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Chromatin regulators (CRs) regulate epigenetic patterns on a partial or global scale, playing a critical role in affecting multi-target gene expression. As chromatin immunoprecipitation sequencing (ChIP-seq) data associated with CRs are rapidly accumulating, a comprehensive resource of CRs needs to be built urgently for collecting, integrating, and processing these data, which can provide abundant annotated information on CR upstream and downstream regulatory analyses as well as CR-related analysis functions. This study established an integrative CR resource, named CRdb (http://cr.liclab.net/crdb/), with the aim of curating a large number of available resources for CRs and providing extensive annotations and analyses of CRs to help biological researchers clarify the regulation mechanism and function of CRs. The CRdb database comprised a total of 647 CRs and 2,591 ChIP-seq samples from more than 300 human tissues and cell types. These samples have been manually curated from NCBI GEO/SRA and ENCODE. Importantly, CRdb provided the abundant and detailed genetic annotations in CR-binding regions based on ChIP-seq. Furthermore, CRdb supported various functional annotations and upstream regulatory information on CRs. In particular, it embedded four types of CR regulatory analyses: CR gene set enrichment, CR-binding genomic region annotation, CR-TF co-occupancy analysis, and CR regulatory axis analysis. CRdb is a useful and powerful resource that can help in exploring the potential functions of CRs and their regulatory mechanism in diseases and biological processes.
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Cromatina , Bases de Datos Genéticas , Genómica , Humanos , Cromatina/genética , Bases de Datos Factuales , Genoma , Anotación de Secuencia MolecularRESUMEN
BACKGROUND: The C2H2 zinc finger protein family plays important roles in plants. However, precisely how C2H2s function in Opisthopappus (Opisthopappus taihangensis and Opisthopappus longilobus) remains unclear. RESULTS: In this study, a total of 69 OpC2H2 zinc finger protein genes were identified and clustered into five Groups. Seven tandem and ten fragment repeats were found in OpC2H2s, which underwent robust purifying selection. Of the identified motifs, motif 1 was present in all OpC2H2s and conserved at important binding sites. Most OpC2H2s possessed few introns and exons that could rapidly activate and react when faced with stress. The OpC2H2 promoter sequences mainly contained diverse regulatory elements, such as ARE, ABRE, and LTR. Under salt stress, two up-regulated OpC2H2s (OpC2H2-1 and OpC2H2-14) genes and one down-regulated OpC2H2 gene (OpC2H2-7) might serve as key transcription factors through the ABA and JA signaling pathways to regulate the growth and development of Opisthopappus species. CONCLUSION: The above results not only help to understand the function of C2H2 gene family but also drive progress in genetic improvement for the salt tolerance of Opisthopappus species.
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Dedos de Zinc CYS2-HIS2 , Dedos de Zinc CYS2-HIS2/genética , Estrés Salino/genética , Genoma de Planta , Factores de Transcripción/metabolismo , Dedos de Zinc/genética , Proteínas de Plantas/metabolismo , Regulación de la Expresión Génica de las Plantas , FilogeniaRESUMEN
BACKGROUND: Dietary assessment methods have limitations in capturing real-time eating behaviour accurately. Equipped with automated dietary-data-collection capabilities, the "intelligent ordering system" (IOS) has potential applicability in obtaining long-term consecutive, relatively detailed on-campus dietary records among university students with little resource consumption. We investigated (1) the relative validity of IOS-derived nutrient/food intakes compared to those from the 7-day food diary (7DFD); (2) whether including a supplemental food frequency questionnaire (SFFQ) improves IOS accuracy; and (3) sex differences in IOS dietary intake estimation. METHODS: Medical students (n = 221; age = 22.2 ± 2.4 years; 38.5% male and 61.5% female) completed the 7DFD and SFFQ. During the consecutive 7-day survey period, students weighed and photographed each meal before and after consumption. Then, students reviewed their 3-month diet and completed the SFFQ, which includes eight underprovided school-canteen food items (e.g., dairy, fruits, nuts). Meanwhile, 9385 IOS dietary data entries were collected. We used Spearman coefficients and linear regression models to estimate the associations among the different dietary intake assessment methods. Individual- and group-level agreement was assessed using the Wilcoxon signed-rank test, cross-classification, and BlandâAltman analysis. RESULTS: IOS mean daily energy, protein, fat, and carbohydrate intake estimations were significantly lower (-15-20%) than those of the 7DFD. The correlation coefficients varied from 0.52 (for added sugar) to 0.88 (for soybeans and nuts), with fruits (0.37) and dairy products (0.29) showing weaker correlations. Sixty-two (milk and dairy products) to 97% (soybeans and nuts) of participants were classified into the same or adjacent dietary intake distribution quartile using both methods. The energy and macronutrient intake differences between the IOS + SFFQ and 7DFD groups decreased substantially. The separate fruit intake measurements from each assessment method did not significantly differ from each other (p > 0.05). IOS and IOS + SFFQ regression models generally yielded higher R2 values for males than for females. CONCLUSION: Despite estimation differences, the IOS can be reliable for medical student dietary habit assessment. The SFFQ is useful for measuring consumption of foods that are typically unavailable in school cafeterias, improving the overall dietary evaluation accuracy. The IOS assessment was more accurate for males than for females.
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Registros de Dieta , Dieta , Conducta Alimentaria , Estudiantes de Medicina , Humanos , Femenino , Masculino , Adulto Joven , Estudiantes de Medicina/estadística & datos numéricos , China , Universidades , Reproducibilidad de los Resultados , Facultades de Medicina , Encuestas y Cuestionarios , Ingestión de Energía , Evaluación Nutricional , Encuestas sobre Dietas/métodos , AdultoRESUMEN
OBJECTIVES: (1) Assess the prevalence of postoperative insomnia; (2) identify the risk factors for postoperative insomnia before exposure to surgery; (3) explore the impact of postoperative insomnia on rehabilitation. METHODS: A study was conducted with 132 participants aged ≥ 65 undergoing spine interbody fusion. We collected the basic demographic data, Numeric Rating Scales (NRS), Pittsburgh Sleep Quality Index (PSQI), Geriatric Depression Scale (GDS), and Beck Anxiety Inventory (BAI). We measured Quality of Recovery 40 (QoR-40), GDS, BAI, NRS, and PSQI on the first and third nights post-surgery, followed by QoR-40 and NRS assessments two weeks after surgery. RESULTS: The cases of postoperative insomnia on the first and third nights and after two weeks were 81 (61.36%), 72 (54.55%), and 64 (48.48%), respectively, and the type of insomnia was not significantly different (P = 0.138). Sleep efficiency on the first night was 49.96% ± 23.51. On the first night of postoperative insomnia, 54 (66.67%) cases were depression or anxiety, and the PSQI was higher in this group than in the group without anxiety or depression (P < 0.001). PSQI, GDS, and the time of surgery were related factors for postoperative insomnia (PPSQI < 0.001, PGDS = 0.008, and PTime = 0.040). Postoperative rehabilitation showed differences between the insomnia and non-insomnia groups (P < 0.001). CONCLUSIONS: The prevalence of postoperative insomnia in the elderly was high, and postoperative insomnia had a significant correlation with postoperative rehabilitation. Interventions that target risk factors may reduce the prevalence of postoperative insomnia and warrant further research. CLINICAL TRIAL REGISTRATION: Multivariate analysis of postoperative insomnia in elderly patients with spinal surgery and its correlation with postoperative rehabilitation ( https://www.chictr.org.cn/bin/project/edit?pid=170201 ; #ChiCTR2200059827).
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Transcription co-factors (TcoFs) play crucial roles in gene expression regulation by communicating regulatory cues from enhancers to promoters. With the rapid accumulation of TcoF associated chromatin immunoprecipitation sequencing (ChIP-seq) data, the comprehensive collection and integrative analyses of these data are urgently required. Here, we developed the TcoFBase database (http://tcof.liclab.net/TcoFbase), which aimed to document a large number of available resources for mammalian TcoFs and provided annotations and enrichment analyses of TcoFs. TcoFBase curated 2322 TcoFs and 6759 TcoFs associated ChIP-seq data from over 500 tissues/cell types in human and mouse. Importantly, TcoFBase provided detailed and abundant (epi) genetic annotations of ChIP-seq based TcoF binding regions. Furthermore, TcoFBase supported regulatory annotation information and various functional annotations for TcoFs. Meanwhile, TcoFBase embedded five types of TcoF regulatory analyses for users, including TcoF gene set enrichment, TcoF binding genomic region annotation, TcoF regulatory network analysis, TcoF-TF co-occupancy analysis and TcoF regulatory axis analysis. TcoFBase was designed to be a useful resource that will help reveal the potential biological effects of TcoFs and elucidate TcoF-related regulatory mechanisms.
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Bases de Datos Genéticas , Redes Reguladoras de Genes , Programas Informáticos , Factores de Transcripción/genética , Transcripción Genética , Animales , Cromatina/química , Cromatina/metabolismo , Conjuntos de Datos como Asunto , Elementos de Facilitación Genéticos , Regulación de la Expresión Génica , Humanos , Internet , Ratones , Anotación de Secuencia Molecular , Regiones Promotoras Genéticas , Factores de Transcripción/clasificación , Factores de Transcripción/metabolismoRESUMEN
The use of eye-tracking technology in dental esthetics has gained popularity over the past decade because of its ability to assess observers' visual preferences in an objective manner. The goal of this study was to provide a comprehensive review of eye-tracking studies in dentistry, which could provide a reference for the rational and effective application of eye-tracking technology by dentists in the future. A comprehensive search of articles on eye tracking, published from January 1946 to June 2023, was conducted across several databases using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The major criterion for inclusion was that the study evaluated the use of eye-tracking technology in the field of dentistry. Two independent reviewers screened the eligible studies. A total of 67 articles were identified, 41 of which met our inclusion criteria. The most common application of eye tracking was the assessment of perceptions of changes in specific dental conditions among different classes of observers. Overall differences between groups (different classes of observers, different types of conditions) among different areas or regions of interest were analyzed. This systematic review demonstrated the utility of eye-tracking technology as a quantifiable objective assessment and emerging research tool for evaluating outcomes in several domains of dentistry.
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Estética Dental , Tecnología de Seguimiento Ocular , HumanosRESUMEN
Salt stress profoundly affects plant growth, prompting intricate molecular responses, such as alternative splicing (AS), for environmental adaptation. However, the response of AS events to salt stress in Opisthopappus (Opisthopappus taihangensis and Opisthopappus longilobus) remains unclear, which is a Taihang Mountain cliff-dwelling species. Using RNA-seq data, differentially expressed genes (DEGs) were identified under time and concentration gradients of salt stress. Two types of AS, skipped exon (SE) and mutually exclusive exons (MXE), were found. Differentially alternative splicing (DAS) genes in both species were significantly enriched in "protein phosphorylation", "starch and sucrose metabolism", and "plant hormone signal transduction" pathways. Meanwhile, distinct GO terms and KEGG pathways of DAS occurred between two species. Only a small subset of DAS genes overlapped with DEGs under salt stress. Although both species likely adopted protein phosphorylation to enhance salt stress tolerance, they exhibited distinct responses. The results indicated that the salt stress mechanisms of both Opisthopappus species exhibited similarities and differences in response to salt stress, which suggested that adaptive divergence might have occurred between them. This study initially provides a comprehensive description of salt responsive AS events in Opisthopappus and conveys some insights into the molecular mechanisms behind species tolerance on the Taihang Mountains.
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Empalme Alternativo , Estrés Salino , Estrés Salino/genética , RNA-Seq , Tolerancia a la Sal/genética , Reguladores del Crecimiento de las Plantas , Regulación de la Expresión Génica de las Plantas , Transcriptoma , Perfilación de la Expresión GénicaRESUMEN
We present a case report on a spot diagnosis of Thyrotoxic Periodic Paralysis (TPP) with a unique first-person account of events from the patient. It illustrates the importance of pattern recognition and exemplifies how timely treatment enables quick resolution of a life-threatening medical emergency. Patient X's account affirms the condition's insidious onset and rapid deterioration. This case highlights the need for raising awareness of diseases that are more prevalent in specific ethnic groups and is particularly crucial for work in culturally diverse environments. We hope by sharing our experience, readers will be prompted to consider TPP as a differential diagnosis for acute limb weakness in an acute setting; with prompt testing of thyroid function and initiation of the appropriate treatments.
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Antitiroideos , Humanos , Diagnóstico Diferencial , Masculino , Adulto , Antitiroideos/uso terapéutico , Tirotoxicosis/complicaciones , Tirotoxicosis/diagnósticoRESUMEN
Insect kinins are endogenous, biologically active peptides with various physiological functions. The use of insect kinins in plant protection is being evaluated by many groups. Some kinins have been chosen as lead compounds for pest control. We previously reported an insect kinin mimic IV-3 that had insecticidal activity. And by introducing a strong electron withdrawing group (-CF3 ) on the benzene ring (Phe2 ), we discovered a compound, L7 , with better activity than lead IV-3. In this work, taking L7 as the lead compound, we designed and synthesized 13 compounds to evaluate the influence of position 4 (Trp4 ) of insect kinin on insecticidal activity, by replacing the H atom on tryptophan with -CH3 and -Cl or substituting the indole ring of tryptophan with the benzene, naphthalene, pyridine, imidazole, cyclohexane, and alkyl carboxamides. The aphid bioassay results showed that the compounds M1 , M3 , and M5 were more active than the positive control, pymetrozine. Especially, replacing the side chain by an indole ring with 4-Cl substitution (M1 , LC50 = 0.0029 mmol/L) increased the aphicidal activity. The structure-activity relationships (SARs) indicated that the side chain benzene ring at this position may be important to the aphicidal activity. In addition, the toxicity prediction by Toxtree, and the toxicity experiments on Apis mellifera suggested that M1 was no toxicity risk on a non-target organism. It could be used as a selective and bee-friendly insecticide to control aphids.
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Áfidos , Animales , Abejas , Benceno , Cininas , TriptófanoRESUMEN
BACKGROUND: Generalized pustular psoriasis (GPP) is a rare and life-threatening autoinflammatory dermatological disease. IL36RN was reported to be the main pathogenetic basis for GPP. Only a few studies have reported on the correlation analysis of IL36RN variants and the phenotype of pediatric-onset GPP. METHODS: IL36RN was screened in 60 children diagnosed with GPP from January 2013 to January 2020, and their detailed clinical profiles were obtained. RESULTS: Forty-six out of 60 (76.67%) patients harbored IL36RN variants, and six IL36RN variants were found, of which two were novel variants that were reported for the first time. The frequency of IL36RN variants was significantly different among the subtypes of GPP (GPP with acrodermatitis continua of Hallopeau group (ACH), 100%; GPP without plaque psoriasis (PV) and ACH, 78.05%; GPP with PV group, 44.44%) (p = 0.018), while the percentage of IL36RN variants in the GPP with ACH group was higher than that in the GPP with PV group (p < 0.05). IL36RN variants were associated with a lower percentage of PV, longer length of hospitalization, and longer time to reach normal body temperature after treatment (p < 0.05). After treatment, marked responses, moderate responses, and no responses were recorded in 75.00%, 8.33%, and 16.67% of patients, respectively. No significant difference was observed during efficacy assessment in patients with or without IL36RN variants (χ2 = 1.122, p > 0.05). CONCLUSIONS: IL36RN variants are associated with GPP with ACH subtypes, an absence of concurrent PV, and a greater extent of severe inflammation. Acitretin was an effective treatment for patients in our study and mostly resulted in a marked response in our cohort.
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Psoriasis , Enfermedades Cutáneas Vesiculoampollosas , Humanos , Acitretina/uso terapéutico , Enfermedad Aguda , Enfermedad Crónica , Interleucinas/genética , Psoriasis/tratamiento farmacológico , Psoriasis/genética , Psoriasis/patología , Enfermedades Cutáneas Vesiculoampollosas/genética , Resultado del TratamientoRESUMEN
In this paper, high-throughput sequencing technology was adopted to visualize the microbial communities on the surfaces of two types of carbon steel immersed in Sea Area â . The results showed that different microbial communities were formed on different carbon steel surfaces, in which the genus with the highest abundance on the surface of Q235 was Escherichia-Shigella, while anaerobic Desulfovibrio on the surface of 921a was the most abundant, and the dominant genus varied with the depth of the rust layer. In addition, the distribution of sulfate-reducing bacteria (SRB) on the surface of Q235 submerged in Sea Area â ¡ was compared with the sulfate-reducing bacteria's distribution in Sea Area â , using the environmental factors correlation analysis. The results showed that the concentrations of Ca2+, Na+, K+, Mg2+, and Al3+ were positively correlated with the distribution of SRB, while the concentrations of Cu2+, Zn2+, SO4 2-, Cl-, NO3 -, and organic carbon were negatively correlated with it. Furthermore, there was a highly significant correlation between each geochemical factor and Desulfotomaculum (p < 0.01).
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Cáusticos , Microbiota , Acero , Agua de Mar/microbiología , Sulfatos , CarbonoRESUMEN
BACKGROUND: Glioma stem cells (GSCs) are responsible for glioma recurrence and drug resistance, yet the mechanisms underlying their maintenance remains unclear. This study aimed to identify enhancer-controlled genes involved in GSCs maintenance and elucidate the mechanisms underlying their regulation. METHODS: We analyzed RNA-seq data and H3K27ac ChIP-seq data from GSE119776 to identify differentially expressed genes and enhancers, respectively. Gene Ontology analysis was performed for functional enrichment. Transcription factors were predicted using the Toolkit for Cistrome Data Browser. Prognostic analysis and gene expression correlation was conducted using the Chinese Glioma Genome Atlas (CGGA) data. Two GSC cell lines, GSC-A172 and GSC-U138MG, were isolated from A172 and U138MG cell lines. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to detect H3K27ac of enhancers, and binding of E2F4 to target gene enhancers. Western blot was used to analyze protein levels of p-ATR and γH2AX. Sphere formation, limiting dilution and cell growth assays were used to analyze GSCs growth and self-renewal. RESULTS: We found that upregulated genes in GSCs were associated with ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) pathway activation, and that seven enhancer-controlled genes related to ATR pathway activation (LIN9, MCM8, CEP72, POLA1, DBF4, NDE1, and CDKN2C) were identified. Expression of these genes corresponded to poor prognosis in glioma patients. E2F4 was identified as a transcription factor that regulates enhancer-controlled genes related to the ATR pathway activation, with MCM8 having the highest hazard ratio among genes positively correlated with E2F4 expression. E2F4 bound to MCM8 enhancers to promote its transcription. Overexpression of MCM8 partially restored the inhibition of GSCs self-renewal, cell growth, and the ATR pathway activation caused by E2F4 knockdown. CONCLUSION: Our study demonstrated that E2F4-mediated enhancer activation of MCM8 promotes the ATR pathway activation and GSCs characteristics. These findings offer promising targets for the development of new therapies for gliomas.
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Glioma , Humanos , Glioma/genética , Glioma/metabolismo , Factores de Transcripción/metabolismo , Proliferación Celular/genética , Células Madre Neoplásicas/metabolismo , Proteínas de Mantenimiento de Minicromosoma/metabolismo , Factor de Transcripción E2F4/metabolismo , Proteínas Asociadas a Microtúbulos , Proteínas de la Ataxia Telangiectasia Mutada/metabolismoRESUMEN
Allatostatin (AS) or Allatotropin (AT) is a class of insect short neuropeptide F (sNPF) that affects insect growth and development by inhibiting or promote the synthesis of juvenile hormone (JH) in different insects. III-2 is a novel sNPF analog derived from a group of nitroaromatic groups connected by different amino acids. In this study, we found that III-2 showed high insecticidal activity against S. frugiperda larvae with a LC50 of 18.7 mg L-1. As demonstrated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), III-2 particularly facilitated JH III and hindered 20E synthesis in S. frugiperda. The results of RNA-Seq and quantitative real-time polymerase chain reaction (qPCR) showed that III-2 treatment promoted the expression of key genes such as SfCYP15C1 in JH synthesis pathway and inhibited the expression of SfCYP314A1 and other genes in the 20E synthetic pathway. Significant differences were also observed in the expression of the genes related to cuticle formation. We report for the first time that sNPF compounds specifically interfere with the synthesis and secretion of a certain JH in insects, thus affecting the ecdysis and growth of insects, and leading to death. This study may provide a new plant conservation concept for us to seek the targeted control of certain insects based on specific interference with different JH.
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Hormonas Juveniles , Espectrometría de Masas en Tándem , Animales , Spodoptera/genética , Spodoptera/metabolismo , Cromatografía Liquida , Hormonas Juveniles/farmacología , Hormonas Juveniles/metabolismo , Larva/metabolismo , InsectosRESUMEN
OBJECTIVES: The purpose of this study was to survey the prevalence of C-shaped root canal system in mandibular first premolar in Chinese population by reading Cone-beam computed tomography (CBCT) images and to analyze its anatomical characteristics by CBCT and Micro-computed tomography (Micro-CT). METHODS AND MATERIALS: The prevalence and the morphologic features of C-shaped root canal system were evaluated by observing CBCT images of 760 patients (1520 mandibular first premolars). 66 mandibular first premolars with C-shaped root canal system were scanned by Micro-CT. The morphologic features including radicular groove, C-shaped root canal categories in the cross-sections and in the 3D models, accessory and connecting canals, apical foramina and accessory foramina, were analyzed using image software. RESULTS: C-shaped root canal system was identified in 16.9% of mandibular first premolars. The minimum mesial wall thickness most commonly occurred at the lingual site (69.7%). Regarding to the cross-sectional classification, the maximum was C2 (41.5%). In the 3D classification, the most common was S (34.8%). Accessory canals were observed in 36.4% of the samples and occurred mostly in the middle and apical regions. 42.4% samples had 1-3 variable connecting canals, and 40.9% samples had only one apical foramen. CONCLUSIONS: The incidence of C-shaped root canal system in mandibular first premolars was 16.9% in the Chinese population. The anatomy was very complex and variable, mostly distributed in the middle and apical regions of the root canal. The mesial wall of C-shaped canal was extremely thin on the lingual side.
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Pueblos del Este de Asia , Tomografía Computarizada de Haz Cónico Espiral , Humanos , Microtomografía por Rayos X , Diente Premolar/diagnóstico por imagen , Diente Premolar/anatomía & histología , Estudios Transversales , Mandíbula/diagnóstico por imagen , Mandíbula/anatomía & histología , Cavidad Pulpar/diagnóstico por imagen , Cavidad Pulpar/anatomía & histología , Tomografía Computarizada de Haz Cónico/métodos , Raíz del Diente/anatomía & histologíaRESUMEN
BACKGROUND: The purpose of this study is to investigate the long-term efficacy and stability of Miniscrew-assisted Rapid Palatal Expansion (MARPE), including its primary outcomes, namely the nasomaxillary complex transverse skeletal and dental expansion, and related secondary outcomes. METHODS: Electronic databases and manual literature searches, up to October 31, 2022, were performed. The eligibility criteria were the following: studies on patients with transverse maxillary deficiency treated with MARPE in adults and adolescents over 13.5 years of age. RESULTS: Ultimately, twelve articles were included in the analysis, one prospective and eleven retrospective observational studies. Five studies showed a moderate risk of bias, while the remaining seven studies were at a serious risk of bias. The GRADE quality of evidence was very low. MARPE is an effective treatment modality for transverse maxillary deficiency (mean success rate: 93.87%). Patients showed increased mean in the skeletal and dental transverse expansion. The basal bone composition, mean alveolar bone and mean dental expansion accounted for 48.85, 7.52, and 43.63% of the total expansion, respectively. There was a certain degree of skeletal and dental relapse over time. MARPE could also cause dental, alveolar, and periodontal side effects, and have an impact on other craniofacial bones, upper airway, and facial soft tissue. CONCLUSIONS: MARPE is an effective treatment for transverse maxillary deficiency, with a high success rate and a certain degree of skeletal and dental relapse over time.
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Recurrencia Local de Neoplasia , Técnica de Expansión Palatina , Humanos , Adulto , Adolescente , Estudios Retrospectivos , Estudios Prospectivos , Hueso Paladar , Recurrencia , Maxilar , Tomografía Computarizada de Haz CónicoRESUMEN
Doxorubicin (Dox), an anthracycline antibiotic with potent antitumor effects, has limited clinical applications due to cumulative cardiotoxicity. Ca2+ /calmodulin-dependent protein kinase II (CaMKII) is implicated in the pathological progression of Dox-induced cardiotoxicity. This study examined the hypothesis that CaMKII exacerbates Dox-induced cardiotoxicity by promoting endoplasmic reticulum stress and apoptosis through regulation of the inositol-requiring enzyme 1α (IRE1α)/spliced X-box binding protein 1 (XBP1s) pathway. Our results demonstrated that CaMKII activation and IRE1α/XBP1s pathway were involved in Dox-treated hearts. CaMKII inhibition with KN-93 ameliorated Dox-induced cardiac dysfunction and pathological myocardial changes. In addition, CaMKII inhibition prevented Dox-induced endoplasmic reticulum stress and apoptosis. Moreover, CaMKII inhibition increased the expression of IRE1α and XBP1s in Dox-treated hearts. The IRE1α inhibitor 4µ8C blocked the protective effect of CaMKII inhibition against Dox-induced cardiotoxicity. Mechanistically, 4µ8C prevented the effects of CaMKII inhibition on Dox-induced endoplasmic reticulum stress and apoptosis by inhibiting the expression of IRE1α and XBP1s. Additionally, treatment with rhADAMTS13 decreased the protein level of thrombospondin 1 (TSP1) and the phosphorylation of CaMKII in Dox-treated human AC16 cardiomyocytes. Taken together, these results demonstrate that the ADAMTS13-TSP1 axis regulates CaMKII activation and exacerbates Dox-induced cardiotoxicity by triggering endoplasmic reticulum stress and apoptosis by inhibiting the IRE1α/XBP1s pathway.
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Cardiotoxicidad , Estrés del Retículo Endoplásmico , Antibacterianos/toxicidad , Apoptosis , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cardiotoxicidad/patología , Doxorrubicina/toxicidad , Endorribonucleasas/metabolismo , Humanos , Inositol/farmacología , Miocitos Cardíacos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Trombospondina 1/metabolismo , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
Renal fibrosis is the ultimate presentation of chronic kidney disease, which progresses to end-stage renal disease. Hydroxychloroquine (HCQ) has been adapted for the treatment of autoimmune diseases; however, the potential mechanism underlying the role of HCQ in renal fibrosis remains unclear. C57BL/6 J mice were randomly divided into three groups (sham group, UUO group, and UUO + HCQ group (20 mg/kg)). HE and Masson staining were performed to assess kidney tissue damage and fibrosis, and western blotting was performed to assess the expression of epithelial-mesenchymal transition (EMT), extracellular matrix (ECM), PI3K/AKT, and NF-κB-related proteins. PCR and TUNEL were adopted to detect inflammatory factors and cell apoptosis. HK-2 cells treated with TGF-ß1 were used for the in vitro experiments. HCQ may potentially have therapeutic effects on renal fibrosis mediated through 122 target genes, and the Kyoto Encyclopedia of Genes and Genomes pathways of these genes were enriched for PI3K/AKT signaling based on network pharmacology. UUO mice that received HCQ demonstrated significantly less tubular damage than the UUO mice. HCQ treatment additionally blunted EMT in UUO kidneys and TGF-ß1-treated renal tubular epithelial cells, and alleviated ECM deposition in kidney tissue. Furthermore, HCQ treatment reduced UUO-induced inflammation and apoptosis. Mechanistically, HCQ treatment suppressed the activation of the PI3K/Akt and NF-kB pathways. This study demonstrated that HCQ ameliorated renal fibrosis by inhibiting the PI3K/AKT and NF-κB signaling pathways to attenuate inflammatory factors and the apoptotic function of renal tubular epithelial cells, thus providing renewed theoretical evidence for HCQ treatment of renal fibrosis.
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Insuficiencia Renal Crónica , Obstrucción Ureteral , Animales , Transición Epitelial-Mesenquimal , Femenino , Fibrosis , Humanos , Hidroxicloroquina/metabolismo , Hidroxicloroquina/farmacología , Hidroxicloroquina/uso terapéutico , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Insuficiencia Renal Crónica/patología , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismo , Obstrucción Ureteral/metabolismoRESUMEN
System identification techniques-projection pursuit regression models (PPRs) and convolutional neural networks (CNNs)-provide state-of-the-art performance in predicting visual cortical neurons' responses to arbitrary input stimuli. However, the constituent kernels recovered by these methods are often noisy and lack coherent structure, making it difficult to understand the underlying component features of a neuron's receptive field. In this paper, we show that using a dictionary of diverse kernels with complex shapes learned from natural scenes based on efficient coding theory, as the front-end for PPRs and CNNs can improve their performance in neuronal response prediction as well as algorithmic data efficiency and convergence speed. Extensive experimental results also indicate that these sparse-code kernels provide important information on the component features of a neuron's receptive field. In addition, we find that models with the complex-shaped sparse code front-end are significantly better than models with a standard orientation-selective Gabor filter front-end for modeling V1 neurons that have been found to exhibit complex pattern selectivity. We show that the relative performance difference due to these two front-ends can be used to produce a sensitive metric for detecting complex selectivity in V1 neurons.
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Modelos Neurológicos , Neuronas/fisiología , Corteza Visual/fisiología , Algoritmos , Animales , Biología Computacional , Macaca , Redes Neurales de la ComputaciónRESUMEN
BACKGROUND: Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease affecting the spine and sacroiliac joints. To investigate whether there are differences in inflammatory and chronic structural damages, as assessed by a semiquantitative MRI scoring method, between non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) patients with active inflammation at baseline, and to evaluate the treatment response in these patients after 3 months of tumor necrosis factor-alpha (TNF-α) inhibitor treatment. METHODS: Fifty-eight axSpA patients with active inflammation were included in the study. The patients were divided into nr-axSpA group and AS group. MRI examinations of the sacroiliac joints were performed before and after treatment. Inflammatory and structural damages in these patients were assessed using the established Spondyloarthritis Research Consortium of Canada (SPARCC) inflammation and sacroiliac joint structural (SSS) scoring methods, which are two MRI-based scoring methods. The SPARCC score, SSS score, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level were compared between the two groups. RESULTS: At baseline, SPARCC scores for patients in the nr-axSpA and AS groups did not differ significantly (P > 0.05); however, SSS scores for fat metaplasia, erosion, and backfill for patients in the AS group were significantly higher (P < 0.001). Compared with baseline, SPARCC scores were significantly decreased in both groups after treatment (P < 0.001); however, after treatment, no statistically significant difference was found regarding SPARCC scores between the AS and nr-axSpA groups. Compared with baseline, a significant increase in the SSS scores for fat metaplasia and backfill (P < 0.001) and a significant decrease in the SSS scores for erosion (P < 0.001) were observed in all axSpA patients. Changes in the SPARCC score was inversely correlated with the changes in the SSS score for fat metaplasia (r = - 0.634, P < 0.001). Changes in the SSS score for backfill were positively correlated with the changes in the SSS score for fat metaplasia (r = 0.277, P < 0.05) and inversely correlated with those for erosion (r = - 0.443, P < 0.001). CONCLUSION: The SPARCC and SSS scoring systems can be used to assess inflammatory and chronic structural damages as well as treatment responses in patients with axSpA. More severe structural damages were seen in AS patients. TNF-α inhibitor treatment for 3 months could effectively reduce inflammation in axSpA patients.
Asunto(s)
Espondiloartritis Axial , Sacroileítis , Espondiloartritis , Espondilitis Anquilosante , Humanos , Inflamación/diagnóstico por imagen , Inflamación/tratamiento farmacológico , Inflamación/patología , Imagen por Resonancia Magnética/métodos , Metaplasia/patología , Articulación Sacroiliaca/diagnóstico por imagen , Articulación Sacroiliaca/patología , Sacroileítis/diagnóstico por imagen , Sacroileítis/tratamiento farmacológico , Sacroileítis/patología , Índice de Severidad de la Enfermedad , Espondiloartritis/diagnóstico por imagen , Espondiloartritis/tratamiento farmacológico , Espondiloartritis/patología , Espondilitis Anquilosante/patología , Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND: Modification of the surgical technique to a 2-incision technique with skin bridge from the traditional lazy S (LS) incision, as well as use of prophylactic incisional negative-pressure wound therapy (iNPWT), are theorized to reduce the risk of surgical site infection (SSI) after inguinal lymph node dissection (ILND). We sought to investigate the role of a perioperative ILND bundle on adverse events after ILND and lymph node harvest. METHODS: We performed a retrospective review of patients who underwent ILND before and after implementation of the ILND bundle (September 2016) at 1 centre in southeastern Ontario between 2013 and 2018. The ILND bundle included a skin bridge incision, running subcuticular skin closure and NPWT. Previously, an LS incision was used, with stapled skin closure and conventional dressing. Development of SSI was the primary outcome, and dehiscence and seroma and hematoma formation were secondary outcomes. We estimated the associations using multivariable logistic regression. RESULTS: Thirty-four ILNDs in 33 patients were included, 15 in the LS incision group and 19 in the perioperative bundle group. The baseline demographic characteristics of the 2 groups were similar. The perioperative bundle was associated with a reduction in the SSI rate (11 [73%] v. 6 [32%], p = 0.02) and elimination of wound dehiscence (0 [0%] v. 5 [33%], p = 0.006). On multivariable logistic regression, it was associated with a 5.9-fold reduction in the SSI rate (odds ratio 0.17, 95% confidence interval 0.03-0.74). CONCLUSION: The results suggest a decrease in SSI rates with use of a perioperative bundle compared to the LS incision and a standard dressing. Randomized controlled trials are required to better understand the associations among the skin bridge incision, iNPWT and SSI.