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1.
Acta Pharmacol Sin ; 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918411

RESUMO

The B-cell lymphoma 2 (BCL-2) protein family plays a pivotal role in regulating the apoptosis process. BCL-2, as an antiapoptotic protein in this family, mediates apoptosis resistance and is an ideal target for cell death strategies in cancer therapy. Traditional treatment modalities target BCL-2 by occupying the hydrophobic pocket formed by BCL-2 homology (BH) domains 1-3, while in recent years, the BH4 domain of BCL-2 has also been considered an attractive novel target. Herein, we describe the discovery and identification of DC-B01, a novel BCL-2 inhibitor targeting the BH4 domain, through virtual screening combined with biophysical and biochemical methods. Our results from surface plasmon resonance and cellular thermal shift assay confirmed that the BH4 domain is responsible for the interaction between BCL-2 and DC-B01. As evidenced by further cell-based experiments, DC-B01 induced cell killing in a BCL-2-dependent manner and triggered apoptosis via the mitochondria-mediated pathway. DC-B01 disrupted the BCL-2/c-Myc interaction and consequently suppressed the transcriptional activity of c-Myc. Moreover, DC-B01 inhibited tumor growth in vivo in a BCL­2­dependent manner. Collectively, these results indicate that DC-B01 is a promising BCL-2 BH4 domain inhibitor with the potential for further development.

2.
BMC Infect Dis ; 22(1): 675, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35931956

RESUMO

BACKGROUND: Infected pancreatic necrosis (IPN) is a life-threatening complication of acute pancreatitis (AP). Timely diagnosis of IPN could facilitate appropriate treatment, but there is a lack of reliable non-invasive screening tests. In this study, we aimed to evaluate the diagnostic value of plasma metagenomic next-generation sequencing (mNGS) based on circulating microbial cell-free DNA in patients with suspected IPN. METHODS: From October 2020 to October 2021, 44 suspected IPN patients who underwent plasma mNGS were reviewed. Confirmatory diagnosis of IPN within two weeks after the index blood sampling was considered the reference standard. The confirmation of IPN relied on the microbiological results of drains obtained from the necrotic collections. The distribution of the pathogens identified by plasma mNGS was analyzed. Positive percent agreement (PPA) and negative percent agreement (NPA) were evaluated based on the conformity between the overall mNGS results and culture results of IPN drains. In addition, the clinical outcomes were compared between mNGS positive and negative patients. RESULTS: Across all the study samples, thirteen species of bacteria and five species of fungi were detected by mNGS. The positivity rate of plasma mNGS was 54.55% (24/44). Of the 24 mNGS positive cases, twenty (83.33%, 95% CI, 68.42-98.24%) were consistent with the culture results of IPN drains. The PPA and NPA of plasma mNGS for IPN were 80.0% (20/25; 95% CI, 64.32-95.68%) and 89.47% (17/19; 95% CI, 75.67-100%), respectively. Compared with the mNGS negative group, patients in the positive group had more new-onset septic shock [12 (50.0%) vs. 4 (20.0%), p = 0.039]. CONCLUSION: IPN relevant pathogens can be identified by plasma mNGS, potentially facilitating appropriate treatment. The clinical application of mNGS in this cohort appears feasible.


Assuntos
Ácidos Nucleicos Livres , Infecções Intra-Abdominais , Pancreatite Necrosante Aguda , Doença Aguda , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pancreatite Necrosante Aguda/diagnóstico , Sensibilidade e Especificidade
3.
Commun Biol ; 5(1): 774, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915136

RESUMO

While the exact mechanism remains unclear, type 2 diabetes mellitus increases the risk of sarcopenia which is characterized by decreased muscle mass, strength, and function. Whole-transcriptome RNA sequencing and informatics were performed on the diabetes-induced sarcopenia model of db/db mice. To determine the specific function of lncRNA Gm20743, the detection of Mito-Sox, reactive oxygen species, Ethynyl-2'-deoxyuridine, and myosin heavy chain was performed in overexpressed and knockdown-Gm20743 C2C12 cells. RNA-seq data and informatics revealed the key lncRNA-mRNA interactions and indicated a potential regulatory role of lncRNAs. We characterized three core candidate lncRNAs Gm20743, Gm35438, 1700047G03Rik, and their potential function. Furthermore, the results suggested lncRNA Gm20743 may be involved in regulating mitochondrial function, oxidative stress, cell proliferation, and myotube differentiation in skeletal muscle cells. These findings significantly improve our understanding of lncRNAs that may mediate muscle mass, strength, and function in diabetes and represent potential therapeutic targets for diabetes-induced sarcopenia.


Assuntos
Diabetes Mellitus Tipo 2 , RNA Longo não Codificante , Sarcopenia , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Camundongos , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Sarcopenia/genética , Transcriptoma
4.
Sci Rep ; 12(1): 13424, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927571

RESUMO

The angle and position of the scapular glenoid are important in shoulder mechanics, the interpretation of diseases, and planning shoulder replacement surgery. In total shoulder replacement, understanding the bony parameters of the glenoid is also of considerable guiding significance for designing implant size and improving material adaptability. To compare glenoid parameters measured from skeletal scapula specimens with those measured by 3D modeling of CT scanning images, analyze correlations between these data, and draw conclusions to guide clinical treatment of shoulder joint injury and total shoulder joint replacement. The data of manual and CT measurements from the same Chinese dry glenoid was compared. Three-dimensional measurement data were collected from the Japanese population and compared with the Chinese population data generated in this study. There were no significant differences between manual measurement and CT measurement in the inclination angle, glenopolar angle, anteroposterior transverse diameter, upper to lower vertical diameter, and depth of the glenoid (P = 0.288, 0.524, 0.111, 0.194, and 0.055, respectively). Further, there were no significant differences between Japanese and Chinese glenoid bones in the upper and lower vertical diameters or anteroposterior transverse diameters (P > 0.05). There were no significant differences between CT and manual measurements, suggesting that the CT method may provide measurements very close to the actual specimen size. This result, however, indicated that the measurer should be careful when measuring the depth of the glenoid.


Assuntos
Artroplastia do Ombro , Cavidade Glenoide , Lesões do Ombro , Articulação do Ombro , Artroplastia do Ombro/métodos , Cavidade Glenoide/diagnóstico por imagem , Cavidade Glenoide/cirurgia , Humanos , Imageamento Tridimensional , Escápula/diagnóstico por imagem , Articulação do Ombro/diagnóstico por imagem , Articulação do Ombro/cirurgia
5.
Curr Alzheimer Res ; 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35929621

RESUMO

Aging is an inevitable process characterized with progressive loss of physiological integrity and increased susceptibility to cancer, diabetes, cardiovascular, and neurodegenerative diseases; regarding the last, aging is the primary risk factor for Alzheimer's disease (AD), the most common cause of dementia. AD is characterized by brain pathology including extracellular deposition of amyloid aggregation and intracellular accumulation of neurofibrillary tangles composed of hyperphosphorylated tau protein. In addition, losses of synapses and a wide range of neurons are pivotal pathologies in AD brain. Accumulating evidence demonstrates hypoactivation of hippocampal neural networks in the aging brain, whereas AD-related mild cognitive impairment (AD-MCI) is begins with hyperactivation, followed by diminution of hippocampal activity as AD develops. The biphasic trends of the activity of hippocampal neural network are consistent with the alteration of N-methyl-D-aspartate receptor (NMDA-R) activity from aging to prodromal (AD-MCI) to mid-/late stage AD. D-Serine, a product of racemization catalyzed by serine racemase (SR), is an important co-agonist of the NMDA-R which is involved in synaptic events including neurotransmission, synaptogenesis, long-term potentiation (LTP), development, and excitotoxicity. SR and D-serine are decreased in the hippocampus of the aging brain, correlating with impairment of cognitive function. By contrast, SR is increased in AD brain, which is associated with a greater degree of cognitive dysfunction. Emerging studies suggest that D-serine levels in the brain or in cerebral spinal fluid from AD patients are higher than in age-matched controls, but the results are inconsistent. Very recently, serum D-serine levels in AD were reported to correlate with sex and clinical dementia rating (CDR) stage. This review will discuss alterations of NMDA-R and SR in aging and brain, and the mechanisms underlying the differential regulation of SR will be probed. Collectively, we propose that SR may be a molecular switch that distinguishes the effects of aging from those of AD on the brain.

6.
Dig Liver Dis ; 2022 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35948458

RESUMO

BACKGROUND: Timely and accurate microbial diagnosis is important in managing patients with infected pancreatic necrosis (IPN). AIMS: To evaluate the diagnostic performance of Metagenomic next-generation sequencing (mNGS) in patients with suspected IPN. METHODS: The clinical data of 40 patients with suspected IPN who underwent CT-guided pancreatic fluid aspiration were retrospectively analyzed. Microbial culture and mNGS were simultaneously applied to identify the potential pathogens. The diagnostic performance of the mNGS was assessed by sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The mNGS report can be obtained significantly earlier than culture methods (42 (36-62 h) vs. 60 (42-124 h), P = 0.032). Across all the study samples, seven species of bacteria and two species of fungi were reported accordingly to the culture results, while 22 species of bacteria and two species of fungi were detected by mNGS. The sensitivity, specificity, NPV, and PPV of mNGS were 88.0%, 100%, 83.33%, and 100%, respectively. CONCLUSIONS: The diagnostic accuracy of mNGS in patients with suspected IPN is satisfactory. Moreover, mNGS may broaden the range of identifiable infectious pathogens and provide a more timely diagnosis.

7.
Clin Appl Thromb Hemost ; 28: 10760296221118483, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35924377

RESUMO

Objective: Evaluate the technical performance of the pre-analytical hemolysis-icterus-lipemia (HIL) check module on the ACL-TOP-750. Methods: 8433 routine coagulation samples were evaluated for HIL, the presence of clotting and low sample volume by both visual inspection and the pre-analytical HIL check module on the ACL-TOP-750. Results: 7726 samples were in agreement with both methods and 707 were not consistent. 356 samples with low volume were identified by visual inspection and 920 by the instrument (2.7 mL threshold). Visual inspection identified 56 lipemic samples while 13 of those with moderate or high lipemia were identified by the instrument. Visual inspection identified 47 hemolyzed samples while 7 with moderate or high hemolysis were identified by the instrument. Both visual inspection and the instrument identified 36 icteric samples. For triglyceride concentration and bilirubin concentration, there was good correlation between the ACL-TOP-750 and the DXC800 biochemistry analyzer. Among 30 samples with varying amounts of clotting, 27 were discovered by visual inspection and 3 were discovered by the instrument. Conclusion: The pre-analytical check module on the ACL-TOP-750 improved the detection rate of samples below the target 2.7 mL volume, and the accuracy in detection of HIL. However, the automated method could not replace visual assessment of clotting in samples.


Assuntos
Hiperlipidemias , Icterícia , Testes de Coagulação Sanguínea/métodos , Hemólise , Hemostasia , Humanos
8.
J Ethnopharmacol ; : 115601, 2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-35963422

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Chang-Kang-Fang (CKF) is a traditional Chinese herbal formula used for treatment of irritable bowel syndrome (IBS) in China. Decoction is the administration form of CKF in clinical practice. Previously, CKF has been confirmed with activities of releasing pain and reversing disorders of intestinal propulsion. And alkaloids, monoglycosides, chromones were found as the main bioactive components potentially contributing to the efficacy of CKF. Polysaccharide was also a major constituent in CKF. But if and how polysaccharides influence the systemic exposure of bioactive components in CKF is unknown. AIM OF THE STUDY: In this study, we aimed to demonstrate the contribution of the co-existed polysaccharides on the systemic exposure of the major bioactive components from CKF in normal and IBS model rats. MATERIALS AND METHODS: An UPLC-TQ-MS with multiple reaction monitoring (MRM) scan method was developed and validated for quantifying six major small molecular bioactive ingredients of CKF in the plasma samples, including magnoflorine (MAG), berberine (BBR), albiflorin (ALB), paeoniflorin (PAE), 5-O-methylvisamminol (5-OM) and prim-O-glucosylcimifugin (POG). The rats received CKF decoction (CKF) and CKF small molecule portion (knockout of polysaccharides, CKFSM), respectively. IBS model rats were induced by daily bondage and gavage of Sennae Folium decoction (derived from the leaf of Cassia angustifolia Vahl). The effects of the co-existing polysaccharides on the pharmacokinetic parameters of six small molecular bioactive components in normal and IBS model rats were systematically evaluated. The potential gut microbiota involved mechanisms of the effects was validated by broad-spectrum antibiotic (ABX) treatment. RESULTS: The selectivity, precision, accuracy, recovery and matrix effect of the established quantification method were all within acceptable limits of biological sample. In normal rats, the co-existing polysaccharides significantly reduced the AUC(0-t) of MAG and PAE compared with CKFSM group. The Cmax and AUC(0-t) of other four compound were not influenced by co-existing polysaccharides. However, in IBS model rats, compared with CKFSM group, the Cmax and AUC(0-t) of the six ingredients significantly increased in CKF group. For CKF + ABX group, the Cmax of six ingredients decreased significantly when compared with CKF group, and the AUC(0-t) of MAG, BBR, ALB, PAE also reduced with significant differences. CONCLUSIONS: A reliable and sensitive UPLC-TQ-MS method was successfully developed and validated for evaluating influence of co-existing polysaccharides on pharmacokinetic behavior of six major small molecules components in CKF. The co-existing polysaccharides enhanced the systemic exposure of six bioactive small molecules in CKF under IBS pathological state potentially via gut microbiota involvement.

9.
Proc Natl Acad Sci U S A ; 119(33): e2203318119, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35939687

RESUMO

γδ T cells are an abundant T cell population at the mucosa and are important in providing immune surveillance as well as maintaining tissue homeostasis. However, despite γδ T cells' origin in the thymus, detailed mechanisms regulating γδ T cell development remain poorly understood. N6-methyladenosine (m6A) represents one of the most common posttranscriptional modifications of messenger RNA (mRNA) in mammalian cells, but whether it plays a role in γδ T cell biology is still unclear. Here, we show that depletion of the m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells, which confers enhanced protection against gastrointestinal Salmonella typhimurium infection. Mechanistically, loss of ALKBH5 favors the development of γδ T cell precursors by increasing the abundance of m6A RNA modification in thymocytes, which further reduces the expression of several target genes including Notch signaling components Jagged1 and Notch2. As a result, impairment of Jagged1/Notch2 signaling contributes to enhanced proliferation and differentiation of γδ T cell precursors, leading to an expanded mature γδ T cell repertoire. Taken together, our results indicate a checkpoint role of ALKBH5 and m6A modification in the regulation of γδ T cell early development.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase , RNA , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Animais , Mamíferos/genética , Estabilidade de RNA/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genética
10.
Front Plant Sci ; 13: 871859, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35923874

RESUMO

Potato is one of the most significant food crops globally due to its essential role in the human diet. The growing demand for potato, coupled with severe environmental losses caused by extensive farming activities, implies the need for better crop protection and management practices. Precision agriculture is being well recognized as the solution as it deals with the management of spatial and temporal variability to improve agricultural returns and reduce environmental impact. As the initial step in precision agriculture, the traditional methods of crop and field characterization require a large input in labor, time, and cost. Recent developments in remote sensing technologies have facilitated the process of monitoring crops and quantifying field variations. Successful applications have been witnessed in the area of precision potato farming. Thus, this review reports the current knowledge on the applications of remote sensing technologies in precision potato trait characterization. We reviewed the commonly used imaging sensors and remote sensing platforms with the comparisons of their strengths and limitations and summarized the main applications of the remote sensing technologies in potato. As a result, this review could update potato agronomists and farmers with the latest approaches and research outcomes, as well as provide a selective list for those who have the intentions to apply remote sensing technologies to characterize potato traits for precision agriculture.

11.
Front Surg ; 9: 953802, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910473

RESUMO

Backgroud: Delayed postoperative hyponatremia (DPH) is common for sellar lesions. However, the true prevalence and associated factors of DPH after endoscopic endonasal surgery (EES) for Rathke's cleft cyst (RCC) have not been studied in a large patient cohort. Methods: A retrospective analysis was conducted over 6 years at our institution, and patients with RCC treated by EES were enrolled according to our inclusion criteria. Patient demographics, clinical characteristics, images, and surgical procedures were documented. Serum sodium was routinely measured before surgery, on postoperative day 1, and every 2 days thereafter until discharge. For patients with DPH, electrolyte, hematocrit, serum protein levels, and plasma and urinary osmolality were daily measured to explore potential etiology. Results: Of the 149 eligible patients, 25 (16.8%) developed DPH, which was similar to other sellar lesions, except craniopharyngioma, in the same period in our institution. Significant risk factors suggested by univariate analysis were cyst location, requirement of postoperative hydrocortisone therapy, postoperative meningitis, intraoperative cerebrospinal fluid (CSF) leakage, and subtotal resection (STR) of the cyst wall (all p < 0.05). In addition, other supplementary 11 cases of suprasellar RCC with different surgical strategies (aggressive resection) and relevant factors were enrolled into multivariate analysis. Suprasellar location [odds ratio (OR) 8.387, 95% confidence interval (CI) 1.014-69.365, p = 0.049], requirement of postoperative hydrocortisone therapy (OR 4.208, 95%CI 1.246-14.209, p = 0.021), and intraoperative CSF leakage (OR 6.631, 95%CI 1.728-25.440, p = 0.006) were found to be the independent predictors of DPH. Conclusion: DPH is a common complication after EES for RCC. Suprasellar location, requirement of postoperative hydrocortisone therapy, and intraoperative CSF leakage are the most reliable risk factors. Cortisol deficiency and syndrome of inappropriate antidiuretic hormone (SIADH) are considered as the main etiologies of DPH in RCC. Conservative excision of the cyst wall may reduce DPH occurrence.

12.
Sci Total Environ ; : 157854, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35940274

RESUMO

The mining of ionic rare earth elements in Ganzhou left large area of barren tailings with severe vegetation destruction in pressing needs of remediation. However, the remediating effects of soil additives combined with revegetation on the preservation of nutrients in the tailings and microbial communities were rarely studied. For this purpose, pilot experiments were implemented in a field, with the control group (CK) only cultivating plants without adding materials, and three treatments including peanut straw biochar composite (T1), phosphorus­magnesium composite (T2) and modified zeolite composite (T3) along with the cultivation of Medicago sativa L., Paspalum vaginatum Sw. and Lolium perenne L. Soil pH and organic matter in CK significantly decreased from 4.90 to 4.17 and from 6.62 g/kg to 3.87 g/kg after six months, respectively (p ≤ 0.05), while all the treatments could effectively buffer soil acidification (over 5.74) and delay the loss of soil organic matter. Soil cation exchange capacity was still below the detection limit in all the groups except T2. The results of rainfall runoff monitoring indicated that compared with CK, only T2 could significantly reduce the runoff loss of soil NO3- and SO42- by 45.61 %-75.78 % and 64.03 %-76.12 %, respectively (p ≤ 0.05). Compared with CK, the bacterial diversity in T2 and T3 significantly increased 21.18 % and 28.15 %, respectively (p ≤ 0.05), while T1 didn't change the bacterial or fungal diversity (p > 0.05). Co-occurrence network analysis showed that compared with CK, the whole microbial communities interacted more closely in the three treatments. Functional prediction of the microbial communities revealed all the treatments were dominated by carbon transforming bacteria and saprotrophic fungi except T2. This study demonstrated that the composite materials combined with revegetation couldn't retain soil nitrogen compounds and sulfate in rare earth tailings in the long term.

13.
Chem Commun (Camb) ; 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35942652

RESUMO

Wavelength-dependent absorbance of blood has impeded the development of fluorescence biodetection in whole blood. Here, by replacing the fluorescence working signal with a temperature signal, reliable H2S detection was performed in samples of whole blood. The developed system was based on a dual-channel lanthanide-doped nanoprobe, which further allowed precise serodiagnosis of acute pancreatitis.

14.
Biochem Pharmacol ; 203: 115199, 2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35917871

RESUMO

Acute ethanol intoxication has become an alarming health problem. In the present study, we discover the beneficial effect of lamivudine on alcoholism in mice. Our results indicate that lamivudine decreases serum alcohol concentration dramatically, and potently activates acetaldehyde dehydrogenase (ALDH) to accelerate the conversion of acetaldehyde to acetic acid, which is finally metabolized by tricarboxylic acid cycle to be CO2 and H2O. Also, lamivudine significantly improves symptoms post drinking, such as prolonging alcohol tolerance time and shortening sobering time, as well as reducing the death rate. This work will provide new strategies for the prevention and treatment of acute alcoholism.

15.
Neurochem Res ; 2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-35960484

RESUMO

Astrocytes act as "housekeeping cells" for maintaining cerebral homeostasis and play an important role in many disorders. Recent studies further highlight the contribution of autophagy to astrocytic functions, including astrogenesis, the astrocytic removal of neurotoxins or stressors, and astrocytic polarization. More importantly, genetic and pharmacological approaches have provided evidence that outlines the contributions of astrocytic autophagy to several brain disorders, including neurodegeneration, cerebral ischemia, and depression. In this study, we summarize the emerging role of autophagy in regulating astrocytic functions and discuss the contributions of astrocytic autophagy to different CNS disorders.

16.
Artigo em Inglês | MEDLINE | ID: mdl-35804256

RESUMO

BACKGROUND: Although fluoroless transseptal puncture (TSP) guided by intracardiac echocardiography (ICE) has been used for many years, there are no reports of an accurate site-specific method for TSP in detail, especially about the safety and efficiency of the method. This study aimed to compare the efficacy and safety of TSP guided by three-dimensional ICE using a fluoroless site-specific method with that of the conventional fluoroless method in patients with atrial fibrillation (AF). METHODS: This prospective study included 60 patients with AF scheduled for radiofrequency ablation who were assigned to undergo modified fluoroless site-specific TSP (SS-ICE group, n = 30) or conventional fluoroless TSP (C-ICE group, n = 30). TSP was guided by three-dimensional ICE in both study groups. RESULTS: All fluoroless TSP were performed successfully in both groups. There were no significant differences in patient characteristics, Pre-TSP time (11.3 ± 1.7 min vs. 11.1 ± 1.6 min, P = 0.822) and TSP time (3.4 ± 0.9 min vs. 3.5 ± 1.1 min, P = 0.772) between the SS-ICE group and the C-ICE group. The distance between the actual traversing point and the presetting point in the fossa ovalis was less than 5 mm in 87% of patients (26/30, 3.1 ± 1.2 mm) in the SS-ICE group. There were no TSP-related complications in either group. CONCLUSION: SS-ICE method is a simple, safe, and effective approach for fluoroless site-specific TSP.

17.
J Exp Bot ; 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35816329

RESUMO

Oomycete pathogens secrete hundreds of cytoplasmic RxLR effectors to modulate host immunity by targeting diverse plant proteins. Revealing how effectors manipulate host proteins is pivotal to understand infection processes and to develop new strategies to control plant disease. Here we show that the Phytophthora infestans RxLR effector Pi22798 interacts in the nucleus with a potato class II knotted-like homeobox (KNOX) transcription factor, StKNOX3. Silencing the orthologue NbKNOX3 in Nicotiana benthamiana reduces host colonization by P. infestans, whereas transient and stable overexpression of StKNOX3 enhances infection. StKNOX3 forms a homodimer which is dependent on its KNOX II domain. The KNOX II domain is also essential for Pi22798 interaction and for StKNOX3 to enhance P. infestans colonization, indicating that StKNOX3 homodimerization contributes to susceptibility. However, critically, the effector Pi22798 promotes StKNOX3 homodimerization, rather than heterodimerization to another KNOX transcription factor StKNOX7. These results demonstrate that the Oomycete effector Pi22798 increases pathogenicity by promoting homodimerization specifically of StKNOX3 to enhance susceptibility.

18.
Front Oncol ; 12: 897898, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35847864

RESUMO

Epigenetic dysregulation of cancer-associated genes has been identified to contribute to the pathogenesis of myelodysplastic syndromes (MDS). However, few studies have elucidated the whole-genome DNA methylation in the initiation pathogenesis of MDS. Reduced representation bisulfite sequencing was performed in five de novo MDS patients and four controls to investigate epigenetic alterations in MDS pathogenesis. The mean global methylation in five MDS patients showed no significant difference compared with the four controls. In depth, a total of 1,459 differentially methylated fragments, including 759 hypermethylated and 700 hypomethylated fragments, were identified between MDS patients and controls. Targeted bisulfite sequencing further identified that hypermethylation of DLEU7, FOXR1, LEP, and PANX2 were frequent events in an additional cohort of MDS patients. Subsequently, LEP hypermethylation was confirmed by real-time quantitative methylation-specific PCR in an expanded cohort of larger MDS patients. In clinics, LEP hypermethylation tended to be associated with lower bone marrow blasts and was significantly correlated with U2AF1 mutation. Survival analysis indicated that LEP hypermethylation was associated with a markedly longer survival time but was not an independent prognostic biomarker in MDS patients. Functional studies revealed pro-proliferative and anti-apoptotic effects of leptin in the MDS cell line SKM-1, and it was significantly associated with cell growth and death as well as the Toll-like receptor and NF-kappa B signaling pathways. Collectively, our findings demonstrated that whole-genome DNA methylation analysis identified novel epigenetic alterations such as DLEU7, FOXR1, LEP, and PANX2 methylations as frequent events in MDS. Moreover, LEP might play a role in MDS pathogenesis, and LEP hypermethylation was associated with longer survival but not as an independent prognostic biomarker in MDS.

19.
Small ; : e2107301, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35869035

RESUMO

GaN-based lateral Schottky barrier diodes (SBDs) have attracted great attention for high-power applications due to its combined high electron mobility and large critical breakdown field. However, the breakdown voltage (BV) of the SBDs are far from exploiting the material advantages of GaN at present, limiting the desire to use GaN for ultra-high voltage (UHV) applications. Then, a golden question is whether the excellent properties of GaN-based materials can be practically used in the UHV field? Here, UHV AlGaN/GaN SBDs are demonstrated on sapphire with a BV of 10.6 kV, a specific on-resistance (RON,SP ) of 25.8 mΩ cm2 , yielding a power figure-of-merit (P-FOM = BV2 /RON,SP ) of 4.35 GW cm-2 . These devices are designed with single channel and 85-µm anode-to-cathode spacing, without other additional electric field management, demonstrating its great potential for the UHV application in power electronics.

20.
Artigo em Inglês | MEDLINE | ID: mdl-35859238

RESUMO

Overactive bladder (OAB) is a group of clinical symptoms that are highly bothersome to the life and spirit of patients. However, little is known about the role of ubiquitous di-(2-ethylhexyl) phthalate (DEHP) exposure in the disorder. Hence, the study was conducted. The data were collected using the 2003-2008 National Health and Nutrition Examination Survey (NHANES) data (n = 2121), and multiple logistic regression was adapted. The concentrations of DEHP (∑DEHP) were calculated for each metabolite and split into quartiles for analysis. After adjusting for confounding factors, ∑DEHP was associated with increased odds of OAB for the highest quartile (OR = 1.15, 95% CI [1.06, 1.25], p < 0.05), and the highest quartile of metabolites showed similar results, such as mono-(2-ethyl-5-hydroxyhexyl) phthalate (OR = 1.09, 95% CI [1.01, 1.19], p < 0.05), mono-(2-ethyl-5-oxohexyl) phthalate (OR = 1.21, 95% CI [1.11, 1.32], p < 0.05) and mono-(2-ethyl-5-carboxypentyl) phthalate (OR = 1.22, 95% CI [1.12, 1.33], p < 0.05). The association remained when the analyses were stratified by age and sex. Our study adds evidence for understanding the potential role of environmental factors in OAB, and further research is needed to determine whether the status of OAB can be changed by controlling DEHP exposure.

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