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1.
J Plant Physiol ; 275: 153742, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35696829

RESUMO

Geminiviruses are a large group of plant viruses that have been a serious threat to worldwide agriculture. Transcription of the virus-encoded genes is necessary for geminiviruses to complete their life cycle, but the host proteins which directly target geminivirus promoters for suppression of viral gene transcription remain to be identified. Using Beet severe curly top virus (BSCTV) which causes severe plant symptoms as a system, we performed a yeast one-hybrid screening and identified ABA INSENSITIVE 5 (ABI5), a critical transcription factor in Abscisic acid (ABA) signaling transduction, as an interactor with the viral promoter. Further data showed that an ABA-responsive element in the viral promoter is necessary for its interaction with ABI5 and symptom development. Overexpression of ABI5 suppresses the transcription activity of the viral promoter and BSCTV infection in Nicotiana benthamiana and Arabidopsis; whilst depletion of ABI5 enhances the infection of BSCTV in Arabidopsis. Taken together, our study uncovered the function of ABI5 in the plant-virus interaction and will provide us with a new strategy to protect crops from geminivirus infection.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Geminiviridae , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacologia , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Geminiviridae/genética , Geminiviridae/metabolismo , Regulação da Expressão Gênica de Plantas , Germinação/genética , Plantas Geneticamente Modificadas/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-35512205

RESUMO

OBJECTIVES: To evaluate MRI changes to define muscle-lesion specific patterns in patients with antisynthetase syndrome (ASS), and compare them with those in other common idiopathic inflammatory myopathy (IIM) subtypes. METHODS: Qualitative and semi-quantitative thigh MRI evaluations were conducted in patients with ASS, dermatomyositis (DM), and immune-mediated necrotising myopathy (IMNM). RESULTS: This study included 51 patients with ASS, 56 with DM and 61 with IMNM. Thigh MRI revealed muscle oedema (62.7%), myofascial oedema (90.2%), subcutaneous-tissue oedema (60.8%), and fatty infiltration of muscles (68.6%) in patients with ASS. Compared with IMNM, ASS and DM were associated with more frequent adductor-muscle relative sparing (40.6% vs 3.6%, p < 0.001, and 25.6% vs 3.6%, p < 0.001) and subcutaneous-tissue oedema (60.8% vs 23.0%, p < 0.001, and 57.1% vs 23.0%, p < 0.001). Although ASS and DM exhibited similar oedema patterns, there were certain subtle differences between them. The ASS group was less frequently symmetric (60.6% vs 88.4%, p = 0.005, and 60.6% vs 80.0%, p = 0.048), but more frequently showed myofascial oedema of the tensor fasciae latae (80.4% vs 48.2%, p < 0.001, and 80.4% vs 31.1%, p < 0.001) than either the DM or IMNM groups. The receiver operating characteristic curve analysis showed an optimal combination of thigh MRI findings had an area under the curve with 0.893 for diagnosing ASS. CONCLUSION: Thigh MRI in ASS exhibited frequent myofascial oedema. ASS oedema patterns resembled those of DM more than those of IMNM. Bilateral asymmetry, adductor-muscle relative sparing and remarkable myofascial oedema of tensor fasciae latae were the most characteristic ASS imaging findings.

3.
Front Neurol ; 13: 843523, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35432159

RESUMO

Background and Purpose: Previous studies have found tacrolimus to be a favorable drug for treating different types of myasthenia gravis (MG), but few have focused on very-late-onset MG (VLOMG). This study evaluated the efficacy and safety of tacrolimus for VLOMG therapy. Methods: This was a retrospective single-center cohort study of 70 patients with VLOMG (onset ≥65 years) who visited Peking University First Hospital in 2019. Participants were divided into the tacrolimus (Tac) group and the control group based on tacrolimus usage. We further divided the Tac group into patients treated without corticosteroids and with corticosteroids. Sociodemographic features, clinical profiles, and outcomes were compared between different therapies and further analyzed by multivariate regression. Details of tacrolimus treatment, comorbidities, and adverse drug reactions (ADRs) were described. Results: Among 70 patients, the median (interquartile range) age at onset was 71 (68-77) years, and the follow-up duration was 27 (27-29) months. Most patients were types I (28%) and III (40%) according to the MG Foundation of America (MGFA) classification. In the Tac group, tacrolimus treatment was maintained for 36 (27-38) months. The dosage at the final evaluation was 1.0 (1.0-1.75) mg/day, and the last blood concentration test was 4.25 (2.85-5.7) ng/ml. A total of 43% reached remission, and 37% improved based on MGFA postintervention status (MGFA-PIS). For the 9 patients, newly diagnosed at enrollment within this group, MG activities of daily living (MG-ADL) decreased significantly from 3 (2-5) to 2 (1-2) (p = 0.041). Regarding the 13 patients, coadministering Wuzhi capsules the tacrolimus concentration increased from 2.75 (1.4-3.8) ng/ml to 5.95 (5.1-7.0) ng/ml (p = 0.012). No significant differences in outcomes were observed between tacrolimus treatment without and with corticosteroids or between the Tac group and the control group. A total of 93% had at least one comorbidity. ADRs related to tacrolimus emerged in 25% (9/36) of patients, most of which were not serious and reversible. Conclusions: Tacrolimus is effective and safe in treating VLOMG. Tacrolimus monotherapy without corticosteroids can be used as an initial and maintenance treatment for VLOMG. Wuzhi capsules work well in elevating tacrolimus concentrations in this population.

4.
Front Cell Dev Biol ; 10: 784920, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35445014

RESUMO

Aim: Increasing studies have demonstrated lymph node ratio (LNR) to be an accurate prognostic indicator in breast cancer and an alternative to pN staging; however, the AJCC-TNM staging system classified apical or infraclavicular/ipsilateral supraclavicular lymph node-positive (APN(+)) patients with a worse prognosis as the pN3 stage. Until now, different reports on LNR in breast cancer have ignored this possibility. Consequently, it is necessary to discuss the role of APN(+) patients in the LNR system to obtain a precise LNR that predicts the prognosis accurately. Materials and Methods: We collected data on 10,120 breast cancer patients, including 3,936 lymph node-positive patients (3,283 APN(-) and 653 APN(+) patients), who visited our hospital from 2007 to 2012. Then we applied X-tile analysis to calculate cut-off values and conduct survival analysis and multivariate analysis to evaluate patients' prognosis. Results: We confirmed that some APN(+) patients were mis-subgrouped according to previously reported LNR, indicating that APN(+) patients should be excluded in the application of LNR to predict prognosis. Then we applied X-tile analysis to calculate two cut-off values (0.15 and 0.34) for LNR-APN(-) patients and conducted survival analysis and found that LNR-APN(-) staging was superior to pN staging in predicting the prognosis of APN(-) breast cancer patients. Conclusion: From this study, we conclude that excluding APN(+) patients is the most necessary condition for effective implementation of the LNR system. LNR-APN(-) staging could be a more comprehensive approach in predicting prognosis and guiding clinicians to provide accurate and appropriate treatment.

5.
J Neurol ; 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35486214

RESUMO

BACKGROUND: There is increasing evidence for the role of inflammation in the pathogenesis of mitochondrial diseases (MDs). However, the mechanisms underlying mutation-induced inflammation in MD remain elusive. Our previous study suggested that mitophagy is impaired in the skeletal muscle of those with MD, likely causing mitochondrial DNA (mtDNA) release and thereby triggering inflammation. We here aimed to decipher the role of the cGAS-STING pathway in inflammatory process in MDs. METHODS: We investigated the levels of circulating cell-free mtDNA (ccf-mtDNA) in the serum of 104 patients with MDs. Immunofluorescence was performed in skeletal muscles in MDs and control. Biochemical analysis of muscle biopsies was conducted with western blot to detect cGAS, STING, TBK1, IRF3 and phosphorylated IRF3 (p-IRF3). RT-qPCR was performed to detect the downstream genes of type I interferon in skeletal muscles. Furthermore, a protein microarray was used to examine the cytokine levels in the serum of patients with MDs. RESULTS: We found that ccf-mtDNA levels were significantly increased in those with MDs compared to the controls. Consistently, the immunofluorescent results showed that cytosolic dsDNA levels were increased in the muscle samples of MD patients. Biochemical analysis of muscle biopsies showed that cGAS, IRF3, and TBK1 protein levels were significantly increased in those with MDs, indicating that there was activation of the cGAS-STING pathway. RT-qPCR showed that downstream genes of type I interferon were upregulated in muscle samples of MDs. Protein microarray results showed that a total of six cytokines associated with the cGAS-STING pathway were significantly increased in MD patients (fold change > 1.2, p value < 0.05). CONCLUSIONS: These findings suggest that increases in ccf-mtDNA levels is associated with the activation of the cGAS-STING pathway, thereby triggering inflammation in MDs.

6.
Sensors (Basel) ; 22(3)2022 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-35161998

RESUMO

Florescence information monitoring is essential for strengthening orchard management activities, such as flower thinning, fruit protection, and pest control. A lightweight object recognition model using cascade fusion YOLOv4-CF is proposed, which recognizes multi-type objects in their natural environments, such as citrus buds, citrus flowers, and gray mold. The proposed model has an excellent representation capability with an improved cascade fusion network and a multi-scale feature fusion block. Moreover, separable deep convolution blocks were employed to enhance object feature information and reduce model computation. Further, channel shuffling was used to address missing recognition in the dense distribution of object groups. Finally, an embedded sensing system for recognizing citrus flowers was designed by quantitatively applying the proposed YOLOv4-CF model to an FPGA platform. The mAP@.5 of citrus buds, citrus flowers, and gray mold obtained on the server using the proposed YOLOv4-CF model was 95.03%, and the model size of YOLOv4-CF + FPGA was 5.96 MB, which was 74.57% less than the YOLOv4-CF model. The FPGA side had a frame rate of 30 FPS; thus, the embedded sensing system could meet the demands of florescence information in real-time monitoring.


Assuntos
Citrus , Algoritmos , Computadores , Flores , Frutas
7.
Am J Hum Genet ; 109(3): 533-541, 2022 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-35148830

RESUMO

Recent studies indicate that CGG repeat expansions in LRP12, GIPC1, and NOTCH2NLC are associated with oculopharyngodistal myopathy (OPDM) types 1, 2, and 3, respectively. However, some clinicopathologically confirmed OPDM cases continue to have unknown genetic causes. Here, through a combination of long-read whole-genome sequencing (LRS), repeat-primed polymerase chain reaction (RP-PCR), and fluorescence amplicon length analysis PCR (AL-PCR), we found that a CGG repeat expansion in the 5' UTR of RILPL1 is associated with familial and simplex OPDM type 4 (OPDM4). The number of repeats ranged from 139 to 197. Methylation analysis indicates that the methylation levels in RILPL1 were unaltered in OPDM4 individuals. Analyses of muscle biopsies suggested that the expanded CGG repeat might be translated into a toxic poly-glycine protein that co-localizes with p62 in intranuclear inclusions. Moreover, analyses suggest that the toxic RNA gain-of-function effects also contributed to the pathogenesis of this disease. Intriguingly, all four types of OPDM have been found to be associated with the CGG repeat expansions located in 5' UTRs. This finding suggests that a common pathogenic mechanism, driven by the CGG repeat expansion, might underlie all cases of OPDM.


Assuntos
Distrofias Musculares , Expansão das Repetições de Trinucleotídeos , Regiões 5' não Traduzidas , Proteínas Adaptadoras de Transdução de Sinal , Humanos , Corpos de Inclusão Intranuclear/genética , Distrofias Musculares/genética , Expansão das Repetições de Trinucleotídeos/genética
8.
Sensors (Basel) ; 22(2)2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35062541

RESUMO

Green citrus detection in citrus orchards provides reliable support for production management chains, such as fruit thinning, sunburn prevention and yield estimation. In this paper, we proposed a lightweight object detection YOLOv5-CS (Citrus Sort) model to realize object detection and the accurate counting of green citrus in the natural environment. First, we employ image rotation codes to improve the generalization ability of the model. Second, in the backbone, a convolutional layer is replaced by a convolutional block attention module, and a detection layer is embedded to improve the detection accuracy of the little citrus. Third, both the loss function CIoU (Complete Intersection over Union) and cosine annealing algorithm are used to get the better training effect of the model. Finally, our model is migrated and deployed to the AI (Artificial Intelligence) edge system. Furthermore, we apply the scene segmentation method using the "virtual region" to achieve accurate counting of the green citrus, thereby forming an embedded system of green citrus counting by edge computing. The results show that the mAP@.5 of the YOLOv5-CS model for green citrus was 98.23%, and the recall is 97.66%. The inference speed of YOLOv5-CS detecting a picture on the server is 0.017 s, and the inference speed on Nvidia Jetson Xavier NX is 0.037 s. The detection and counting frame rate of the AI edge system-side counting system is 28 FPS, which meets the counting requirements of green citrus.


Assuntos
Inteligência Artificial , Citrus , Algoritmos , Computadores , Frutas
9.
J Dent Sci ; 17(1): 204-210, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35028039

RESUMO

BACKGROUND/PURPOSE: The scanning accuracy of intraoral scanners' data collection plays a key role in the success of the final treatment. However, few studies start from scanning technology itself to directly evaluate it. The aim of this study was to evaluate the scanning accuracy of three intraoral scanners, to provide a reference for relevant research and clinical applications. MATERIALS AND METHODS: Six types of resin models containing different numbers of crown-prepared abutments were three-dimensionally printed, and a model scanner, as well as three intraoral scanners, were used to digitally scan the six models. The obtained data were uploaded to three-dimensional reverse software for registration and comparison, and the accuracy of the models were analyzed. RESULTS: When scanning the six groups of models, the Omnicam outperformed both the TRIOS and iTero in terms of accuracy in all groups except the second molar group. The TRIOS and iTero scanners also exhibited decreased degrees of accuracy when scanning the long dental arch. The accuracy decreased as the scanning scope increased; however, the Omnicam scanner exhibited a relatively high degree of accuracy when scanning the three-unit fixed bridge and anterior areas. All scanners exhibited the lowest degree of accuracy when scanning the full-arch model. Certain deviations were observed, and the scanning areas at the incisal edges of the anterior teeth and end of the dental arch exhibited relatively large deviations. CONCLUSION: With the model scanner data as reference, the scanning accuracy of the three scanners exhibited differences and certain deviations, which were within clinical tolerance.

10.
Front Oncol ; 11: 724250, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34631552

RESUMO

BACKGROUND: Breast cancer is the most commonly diagnosed cancer worldwide. However, the well-known biomarkers are not enough to meet the needs of precision medicine. Novel targets are desirable and highly valuable for improved patient survival. In this regard, we identified complement component C7 as one of the candidates based on data from the OCOMINE database. METHODS: C7 expression was examined by immunohistochemistry in 331 cases of invasive ductal carcinoma (IDC), 45 cases of ductal carcinoma in situ (DCIS), and 52 cases of non-neoplastic tissues adjacent to tumor. Then, C7 expression was further confirmed by Western blot analysis based on IDC specimens and non-neoplastic breast specimens. The relationship between the C7 expression and prognosis of breast cancer patients was analyzed in order to investigate the function of C7 in breast cancer patients. Meanwhile, we also analyzed the relationship between the C7 expression and prognosis of 149 patients treated with conventional TE (taxane and anthracycline)-based chemotherapy. Then, a cohort of patients (22 cases) treated with TE neoadjuvant chemotherapy was used to further confirm the relationship between the C7 expression and TE-based chemosensitivity. RESULTS: In our present study, we reported for the first time that C7 was an independent prognostic factor of breast cancer and C7 expression of IDC tissues was higher than non-neoplastic tissues adjacent to tumor and DCIS. In a cohort of 331 IDC patients, high expression of C7 indicated poor prognosis especially in the triple negative subtype and luminal B subtype. Furthermore, C7 was also a promoting factor for triple negative subtype patients to develop bone metastasis. Meanwhile, we provided the first evidence that patients with high C7 expression were insensitive to TE (taxane and anthracycline)-based chemotherapy by analyzing a cohort of 149 patients treated with TE-based chemotherapy and another cohort of 22 patients treated with TE neoadjuvant chemotherapy. CONCLUSIONS: In summary, high expression of C7 may promote breast cancer development and might be insensitive to TE-based chemotherapy. Our present study laid a foundation to help clinicians improve the identification of patients for TE-based chemotherapy by C7 in the era of precision medicine.

11.
Cell Death Dis ; 12(10): 922, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34625530

RESUMO

Breast cancer is the most common type of cancer worldwide. However, the well-known molecular biomarkers are not enough to meet the needs of precision medicine. In search for novel targets in this regard, we reported ITSN1 (intersectin1) as one of the candidates through mRNA microarray analysis. In the present study, we reported that endocytic protein ITSN1-S exists not only in the cytoplasm but also in nuclei of breast cancer cells. ITSN1-S' functional nuclear localization signal is within its residues 306-312. Its nuclear export signal (NES) resides within its SH3 domains. We also found, the interaction between the CC domain of nuclear ITSN1-S and the NT domain of nuclear DNA helicase II (NDH II) directly suppressed the DNA replication and nascent DNA synthesis by inhibiting the R-loops resolution in breast cancer cells. Furthermore, the interaction between the EH domains of cytoplasmic ITSN1-S and PI3KC2α inhibit cell migration and invasion by inactivating the PI3KC2α-AKT pathway. Our results were confirmed in both ITSN1 gene knockout cells and in vivo assays. Finally, our clinical data showed a potential application of the combined consideration of the cytoplasmic and nuclear ITSN1-S as an independent prognosis factor. In conclusion, our study revealed ITSN1-S' novel positioning in the nuclei of breast cancer cells, its function in suppressing DNA replication, and its potential application in improved breast cancer prognosis.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Neoplasias da Mama/metabolismo , Núcleo Celular/metabolismo , Replicação do DNA , Proteínas Adaptadoras de Transporte Vesicular/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , DNA de Neoplasias/biossíntese , Endocitose , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Sinais de Localização Nuclear , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Cicatrização , Domínios de Homologia de src
12.
Plant Cell ; 33(10): 3235-3249, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34338800

RESUMO

Protein S-acylation is an important post-translational modification in eukaryotes, regulating the subcellular localization, trafficking, stability, and activity of substrate proteins. The dynamic regulation of this reversible modification is mediated inversely by protein S-acyltransferases and de-S-acylation enzymes, but the de-S-acylation mechanism remains unclear in plant cells. Here, we characterized a group of putative protein de-S-acylation enzymes in Arabidopsis thaliana, including 11 members of Alpha/Beta Hydrolase Domain-containing Protein 17-like acyl protein thioesterases (ABAPTs). A robust system was then established for the screening of de-S-acylation enzymes of protein substrates in plant cells, based on the effects of substrate localization and confirmed via the protein S-acylation levels. Using this system, the ABAPTs, which specifically reduced the S-acylation levels and disrupted the plasma membrane localization of five immunity-related proteins, were identified respectively in Arabidopsis. Further results indicated that the de-S-acylation of RPM1-Interacting Protein 4, which was mediated by ABAPT8, resulted in an increase of cell death in Arabidopsis and Nicotiana benthamiana, supporting the physiological role of the ABAPTs in plants. Collectively, our current work provides a powerful and reliable system to identify the pairs of plant protein substrates and de-S-acylation enzymes for further studies on the dynamic regulation of plant protein S-acylation.


Assuntos
Arabidopsis/enzimologia , Ensaios de Triagem em Larga Escala/instrumentação , Hidrolases/química , Células Vegetais/enzimologia , Proteínas de Plantas/análise , Acilação
13.
Inorg Chem ; 60(16): 12109-12115, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34313442

RESUMO

Chromium(III)-based metal-organic frameworks (Cr-MOFs) are highly robust and porous and have been very attractive in a wide range of investigations. However, the harsh direct synthetic conditions not only impede the synthesis of new Cr-MOFs but also restrict the introduction of functional groups into them. Postsynthetic modification has somewhat alleviated such difficulties; nevertheless, it still suffered from procedures that are tedious and conditions that are not mild, which often result in low concentration of the functional groups introduced. To overcome these shortcomings, here, in this paper, we supplied a new route and prepared a benzyl alcohol functionalized Cr-SXU-2 from the judiciously designed benzyl alcohol functionalized Fe-SXU-2 through solvent-assisted metal metathesis strategy. The functionalized Cr-SXU-2 shows well-preserved crystallinity, porosity, and high chemical stability. The benzyl alcohol group can be converted into a very active benzyl bromide group in an almost quantitative yield and thus for the first time produce the benzyl bromide functionalized MOF, Cr-SXU-2-Br, in which the -Br group can be exchanged by a nucleophilic group. As a proof of concept, -N3 was introduced and transformed into other active sites via "click reaction" to further tailor the interior of Cr-SXU-2. All these functionalized Cr-MOFs showed improved adsorption performance in contrast to the nonfunctionalized one. This step-by-step postmodification process not only diversifies the functionalization of robust MOFs but also opens a new route to employ many different functional groups in the demanding highly stable Cr-MOF platforms.

14.
Proc Natl Acad Sci U S A ; 118(20)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-33975955

RESUMO

Bismuth and rare earth elements have been identified as effective substituent elements in the iron garnet structure, allowing an enhancement in magneto-optical response by several orders of magnitude in the visible and near-infrared region. Various mechanisms have been proposed to account for such enhancement, but testing of these ideas is hampered by a lack of suitable experimental data, where information is required not only regarding the lattice sites where substituent atoms are located but also how these atoms affect various order parameters. Here, we show for a Bi-substituted lutetium iron garnet how a suite of advanced electron microscopy techniques, combined with theoretical calculations, can be used to determine the interactions between a range of quantum-order parameters, including lattice, charge, spin, orbital, and crystal field splitting energy. In particular, we determine how the Bi distribution results in lattice distortions that are coupled with changes in electronic structure at certain lattice sites. These results reveal that these lattice distortions result in a decrease in the crystal-field splitting energies at Fe sites and in a lifted orbital degeneracy at octahedral sites, while the antiferromagnetic spin order remains preserved, thereby contributing to enhanced magneto-optical response in bismuth-substituted iron garnet. The combination of subangstrom imaging techniques and atomic-scale spectroscopy opens up possibilities for revealing insights into hidden coupling effects between multiple quantum-order parameters, thereby further guiding research and development for a wide range of complex functional materials.

15.
Ann Clin Transl Neurol ; 8(4): 898-907, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33756069

RESUMO

OBJECTIVE: We aimed to summarize the clinical, genetic, and myopathological features of a cohort of Chinese patients with congenital myasthenic syndrome, and follow up on therapeutic outcomes. METHODS: The clinical spectrum, mutational frequency of genes, and pathological diagnostic clues of various subtypes of patients with congenital myasthenic syndrome were summarized. Therapeutic effects were followed up. RESULTS: Thirty-five patients from 29 families were recruited. Ten genes were identified: GFPT1 (27.6%), AGRN (17.2%), CHRNE (17.2%), COLQ (13.8%), GMPPB (6.9%), CHAT, CHRNA1, DOK7, COG7, and SLC25A1 (3.4% each, respectively). Sole limb-girdle weakness was found in patients with AGRN (1/8) and GFPT1 (7/8) mutations, whereas distal weakness was all observed in patients with AGRN (6/8) mutations. Tubular aggregates were only found in patients with GFPT1 mutations (5/6). The patients with GMPPB mutations (2/2) had decreased alpha-dystroglycan. Acetylcholinesterase inhibitor therapy resulted in no response or worsened symptoms in patients with COLQ mutations, a diverse response in patients with AGRN mutations, and a good response in patients with other subtypes. Albuterol therapy was effective or harmless in most subtypes. Therapy effects became attenuated with long-term use in patients with COLQ or AGRN mutations. INTERPRETATION: The genetic distribution of congenital myasthenic syndrome in China is distinct from that of other ethnic origins. The appearance of distal weakness, selective limb-girdle myasthenic syndrome, tubular aggregates, and decreased alpha-dystroglycan were indicative of the specific subtypes. Based on the follow-up findings, we suggest cautious evaluation of the long-term efficacy of therapeutic agents in congenital myasthenic syndrome.


Assuntos
Inibidores da Colinesterase/farmacologia , Músculo Esquelético/patologia , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/patologia , Adolescente , Adulto , Criança , Pré-Escolar , China , Feminino , Seguimentos , Humanos , Masculino , Síndromes Miastênicas Congênitas/tratamento farmacológico , Síndromes Miastênicas Congênitas/fisiopatologia , Linhagem , Resultado do Tratamento , Adulto Jovem
16.
Brain ; 144(6): 1819-1832, 2021 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-33693509

RESUMO

Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ocular, facial, pharyngeal and distal limb muscle involvement. Trinucleotide repeat expansions in LRP12 or GIPC1 were recently reported to be associated with OPDM. However, a significant portion of OPDM patients have unknown genetic causes. In this study, long-read whole-genome sequencing and repeat-primed PCR were performed and we identified GGC repeat expansions in the NOTCH2NLC gene in 16.7% (4/24) of a cohort of Chinese OPDM patients, designated as OPDM type 3 (OPDM3). Methylation analysis indicated that methylation levels of the NOTCH2NLC gene were unaltered in OPDM3 patients, but increased significantly in asymptomatic carriers. Quantitative real-time PCR analysis indicated that NOTCH2NLC mRNA levels were increased in muscle but not in blood of OPDM3 patients. Immunofluorescence on OPDM muscle samples and expressing mutant NOTCH2NLC with (GGC)69 repeat expansions in HEK293 cells indicated that mutant NOTCH2NLC-polyglycine protein might be a major component of intranuclear inclusions, and contribute to toxicity in cultured cells. In addition, two RNA-binding proteins, hnRNP A/B and MBNL1, were both co-localized with p62 in intranuclear inclusions in OPDM muscle samples. These results indicated that a toxic protein gain-of-function mechanism and RNA gain-of-function mechanism may both play a vital role in the pathogenic processes of OPDM3. This study extended the spectrum of NOTCH2NLC repeat expansion-related diseases to a predominant myopathy phenotype presenting as OPDM, and provided evidence for possible pathogenesis of these diseases.


Assuntos
Distrofias Musculares/genética , Expansão das Repetições de Trinucleotídeos/genética , /genética , China , Estudos de Coortes , Feminino , Humanos , Masculino , Distrofias Musculares/patologia , Linhagem
17.
Hear Res ; 404: 108211, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33684887

RESUMO

The cochlear implant (CI) has an effective habilitation modality for hearing-impaired children by promoting sound perception, vocalization, and language ability. However, the major challenge that remained was the lack of assessment standards for pediatric CI users, especially prelingually deaf children, to evaluate hearing rehabilitation effectiveness. In the present study, we conducted an oddball paradigm with stimuli varying in pure-tone, syllable, and tonal sounds. After implantation, we utilized cortical auditory evoked potential (CAEP) and mismatch negativity (MMN) to obtain time-domain analysis; meanwhile, the source localization was investigated to obtain spatial accuracy of the plasticity in the auditory cortex. P1 started to emerge at the third month after implantation, but its peak level was not significant until the sixth month. The temporal lobe was activated between the third and sixth months after implantation. The MMN waveform was basically normal approximately after 12 months. These results suggest that the auditory system goes through a critical period of rapid development between three and six months and enters a maturation period after 12 months. This work indicates that CAEPs are more suitable for assessing the early auditory system reconstruction, while MMN performs better in evaluating the advanced auditory function. Furthermore, source localization has proven to be an efficient tool in exploring auditory cortex plasticity, especially for pediatric CI users.


Assuntos
Córtex Auditivo , Implante Coclear , Implantes Cocleares , Surdez , Percepção da Fala , Criança , Surdez/diagnóstico , Surdez/cirurgia , Eletroencefalografia , Potenciais Evocados Auditivos , Humanos
18.
Ann Clin Transl Neurol ; 8(3): 677-686, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33576578

RESUMO

OBJECTIVE: This study aimed to investigate mitochondrial changes and the mitochondrial antiviral-signaling protein (MAVS)-type I interferon (IFN1) signaling pathway in the muscles of anti-melanoma differentiation gene 5(MDA5) dermatomyositis (DM) patients. METHODS: Eleven anti-MDA5 DM and ten antibody-negative DM patients were included. Muscle biopsies were performed in all patients. Muscle pathology and mitochondrial morphology in particular were compared between two groups. The expression of MDA5, MAVS, interferon (IFN) regulatory factor 7, and IFN-stimulated gene 15, which are components of the MAVS-IFN1 signaling pathway, was measured in muscle specimen. The correlation between MAVS expression in muscles and disease phenotypes and muscle pathology were analyzed. RESULTS: Anti-MDA5 DM showed a significantly lower incidence of the characteristic DM pathology (P < 0.05) than antibody-negative DM, including perifascicular fiber atrophy, inflammation, and vasculopathy. Mitochondrial abnormalities in anti-MDA5 patients revealed a high incidence of (8/11,72.7%) and different pattern from that in antibody-negative DM. MDA5, MAVS, IFN regulatory factor 7, and IFN stimulated gene 15 expression levels in the muscles of anti-MDA5 DM patients were higher than those of the controls (P < 0.05) but lower than those of antibody-negative DM patients (P < 0.05). The MAVS levels negatively correlated with manual muscle test 8 scores (r = 0.701, P = 0.016). CONCLUSIONS: Compared to antibody-negative DM, we presented a different distribution of the mitochondrial pathology and less severe morphology in anti-MDA5 DM. We also revealed the enhanced but less intensive MAVS-IFN1 signaling pathway activity in muscles of anti-MDA5 DM. Such disparity suggested the potentially different mechanism of muscle injury in two DM groups.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Dermatomiosite , Interferon Tipo I/metabolismo , Helicase IFIH1 Induzida por Interferon/imunologia , Mitocôndrias/patologia , Músculo Esquelético/metabolismo , Adulto , Idoso , Dermatomiosite/imunologia , Dermatomiosite/metabolismo , Dermatomiosite/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transdução de Sinais/fisiologia
19.
Exp Appl Acarol ; 83(2): 271-283, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33452939

RESUMO

Defensins are the most diverse groups of antimicrobial peptides in invertebrate animals. In ticks, defensins show great potential as targets for tick control, and display future prospect for therapeutic drug development. In the present study, a novel defensin-like gene (Ds-defensin) contributing to the antimicrobial and antioxidant capacity of the tick Dermacentor silvarum was characterized. The full-length of the Ds-defensin gene was 382 bp, which displayed tissue-specific expression and was highly abundant in the salivary glands and carcasses of the adults. It encodes a 71-amino acid defensin-like protein, and the protein precursor is characterized by a 22-amino acid signal peptide and a 34-amino acid mature peptide. The peptide displayed potent activity against most of the tested gram-positive bacteria, including Staphylococcus aureus, S. carnosus and Nocardia asteroides, and one tested gram-negative bacterium, Psychrobacter faecalis. Scanning electron microscopy revealed that the cell wall and surface of treated bacteria became rough and gradually formed pores after a 30-min exposure to the Ds-defensin peptide. Additionally, the peptide also showed significant antioxidant capacity. The above results implied that the defensin-like peptide may play an important role in tick defense and the interaction with microorganisms.


Assuntos
Anti-Infecciosos , Dermacentor , Ixodidae , Sequência de Aminoácidos , Animais , Anti-Infecciosos/farmacologia , Antioxidantes , Defensinas/genética , Peptídeos , Psychrobacter
20.
Colloids Surf B Biointerfaces ; 197: 111355, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33010720

RESUMO

Physiological reflexes and anatomical barriers render traditional eye drop delivery inefficient. We previously reported that drug-loaded nanoparticles and microspheres prepared from montmorillonite and Eudragit polymers exhibited good sustained-release and lowered intraocular pressure. Here, we compared the performance of optimized formulations to select the most suitable formulation for glaucoma therapy. We found that the microspheres had much higher encapsulation efficiency and drug loading than nanoparticles. Moreover, cytocompatibility experiments demonstrated that nanoparticles showed more severe cytotoxicity than microspheres, probably due to their smaller particles, enhanced cell uptake, and intracellular solubility. Interestingly, the pre-corneal retention time of nanoparticles reflected a clear advantage over microspheres, while the duration of the pharmacological effect of nanoparticles was not as good as that of microspheres: compared with the nanoparticle depressurization duration of only 8 h, the microspheres continuously depressurized for 12 h. The slower release of the microspheres and its micro-interaction mechanism with the discontinuous mucin layer of the tear film led to the inconsistency between duration of pharmacodynamics and fluorescence ocular retention time. In summary, the lower cytotoxicity and longer pharmacological effect of microspheres indicate their potential advantages for glaucoma applications.


Assuntos
Mucinas , Nanopartículas , Preparações de Ação Retardada , Troca Iônica , Microesferas , Tamanho da Partícula
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