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1.
Environ Sci Technol ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34623137

RESUMO

Photolysis of oxygenated volatile organic compounds (OVOCs) produces a primary source of free radicals, including OH and inorganic and organic peroxy radicals (HO2 and RO2), consequently increasing photochemical ozone production. The amplification of radical cycling through OVOC photolysis provides an important positive feedback mechanism to accelerate ozone production. The large production of OVOCs near the surface helps promote photochemistry in the whole boundary layer. This amplifier effect is most significant in regions with high nitrogen oxides (NOx) and VOC concentrations such as Wangdu, China. Using a 1-D model with comprehensive observations at Wangdu and the Master Chemical Mechanism (MCM), we find that OVOC photolysis is the largest free-radical source in the boundary layer (46%). The condensed chemistry mechanism we used severely underestimates the OVOC amplifier effect in the boundary layer, resulting in a lower ozone production rate sensitivity to NOx emissions. Due to this underestimation, the model-simulated threshold NOx emission value, below which ozone production decreases with NOx emission decrease, is biased low by 24%. The underestimated OVOC amplifier effect in a condensed mechanism implies a low bias in the current 3-D model-estimated efficacy of NOx emission reduction on controlling ozone in polluted urban and suburban regions of China.

2.
Theor Appl Genet ; 134(10): 3443-3457, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34390352

RESUMO

KEY MESSAGE: A dwarfism gene LacDWARF1 was mapped by combined BSA-Seq and comparative genomics analyses to a 65.4 kb physical genomic region on chromosome 05. Dwarf architecture is one of the most important traits utilized in Cucurbitaceae breeding because it saves labor and increases the harvest index. To our knowledge, there has been no prior research about dwarfism in the sponge gourd. This study reports the first dwarf mutant WJ209 with a decrease in cell size and internodes. A genetic analysis revealed that the mutant phenotype was controlled by a single recessive gene, which is designated Lacdwarf1 (Lacd1). Combined with bulked segregate analysis and next-generation sequencing, we quickly mapped a 65.4 kb region on chromosome 5 using F2 segregation population with InDel and SNP polymorphism markers. Gene annotation revealed that Lac05g019500 encodes a gibberellin 3ß-hydroxylase (GA3ox) that functions as the most likely candidate gene for Lacd1. DNA sequence analysis showed that there is an approximately 4 kb insertion in the first intron of Lac05g019500 in WJ209. Lac05g019500 is transcribed incorrectly in the dwarf mutant owing to the presence of the insertion. Moreover, the bioactive GAs decreased significantly in WJ209, and the dwarf phenotype could be restored by exogenous GA3 treatment, indicating that WJ209 is a GA-deficient mutant. All these results support the conclusion that Lac05g019500 is the Lacd1 gene. In addition, RNA-Seq revealed that many genes, including those related to plant hormones, cellular process, cell wall, membrane and response to stress, were significantly altered in WJ209 compared with the wild type. This study will aid in the use of molecular marker-assisted breeding in the dwarf sponge gourd.


Assuntos
Cromossomos de Plantas/genética , Regulação da Expressão Gênica de Plantas , Giberelinas/metabolismo , Luffa/crescimento & desenvolvimento , Mutação , Fenótipo , Proteínas de Plantas/metabolismo , Íntrons , Luffa/genética , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Melhoramento Vegetal , Proteínas de Plantas/genética
3.
EBioMedicine ; 70: 103532, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34392144

RESUMO

BACKGROUND: The underlying pathology of inguinal hernia is still not fully known; thus, further investigations of genetic backgrounds is needed. Here, we aimed to identify genetic factors attributing to inguinal hernias and explore the polygenic architecture of which some components are population-specific, while others are more common among populations. METHODS: We performed a genome-wide association study (GWAS) on subjects with inguinal hernias using BioBank Japan (BBJ) data with 1,983 cases and 172,507 controls, followed by a trans-ethnic meta-analysis with UK Biobank (UKBB) data. We performed downstream analyses in order to identify the mechanisms underlying inguinal hernias supported by genetic findings. FINDINGS: We identified a locus closest to ELN, which encodes elastin, at the GWAS significant level. The trans-ethnic meta-analysis revealed 23 additional significant loci, including five loci newly identified not significant in BBJ or UKBB GWAS: TGFB2, RNA5SP214/VGLL2, LOC646588, HMCN2, and ATP5F1CP1/CDKN3. Downstream analyses revealed the overlap of GWAS significant signals in extracellular components, including elastin fiber formation. We also found a highly shared polygenic architecture across different populations (trans-ethnic genetic-effect correlation = 0•77, standard error = 0•26) and population-specific lead variants in ELN, indicating the critical role of elastin in inguinal hernias. INTERPRETATION: We identified a significant locus of the ELN gene in the Japanese population and five additional loci across different populations. Downstream analyses revealed highly shared genetic architectures across populations and highlighted the important roles of extracellular components in the development of inguinal hernias. These findings deepen our understanding of the mechanisms underlying inguinal hernia. FUNDING: The Japan Agency for Medical Research and Development (AMED) (Grant Number: JP19km0605001).

4.
J Hum Genet ; 66(9): 879-885, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34321609

RESUMO

Mosaic chromosomal alterations (mCAs) are frequently observed in cancer cells and are regarded as one of the common features of cancers. Strikingly, accumulating studies demonstrated that mCAs are also prevalent in elderly individuals without cancer, implying mCA could be a feature of aging and not necessarily a cancerous state. However, the genetic basis of mCA has been mostly unknown. Recent studies of autosomal mCA based on biobank-scale datasets, including UK Biobank and Biobank Japan, provided a glimpse into the underlying genetic mechanism. In this concise review, we briefly introduced mCA, its link with cancer and aging, and the emerging genetic mechanisms of this phenomenon. We highlighted the following aspects: (1) the interplay between somatic and inherited germline mutations in generating mosaicism; (2) monogenic and polygenic architectures of mCA; and (3) population-specific profiles of mCA. We provided a future perspective emphasizing the need to understand the connection between mCA and other characteristics of aging, in particular, the epigenetic and immunologic features.

5.
J Med Internet Res ; 23(9): e29329, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34280115

RESUMO

BACKGROUND: The control of vaccine hesitancy and the promotion of vaccination are key protective measures against COVID-19. OBJECTIVE: This study assesses the prevalence of vaccine hesitancy and the vaccination rate and examines the association between factors of the health belief model (HBM) and vaccination. METHODS: A convenience sample of 2531 valid participants from 31 provinces and autonomous regions of mainland China were enrolled in this online survey study from January 1 to 24, 2021. Multivariable logistic regression was used to identify the associations of the vaccination rate and HBM factors with the prevalence of vaccine hesitancy after other covariates were controlled. RESULTS: The prevalence of vaccine hesitancy was 44.3% (95% CI 42.3%-46.2%), and the vaccination rate was 10.4% (9.2%-11.6%). The factors that directly promoted vaccination behavior were a lack of vaccine hesitancy (odds ratio [OR] 7.75, 95% CI 5.03-11.93), agreement with recommendations from friends or family for vaccination (OR 3.11, 95% CI 1.75-5.52), and absence of perceived barriers to COVID-19 vaccination (OR 0.51, 95% CI 0.35-0.75). The factors that were directly associated with a higher vaccine hesitancy rate were a high level of perceived barriers (OR 1.63, 95% CI 1.36-1.95) and perceived benefits (OR 0.51, 95% CI 0.32-0.79). A mediating effect of self-efficacy, influenced by perceived barriers (standardized structure coefficient [SSC]=-0.71, P<.001), perceived benefits (SSC=0.58, P<.001), agreement with recommendations from authorities (SSC=0.27, P<.001), and agreement with recommendations from friends or family (SSC=0.31, P<.001), was negatively associated with vaccination (SSC=-0.45, P<.001) via vaccine hesitancy (SSC=-0.32, P<.001). CONCLUSIONS: It may be possible to increase the vaccination rate by reducing vaccine hesitancy and perceived barriers to vaccination and by encouraging volunteers to advocate for vaccination to their friends and family members. It is also important to reduce vaccine hesitancy by enhancing self-efficacy for vaccination, due to its crucial mediating function.


Assuntos
COVID-19 , Vacinas , Vacinas contra COVID-19 , China , Estudos Transversais , Modelo de Crenças de Saúde , Humanos , Internet , SARS-CoV-2 , Vacinação
6.
J Phys Condens Matter ; 33(40)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34229301

RESUMO

Magnetic skyrmions are potential building blocks for future information storage and computing devices. Here, we computationally study the skyrmion dynamics in a cross structure made of two ferromagnetic nanotracks. We show that by controlling the skyrmion motion in the cross structure using spin currents, it is possible to realize the transcription of skyrmion at the intersection of the cross structure at certain conditions. Based on the transcription of skyrmion, we computationally demonstrate the AND, OR and NOT logical gates using the cross structures with modified geometries and appropriate magnetic parameters. Our results may provide guidelines to design future three-dimensional spintronics devices based on magnetic skyrmions.

7.
Leukemia ; 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34326465

RESUMO

Mutations in the Janus Kinase 2 (JAK2) gene resulting in constitutive kinase activation represent the most common genetic event in myeloproliferative neoplasms (MPN), a group of diseases involving overproduction of one or more kinds of blood cells, including red cells, white cells, and platelets. JAK2 kinase inhibitors, such as ruxolitinib, provide clinical benefit, but inhibition of wild-type (wt) JAK2 limits their clinical utility due to toxicity to normal cells, and small molecule inhibition of mutated JAK2 kinase activity can lead to drug resistance. Here, we present a strategy to target mutated JAK2 for degradation, using the cell's intracellular degradation machinery, while sparing non-mutated JAK2. We employed a chemical genetics screen, followed by extensive selectivity profiling and genetic studies, to identify the deubiquitinase (DUB), JOSD1, as a novel regulator of mutant JAK2. JOSD1 interacts with and stabilizes JAK2-V617F, and inactivation of the DUB leads to JAK2-V617F protein degradation by increasing its ubiquitination levels, thereby shortening its protein half-life. Moreover, targeting of JOSD1 leads to the death of JAK2-V617F-positive primary acute myeloid leukemia (AML) cells. These studies provide a novel therapeutic approach to achieving selective targeting of mutated JAK2 signaling in MPN.

8.
Cell Chem Biol ; 28(7): 1090-1100, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34089649

RESUMO

Deubiquitinating enzymes (DUBs) are a largely understudied and untapped resource in the toolkit of protein degradation functionalities. They comprise a large repertoire of enzymes that remove ubiquitin from substrates in a variety of cellular and pathophysiological contexts, and have enormous potential for research and clinical use. It is only within the last 5 years that potent, selective, and well-characterized small-molecule inhibitors of DUBs have been described. These compounds are now being used to study the biological roles of DUBs. Here, we describe downstream applications of small-molecule inhibitors for studying DUBs and provide a framework for future studies. We highlight recent examples of using these inhibitors to confirm and explore the role of these enzymes in both normal and pathological contexts. These studies represent the first steps in the burgeoning field of pharmacological and chemoproteomic studies of DUBs, which will be critical for the continued advancement of DUB field.

9.
Cell Chem Biol ; 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34129829

RESUMO

Deubiquitinating enzymes (DUBs) are a class of isopeptidases that regulate ubiquitin dynamics through catalytic cleavage of ubiquitin from protein substrates and ubiquitin precursors. Despite growing interest in DUB biological function and potential as therapeutic targets, few selective small-molecule inhibitors and no approved drugs currently exist. To identify chemical scaffolds targeting specific DUBs and establish a broader framework for future inhibitor development across the gene family, we performed high-throughput screening of a chemically diverse small-molecule library against eight different DUBs, spanning three well-characterized DUB families. Promising hit compounds were validated in a series of counter-screens and orthogonal assays, as well as further assessed for selectivity across expanded panels of DUBs. Through these efforts, we have identified multiple highly selective DUB inhibitors and developed a roadmap for rapidly identifying and validating selective inhibitors of related enzymes.

10.
Nat Med ; 27(6): 1012-1024, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34099924

RESUMO

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.


Assuntos
Envelhecimento/genética , Doenças Transmissíveis/genética , Pneumonia/genética , Sepse/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Bancos de Espécimes Biológicos , Aberrações Cromossômicas , Doenças Transmissíveis/complicações , Doenças Transmissíveis/microbiologia , Doenças do Sistema Digestório/epidemiologia , Doenças do Sistema Digestório/genética , Doenças do Sistema Digestório/microbiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Pneumonia/epidemiologia , Pneumonia/microbiologia , Fatores de Risco , Sepse/epidemiologia , Sepse/microbiologia , Anormalidades Urogenitais/epidemiologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/microbiologia , Adulto Jovem
11.
Ren Fail ; 43(1): 1028-1040, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34187277

RESUMO

Sepsis-induced acute kidney injury (AKI) continues to be associated with poor outcomes in critical care patients. Previous research has revealed that tetrahydrocurcumin (THC) exerts renoprotective effects in multiple nephritic disorders by modulating inflammation and oxidative stress. However, the effects of THC on sepsis-induced AKI and the underlying mechanisms remain unclear. In this study, a mouse model of sepsis-induced AKI, generated by cecal ligation and puncture operation, was used to investigate the protective effects of THC and the role of SIRT1. Histological manifestation and TUNEL analysis were observed to determine the severity of kidney damage. Levels of BUN, SCr, KIM-1, and UAlb/Cr were calculated to assess the renal function. Expressions of IL-1ß, IL-6, and TNF-α were measured to evaluate the inflammatory response. MDA content, SOD, GSH, CAT, and GPx activities and DHE staining were analyzed to estimate the degree of oxidative stress. Protein expressions of SIRT1, Ac-p65, and Ac-foxo1 were detected to explore the underlying mechanisms. We observed that THC not only increased the survival rate, improved the kidney function and ameliorated the renal histological damage of septic mice, but also inhibited inflammatory response, prohibited oxidative stress, and prevented cell apoptosis in renal tissues in septic mice. Mechanistically, THC remarkably increased the expression of SIRT1, accompanied by decreased expressions of downstream molecules Ac-p65 and Ac-foxo1. Meanwhile, the beneficial effects of THC were clearly abolished by the SIRT1-specific inhibitor EX527. These results delineate that THC prevents sepsis-induced AKI by suppressing inflammation and oxidative stress through activating the SIRT1 signaling.Abbreviation: Ac-p65: acetylated p65; Ac-foxo 1: acetylated forkhead box O1; AKI: acute kidney injury; BUN: blood urea nitrogen; CAT: catalase; DHE: dihydroethidium; GPx: glutathione peroxidase; GSH: reduced glutathione; IL-1ß: Interleukin-1 beta; IL-6: Interleukin-6; KIM-1: kidney injury molecule 1; MDA: malondialdehyde; SCr: serum creatinine; SIRT1: silent information regulator 1; SOD: superoxide dismutase; THC: tetrahydrocurcumin; TNF-α: tumor necrosis factor-alpha; TUNEL: TdT-mediated dUTP Nick-End Labeling; UAlb/Cr: urine micro albumin/creatinine.

12.
Nano Lett ; 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33950694

RESUMO

Magnetic skyrmions are versatile topological excitations that can be used as nonvolatile information carriers. The confinement of skyrmions in channels is fundamental for any application based on the accumulation and transport of skyrmions. Here, we report a method that allows effective position control of skyrmions in designed channels by engineered energy barriers and wells, which is realized in a magnetic multilayer film by harnessing the boundaries of patterns with modified magnetic properties. We experimentally and computationally demonstrate that skyrmions can be attracted or repelled by the boundaries of areas with modified perpendicular magnetic anisotropy and Dzyaloshinskii-Moriya interaction. By fabricating square and stripe patterns with modified magnetic properties, we show the possibility of building reliable channels for confinement, accumulation, and transport of skyrmions, which effectively protect skyrmions from being destroyed at the device edges. Our results are useful for the design of spintronic applications using either static or dynamic skyrmions.

13.
Brain Behav ; 11(5): e02118, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33835731

RESUMO

BACKGROUND: Previous studies have shown that the brain-derived neurotrophic factor (BDNF) rs6265 G > A polymorphism is closely related post-traumatic stress disorder (PTSD) risk. However, the results were not consistent. We therefore conducted a meta-analysis to explore the underlying relationships between BDNF rs6265 G > A polymorphism and PTSD risk. MATERIALS AND METHODS: Five online databases were searched, and all related studies were reviewed up to July 1, 2020. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to examine the statistical power of each genetic model. In addition, heterogeneity, sensitivity accumulative analysis, and publication bias were examined to check the statistical power. RESULT: Overall, 16 publications involving 5,369 subjects were included in this systematic review and 11 case-control studies were analyses in meta-analysis. The pooled results indicated an increasing risk of A allele mutations with PTSD risk. Moreover, the sequential subgroup analysis also demonstrated some similar situations in Asian populations and other groups. CONCLUSION: Current meta-analysis suggests that the BDNF rs6265 G > A polymorphism might be involved in PTSD susceptibility.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos de Estresse Pós-Traumáticos/genética , Alelos , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
14.
Artigo em Inglês | MEDLINE | ID: mdl-33820418

RESUMO

Magnetic invisible cloaking has been previously demonstrated but only limited to objects with rotational geometries either in spherical or cylindrical shapes, for which the classic analytical bilayer scheme could be strictly applied to design the hiding coat. In this work, we show that a quasi-static cloaking effect could be achieved for irregular objects, e.g., metals with sharp edges, using a numerical optimization scheme. In the quasi-static limit, it is unambiguously proved that the disturbance of the irregular geometries could be well compensated by the inhomogeneous distribution of the soft ferromagnetic (FM) layer either in permeability values or in shapes under the framework of a bilayer cloak. An FM mesh coat with a constant thickness of 0.5 mm was successfully engineered to meet the specific requirements. Experimentally, good cloaking performance with a field disturbance of less than 0.5% has been achieved for a 2 × 2 × 5 cm3 brass bar in a wide frequency range from ∼10 to 250 kHz. A commercial metal scanner was also applied to verify the practical potential. The general strategy to hide almost arbitrary objects was discussed in the end. In principle, the numerical conformal coat engineered by the composite material proposed here could be broadly extended for objects with various geometries.

15.
CPT Pharmacometrics Syst Pharmacol ; 10(4): 291-308, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33715307

RESUMO

Missing or erroneous information is a common problem in the analysis of pharmacokinetic (PK) data. This may present as missing or inaccurate dose level or dose time, drug concentrations below the analytical limit of quantification, missing sample times, or missing or incorrect covariate information. Several methods to handle problematic data have been evaluated, although no single, broad set of recommendations for commonly occurring errors has been published. In this tutorial, we review the existing literature and present the results of our simulation studies that evaluated common methods to handle known data errors to bridge the remaining gaps and expand on the existing knowledge. This tutorial is intended for any scientist analyzing a PK data set with missing or apparently erroneous data. The approaches described herein may also be useful for the analysis of nonclinical PK data.

16.
BMC Microbiol ; 21(1): 81, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711926

RESUMO

BACKGROUND: Hispidin (HIP) and its derivatives, a class of natural fungal metabolites, possess complex chemical structures with extensive pharmacological activities. Phellinus igniarius, the most common source of HIP, can be used as both medicine and food. However, the biosynthetic pathway of HIP in P. igniarius remains unclear and we have a limited understanding of the regulatory mechanisms related to HIP. In this work, we sought to illustrate a biosynthesis system for hispidin and its derivatives at the protein level. RESULTS: We found that tricetolatone (TL) is a key biosynthetic precursor in the biosynthetic pathway of hispidin and that its addition led to increased production of hispidin and various hispidin derivatives. Based on the changes in the concentrations of precursors and intermediates, key timepoints in the biosynthetic process were identified. We used isobaric tags for relative and absolute quantification (iTRAQ) to study dynamic changes of related proteins in vitro. The 270 differentially expressed proteins were determined by GO enrichment analysis to be primarily related to energy metabolism, oxidative phosphorylation, and environmental stress responses after TL supplementation. The differentially expressed proteins were related to ATP synthase, NAD binding protein, oxidoreductase, and other elements associated with electron transfer and dehydrogenation reactions during the biosynthesis of hispidin and its derivatives. Multiple reaction monitoring (MRM) technology was used to selectively verify the iTRAQ results, leading us to screen 11 proteins that were predicted to be related to the biosynthesis pathways. CONCLUTION: These findings help to clarify the molecular mechanism of biosynthesis of hispidin and its derivatives and may serve as a foundation for future strategies to identify new hispidin derivatives.

17.
Medicine (Baltimore) ; 100(9): e25070, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33655985

RESUMO

RATIONALE: Thyroid nodule rupture is a rare complication after microwave ablation (MWA). The ultrasonographic characteristics, clinical course, treatment, or prognosis of thyroid nodule rupture after ablation have not been systematically summarized. Three cases with thyroid nodule rupture after MWA were reported in this study, including the characteristic ultrasound images before ablation and after rupture. Meanwhile, we investigated the etiology, diagnosis, treatment and prevention of the rupture. These findings can provide references for the future clinical practice. PATIENTS CONCERNS: All 3 patients were pathologically diagnosed as benign thyroid nodules by core needle biopsy and then received 1 session of MWA. DIAGNOSES: Fourteen days to 1 month after MWA later, all 3 patients presented with abrupt neck pain and swelling, and 1 of them had a fever. Ultrasound examinations shared common features that the rupture of thyroid capsule and a soft-tissue mass with unclear margin in front of the thyroid gland, which connected with the post-ablation nodule. Three patients were diagnosed as thyroid nodule ruptures. INTERVENTIONS: All 3 patients received conservative management after the ruptures. With the treatment of intravenous antibiotics for 1 week, the neck swelling of patients 1 and 2 both disappeared. The aggravation of neck swelling was found in patient 3. Ultrasonography of the neck revealed irregular fluid echo in the soft-tissue mass, suggesting abscess formation. Aspiration and irrigation were performed. The neck swelling regressed gradually over another 2 weeks with the treatment of antibiotics. Two months after ablation, ultrasound examination showed that the mass had completely disappeared. OUTCOMES: None of the 3 patients underwent open surgery due to thyroid nodule rupture. At 1-year follow-up, the volume reduction rate of thyroid nodules in 3 patients were as follows: 100%, 98.1% and 90.7%. LESSONS: Nodule rupture is a rare but severe complication after MWA of the thyroid nodules. The diagnosis can be confirmed by clinical symptoms and ultrasound examination, and most nodule ruptures could be cured with conservative treatment. Grasping the characteristics of ultrasound imaging during the course of disease, and dynamically assessing course of disease progression by ultrasonography could avoid unnecessary imaging examinations or invasive procedures.


Assuntos
Micro-Ondas/uso terapêutico , Terapia por Radiofrequência/efeitos adversos , Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/diagnóstico , Ultrassonografia/métodos , Adulto , Feminino , Humanos , Masculino , Micro-Ondas/efeitos adversos , Ruptura , Nódulo da Glândula Tireoide/terapia
18.
ACS Appl Mater Interfaces ; 13(9): 10667-10673, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33646740

RESUMO

In this study, we demonstrated that arrays of cell clusters can be fabricated by self-assembled hexagonal superparamagnetic cone structures. When a strong out-of-plane magnetic field was applied to the ferrofluid on a glass substrate, it will induce the magnetic poles on the upper/lower surfaces of the continuous ferrofluid to increase the magnetostatic energy. The ferrofluid will then experience hydrodynamic instability and be split into small droplets with cone structures because of the compromising surface tension energy and magnetostatic energy to minimize the system's total energy. Furthermore, the ferrofluid cones were orderly self-assembled into hexagonal arrays to reach the lowest energy state. After dehydration of these liquid cones to form solid cones, polydimethylsiloxane was cast to fix the arrangement of hexagonal superparamagnetic cone structures and prevent the leakage of magnetic nanoparticles. The U-343 human neuronal glioblastoma cells were labeled with magnetic nanoparticles through endocytosis in co-culture with a ferrofluid. The number of magnetic nanoparticles internalized was (4.2 ± 0.84) × 106 per cell by the cell magnetophoresis analysis. These magnetically labeled cells were attracted and captured by hexagonal superparamagnetic cone structures to form cell cluster arrays. As a function of the solid cone size, the number of cells captured by each hexagonal superparamagnetic cone structure was increased from 48 to 126 under a 2000 G out-of-plane magnetic field. The local magnetic field gradient of the hexagonal superparamagnetic cone was 117.0-140.9 G/mm from the cell magnetophoresis. When an external magnetic field was applied, we observed that the number of protrusions of the cell edge decreased from the fluorescence images. It showed that the local magnetic field gradient caused by the hexagonal superparamagnetic cones restricted the cell growth and migration.


Assuntos
Técnicas de Cultura de Células/métodos , Dimetilpolisiloxanos/química , Nanopartículas Magnéticas de Óxido de Ferro/química , Técnicas de Cultura de Células/instrumentação , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Coloides/química , Humanos , Fenômenos Magnéticos , Poliestirenos/química , Água/química
19.
Sci Adv ; 7(6)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33547076

RESUMO

Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcription factors IKZF1 and IKZF3 by recruiting them to the cereblon E3 ubiquitin ligase. Current loss of signal ("down") assays for identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic ranges, and false positives from compounds that nonspecifically suppress transcription or translation. Here, we describe a gain of signal ("up") assay for degraders. In arrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner. In a pooled CRISPR-Cas9-based screen, we found that CDK2 regulates the abundance of the ASCL1 oncogenic transcription factor. This methodology should facilitate the identification of drugs that directly or indirectly degrade undruggable proteins.

20.
Int Immunopharmacol ; 93: 107434, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33556668

RESUMO

Leflunomide, an immunosuppressive disease-modifying anti-rheumatic drug (DMARD), is widely used in the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA) as well as multiple sclerosis. However, its role in myasthenia gravis (MG) has not yet been clearly explored. Here, we investigated the effect of leflunomide on experimental autoimmune myasthenia gravis (EAMG) in vivo and in vitro. The results demonstrated that leflunomide alleviated the severity of EAMG associated with reduced serum total anti-acetylcholine receptor (AChR) IgG levels. During the development of EAMG, the increase of follicular helper T cells (Tfh) 1, Tfh 17 cells and decrease of follicular regulatory T cells (Tfr) were reversely altered after leflunomide administration. Our work further found that leflunomide might inhibit Tfh cells through the IL-21/STAT3 pathway to reduce the secretion of antibodies by B cells. In addition, leflunomide rebuilt the balance of Th1/Th2/Th17/Treg subsets. These results suggested that leflunomide ameliorated EAMG severity by regulating humoral immune responses and Th cell profiles thereby providing a novel effective treatment strategy for MG.


Assuntos
Centro Germinativo/imunologia , Imunossupressores/uso terapêutico , Leflunomida/uso terapêutico , Miastenia Gravis Autoimune Experimental/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Células Cultivadas , Feminino , Humanos , Imunidade Humoral/efeitos dos fármacos , Interleucinas/metabolismo , Ratos , Ratos Endogâmicos Lew , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Equilíbrio Th1-Th2/efeitos dos fármacos
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