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1.
Curr Med Sci ; 41(3): 405-419, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34218354

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy characterized by recurrent skin nodules, an aggressive clinical course with rapid involvement of hematological organs, and a poor prognosis with poor overall survival. BPDCN is derived from plasmacytoid dendritic cells (pDCs) and its pathogenesis is unclear. The tumor cells show aberrant expression of CD4, CD56, interleukin-3 receptor alpha chain (CD123), blood dendritic cell antigen 2 (BDCA 2/CD303), blood dendritic cell antigen 4 (BDCA4) and transcription factor (E protein) E2-2 (TCF4). The best treatment drugs are based on experience by adopting those used for either leukemia or lymphoma. Relapse with drug resistance generally occurs quickly. Stem cell transplantation after the first complete remission is recommended and tagraxofusp is the first targeted therapy. In this review, we summarize the differentiation of BPDCN from its cell origin, its connection with normal pDCs, clinical characteristics, genetic mutations and advances in treatment of BPDCN. This review provides insights into the mechanisms of and new therapeutic approaches for BPDCN.

2.
Nat Chem ; 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282307

RESUMO

The development of innovative strategies for the synthesis of N-heterocyclic compounds is an important topic in organic synthesis. Ring expansion methods to form large N-heterocycles often involve the cycloaddition of strained aza rings with π bonds. However, in some cases such strategies suffer from some limitations owing to the difficulties in controlling the regioselectivity and the accessibility of specific π-bond synthons. Here, we report the development of a general ring expansion strategy that involves a formal cross-dimerization between three-membered aza heterocycles and three- and four-membered-ring ketones through synergistic bimetallic catalysis. These formal cross-dimerizations of two different strained rings are efficient and scalable, and provide a straightforward and broadly applicable means of assembling diverse N-heterocycles, such as 3-benzazepinones, dihydropyridinones and uracils, which are versatile units in numerous drugs and biologically active compounds. Preliminary mechanistic studies revealed that the C-C bond of strained ring ketones is first cleaved by the Pd0 species during the reaction.

3.
Eur Phys J E Soft Matter ; 44(7): 93, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34236552

RESUMO

As part of the immune response, leukocytes can directly transmigrate through the body of endothelial cells or through the gap between adjacent endothelial cells. These are known, respectively, as the transcellular and paracellular route of diapedesis. What determines the usage of one route over the other is unclear. A recently proposed tenertaxis hypothesis claims that leukocytes choose the path with less mechanical resistance against leukocyte protrusions. We examined this hypothesis using numerical simulation of the mechanical resistance during paracellular and transcellular protrusions. By using parameters based on human lung endothelium, our results show that the required force to breach the endothelium through the transcellular route is greater than paracellular route, in agreement with experiments. Moreover, experiments have demonstrated that manipulation of the relative strength between the two routes can make the transcellular route preferable. Our simulations have demonstrated this reversal and thus tentatively confirmed the hypothesis of tenertaxis.

4.
Elife ; 102021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34254583

RESUMO

Autophagy acts as a pivotal innate immune response against infection. Some virulence effectors subvert the host autophagic machinery to escape the surveillance of autophagy. The mechanism by which pathogens interact with host autophagy remains mostly unclear. However, traditional strategies often have difficulty identifying host proteins that interact with effectors due to the weak, dynamic, and transient nature of these interactions. Here, we found that Enteropathogenic Escherichia coli (EPEC) regulates autophagosome formation in host cells dependent on effector NleE. The 26S Proteasome Regulatory Subunit 10 (PSMD10) was identified as a direct interaction partner of NleE in living cells by employing genetically incorporated crosslinkers. Pairwise chemical crosslinking revealed that NleE interacts with the N-terminus of PSMD10. We demonstrated that PSMD10 homodimerization is necessary for its interaction with ATG7 and promotion of autophagy, but not necessary for PSMD10 interaction with ATG12. Therefore, NleE-mediated PSMD10 in monomeric state attenuates host autophagosome formation. Our study reveals the mechanism through which EPEC attenuates host autophagy activity.

5.
Heart Lung Circ ; 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34244065

RESUMO

BACKGROUND: Spinal cord injury (SCI) is one of the serious complications of thoracoabdominal aortic aneurysm (TAAA) repair. Cardiopulmonary bypass (CPB) and left heart bypass (LHB) are well-established extracorporeal circulatory assistance methods to increase distal aortic perfusion and prevent spinal cord ischaemia in TAAA repair. Aorto-iliac bypass, a new surgical adjunct offering distal aortic perfusion without the need of complex perfusion skills, was developed as a substitute for CPB and LHB. However, its spinal cord protective effect is unknown. METHODS: The perioperative data of 183 patients who had elective open Crawford extent II and III TAAA repair at our aortic centre from July 2011 to May 2019 were retrospectively analysed. Spinal cord protection was compared between the aorto-iliac bypass group (n=106) and the extracorporeal circulatory assistance group (n=77 [65 CPB, 12 LHB]), and the risk factors for SCI in these patients were explored. RESULTS: Eleven (11) patients had postoperative SCI: five (6.5%) in the extracorporeal circulatory assistance group (four with CPB and one with LHB), and six (5.7%) in the aorto-iliac bypass group. The incidence of SCI was 6.0% (11/183 cases). There was no difference between the aorto-iliac bypass group and the extracorporeal circulatory assistance group (p=1.0), while operation time, proximal aortic clamp time, intercostal artery clamp time, and length of intensive care unit stay were all increased in the latter group. Multivariate logistic regression analysis showed that cerebrospinal fluid pressure (odds ratio [OR], 1.270; 95% confidence interval [CI], 1.092-1.478 [p=0.002]) and lowest haemoglobin on the first postoperative day (OR, 0.610; 95% CI, 0.416-0.895 [p=0.011]) were the independent predictors of SCI in TAAA repair. CONCLUSIONS: Spinal cord protection of aorto-iliac bypass is comparable to that of CPB and LHB in open TAAA repair.

6.
Genes (Basel) ; 12(6)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207210

RESUMO

Osteoporosis is a rising health threat in the increasingly aging world population. It is a common skeletal disease strongly linked to genetic predisposition. We aim to identify the effects of the anti-inflammatory TGF-ß1- and IL-10-specific single-nucleotide polymorphism (SNP) combination on the risk for osteoporosis. We investigated and analyzed the relationships between three TGF-ß1 SNPs (-509C/T, +869 T/C and +29T/C), one IL-10 SNP (+1927A/C) and the level of bone mineral density (BMD), as well as the risk of osteoporosis in Taiwanese osteoporotic patients. A total of 217 subjects were recruited, including 88 osteoporotic patients and 129 healthy controls, for SNPs, BMD and clinical characteristics statistical analyses. Females with TGF-ß1 SNP (-509 C/C) and IL-10 SNP (+1927 C/C) genotypes showed a great benefit for femoral neck T-scores. However, the combination of TGF-ß1 SNP (-509 T/T) and IL-10 SNP (+1927 A/A) genotypes in all subjects showed a significant decrease in total hip BMD T-scores. The TGF-ß1 SNP (-509 C/T) genotype in all subjects and TGF-ß1 SNP (-509 T/T) and IL-10 SNP (+1927 A/C) genotypes in males showed positive effects on body height. The combination of the many SNPs in the anti-inflammatory TGF-ß1 and IL-10 genes may be cooperatively involved in the development of osteoporosis. Our data suggested that the specific SNP combination of TGF-ß1 (-509) and IL-10 (+1927) may act as a predictive factor for postmenopausal osteoporosis in Taiwanese women.

7.
Bioengineered ; 12(1): 3252-3262, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34238128

RESUMO

Prostate cancer (PCa) is the most common male reproductive tract malignant tumor, accurate evaluation of PCa characterization and prognostic prediction at diagnosis are vital for the effective administration of the disease, especially at the molecular level. In this study, 48 CpG sites with differential methylation associated with overall survival (OS) were screened out between PCa and normal adjacent tissues. 16 CpG sites were selected by the least absolute shrinkage and selection operator (LASSO) and the risk score formula for methylated-based classifier was established. For 16-lncRNAs-CpG-classifier, the area under the curve (AUC) were 0.890, 0.917, and 0.932 at 3 years, 5 years and 7 years, respectively. Kaplan-Meier curves indicated that patients with high-risk scores had worse OS than those with low-risk scores. Prognostic methylation model of lncRNAs was identified from the whole genome in patients with PCa. This novel finding provides a novel insight for screening biomarkers of a prognosis for PCa.

8.
Phys Rev Lett ; 126(25): 253601, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34241507

RESUMO

Harmonic oscillators count among the most fundamental quantum systems with important applications in molecular physics, nanoparticle trapping, and quantum information processing. Their equidistant energy level spacing is often a desired feature, but at the same time a challenge if the goal is to deterministically populate specific eigenstates. Here, we show how interference in the transition amplitudes in a bichromatic laser field can suppress the sequential climbing of harmonic oscillator states (Kapitza-Dirac blockade) and achieve selective excitation of energy eigenstates, cat states, and other non-Gaussian states. This technique can transform the harmonic oscillator into a coherent two-level system or be used to build a large-momentum-transfer beam splitter for matter waves. To illustrate the universality of the concept, we discuss feasible experiments that cover many orders of magnitude in mass, from single electrons over large molecules to dielectric nanoparticles.

10.
Korean J Radiol ; 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34269528

RESUMO

OBJECTIVE: This study used cardiac magnetic resonance imaging (MRI) to compare the characteristics of left ventricular remodeling in patients with primary aldosteronism (PA) with those of patients with essential hypertension (EH) and healthy controls (HCs). MATERIALS AND METHODS: This prospective study enrolled 35 patients with PA, in addition to 35 age- and sex-matched patients with EH, and 35 age- and sex-matched HCs, all of whom underwent comprehensive clinical and cardiac MRI examinations. The analysis of variance was used to detect the differences in the characteristics of left ventricular remodeling among the three groups. Univariable and multivariable linear regression analyses were used to determine the relationships between left ventricular remodeling and the physiological variables. RESULTS: The left ventricular end-diastolic volume index (EDVi) (mean ± standard deviation [SD]: 85.1 ± 13.0 mL/m² for PA, 75.9 ± 14.3 mL/m² for EH, and 77.3 ± 12.8 mL/m² for HC; p = 0.010), left ventricular end-systolic volume index (ESVi) (mean ± SD: 35.2 ± 9.8 mL/m² for PA, 30.7 ± 8.1 mL/m² for EH, and 29.5 ± 7.0 mL/m² for HC; p = 0.013), left ventricular mass index (mean ± SD: 65.8 ± 16.5 g/m² for PA, 56.9 ± 12.1 g/m² for EH, and 44.1 ± 8.9 g/m² for HC; p < 0.001), and native T1 (mean ± SD: 1224 ± 39 ms for PA, 1201 ± 47 ms for EH, and 1200 ± 44 ms for HC; p = 0.041) values were higher in the PA group compared to the EH and HC groups. Multivariable linear regression demonstrated that log (plasma aldosterone-to-renin ratio) was independently correlated with EDVi and ESVi. Plasma aldosterone was independently correlated with native T1. CONCLUSION: Patients with PA showed a greater degree of ventricular hypertrophy and enlargement, as well as myocardial fibrosis, compared to those with EH. Cardiac MRI T1 mapping can detect left ventricular myocardial fibrosis in patients with PA.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34269560

RESUMO

Hydrogen evolution by alternating conjugated copolymers has attracted much attention in recent years. To study alternating copolymers with data-driven strategies, two types of multidimension fragmentation descriptors (MDFD), structure-based MDFD (SMDFD), and electronic property-based MDFD (EPMDFD), have been developed with machine learning (ML) algorithms for the first time. The superiority of SMDFD-based models has been demonstrated by the highly accurate and universal predictions of electronic properties. Moreover, EPMDFD-based, experimental-parameter-free ML models were developed for the prediction of the hydrogen evolution reaction, displaying excellent accuracy (real-test accuracy = 0.91). The combination of explainable ML approaches and first-principles calculations was employed to explore photocatalytic dynamics, revealing the importance of electron delocalization in the excited state. Virtual designing of high-performance candidates can also be achieved. Our work illustrates the huge potential of ML-based material design in the field of polymeric photocatalysts toward high-performance photocatalysis.

12.
J Am Chem Soc ; 143(27): 10403-10412, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34224242

RESUMO

Dibenzo[hi,st]ovalene (DBOV) has excellent photophysical properties, including strong fluorescence and high ambient stability. Moreover, the optical blinking properties of DBOV have enabled optical super-resolution single-molecule localization microscopy with an imaging resolution beyond the diffraction limit. Various organic and inorganic fluorescent probes have been developed for super-resolution imaging, but those sensitive to pH and/or metal ions have remained elusive. Here, we report a diaza-derivative of DBOV (N-DBOV), synthesized in eight steps with a total yield of 15%. Nitrogen (N)-bearing zigzag edges were formed through oxidative cyclization of amino groups in the last step. UV-vis and fluorescence spectroscopy of N-DBOV revealed its promising optical properties comparable to those of the parent DBOV, while cyclic voltammetry and density functional theory calculations highlighted its lower orbital energy levels and potential n-type semiconductor character. Notably, in contrast to that of the parent DBOV, the strong luminescence of N-DBOV is dependent on pH and the presence of heavy metal ions, indicating the potential of N-DBOV in sensing applications. N-DBOV also exhibited pH-responsive blinking, which enables pH-sensitive super-resolution imaging. Therefore, N-DBOV appears to be a highly promising candidate for fluorescence sensing in biology and environmental analytics.

13.
PLoS One ; 16(7): e0254711, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34265005

RESUMO

GRF genes have been confirmed to have important regulatory functions in plant growth, development and response to abiotic stress. Although the genome of Jatropha curcas is sequenced, knowledge about the identification of the species' GRF genes and their expression patterns is still lacking. In this study, we characterized the 10 JcGRF genes. A detailed investigation into the physic nut GRF gene family is performed, including analysis of the exon-intron structure, conserved domains, conserved motifs, phylogeny, chromosomal locations, potential small RNA targets and expression profiles under both normal growth and abiotic stress conditions. Phylogenetic analysis indicated that the 10 JcGRF genes were classified into five groups corresponding to group I, II, III, IV and V. The analysis of conserved domains showed that the motifs of JcGRF genes were highly conserved in Jatropha curcas. Expression analysis based on RNA-seq and qRT-PCR showed that almost all JcGRF genes had the highest expression in seeds, but very low expression was detected in the non-seed tissues tested, and four JcGRF genes responded to at least one abiotic stress at at least one treatment point. Our research will provide an important scientific basis for further research on the potential functions of JcGRF genes in Jatropha curcas growth and development, and response to abiotic stress, and will eventually provide candidate genes for the breeding of Jatropha curcas.

14.
Thorax ; 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312316

RESUMO

OBJECTIVES: To investigate superiority of a telerehabilitation programme for COVID-19 (TERECO) over no rehabilitation with regard to exercise capacity, lower limb muscle strength (LMS), pulmonary function, health-related quality of life (HRQOL) and dyspnoea. DESIGN: Parallel-group randomised controlled trial with 1:1 block randomisation. SETTING: Three major hospitals from Jiangsu and Hubei provinces, China. PARTICIPANTS: 120 formerly hospitalised COVID-19 survivors with remaining dyspnoea complaints were randomised with 61 allocated to control and 59 to TERECO. INTERVENTION: Unsupervised home-based 6-week exercise programme comprising breathing control and thoracic expansion, aerobic exercise and LMS exercise, delivered via smartphone, and remotely monitored with heart rate telemetry. OUTCOMES: Primary outcome was 6 min walking distance (6MWD) in metres. Secondary outcomes were squat time in seconds; pulmonary function assessed by spirometry; HRQOL measured with Short Form Health Survey-12 (SF-12) and mMRC-dyspnoea. Outcomes were assessed at 6 weeks (post-treatment) and 28 weeks (follow-up). RESULTS: Adjusted between-group difference in change in 6MWD was 65.45 m (95% CI 43.8 to 87.1; p<0.001) at post-treatment and 68.62 m (95% CI 46.39 to 90.85; p<0.001) at follow-up. Treatment effects for LMS were 20.12 s (95% CI 12.34 to 27.9; p<0.001) post-treatment and 22.23 s (95% CI 14.24 to 30.21; p<0.001) at follow-up. No group differences were found for lung function except post-treatment maximum voluntary ventilation. Increase in SF-12 physical component was greater in the TERECO group with treatment effects estimated as 3.79 (95% CI 1.24 to 6.35; p=0.004) at post-treatment and 2.69 (95% CI 0.06 to 5.32; p=0.045) at follow-up. CONCLUSIONS: This trial demonstrated superiority of TERECO over no rehabilitation for 6MWD, LMS, and physical HRQOL. TRIAL REGISTRATION NUMBER: ChiCTR2000031834.

15.
ACS Sens ; 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34324312

RESUMO

The BCR/ABLp210 fusion gene is a classic biomarker of chronic myeloid leukemia, which can be divided into e13a2 and e14a2 isoforms according to different breakpoints. These two isoforms showed distinct differences in clinical manifestation, treatment effect, and prognosis risk. Herein, a strategy based on nanocluster beacon (NCB) fluorescence was developed to identify the e13a2 and e14a2 isoforms in one-pot. Because the fluorescence of AgNCs can be activated when they are placed in proximity to the corresponding enhancer sequences, thymine-rich (T-rich) or guanine-rich (G-rich). In this work, we explored an ideal DNA-AgNCs template as an excellent molecular reporter with a high signal-to-noise ratio. After recognition with the corresponding isoforms, the AgNCs can be pulled closer to the T-rich or G-rich sequences to form a three-way junction structure and generate fluorescence with corresponding wavelengths. Therefore, by distinguishing the corresponding wavelengths of AgNCs, we successfully identified two isoforms in one tube with the limitation of 16 pM for e13a2 and 9 pM for e14a2. Moreover, this strategy also realized isoform identification in leukemia cells and newly diagnosed CML patients within 40 min, which provides a powerful tool to distinguish fusion gene subtypes at the same time.

16.
BMC Infect Dis ; 21(1): 583, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34134659

RESUMO

BACKGROUND: Previous studies showed that type 2 short bowel syndrome (SBS) rats were accompanied by severe intestinal bacterial dysbiosis. Limited data are available for intestinal fungal dysbiosis. Moreover, no effective therapeutic drugs are available for these microbiota dysbiosis. The aims of our study were to investigate the therapeutic potential of glucagon-like peptide 2 (GLP-2) for these microbiota dysbiosis in type 2 SBS rats. METHODS: 8-week-old male SD rats which underwent 80% small bowel resection, ileocecum resection, partial colon resection and jejunocolostomy, were treated with saline (SBS group, n = 5) or GLP-2 (GLP2.SBS group, n = 5). The Sham group rats which underwent transection and re-anastomosis were given a saline placebo (Sham group, n = 5). 16S rRNA and ITS sequencing were applied to evaluate the colonic bacterial and fungal composition at 22 days after surgery, respectively. RESULTS: The relative abundance of Actinobacteria, Firmicutes and proinflammatory Proteobacteria increased significantly in SBS group rats, while the relative abundance of Bacteroidetes, Verrucomicrobia and Tenericutes decreased remarkably. GLP-2 treatment significantly decreased Proteus and increased Clostridium relative to the saline treated SBS rats. The diversity of intestinal fungi was significantly increased in SBS rats, accompanied with some fungi abnormally increased and some resident fungi (e.g., Penicillium) significantly decreased. GLP-2 treatment significantly decreased Debaryomyces and Meyerozyma, and increased Penicillium. Moreover, GLP-2 partially restored the bacteria-fungi interkingdom interaction network of SBS rats. CONCLUSION: Our study confirms the bacterial and fungal dysbiosis in type 2 SBS rats, and GLP-2 partially ameliorated these microbiota dysbiosis.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Intestinos/microbiologia , Síndrome do Intestino Curto/patologia , Actinobacteria/genética , Actinobacteria/isolamento & purificação , Animais , Colo/cirurgia , Colostomia , Análise Discriminante , Modelos Animais de Doenças , Disbiose , Fungos/genética , Fungos/isolamento & purificação , Peptídeo 2 Semelhante ao Glucagon/uso terapêutico , Análise dos Mínimos Quadrados , Masculino , Análise de Componente Principal , RNA Ribossômico 16S/análise , RNA Ribossômico 16S/metabolismo , Ratos , Ratos Sprague-Dawley , Síndrome do Intestino Curto/tratamento farmacológico , Síndrome do Intestino Curto/microbiologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-34189586

RESUMO

The aim was to investigate with very large scale analyses whether there are underlying functional connectivity differences between humans that relate to food reward; and whether these in turn are associated with being overweight. In 37,286 humans from the UK Biobank resting state functional connectivities of the orbitofrontal cortex, especially with the anterior cingulate cortex, were positively correlated with the liking for sweet foods (FDR p < 0.05). They were also positively correlated with the body mass index (BMI) (FDR p < 0.05). Moreover, in a sample of 502,492 people, the 'liking for sweet foods' was correlated with their BMI (r=0.06, p<10-125). In a cross-validation with 545 participants from the Human Connectome Project, higher functional connectivity involving the orbitofrontal cortex relative to other brain areas was associated with high BMI (≥30) compared to a mid-BMI group (22-25; p=6x10-5); and low orbitofrontal cortex functional connectivity was associated with low BMI (≤20.5; p<0.024). It is proposed that high BMI relates to increased efficacy of orbitofrontal cortex food reward systems, and low BMI to decreased efficacy. This was found with no stimulation by food, so may be an underlying individual difference in brain connectivity that is related to food reward and BMI.

18.
Nat Commun ; 12(1): 3769, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145259

RESUMO

Children's behavioral problems have been associated with their family environments. Here, we investigate whether specific features of brain structures could relate to this link. Using structural magnetic resonance imaging of 8756 children aged 9-11 from the Adolescent Brain Cognitive Developmental study, we show that high family conflict and low parental monitoring scores are associated with children's behavioral problems, as well as with smaller cortical areas of the orbitofrontal cortex, anterior cingulate cortex, and middle temporal gyrus. A longitudinal analysis indicates that psychiatric problems scores are associated with increased family conflict and decreased parental monitoring 1 year later, and mediate associations between the reduced cortical areas and family conflict, and parental monitoring scores. These results emphasize the relationships between the brain structure of children, their family environments, and their behavioral problems.


Assuntos
Conflito Familiar/psicologia , Giro do Cíngulo/fisiologia , Relações Pais-Filho , Córtex Pré-Frontal/fisiologia , Comportamento Problema/psicologia , Lobo Temporal/fisiologia , Criança , Cognição/fisiologia , Meio Ambiente , Saúde da Família , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino
19.
Nat Commun ; 12(1): 3686, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140498

RESUMO

Tumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways.


Assuntos
Hipóxia Celular , Dano ao DNA/genética , DNA Helicases/metabolismo , Regulação da Expressão Gênica/genética , Enzimas Multifuncionais/metabolismo , Estruturas R-Loop/genética , RNA Helicases/metabolismo , Resposta a Proteínas não Dobradas/genética , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Imunoprecipitação da Cromatina , DNA Helicases/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Enzimas Multifuncionais/genética , Inibidores da Síntese de Ácido Nucleico/farmacologia , Oxigênio/farmacologia , Estruturas R-Loop/efeitos dos fármacos , RNA Helicases/genética , RNA-Seq , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Regulação para Cima , Zinostatina/farmacologia , eIF-2 Quinase/metabolismo
20.
Behav Brain Res ; 412: 113412, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34118296

RESUMO

Some anxiety-related disorders, such as panic disorder, specific phobia, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD), develop because of the poor regulation and inappropriate expression of fear-related behavior at the wrong place and wrong time. In clinical settings, exposure therapy, which consists of repeated presentation of trauma-related stimuli without real threats in the therapeutic context, is commonly used to treat these disorders. However, 30-50 % of patients suffer from the recurrence of anxiety symptoms after they leave the therapeutic context. This behavioral phenomenon is called renewal. In this study, ABA Pavlovian fear renewal paradigm was used to assess the role of the aberrant orbitofrontal cortex (OFC) activation, a symptom of OCD patients, on fear regulation in laboratory settings. The rats were fear conditioned in one context (context A), extinguished to the tones in another context (context B), and then tested in either context A or B. During extinction, rats were subjected to lateral or medial OFC activation. We found that rats that underwent extinction with either lateral or medial OFC activation were unable to use the context to determine whether it was a safe or dangerous context during renewal test. Interestingly, the rats with lateral OFC activation during extinction showed generally high fear, whereas the rats with medial OFC activation during extinction showed generally low fear. In conclusion, our results suggested that aberrant activation of specifically the lateral OFC may have a negative impact during exposure therapy treatments and results in their poor regulation of fear-related behavior.

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