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1.
J Clin Invest ; 131(1)2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33393492

RESUMO

DYRK1A, the dual-specificity kinase, is again doubling up on function, as reported by Bhansali, Rammohan, and colleagues in this issue of the JCI. DYRK1A is an evolutionarily conserved protein kinase with dual specificity; it adds phosphates to serine/threonine residues of diverse regulatory proteins and activates its own function by autophosphorylating a critical tyrosine at position 321 in the activation loop. Bhansali, Rammohan, and colleagues investigated B cell acute lymphoblastic leukemia (B-ALL) in individuals with Down syndrome (DS) and in children with leukemia characterized by aneuploidy. The study revealed a DYRK1A/FOXO1 and STAT3 signaling pathway in B-ALL that could be targeted pharmacologically, thus opening the door to therapeutic strategies for patients with leukemia with or without DS.

2.
J Environ Qual ; 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33462853

RESUMO

Wheat flour consumption may be a major source of human metal intake, especially when wheat is cultivated in metal-contaminated soils. This work investigated Cd, Cu, Pb and Zn distribution in whole wheat flour, wheat flour and wheat bran when grown in a Pb smelting polluted area. Wheat product heavy metal concentrations were analyzed and the (non)carcinogenic risks were assessed. Mean Cd, Cu, Pb and Zn concentrations in whole wheat flour were 0.38, 3.83, 0.48 and 29.3 mg kg-1 , respectively, while those in flour were only slightly reduced. The ratios between non-carcinogenic average daily dose (ADD) of whole wheat flour and wheat flour consumption ranged from 1.06 to 3.76, with Pb having the greatest values compared to other metals. For children, the average hazard quotient (HQ) of whole wheat flour consumption of Cd, Cu, Pb and Zn were 4.19, 1.06, 1.53 and 1.07, while those for wheat flour consumption were 3.81, 0.68, 0.70 and 0.98, respectively. The HQ of adults were less than those of children. Overall results indicated that consumption of wheat products may lead to health concerns in the heavy metal contaminated area, yet when wheat flour rather than whole wheat flour is consumed, only the human health risk from Pb ingestion is reduced. Altering or removing human edible crops in the most contaminated areas should be considered. This article is protected by copyright. All rights reserved.

3.
Int Orthop ; 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33452537

RESUMO

PURPOSE: This study aims to analyze the gait characteristics of the elderly patients with lumbar spinal stenosis by an intelligent device for energy expenditure and activity (IDEEA) to assist clinical work. METHODS: A total of 98 subjects were included in this study from January 2017 to December 2018. A total of 49 elderly outpatients with symptomatic lumbar spinal stenosis in unilateral lower extremity were included as the experimental group, and another 49 healthy subjects matched with gender, age, and body mass index (BMI) were analyzed as the control group. The gait data of the subjects (including single support, double support, SLS/DLS, swing duration, step duration, cycle duration, pulling accel, swing power, ground impact, foot fall, foot off, push off, speed, cadence, step length, and stride length) were collected to compare between the experience group and control group, the affected leg and the healthy leg in experimental group. RESULTS: The results of this study presented that small intermittent claudication occurred in all patients. The time of single support was significantly increased (p < 0.05). Double support, step duration, and pulling accel were increased (p < 0.05), and the Push off, speed, step length, and Stride length were decreased (p < 0.05) in the experimental group compared with the control group. CONCLUSION: Small intermittent claudication was the basic gait composition of the elderly patients with lumbar spinal stenosis that can reflect the abnormal gait characteristics by IDEEA.

4.
Arch Gynecol Obstet ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33471216

RESUMO

PURPOSE: Adenomyosis is a diffuse or localized disease. Our previous study has indicated that tanshinone IIA (TSIIA) inhibits the proliferation, migration, and induces apoptosis of ectopic endometrial stromal cells (EESCs) of adenomyosis. However, the complex molecular mechanism of TSIIA in adenomyosis remains unclear. The objective of this study was to explore the complex molecular mechanism of TSIIA on EESCs. METHODS: In our present study, we used the proteomics approach iTRAQ (isobaric tags for relative and absolute quantitation) combined with LC-MS/MS (liquid chromatography-mass spectrometry) to investigate changes in the protein profile of EESCs treated with TSIIA. Differential proteins were analyzed by employing bioinformatics tools and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. In TSIIA treated EESCs, the protein expression levels of TNFRSF10D, PLEKHM1, FECH, and TPM1A were detected by western blotting. RESULTS: Quantitative results revealed 267 significantly differential proteins in TSIIA pretreated EESCs. Gene Ontology (GO) analysis presented an overview of dysregulated proteins in the biological process (BP), cell component (CC), and molecular function (MF) categories. Interestingly, we observed that differential proteins in the extracellular matrix (ECM)-receptor interaction pathway and estrogen signaling pathway were all involved in the focal adhesion pathway, which plays essential roles in the TSIIA-mediated inhibition of EESC proliferation and migration. Furthermore, some significantly differential proteins, which may be potential targets for the treatment of adenomyosis in the future, were validated by western blotting. CONCLUSIONS: Our study provides a useful method to detect the detailed mechanism underlying the efficacy of TSIIA on EESCs.

5.
Inorg Chem ; 60(2): 908-918, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33393292

RESUMO

The postcoordinated interligand-coupling strategy provides a useful and complementary protocol for synthesizing polydentate ligands. Herein, diastereoselective photoreactions of Λ-[Ir(pq)2(d-AA)] (Λ-d) and Λ-[Ir(pq)2(l-AA)] (Λ-l, where pq is 2-phenylquinoline and AA is an amino acid) are reported in the presence of O2 under mild conditions. Diastereomer Λ-d is dehydrogenatively oxidized into an imino acid complex, while diastereomer Λ-l mainly occurs via interligand C-N cross-dehydrogenative coupling between quinoline at the C8 position and AA ligands at room temperature, affording Λ-[Ir(pq)(l-pq-AA)]. Furthermore, the photoreaction of diastereomer Λ-l is temperature-dependent. Mechanistic experiments reveal the ligand-radical intermediates may be involved in the reaction. Density functional theory calculations were used to eluciate the origin of diastereoselectivity and temperature dependence. This will provide a new protocol for the amination of quinoline at the C8 position via the postcoordinated interligand C-N cross-coupling strategy under mild conditions.

6.
Hum Psychopharmacol ; 36(1): 1-9, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32976675

RESUMO

OBJECTIVES: The objective of this study was to estimate the features of suicide rate and its association with antidepressant prescriptions during the past decade in China. METHODS: Official data on suicides were obtained and stratified by four age groups, gender, urban/rural areas, and regions (East, Central, and West). The annual antidepressant prescriptions were expressed in pills per 100 persons calculated as the volume of prescriptions divided by the total population. Negative binomial regression was carried out to examine the association between suicide and other variables. RESULTS: Suicide rates in each stratum typically decreased from 2008 to 2015, while annual antidepressant prescriptions were generally increased by the year. The suicide rate increased with age and was greater in adult males than in females; higher in the central area and greater in rural than in urban areas. Suicide rates are negatively associated with antidepressant prescriptions including selective serotonin reuptake inhibitors (Incidence rate ratio [IRR] 0.983, 95% confidence interval [CI] 0.983-0.983), serotonin-norepinephrine reuptake inhibitors (IRR 0.951, 95% CI 0.951-0.951), tricyclic antidepressant (IRR 0.925, 95% CI 0.925-0.925) and total antidepressants (IRR 0.990, 95% CI 0.990-0.990) during 2008-2012. CONCLUSION: Suicide varied among different studied stratum. Suicide rates are negatively associated with antidepressant prescriptions.

7.
Ecotoxicol Environ Saf ; 208: 111461, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33091774

RESUMO

Di-(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) are representative phthalic acid esters (PAEs), a class of environmental endocrine disruptors used as plasticizers. PAEs exposure is associated with glucose metabolism, insulin resistance, and glucose tolerance; however, the mechanism and various PAE effects on human glucose metabolism remain largely unknown. In this study, we investigated the effects of DEHP, DBP, and their mixture on rat insulinoma (INS-1) cell apoptosis and the mechanism involved in vitro. The INS-1 cells were cultured in RPMI-1640 + 10% fetal bovine serum for 24 h and pretreated with dimethyl sulfoxide (vehicle, <0.1%), DEHP (30 µM), DBP (30 µM), and their mixture (30 µM DEHP + 30 µM DBP). The methyl-thiazolyl tetrazolium bromide test was used to measure cell viability. Hoechst 33342/propidium iodide (PI) staining and Annexin V-FITC/PI staining, 2',7'-dichlorofluorescein diacetate assay, and glucose-induced insulin secretion assay were used to detect cell apoptosis rates, intracellular reactive oxygen species (ROS), and insulin secretion in INS-1, respectively. The mRNA expression levels of Bcl-2, Bax, Caspase 9, Caspase 8, Caspase 3, phosphoinositide 3-kinase (PI3K), and Akt were detected using real-time quantitative reverse transcription PCR; their protein expression levels were detected using western blotting. To the best of our knowledge, this study was the first to show that the combined effect of the two PAEs promotes a ROS-mediated PI3K/Akt/Bcl-2 pathway-induced pancreatic ß cell apoptosis that is significantly higher than the effects of each PAE. Thus, safety standards and studies do not consider this effect as a significant oversight when blending PAEs. We assert that this must be addressed and corrected for establishing more impactful and safer standards.


Assuntos
Ácidos Ftálicos/toxicidade , Plastificantes/toxicidade , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dibutilftalato/análise , Ésteres , Glucose , Insulinoma , Neoplasias Pancreáticas , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2 , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Bioorg Chem ; 106: 104433, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33213893

RESUMO

The G-quadruplex (G4) DNA, which has been developed as a potential anticancer target in drug screening and design, plays a crucial role in the oncogene transcription and translation. Tanshinone IIA derivatives with a planar heterocycle structure may function as G4 stabilizers. We present an innovative case of imidazole-based tanshinone IIA derivatives (1-8) especially compound 4 that improve the selectivity and the binding affinity with G4 DNA and enhance the target tumor inhibition. Cellular and in vivo experiments indicate that the tanshinone IIA derivative 4 inhibits the growth, metastasis, and angiogenesis of triple-negative breast cancer cells possibly through the stabilization of multiple G4 DNAs (e.g., c-myc, K-ras, and VEGF) to induce DNA damage. Further investigation of the intermolecular interaction and the molecular docking indicates that tanshinone IIA derivatives have better selective binding capability to various G4 DNAs than to double-stranded DNA. These findings provide guidance in modifying the molecular structures of tanshinone IIA derivatives and reveal their potential to function as specific G4 stabilizers.

9.
Biomaterials ; 268: 120587, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33296793

RESUMO

Combination cancer therapy (e.g., radiochemotherapy) is widely used to enhance the therapeutic effects and prevent the recurrence of cancer. However, the side effects of monotherapy are also amplified when treating cancer with combination therapy. A locally activated drug delivery strategy that can release the payload in a tumor-selective manner is greatly needed to overcome the side effects of combination therapy. Here, we explore the potential of combining boron neutron capture therapy and chemotherapy as a new type of radiochemotherapy. Two-dimensional (2D) boron-10-rich nanosheets (BNNSs) were fabricated as a dual-functional delivery system: targeted boron-10 delivery systems for boron neutron capture therapy (BNCT) and drug delivery vehicles to load doxorubicin for chemotherapy. Irradiated by low-energy thermal neutron, BNNSs can produce high linear energy transfer (LET) particles to kill tumor cells, and the loaded doxorubicin can be released in situ at the same time. This neutron-triggered radiochemotherapy shows noteworthy efficacy in suppressing tumor growth in triple-negative breast cancer. To the best of our knowledge, this is the first report to combine BNCT with chemotherapy as a new type of radiochemotherapy. We hope this study could inspire additional BNCT-induced combination cancer therapies and provide insight for the further clinical translation of BNCT.

10.
Ecotoxicol Environ Saf ; 207: 111306, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32949934

RESUMO

Although studies have demonstrated that fine particulate matter (PM2.5) induces ocular surface damage, PM2.5 exposure causes cornea toxicity is not entirely clear. The aim of this study is to investigate the role of the nod-like receptor family pyrin domain containing three (NLRP3) inflammasome-mediated pyroptosis in PM2.5-related corneal toxicity. Human corneal epithelial cells (HCECs) were exposed to different concentrations of PM2.5, and the cell viability, expressions of NLRP3 inflammasome mediated pyroptosis axis molecules and intracellular reactive oxygen species (ROS) formation were measured in HCECs. Animal experiments were undertaken to topically apply PM2.5 suspension to mouse eyes for three months and the pyroptosis related molecules in the mouse corneas were measured. RESULTS: Our results showed a dose-dependent decrease of HCEC viability in the PM2.5-treated cells. NLRP3 inflammasome-mediated pyroptosis axis (NLRP3, ASC, GSDMD, caspase-1, IL-1ß, and IL-18) were activated in the PM2.5-treated HCECs, accompanied by increased ROS formation. Further in vivo study confirmed the activation of this pathway in the mouse corneas exposed to PM2.5. In conclusion, this study provids novel evidence that PM2.5 induces corneal toxicity by triggering cell pyroptosis.


Assuntos
Córnea/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Material Particulado/toxicidade , Piroptose/efeitos dos fármacos , Animais , Caspase 1/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Córnea/patologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Inflamação , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo
11.
J Hazard Mater ; 401: 123447, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32763721

RESUMO

It remains challenging to develop high-performance technologies for uranium (U(VI)) removal/recovery from wastewater/seawater. In this study, MgAl-double oxide (MgAl-LDO-500) was fabricated by calcining MgAl-layered double hydroxide (MgAl-LDH) at 500 ℃ in air. It showed excellent performance in U(VI) removal with an equilibrium time of 15 min and the maximal adsorption capacity of 1098.90 mg g-1. MgAl-LDO-500 also showed good adaptability in a wide range of pH (from 3 to 10), coexisting ions and different water matrices for U(VI) immobilization. It was found that the anion form of U(VI) intercalated into the layer of MgAl-LDO-500 and caused recombination of layered structures. A series of characterizations (XRD, SEM, FTIR, XPS) proved that memory effect and surface complexation were the key mechanism for the enhancement of U(VI) immobilization on MgAl-LDO-500. Due to the remarkable memory effect, the performance of MgAl-LDO-500 for U(VI) immobilization was superior to MgAl-LDH and other high-cost materials. Besides, the fixed-bed column experiments illustrated that the removal rate achieved 99 % before 1500 BV at initial U(VI) concentration of 20 µg L-1, and the breakthrough volumes (BVs) were 4500 BVs. These results confirm that MgAl-LDO-500 is a promising material for extracting U(VI) from seawater and wastewater.

12.
Chemosphere ; 263: 128223, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33297179

RESUMO

Triclosan (TCS) has attracted increasing concern due to its ubiquitous occurrence in aquatic environments as well as its potential adverse effects on human health. This study investigated the toxicity and transformation characteristics of triclosan ozonation and chlorination. The results showed that two hydroxylated by-products were formed via nucleophilic substitution during ozonation, while three chlorinated compounds were generated via electrophilic substitution during chlorination. The toxicity results demonstrated that the parent compound, triclosan, exhibited mild genotoxicity and anti-estrogenic activity. The chlorination of triclosan resulted in a 30-fold increase in anti-estrogenic activity owing to the generation of toxic polychlorinated transformation by-products. In addition, the chlorination by-products were found to be genotoxic like the parent compound. Fortunately, in contrast to chlorination, ozonation could mitigate the genotoxicity and anti-estrogenic activity of triclosan-containing water.


Assuntos
Ozônio , Triclosan , Poluentes Químicos da Água , Purificação da Água , Halogenação , Humanos , Ozônio/toxicidade , Triclosan/toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
13.
BMJ Open ; 10(12): e040865, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33376168

RESUMO

OBJECTIVES: Data on the problem of physical activity-related injury (PARI) in university students and the risk factors for PARI among different genders are rare. We conducted a multicentre population-based study to investigate the occurrence of PARI and to explore the gender-specific risk factors for PARI among Chinese university students. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 5341 students in grades 1-3 at eight universities in four Chinese cities were selected to complete the online questionnaires during March and April 2017. The questionnaires assessed sociodemographic characteristics, physical activity PA) involvement, sleep duration, sedentary behaviour and PARI experiences in the past 12 months. MAIN OUTCOME MEASURES: PARI during the past 12 months. RESULTS: Among the 5341 participants, 1293 suffered from at least one PARI in the past 12 months, with an overall incidence rate of 24.2% (males: 26.2%, females: 23.2%) and an injury risk of 0.38 injuries/student/year (males: 0.48, females: 0.32). Over half of the injured (57.3%) experienced a withdrawal time of PA and nearly two-fifths (39.6%) required medical attention. Irrespective of gender, Shantou and Xi'an students, sports team members and those who engaged in sports and leisure-time vigorous-intensity PA (VPA) at a higher frequency were more likely to suffer from PARI. Male students who participated in sports and leisure-time VPA for long durations had a greater likelihood of sustaining PARI, while having a chronic condition and being involved in sports and leisure-time moderate-intensity PA at a higher frequency and longer duration were potential contributors to PARI among females. CONCLUSIONS: The occurrence of PARI and its risk factors differed by gender, which provides a direction towards developing targeted and effective gender-specific preventative programmes to protect Chinese university students from PARI.

14.
Gait Posture ; 84: 254-259, 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33383536

RESUMO

BACKGROUND: Generalized joint hypermobility (GJH) is a common, but often ignored, condition characterized by general joint laxity, which is reported to increase one's risk of anterior cruciate ligament (ACL) injury and osteoarthritis. Nevertheless, it is not clearly learned in the prevalence and dynamic characteristics in college students. RESEARCH QUESTION: Is the active motion stability in the six-degree-of-freedom (6DOF) kinematics of the knee joint of people with GJH poorer than that of others? METHODS: This is a cross-sectional study. A population of 489 college students was recruited who was divided into two groups: a GJH group (Beighton score ≥ 4, n = 54) and a normal group (Beighton score < 4, n = 435). A paper questionnaire with questions about the participants' demographic characteristics and musculoskeletal disorder symptoms was collected. A three-dimensional gait analysis system was used to collect the participants' knee joint kinematic parameters during treadmill walking. Variables were evaluated using independent t-tests and Wilcoxon signed-rank tests. RESULTS: The prevalence of GJH was found to be 11.0 % among college students. Participants with GJH exhibited a greater active range of motions in the anterior/posterior translation than the normal (P =  0.026). Participants with GJH exhibited greater flexion at the end of the terminal stance (P = 0.039) and greater anterior translation of the tibia during almost the whole gait period than the normal group (P<0.05) during the treadmill gait. A greater external angle was found in GJH group during the periods of middle stance (P = 0.008). SIGNIFICANCE: GJH with a prevalence of 11.0 % among college students should be paid attention. Poor active motion stability in anterior/posterior translation may play an important role in the development of knee joint instability, potentially resulting in subsequent ACL deficiency and the development of knee osteoarthritis among people with GJH.

15.
PLoS One ; 15(12): e0243050, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33347514

RESUMO

Spelling is a literacy skill that must be mastered during children's academic development. It involves a variety of cognitive factors, including morphological awareness. Studies in the alphabet and Chinese systems have shown that there is a close relationship between morphological awareness and spelling. Although there is clearly a significant unidirectional effect of morphological awareness on spelling significantly, few studies have explored the bidirectional relationship between morphological awareness and spelling. This three-time point longitudinal study was designed to investigate the reciprocal effects of morphological awareness and character spelling in Chinese. Participants included 124 children from two primary schools in Mainland China. The students were tracked from first grade to third grade and were administered a battery of tests to measure morphological awareness (e.g., homophone awareness, homograph awareness, and compounding awareness) and spelling to dictation, controlling for IQ, phonological awareness, and orthographic awareness. A structural equation model was utilized to examine the reciprocal relation between the students' morphological awareness and character spelling. Results showed that earlier morphological awareness predicted subsequent spelling abilities from first grade to third grade and spelling in first grade predicted morphological awareness in second grade; however, spelling in second grade did not predict the subsequent morphological awareness in third grade. This study suggests that there is a bidirectional association between morphological awareness and spelling from first grade to second grade in Chinese, and a unidirectional association between morphological awareness and spelling from second grade to third grade. Future studies could examine the causal relationship between morphological awareness and character spelling by using an instructional intervention.


Assuntos
Conscientização , Alfabetização/psicologia , Estudantes/psicologia , Criança , Desenvolvimento Infantil , China , Feminino , Humanos , Testes de Linguagem , Estudos Longitudinais , Masculino , Modelos Teóricos , Fonética , Instituições Acadêmicas , Vocabulário
16.
ACS Nano ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33289535

RESUMO

The cornea provides important protection for human eyes from invasion of alien substances. However, its blockage on the infiltration of molecules also constitutes a great challenge for noninvasive trans-cornea delivery of drugs. Here we report polyamino acid-based S-nitrosothiols with high cationic charge density as a NO carrier to overcome cornea associated blockage in ophthalmological therapy. Our results demonstrate that the cationic nature of the polymer promoted transcytosis, which greatly enhances the trans-cornea delivery of the NO donor and bypasses cornea barriers on passive drug diffusion. The combination of super cation and glutathione responsiveness synergistically enhanced intraocular delivery of topically administered poly(2-acetamido-N-triethylenetetramine-3-nitrosothiol-3-methylbutanamide)aspartamide, effectively alleviating high intraocular pressure in mice with glaucoma. Such a noninvasive "barrier hopping" approach not only serves as an inspiration in improving the efficiency of trans-cornea drug delivery but also has great potential in overcoming drug transporting barriers in other biomedical applications.

17.
Chem Commun (Camb) ; 56(100): 15663-15666, 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33290454

RESUMO

For the first time, bulk-like g-C3N4 was achieved through initiating layer-by-layer assembly, which involves the important process of artificially manipulating protonated and oxygen doped g-C3N4 nanosheets. When acting as a photocatalyst under UV-visible light irradiation, bulk-like g-C3N4 exhibited an excellent photocatalytic H2 production rate of 1538 µmol h-1 g-1, about 8 times higher than that of the bulk g-C3N4 counterpart.

18.
Front Microbiol ; 11: 565438, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193153

RESUMO

Tigecycline, a protein translation inhibitor, is a treatment of last resort for infections caused by the opportunistic multidrug resistance human pathogen Acinetobacter baumannii. However, strains resistant to tigecycline were reported not long after its clinical introduction. Translation inhibitor antibiotics perturb ribosome function and induce the reduction of (p)ppGpp, an alarmone involved in the stringent response that negatively modulates ribosome production. Through RNA sequencing, this study revealed a significant reduction in the transcription of genes in citric acid cycle and cell respiration, suggesting tigecycline inhibits or slows down bacterial growth. Our results indicated that the drug-induced reduction of (p)ppGpp level promoted the production but diminished the degradation of ribosomes, which mitigates the translational inhibition effect by tigecycline. The reduction of (p)ppGpp also led to a decrease of transcription coupled nucleotide excision repair which likely increases the chances of development of tigecycline resistant mutants. Increased expression of genes linked to horizontal gene transfer were also observed. The most upregulated gene, rtcB, involving in RNA repair, is either a direct tigecycline stress response or is in response to the transcription de-repression of a toxin-antitoxin system. The most down-regulated genes encode two ß-lactamases, which is a possible by-product of tigecycline-induced reduction in transcription of genes associated with peptidoglycan biogenesis. This transcriptomics study provides a global genetic view of why A. baumannii is able to rapidly develop tigecycline resistance.

19.
Front Pediatr ; 8: 544894, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194885

RESUMO

Background: BCL11B encodes B-cell lymphoma/leukemia 11B, a transcription factor that participates in the differentiation and migration of neurons and lymphocyte cells. De novo mutations of BCL11B have been associated with neurodevelopmental disorder and immunodeficiency, such as immunodeficiency 49 (IMD49) and intellectual developmental disorder with speech delay, dysmorphic facies, and T-cell abnormalities (IDDSFTA). However, the pathogenesis of the neurodevelopmental disorder and T-cell deficiency is still mysterious. The strategy to distinguish these two diseases in detail is also unclear. Methods: A patient with unique clinical features was identified. Multiple examinations were applied for evaluation. Whole-exome sequencing (WES) and Sanger sequencing were also performed for the identification of the disease-causing mutation. Results: We reported a 17-month-old girl with intellectual disability, speech impairment, and delay in motor development. She presented with mild dysmorphic facial features and weak functional movement. MRI indicated the abnormal myelination of the white matter. Immunological analysis showed normal levels of RTEs and γδT cells but a deficiency of naive T cells. Genetic sequencing identified a de novo heterozygous frameshift mutation c.1192_1196delAGCCC in BCL11B. Conclusions: An IDDSFTA patient of East Asian origin was reported. The unreported neurological display, immunophenotype, and a novel disease-causing mutation of the patient extended the spectrum of clinical features and genotypes of IDDSFTA.

20.
Artigo em Chinês | MEDLINE | ID: mdl-33254330

RESUMO

The clinical manifestations of this patient with hypopharyngeal liposarcoma are dyspnea, dysphagia and aspiration. Fiberlaryngoscopic examination showed a grayish-yellow mass with a smooth surface and a broad base in the left hypopharynx, piriform fossa, and laryngeal entrance. CT examination revealed a solid mass with clear borders in the hypopharynx and a fibrous septum. Pathology revealed a highly differentiated liposarcoma of the hypopharynx.


Assuntos
Transtornos de Deglutição , Neoplasias Hipofaríngeas , Lipossarcoma , Dispneia , Humanos , Hipofaringe
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