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1.
Stem Cells ; 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38829368

RESUMO

Bone marrow mesenchymal stem cells (BMSCs) possess the potential to differentiate into cartilage cells. Long noncoding RNA (lncRNAs) UCA1 has been confirmed to improve the chondrogenic differentiation of marrow mesenchymal stem cells (MSCs). Herein, we further investigated the effects and underlying mechanisms in these processes. the expression of UCA1 was positively associated with chondrogenic differentiation and the knockdown of UCA1 has been shown to attenuate the expression of chondrogenic markers. RNA pull down assay and RNA immunoprecipitation showed that UCA1 could directly bind to PARP1 protein. UCA1 could improve PARP1 protein via facilitating USP9X-mediated PARP1 deubiquitination. Then these processes stimulated the NF-κB signaling pathway. In addition, PARP1 was declined in UCA1 knockdown cells, and silencing of PARP1 could diminishes the increasing effects of UCA1 on the chondrogenic differentiation from MSCs and signaling pathway activation. Collectively, these outcomes suggest that UCA1 could act as a mediator of PARP1 protein ubiquitination and develop the chondrogenic differentiation of MSCs.

2.
J Physiol ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38953534

RESUMO

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

3.
J Org Chem ; 89(9): 6607-6614, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38624206

RESUMO

The trivalent phosphine-catalyzed [4+1] spiro-annulation reaction of allenyl imide and activated methylene cyclocompounds has been developed for the construction of various spiro-2-cyclopenten-1-ones. Oxindoles, 3-isochromanones, and 2-indanones are selected as 1C synthons to capture the in situ-generated bis-electrophilic α,ß-unsaturated ketenyl phosphonium intermediate, affording the corresponding monospiro- and bispiro-cyclopentenones in good to excellent yields (≤91%) under mild conditions. The primary attempt at asymmetric catalysis using monophosphine (R)-SITCP provides promising enantioselectivity (45% ee). A plausible reaction mechanism is also proposed.

4.
Dig Dis Sci ; 69(5): 1562-1570, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38580886

RESUMO

Esophageal carcinoma (ESCA) is an aggressive solid tumor. The 5-year survival rate for patients with ESCA is estimated to be less than 20%, mainly due to tumor invasion and metastasis. Therefore, it is urgent to improve early diagnostic tools and effective treatments for ESCA patients. Tumor microenvironment (TME) enhances the ability of tumor cells to proliferate, migrate, and escape from the immune system, thus promoting the occurrence and development of tumor. TME contains chemokines. Chemokines consist of four major families, which are mainly composed of CC and CXC families. The main purpose of this review is to understand the CC and CXC chemokines and their receptors in ESCA, to improve the understanding of tumorigenesis of ESCA and determine new biomarkers for the diagnosis and prognosis of ESCA. We reviewed the literature on CC and CXC chemokines and their receptors in ESCA identified by PubMed database. This article introduces the general structures and functions of CC, CXC chemokines and their receptors in TME, as well as their roles in the progress of ESCA. Chemokines are involved in the development of ESCA, such as cancer cell invasion, metastasis, angiogenesis, and radioresistance, and are key determinants of disease progression, which have a great impact on patient prognosis and treatment response. In addition, a full understanding of their mechanism of action is essential to further verify that these chemokines and their receptors may serve as biomarkers or therapeutic targets of ESCA.


Assuntos
Quimiocinas , Neoplasias Esofágicas , Microambiente Tumoral , Humanos , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/imunologia , Quimiocinas/metabolismo , Receptores de Quimiocinas/metabolismo , Biomarcadores Tumorais/metabolismo , Prognóstico
5.
BMC Musculoskelet Disord ; 25(1): 538, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38997705

RESUMO

BACKGROUND: How to quickly read and interpret intraoperative ultrasound (IOUS) images of patients with degenerative cervical myelopathy (DCM) to obtain meaningful information? Few studies have systematically explored this topic. PURPOSE: To systematically and comprehensively explore the IOUS characteristics of patients with DCM. MATERIALS AND METHODS: This single-center study retrospectively included patients with DCM who underwent French-door laminoplasty (FDL) with IOUS guidance from October 2019 to March 2022. One-way ANOVA and Pearson's /Spearman's correlation analysis were used to analyze the correlations between the cross-sectional area of the spinal cord (SC) and individual characteristics; the relationships between the morphology, echogenicity, pulsation, decompression statuses, compression types of SC, location of the spinal cord central echo complex (SCCEC) and the disease severity (the preoperative Japanese Orthopedic Association score, preJOA score); the difference of the spinal cord pulsation amplitude(SCPA) and the SCCEC forward movement rate (FMR) between the compressed areas(CAs) and the non-compressed areas (NCAs). RESULTS: A total of 38 patients were successfully enrolled (30 males and 8 females), and the mean age was 57.05 ± 10.29 (27-75) years. The cross-sectional area of the SC was negatively correlated with age (r = - 0.441, p = 0.006). The preJOA score was significantly lower in the heterogeneous group than in the homogeneous group (P < 0.05, p = 0.005). The hyperechoic area (HEA) was negatively while the SCCEC FMR was positively correlated with the preJOA score (r = - 0.334, p = 0.020; r = 0.286, p = 0.041). The SCCEC FMR and SCPA in CAs were significantly greater than those in NCAs (p < 0.05, p = 0.007; P < 0.001, P = 0.000). CONCLUSION: The cross-sectional area of the SC decreases with age in adults. More changes in intramedullary echogenicity and less moving forward of the SCCEC often indicate poor SC status, and the SCCEC FMR and SCPA are more pronounced in CAs.


Assuntos
Vértebras Cervicais , Laminoplastia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Vértebras Cervicais/cirurgia , Vértebras Cervicais/diagnóstico por imagem , Adulto , Laminoplastia/métodos , Doenças da Medula Espinal/cirurgia , Doenças da Medula Espinal/diagnóstico por imagem , Ultrassonografia , Compressão da Medula Espinal/cirurgia , Compressão da Medula Espinal/diagnóstico por imagem
6.
Rev Esp Enferm Dig ; 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38775418

RESUMO

OBJECTIVE: The optimal methods for removing polyps remain controversial especially for polyps ≤10mm. We aim to combine the latest evidence to evaluate and compare the effectiveness and safety of cold snare polypectomy (CSP) and hot snare polypectomy (HSP) in the removal of colorectal polyps ≤10mm in size. METHODS: We performed an extensive search across multiple databases, including PubMed, Embase, Cochrane, and Web of Science, with the search period ending in April 2023 for randomized controlled trials comparing the effectiveness and/or safety of CSP and HSP for the removal of ≤10mm colorectal polyps.The final outcomes included complete resection rate, operation time, and postoperative adverse events (including immediate bleeding, delayed bleeding, and perforation) rates. RESULTS: A total of 14 eligible randomized controlled trials were included, involving 7,460 patients and 15,829 polyps. The incidence of immediate bleeding was observed to be more prevalent in CSP in contrast to HSP, and the disparity was statistically notable (OR=2.18, 95% CI: 1.43-3.30, I2=36%, P=0.0003). The incidence of delayed bleeding was observed to be lower in CSP in contrast to HSP, and this difference was statistically significant (OR=0.30, 95% CI: 0.15-0.58, I2=0%, P=0.0003). Procedure time: both the total colonoscopy time and specific polypectomy time were shorter in CSP than in HSP (MD=-5.92, 95% CI: -9.70 to -2.14, I2=96%, P=0.002; MD=-0.56, 95% CI: -0.91 to -0.20, I2=77%, P=0.002). There were no statistically significant differences in complete resection and the polyp retrieval rate between CSP and HSP. CONCLUSION: CSP is as effective and safe as HSP for ≤10mm colorectal polyps, while effectively reducing the risk of delayed bleeding and shortening the procedure time.

7.
Sheng Li Xue Bao ; 76(1): 105-118, 2024 Feb 25.
Artigo em Zh | MEDLINE | ID: mdl-38444136

RESUMO

Prostaglandin E2 (PGE2) is an important lipid molecule derived from arachidonic acid, which regulates a variety of physiological and pathological activities. Based on the inhibition of inflammatory PGE2 production, non-steroidal anti-inflammatory drugs (NSAIDs) are considered as the most commonly used drugs to treat inflammatory diseases and to relieve fever and pain symptoms. PGE2 mediates its functions via four different G protein-coupled receptors, named EP1-EP4. Though the limited distribution and low PGE2 affinity of EP1, it plays important roles in the maintenance of many physiological functions and homeostasis. Moreover, EP1 is widely involved in the inflammatory response, pain perception and multisystem pathological function regulation. In this review, we will briefly summarize the recent advances on the physiological and pathophysiological function of EP1 and its targeted drugs development.


Assuntos
Dinoprostona , Dor , Humanos , Ácido Araquidônico , Homeostase
8.
Yi Chuan ; 46(5): 373-386, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38763772

RESUMO

Cardioembolic stroke, characterized by severe illness, poor prognosis, and high recurrence rate, is one of the important causes of ischemic stroke. In the field of genetic research, numerous genes associated with cardioembolic stroke have been identified, and their potential in predicting disease risk and evaluating risk factors has been progressively explored. Here, we provide an overview of the latest advancements in genetics for cardioembolic stroke, including genome-wide association studies, copy number variation studies, whole-genome sequencing studies. Furthermore, we also summarize the application of genetic datasets in polygenic risk score and Mendelian randomization. The aim of this overview is to provide insights and references from multiple perspectives for future investigations on the genetic information for cardioembolic stroke.


Assuntos
Variações do Número de Cópias de DNA , AVC Embólico , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , AVC Embólico/genética , AVC Embólico/etiologia , Fatores de Risco
9.
Small ; 19(33): e2301255, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37086139

RESUMO

The electronic regulation and surface reconstruction of earth-abundant electrocatalysts are essential to efficient oxygen evolution reaction (OER). Here, an inverse-spinel Co,S atomic pair codoped Fe3 O4 grown on iron foam (Co,S-Fe3 O4 /IF) is fabricated as a cost-effective electrocatalyst for OER. This strategy of Co and S atomic pair directional codoping features accelerates surface reconstruction and dynamically stabilizes electronic regulation. CoS atomic pairs doped in the Fe3 O4 crystal favor controllable surface reconstruction via sulfur leaching, forming oxygen vacancies and Co doping on the surface of reconstructed FeOOH (Co-FeOOH-Ov /IF). Before and after surface reconstruction via in situ electrochemical process, the Fe sites with octahedral field dynamically maintains an appropriate electronic structure for OER intermediates, thus exhibiting consistently excellent OER performance. The electrochemically tuned Fe-based electrodes exhibit a low overpotential of 349 mV at a current density of 1000 mA cm-2 , a slight Tafel slope of 43.3 mV dec-1 , and exceptional long-term electrolysis stability of 200 h in an alkaline medium. Density functional theory calculations illustrate the electronic regulation of Fe sites, changes in Gibbs free energies, and the breaking of the restrictive scaling relation between OER intermediates. This work provides a promising directional codoping strategy for developing precatalysts for large-scale water-splitting systems.

10.
Cytokine ; 165: 156169, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36933397

RESUMO

PURPOSE: Interstitial cystitis (IC), a chronic pain syndrome characterized by urinary frequency, urgency, and bladder or pelvic floor pain, severely affects the quality of life of patients. The aim of this study was to investigate the role and mechanism of long noncoding RNA Maternally Expressed Gene3 (lncRNA MEG3) in IC. METHODS: An IC rat model was established by intraperitoneal injection of cyclophosphamide combined with bladder perfusion of fisetin and tumor necrosis factor-α (TNF-α) to mimic IC. An in vitro model was established using TNF-α-induced rat bladder epithelium cells. H&E staining was used to assess bladder tissue damage and ELISA was used to measure inflammatory cytokine levels. Western blot analysis was used to examine Nrf2, Bax, Bcl-2, cleaved caspase-3, p-p38, p38, p-NF-κB and NF-κB protein expression levels. RNA immunoprecipitation and RNA pull-down assays were used to examine the interaction between MEG3 and Nrf2. RESULTS: MEG3 levels were upregulated in IC tissues and bladder epithelial cells, whereas Nrf2 expression was found to be downregulated. Knockdown of MEG3 reduced bladder tissue injury, inflammation, oxidative stress and apoptosis. MEG3 was negatively correlated with Nrf2. Downregulation of MEG3 alleviated IC inflammation and injury by upregulating Nrf2 and inhibiting the p38/NF-κB pathway. CONCLUSION: Downregulation of MEG3 alleviated inflammation and injury in IC rats by upregulating Nrf2 and inhibiting the p38/NF-κB pathway.


Assuntos
Cistite Intersticial , RNA Longo não Codificante , Ratos , Animais , NF-kappa B/metabolismo , RNA Longo não Codificante/genética , Fator 2 Relacionado a NF-E2 , Fator de Necrose Tumoral alfa/genética , Qualidade de Vida , Inflamação , Apoptose/genética
11.
Cerebellum ; 22(5): 888-904, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36040660

RESUMO

The classical motor center cerebellum is one of the most consistent structures of abnormality in autism spectrum disorders (ASD), and neuropeptide oxytocin is increasingly explored as a potential pharmacotherapy for ASD. However, whether oxytocin targets the cerebellum for therapeutic effects remains unclear. Here, we report a localization of oxytocin receptor (OXTR) in Purkinje cells (PCs) of cerebellar lobule Crus I, which is functionally connected with ASD-implicated circuits. OXTR activation neither affects firing activities, intrinsic excitability, and synaptic transmission of normal PCs nor improves abnormal intrinsic excitability and synaptic transmission of PCs in maternal immune activation (MIA) mouse model of autism. Furthermore, blockage of OXTR in Crus I in wild-type mice does not induce autistic-like social, stereotypic, cognitive, and anxiety-like behaviors. These results suggest that oxytocin signaling in Crus I PCs seems to be uninvolved in ASD pathophysiology, and contribute to understanding of targets and mechanisms of oxytocin in ASD treatment.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Camundongos , Animais , Receptores de Ocitocina , Ocitocina , Células de Purkinje
12.
Pharmacol Res ; 191: 106773, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37068531

RESUMO

Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.


Assuntos
Ataxia Cerebelar , Camundongos , Animais , Ataxia Cerebelar/induzido quimicamente , Células de Purkinje/fisiologia , Microglia , Fator de Necrose Tumoral alfa/farmacologia , Cerebelo , Citocinas
13.
Proc Natl Acad Sci U S A ; 117(50): 32155-32164, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33257584

RESUMO

Anxiety commonly co-occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL- and not BLA- and vHipp-NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL-NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Agonistas dos Receptores Histamínicos/administração & dosagem , Núcleo Accumbens/fisiopatologia , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Receptores Histamínicos H3/metabolismo , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiopatologia , Animais , Transtornos de Ansiedade/etiologia , Transtornos de Ansiedade/fisiopatologia , Transtornos de Ansiedade/psicologia , Modelos Animais de Doenças , Glutamatos/metabolismo , Histamina/metabolismo , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Humanos , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/fisiopatologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Transtorno Obsessivo-Compulsivo/etiologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/psicologia , Optogenética , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Transgênicos , Técnicas Estereotáxicas , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
14.
J Virol ; 95(12)2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-33789991

RESUMO

Recombinant influenza A viral (IAV) vectors are potential to stimulate systemic and mucosal immunity, but the packaging capacity is limited and only one or a few epitopes can be carried. Here, we report the generation of a replication-competent IAV vector that carries a full-length HIV-1 p24 gene linked to the 5'-terminal coding region of the neuraminidase segment via a protease cleavage sequence (IAV-p24). IAV-p24 was successfully rescued and stably propagated, and P24 protein was efficiently expressed in infected mammalian cells. In BALB/c mice, IAV-p24 showed attenuated pathogenicity compared to that of the parental A/PR/8/34 (H1N1) virus. An intranasal inoculation with IAV-p24 elicited moderate HIV-specific cell-mediated immune (CMI) responses in the airway and vaginal tracts and in the spleen, and an intranasal boost with a replication-incompetent adenovirus type 2 vector expressing the HIV-1 gag gene (Ad2-gag) greatly improved these responses. Importantly, compared to an Ad2-gag prime plus IAV-p24 boost regimen, the IAV-p24 prime plus Ad2-gag boost regimen had a greater efficacy in eliciting HIV-specific CMI responses. P24-specific CD8+ T cells and antibodies were robustly provoked both systemically and in mucosal sites and showed long-term durability, revealing that IAV-p24 may be used as a mucosa-targeted priming vaccine. Our results illustrate that IAV-p24 is able to prime systemic and mucosal immunity against HIV-1 and warrants further evaluation in nonhuman primates.IMPORTANCE An effective HIV-1 vaccine remains elusive despite nearly 40 years of research. CD8+ T cells and protective antibodies may both be desirable for preventing HIV-1 infection in susceptible mucosal sites. Recombinant influenza A virus (IAV) vector has the potential to stimulate these immune responses, but the packaging capacity is extremely limited. Here, we describe a replication-competent IAV vector expressing the HIV-1 p24 gene (IAV-p24). Unlike most other IAV vectors that carried one or several antigenic epitopes, IAV-p24 stably expressed the full-length P24 protein, which contains multiple epitopes and is highly conserved among all known HIV-1 sequences. Compared to the parental A/PR/8/34 (H1N1) virus, IAV-p24 showed an attenuated pathogenicity in BALB/c mice. When combined with an adenovirus vector expressing the HIV-1 gag gene, IAV-p24 was able to prime P24-specific systemic and mucosal immune responses. IAV-p24 as an alternative priming vaccine against HIV-1 warrants further evaluation in nonhuman primates.


Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD8-Positivos/imunologia , Anticorpos Anti-HIV/análise , Proteína do Núcleo p24 do HIV/imunologia , HIV-1/imunologia , Imunidade nas Mucosas , Adenoviridae/genética , Animais , Anticorpos Antivirais/sangue , Líquido da Lavagem Broncoalveolar/imunologia , Feminino , Genes gag , Anticorpos Anti-HIV/sangue , Proteína do Núcleo p24 do HIV/genética , Infecções por HIV/prevenção & controle , Imunidade Celular , Imunização Secundária , Imunogenicidade da Vacina , Imunoglobulina A/análise , Imunoglobulina A/sangue , Imunoglobulina G/análise , Imunoglobulina G/sangue , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/imunologia , Tecido Linfoide/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Vacinação , Vacinas Sintéticas/imunologia
15.
J Virol ; 95(14): e0038321, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-33910950

RESUMO

Zika virus (ZIKV) infection during pregnancy has been linked to congenital abnormalities, such as microcephaly in infants. An efficacious vaccine is desirable for preventing the potential recurrence of ZIKV epidemic. Here, we report the generation of an attenuated ZIKV (rGZ02a) that has sharply decreased virulence in mice but grows to high titers in Vero cells, a widely approved cell line for manufacturing human vaccines. Compared to the wild-type ZIKV (GZ02) and a plasmid-launched rGZ02p, rGZ02a has 3 unique amino acid alterations in the envelope (E, S304F), nonstructural protein 1 (NS1, R103K), and NS5 (W637R). rGZ02a is more sensitive to type I interferon than GZ02 and rGZ02p, and causes no severe neurological disorders in either wild-type neonatal C57BL/6 mice or type I interferon receptor knockout (Ifnar1-/-) C57BL/6 mice. Immunization with rGZ02a elicits robust inhibitory antibody responses with a certain long-term durability. Neonates born to the immunized dams are effectively protected against ZIKV-caused neurological disorders and brain damage. rGZ02a as a booster vaccine greatly improves the protective immunity primed by Ad2-prME, an adenovirus-vectored vaccine expressing ZIKV prM and E proteins. Our results illustrate that rGZ02a-induced maternal immunity can be transferred to the neonates and confer effective protection. Hence, rGZ02a may be developed as an alternative live-attenuated vaccine and warrants further evaluation. IMPORTANCE Zika virus (ZIKV), a mosquito-borne flavivirus that has caused global outbreaks since 2013, is associated with severe neurological disorders, such as Guillian-Barré syndrome in adults and microcephaly in infants. The ZIKV epidemic has gradually subsided, but a safe and effective vaccine is still desirable to prevent its potential recurrence, especially in countries of endemicity with competent mosquito vectors. Here, we describe a novel live-attenuated ZIKV, rGZ02a, that carries 3 unique amino acid alterations compared to the wild-type GZ02 and a plasmid-launched rGZ02p. The growth capacity of rGZ02a is comparable to GZ02 in Vero cells, but the pathogenicity is significantly attenuated in two mice models. Immunization with rGZ02a elicits robust inhibitory antibody responses in the dams and effectively protects their offspring against ZIKV disease. Importantly, in a heterologous prime-boost regimen, rGZ02a effectively boosts the protective immunity primed by an adenovirus-vectored vaccine. Thus, rGZ02a is a promising candidate for a live-attenuated ZIKV vaccine.


Assuntos
Imunogenicidade da Vacina , Vacinas Virais/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Adenoviridae/genética , Animais , Animais Recém-Nascidos , Chlorocebus aethiops , Feminino , Vetores Genéticos , Imunização Secundária , Interferon Tipo I/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Células Vero , Proteínas Virais/genética , Zika virus/genética , Infecção por Zika virus/imunologia
16.
Org Biomol Chem ; 20(17): 3506-3510, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35420611

RESUMO

A copper-catalyzed cascade reaction of α-diazocarbonyl compounds with ethenesulfonyl fluoride (ESF) is developed, affording a variety of highly functionalized pyrazolyl aliphatic sulfonyl fluorides in good to excellent yields (66-98%). This transformation features broad substrates, exclusive regioselectivity, high atom economy and operational simplicity, thus providing a straightforward method for the direct construction of pyrazole-containing aliphatic sulfonyl fluorides, which will provide great applicable value in medicinal chemistry and other related disciplines.


Assuntos
Fluoretos , Ácidos Sulfínicos , Química Farmacêutica , Fluoretos/química , Pirazóis , Ácidos Sulfínicos/química
17.
BMC Med Imaging ; 22(1): 131, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35883116

RESUMO

OBJECTIVE: To investigate the value of contrast-enhanced computed tomography (CECT) radiomics features in predicting the efficacy of epirubicin combined with ifosfamide in patients with pulmonary metastases from soft tissue sarcoma. METHODS: A retrospective analysis of 51 patients with pulmonary metastases from soft tissue sarcoma who received the chemotherapy regimen of epirubicin combined with ifosfamide was performed, and efficacy was evaluated by Recist1.1. ROIs (1 or 2) were selected for each patient. Lung metastases were used as target lesions (86 target lesions total), and the patients were divided into a progression group (n = 29) and a non-progressive group (n = 57); the latter included a stable group (n = 34) and a partial response group (n = 23). Information on lung metastases was extracted from CECT images before chemotherapy, and all lesions were delineated by ITK-SNAP software manually or semiautomatically. The decision tree classifier had a better performance in all radiomics models. A receiver operating characteristic curve was plotted to evaluate the predictive performance of the radiomics model. RESULTS: In total, 851 CECT radiomics features were extracted for each target lesion and finally reduced to 2 radiomics features, which were then used to construct a radiomics model. Areas under the curves of the model for predicting lesion progression were 0.917 and 0.856 in training and testing groups, respectively. CONCLUSION: The model established based on the radiomics features of CECT before treatment has certain predictive value for assessing the efficacy of chemotherapy for patients with soft tissue sarcoma lung metastases.


Assuntos
Neoplasias Pulmonares , Sarcoma , Neoplasias de Tecidos Moles , Epirubicina , Humanos , Ifosfamida , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Sarcoma/diagnóstico por imagem , Sarcoma/tratamento farmacológico , Tomografia Computadorizada por Raios X/métodos
18.
Reprod Domest Anim ; 57(1): 64-71, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34695258

RESUMO

The yak is an important source for the people living and ecological environment in the Qinghai-Tibet Plateau. In every winter, many domestic yaks will lose bodyweight or dead under cold and food scarcity. Moving the plateau yaks to farm in the plain is a useful approach to reduce their environmental stress and gain more production. In this study, we measured growth, slaughter and beef quality traits every month and sequenced mRNA expression levels of muscles of two groups yaks living in plateau and plain respectively. We found there is significant difference (p-value <0.01) in the third (60 days), fourth (90 days), fifth (120 days) and sixth (150 days) weights between subpopulations in the plateau and plain. We identified 540 different expressed genes (DEGs) including 123 known genes and 417 unknown genes. Using the weighted correlation network analysis (WGCNA) to build a co-express network, the modules were strong relative to weight traits. The findings highlighted the underlying way and a relative network to yield a new view about gene expression between the yaks living plateau and plain.


Assuntos
Perfilação da Expressão Gênica , Transcriptoma , Animais , Sequência de Bases , Bovinos/genética , Perfilação da Expressão Gênica/veterinária , Estações do Ano , Tibet
19.
BMC Med Educ ; 22(1): 128, 2022 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-35216585

RESUMO

BACKGROUND: The importance of self-regulated learning (SRL) has been broadly recognised by medical education institutions and medical professionals. Self-regulated learning, which is a context-specific process, is affected by personal, contextual and social factors. Although many studies on exploring the factors that influenced SRL and the relationship of between SRL and clinical achievement levels have been carried out in western countries, little is known about the factors associated with self-regulated learning and its relationship with clinical performance among medical students in China. METHODS: A cross-sectional online survey was distributed to 3rd year clinical medicine students who were in the clinical clerkship stage in a medical college in Wuhan. We used Self-regulated Learning Scale for Undergraduates (SLSU) to measure the self-regulated learning of students and Objective Structured Clinical Examination (OSCE) in the national proficiency test to assess the clinical performance of students. The participation rate was 73.95% (193 students). An independent t-test and analysis of variance were used to analyse the factors associated with self-regulated learning. The relationship between self-regulated learning and clinical performance was analysed with multilinear regression analysis. RESULTS: Univariate analysis showed that having a clear career planning and a professional idol, providing full-time teaching clinical teachers in the clerkship department and seeking the help of the surrounding classmates and the guidance of teachers or senior students were significant predictors of self-regulated learning. Multilinear regression analysis has revealed a positive relationship among extrinsic goals (partial r = 0.171), clinical clerkship evaluation (partial r = 0.197) and clinical performance (F = 4.070, p = 0.004). CONCLUSIONS: Motivation-related personal and social factors related to clinical context could promote the SRL level of medical students in China. Extrinsic goals and clinical clerkship evaluation could facilitate students' clinical achievements on clinical skills. External support, such as clinical clerkship management, might improve clinical performance on clinical skills in clinical clerkship context.


Assuntos
Estágio Clínico , Educação Médica , Estudantes de Medicina , Competência Clínica , Estudos Transversais , Humanos , Aprendizagem
20.
Chem Soc Rev ; 50(1): 658-666, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33283801

RESUMO

This review is covering the recent development of catalytic asymmetric domino reactions for the desymmetrization of alkene-, alkyne- and allene-tethered cyclohexadienones using transition metals and chiral ligands. This desymmetrization has emerged as an important strategy for the rapid construction of complex molecular skeletons, such as fused-polycycles or spirocyclic compounds in controlling multiple stereogenic centers.

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