem Sci ; 12(27): 9372-9378, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34349909

RESUMO

Methanol is an abundant and renewable chemical raw material, but its use as a C1 source in C-C bond coupling reactions still constitutes a big challenge, and the known methods are limited to the use of expensive and noble metal catalysts such as Ru, Rh and Ir. We herein report nickel-catalyzed direct coupling of alkynes and methanol, providing direct access to valuable allylic alcohols in good yields and excellent chemo- and regioselectivity. The approach features a broad substrate scope and high atom-, step- and redox-economy. Moreover, this method was successfully extended to the synthesis of [5,6]-bicyclic hemiacetals through a cascade cyclization reaction of alkynones and methanol.

8.
Cancer Lett ; 521: 71-81, 2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34450198

RESUMO

Non-small cell lung cancer (NSCLC) is one of the most critical health problems worldwide, with high incidence and poor survival rate. A zinc importer ZIP4 has been implicated in the process of tumor growth and metastasis of many cancers. However, its exact role and the underlying mechanism in NSCLC remains to be elucidated. In the present study, we found that human ZIP4 was substantially overexpressed in NSCLC tissues and was correlated with poor overall survival (OS) and progression-free survival (PFS). Overexpression of ZIP4 promoted cell migration, invasion and metastasis both in vitro and in a mouse lung metastasis model. Silencing of ZIP4 attenuated migration, invasion and metastasis. Mechanistically, overexpression of ZIP4 increased the expression of Snail, Slug and N-cadherin while genetic inactivation of ZIP4 downregulated the expression of above-mentioned genes. Further analysis showed that transcriptional factor Snail which modulates N-cadherin was involved in the process of ZIP4-mediated NSCLC migration and invasion. We also demonstrated that ZIP4 positively correlates with the levels of Snail, Slug and N-cadherin in mice lung metastasis tumors. Together, these results suggest that ZIP4 acts as an important regulator of Snail-N-cadherin signaling axis in promoting NSCLC progression and may serve as a novel predictive marker and therapeutic target in NSCLC.

9.
ACS Appl Mater Interfaces ; 13(34): 41012-41020, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34410119

RESUMO

Photodynamic therapy (PDT) is a potential approach to resolve antibiotic resistance, and phenylene/thiophene-ethynylene oligomers have been widely studied as effective antibacterial reagents. Oligomers with thiophene moieties usually exhibit good antibacterial activity under light irradiation and dark conditions. In the previous study, we verified that neutral oligo-p-phenylene-ethynylenes (OPEs) exhibit better antibacterial activity than the corresponding cationic ones; however, whether this regular pattern also operates in other kinds of oligomers such as oligo-thiophene-ethynylene (OTE) is unknown. Also, the antibacterial activity comparison of OTEs bearing cyclic and acyclic amino groups will offer useful information to further understand the role of amino groups in the antibacterial process and guide the antibacterial reagent design as amino groups affect the antibacterial activity a lot. We synthesized four OTEs bearing neutral or cationic, cyclic, or acyclic amino groups and studied their antibacterial activity in detail. The experimental results indicated that the OTEs exhibited better antibacterial activity than the OPEs, the neutral OTEs exhibited better antibacterial activity in most cases, and OTEs bearing cyclic amino groups exhibited better antibacterial activity than those bearing acyclic ones in most cases. This study provides useful guidelines for further antibacterial reagent design and investigations.

11.
Cancer Res ; 81(19): 4964-4980, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34385182

RESUMO

Methylthioadenosine phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20% to 30% of pancreatic cancer. Our previous study revealed that MTAP deficiency indicates a poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion-mediated metabolic reprogramming enhanced glycolysis and de novo purine synthesis in pancreatic cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF1α) protein via posttranslational phosphorylation. RIO kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF1α to regulate its stability. In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) and the de novo purine synthesis inhibitor l-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease. SIGNIFICANCE: This study demonstrates that MTAP status impacts glucose and purine metabolism, thus identifying multiple novel treatment options against MTAP-deficient pancreatic cancer.

13.
Nat Commun ; 12(1): 4144, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230476

RESUMO

To investigate the duration of humoral immune response in convalescent coronavirus disease 2019 (COVID-19) patients, we conduct a 12-month longitudinal study through collecting a total of 1,782 plasma samples from 869 convalescent plasma donors in Wuhan, China and test specific antibody responses. The results show that positive rate of IgG antibody against receptor-binding domain of spike protein (RBD-IgG) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the COVID-19 convalescent plasma donors exceeded 70% for 12 months post diagnosis. The level of RBD-IgG decreases with time, with the titer stabilizing at 64.3% of the initial level by the 9th month. Moreover, male plasma donors produce more RBD-IgG than female, and age of the patients positively correlates with the RBD-IgG titer. A strong positive correlation between RBD-IgG and neutralizing antibody titers is also identified. These results facilitate our understanding of SARS-CoV-2-induced immune memory to promote vaccine and therapy development.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Imunoglobulina G/sangue , Receptores Virais/imunologia , SARS-CoV-2/imunologia , Adulto , Animais , Doadores de Sangue , COVID-19/terapia , Linhagem Celular , China , Chlorocebus aethiops , Convalescença , Feminino , Humanos , Imunidade Humoral/imunologia , Imunização Passiva , Memória Imunológica/imunologia , Estudos Longitudinais , Masculino , Fatores Sexuais , Glicoproteína da Espícula de Coronavírus/imunologia , Células Vero
14.
Oncogene ; 40(31): 5002-5012, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34175886

RESUMO

T cell exhaustion plays critical roles in tumor immune evasion. Novel strategies to suppress immune evasion are in urgent need. We aimed to identify potential compounds to target T cell exhaustion and increase response to immune checkpoint inhibitors (ICIs). Differentially expressed genes (DEGs) were identified between tumors with different immune evasion potential by comparing the transcriptome data. DEGs were then analyzed in the Connectivity Map (CMap) platform to identify potential compounds to increase response to ICIs. Gene set enrichment analysis, LDH release assay, Chromatin immunoprecipitation (ChIP), and Co-IP were performed to explore the potential mechanisms in vitro. Patients derived organoids and humanized xenograft mouse model were utilized to validate the finding ex vivo and in vivo. We identified 25 potential compounds that may play critical roles in regulating tumor immune evasion. We further pinpointed a specific compound, dexamethasone, which shows potent anti-tumor effect in multiple cancer cell lines when cocultured with T cells. Dexamethasone can suppress T cell exhaustion by decreasing the activity of two immune checkpoints simultaneously, including PD-L1 and IDO1. Functional study shows dexamethasone can increase the sensitivity of ICIs in coculture system, 3D organoid model and humanized mouse model. Mechanism study shows dexamethasone mediated transcriptional suppression of PD-L1 and IDO1 depends on the nuclear translocation of GR/STAT3 complex. These findings demonstrate dexamethasone can suppress immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways.

16.
Int J Cancer ; 149(7): 1435-1447, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34019699

RESUMO

Although excess adiposity has been linked with various cancers, association between body composition and some cancers remains unclear, like lung and prostate cancers. We investigated associations of body composition with risk of overall cancer and major site-specific cancers in a prospective cohort of 454 079 cancer-free participants from UK-Biobank. Body composition was measured with bioimpedance analysis. We evaluated hazard ratio (HR) and 95% confidence interval (CI) with multivariate Cox linear and nonlinear models in men and women separately. We identified 27 794 cancers over 7.6 years of follow-up. Multivariable adjusted models including fat-free mass (FFM) and fat mass (FM) showed that FFM was positively associated with overall cancer risk in men and women (HR 1.03, 95% CI 1.01-1.04 and 1.07, 1.04-1.10, respectively); while the association between FM and overall cancer disappeared after adjusting for FFM. FFM was associated with higher risks of obesity-related cancers combined, stomach (women only), malignant melanoma, postmenopausal breast, corpus uteri, prostate, kidney (men only), and blood cancers and lower risk of lung cancer. FM was associated with higher risks of obesity-related cancers combined, esophageal, colon, lung (men only), postmenopausal breast (at the lower end of FM range), and corpus uteri cancers and lower risks of rectal, malignant melanoma (women only), prostate and blood cancers. FFM and FM seemed to have different effects on cancer risk, and the effects varied substantially by cancer type, in both direction and size. Higher FM/FFM ratio was also associated with some cancers risk, and might be a useful predictor of cancer risk.


Assuntos
Adiposidade , Composição Corporal , Índice de Massa Corporal , Neoplasias/classificação , Neoplasias/epidemiologia , Obesidade/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Reino Unido/epidemiologia
17.
Sci Robot ; 6(53)2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-34043565

RESUMO

Although there have been notable advances in adhesive materials, the ability to program attaching and detaching behavior in these materials remains a challenge. Here, we report a borate ester polymer hydrogel that can rapidly switch between adhesive and nonadhesive states in response to a mild electrical stimulus (voltages between 3.0 and 4.5 V). This behavior is achieved by controlling the exposure and shielding of the catechol group through water electrolysis-induced reversible cleavage and reformation of the borate ester moiety. By switching the electric field direction, the hydrogel can repeatedly attach to and detach from various surfaces with a response time as low as 1 s. This programmable attaching/detaching strategy provides an alternative approach for robot climbing. The hydrogel is simply pasted onto the moving parts of climbing robots without complicated engineering and morphological designs. Using our hydrogel as feet and wheels, the tethered walking robots and wheeled robots can climb on both vertical and inverted conductive substrates (i.e., moving upside down) such as stainless steel and copper. Our study establishes an effective route for the design of smart polymer adhesives that are applicable in intelligent devices and an electrochemical strategy to regulate the adhesion.

18.
J Appl Toxicol ; 41(12): 1998-2010, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33977565

RESUMO

Cadmium (Cd) is a toxic heavy metal widely found in the environment. Cd is also a potential neurotoxicant, and its exposure is associated with impairment of cognitive function. However, the underlying mechanisms by which Cd induces neurotoxicity are unclear. In this study, we investigated the in vitro effect of Cd on primary murine neural stem/progenitor cells (mNS/PCs) isolated from the subventricular zone. Our results show that Cd exposure leads to mNS/PCs G1/S arrest, promotes cell apoptosis, and inhibits cell proliferation. In addition, Cd increases intracellular and mitochondrial reactive oxygen species (ROS) that activates mitochondrial oxidative stress, decreases ATP production, and increases mitochondrial proton leak and glycolysis rate in a dose-dependent manner. Furthermore, Cd exposure decreases phosphorylation of protein kinase B (AKT) and glycogen synthase kinase-3 beta (GSK3ß) in mNS/PCs. In addition, pretreatment mNS/PCs with MitoTEMPO, a mitochondrial-targeted antioxidant, improves mitochondrial morphology and functions and attenuates Cd-induced inhibition of mNS/PCs proliferation. It also effectively reverses Cd-induced changes of phosphorylation of AKT and the expression of ß-catenin and its downstream genes. Taken together, our data suggested that AKT/GSK3ß/ß-catenin signaling pathway is involved in Cd-induced mNS/PCs proliferation inhibition via MitoROS-dependent pattern.

19.
Ecol Evol ; 11(9): 4276-4294, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33976810

RESUMO

Habitat fragmentation can lower migration rates and genetic connectivity among remaining populations of native species. Ducetia japonica is one of the most widespread katydids in China, but little is known about its genetic structure and phylogeographic distribution. We combined the five-prime region of cytochrome c oxidase subunit I (COI-5P), 11 newly developed microsatellite loci coupled with an ecological niche model (ENM) to examine the genetic diversity and population structure of D. japonica in China and beyond to Laos and Singapore. Both Bayesian inference (BI) and haplotype network methods revealed six mitochondrial COI-5P lineages. The distribution of COI-5P haplotypes may not demonstrate significant phylogeographic structure (N ST > G ST, p > .05). The STRUCTURE analysis based on microsatellite data also revealed six genetic clusters, but discordant with those obtained from COI-5P haplotypes. For both COI-5P and microsatellite data, Mantel tests revealed a significant positive correlation between geographic and genetic distances in mainland China. Bayesian skyline plot (BSP) analyses indicated that the population size of D. japonica's three major mitochondrial COI-5P lineages were seemingly not affected by last glacial maximum (LGM, 0.015-0.025 Mya). The ecological niche models showed that the current distribution of D. japonica was similar to the species' distribution during the LGM period and only slightly extended in northern China. Further phylogeographic studies based on more extensive sampling are needed to identify specific locations of glacial refugia in northern China.

20.
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