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1.
EMBO Mol Med ; : e15409, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34907647

RESUMO

Multidrug resistance is one of the major public health issues the world is facing today. However, the World Health Organization (WHO) revealed recently that there has been little progress in the development of new antibiotics to tackle drug-resistant infections. By mining the bacterial genome database, Zhu et al, in the last issue of EMBO Molecular Medicine, report a defensin expressed by human oral actinomyces, actinomycesin, and characterize its anti-infectious capacity (Zhu et al, 2021). They demonstrate the safety and efficacy of this bacterial antimicrobial peptide (AMP) against various bacterial strains, describe its mode of action, and validate its use as systemic drug therapy against bacterial infections in mice. This study highlights human oral bacteria as a source of antimicrobial agents that need to be considered in the future to fight multidrug-resistant bacteria.

2.
Small Methods ; 5(12): e2101194, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34928009

RESUMO

In the frontier resistive micro-nano gas sensors, the change rate reliability between the measured quantity and output signals has long been puzzled by the ineluctable device-to-device and run-to-run disparities. Here, a neotype sensing data interpretation method to circumvent these signal inconsistencies is reported. The method is based on discovery of a strong linear relation between the initial resistance in air (Ra ) and the absolute change in resistance after exposure to target gas (Ra -Rg ). Metal oxide gas sensors based on a micro-hot-plate are employed as the model system. The study finds that such correlation has a wide universality, even for devices incorporated with different sensing materials or under different gas atmosphere. Furthermore, this rule can also be extensible to graphene-based interdigital microelectrode. In situ probe scanning analyses illuminate that the linear dependence is closely related to work function matching level between metal electrode and sensitive layer. The Schottky barrier at metal-semiconductor junctions is the prominent parameter, whose height (ϕB ) can fundamentally impact material/electrode contact resistance, thereby further affecting the realistic nature expression of sensing materials. Using this correlation, a calibration procedure is proposed and embed in a fully integrated pocket-size sensor prototype, whose response outcomes demonstrated high credibility as compared to commercial apparatus.

3.
Front Oncol ; 11: 762733, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34926264

RESUMO

Background: An accurate pathological diagnosis of hepatocellular carcinoma (HCC), one of the malignant tumors with the highest mortality rate, is time-consuming and heavily reliant on the experience of a pathologist. In this report, we proposed a deep learning model that required minimal noise reduction or manual annotation by an experienced pathologist for HCC diagnosis and classification. Methods: We collected a whole-slide image of hematoxylin and eosin-stained pathological slides from 592 HCC patients at the First Affiliated Hospital, College of Medicine, Zhejiang University between 2015 and 2020. We propose a noise-specific deep learning model. The model was trained initially with 137 cases cropped into multiple-scaled datasets. Patch screening and dynamic label smoothing strategies are adopted to handle the histopathological liver image with noise annotation from the perspective of input and output. The model was then tested in an independent cohort of 455 cases with comparable tumor types and differentiations. Results: Exhaustive experiments demonstrated that our two-step method achieved 87.81% pixel-level accuracy and 98.77% slide-level accuracy in the test dataset. Furthermore, the generalization performance of our model was also verified using The Cancer Genome Atlas dataset, which contains 157 HCC pathological slides, and achieved an accuracy of 87.90%. Conclusions: The noise-specific histopathological classification model of HCC based on deep learning is effective for the dataset with noisy annotation, and it significantly improved the pixel-level accuracy of the regular convolutional neural network (CNN) model. Moreover, the model also has an advantage in detecting well-differentiated HCC and microvascular invasion.

5.
Plant Cell ; 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34791445

RESUMO

Base excision repair and active DNA demethylation produce repair intermediates with DNA molecules blocked at the 3'-OH end by an aldehyde or phosphate group. However, both the physiological consequences of these accumulated single-strand DNA breaks with 3´-blocked ends (DNA 3'-blocks) and the signaling pathways responding to unrepaired DNA 3'-blocks remain unclear in plants. Here, we investigated the effects of DNA 3'-blocks on plant development using the zinc finger DNA 3'-phosphoesterase (zdp) AP endonuclease2 (ape2) double mutant, in which 3'-blocking residues are poorly repaired. Accumulation of DNA 3'-blocked triggered diverse developmental defects that were dependent on the ATM and RAD3-related (ATR)-suppressor of gamma response 1 (SOG1) signaling module. SOG1 mutation rescued the developmental defects of zdp ape2 leaves by preventing cell endoreplication and promoting cell proliferation. However, SOG1 mutation caused intensive meristematic cell death in the radicle of zdp ape2 following germination, resulting in rapid termination of radicle growth. Notably, mutating FORMAMIDOPYRIMIDINE DNA GLYCOSYLASE (FPG) in zdp ape2 sog1 partially recovered its radicle growth, demonstrating that DNA 3'-blocks generated by FPG caused the meristematic defects. Surprisingly, despite lacking a functional radicle, zdp ape2 sog1 mutants compensated the lack of root growth by generating anchor roots having low levels of DNA damage response. Our results reveal dual roles of SOG1 in regulating root establishment when seeds germinate with excess DNA 3'-blocks.

6.
Front Oncol ; 11: 721460, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34765542

RESUMO

Background: Our aim was to establish a deep learning radiomics method to preoperatively evaluate regional lymph node (LN) staging for hilar cholangiocarcinoma (HC) patients. Methods and Materials: Of the 179 enrolled HC patients, 90 were pathologically diagnosed with lymph node metastasis. Quantitative radiomic features and deep learning features were extracted. An LN metastasis status classifier was developed through integrating support vector machine, high-performance deep learning radiomics signature, and three clinical characteristics. An LN metastasis stratification classifier (N1 vs. N2) was also proposed with subgroup analysis. Results: The average areas under the receiver operating characteristic curve (AUCs) of the LN metastasis status classifier reached 0.866 in the training cohort and 0.870 in the external test cohorts. Meanwhile, the LN metastasis stratification classifier performed well in predicting the risk of LN metastasis, with an average AUC of 0.946. Conclusions: Two classifiers derived from computed tomography images performed well in predicting LN staging in HC and will be reliable evaluation tools to improve decision-making.

7.
New Phytol ; 2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34655488

RESUMO

DNA methylation plays key roles in transposable element (TE) silencing and gene expression regulation. DNA methylation occurs at CG, CHG and CHH sequence contexts in plants. However, the synergistic and redundant roles of CG and non-CG methylation are poorly understood. By introducing CRISPR/Cas9-induced met1 mutation into the ddcc (drm1 drm2 cmt2 cmt3) mutant, we attempted to knock out all five DNA methyltransferases in Arabidopsis and then investigate the synergistic and redundant roles of CG and non-CG DNA methylation. We found that the homozygous ddcc met1 quintuple mutants are embryonically lethal, although met1 and ddcc mutants only display some developmental abnormalities. Unexpectedly, the ddcc met1 quintuple mutations only reduce transmission through the male gametophytes. The ddcc met1+/- mutants show apparent size divergence, which is not associated with difference in DNA methylation patterns, but associated with the difference in the levels of DNA damage. Finally, we show that a group of TEs are specifically activated in the ddcc met1+/- mutants. This work reveals that CG and non-CG DNA methylation synergistically and redundantly regulate plant reproductive development, vegetative development and TE silencing in Arabidopsis. Our findings provide insights into the roles of DNA methylation in plant development.

8.
Artigo em Inglês | MEDLINE | ID: mdl-34671403

RESUMO

Chronic kidney disease (CKD) is a major public health issue that is highly prevalent worldwide. Pyroptosis is an important pathological mechanism underlying kidney cell damage in CKD and is associated with the classic caspase-1-mediated pathway and nonclassic caspase-4/5/11-mediated pathway. The NLRP3-caspase-1-GSDMD signaling pathway is the key mechanism of kidney cell pyroptosis in CKD, and noncoding RNAs such as lncRNAs and miRNAs are important regulators of kidney cell pyroptosis in CKD. In addition, the NLRP1/AIM2-caspase-1-GSDMD and caspase-3-GSDME signaling pathways have also been shown to mediate kidney cell pyroptosis. Traditional Chinese medicine (TCM) and extracts can interfere with the occurrence and development of kidney cell pyroptosis in CKD by inhibiting the NLRP3 signaling pathway and oxidative stress, activating Nrf-2 signaling, protecting mitochondrial integrity, regulating AMPK signaling, and regulating TXNIP/NLRP3 axis, which have become increasingly prominent. It is critical to explore the effects of TCM on kidney cell pyroptosis in CKD and its mechanisms to identify targets and develop new and effective drugs.

9.
Artigo em Inglês | MEDLINE | ID: mdl-34574572

RESUMO

PURPOSE: To examine the effects of three types of school-based exercises on bone health and physical fitness function in Chinese boys and girls. METHODS: One hundred and seventy-four Chinese boys and girls were randomly assigned into four groups: (1) sham exercise (ShEx); (2) high-impact exercise (HiEx); (3) high-impact exercise with various directions (HiExVi); and (4) high-intensity interval exercise (HiInEx). Speed of sound (SOS) and physical fitness parameters were determined before and after six-month intervention. RESULTS: At the end of six-month intervention, participants in all groups show an increment of SOS compared with the baseline (p < 0.05), and the changes were higher in HiEx (mean: 38.878 m/s, 95% CI: 32.885~44.872, p = 0.001) and HiExVi groups (49.317 m/s, 42.737~55.897, p < 0.001) compared with ShEx group (20.049 m/s, 13.751~26.346). Six-month exercise training generated a reduction of percent of body fat (PBF) and waist-hip ratio (WHR) (p < 0.05). The decrease of PBF was greater in HiExVi (-1.222%, -1.820~-0.624, p = 0.012) and HiInEx groups (-1.395%, -1.809~-0.982, p = 0.003), whereas the reduction of WHR was larger in HiEx (-0.026, -0.039~-0.014, p = 0.009), HiExVi (-0.024, -0.036~-0.012, p = 0.021), and HiInEx groups (-0.035, -0.046~-0.024, p < 0.001) compared with ShEx group. Balance function (BLF), vital capacity (VC), standing long jump (SLJ), and sit up (SU) increased in all intervention groups (p < 0.05). The BLF increased in HiEx (6.332 s, 4.136~8.528, p = 0.001), HiExVi (10.489 s, 8.934~12.045, p < 0.001), and HiInEx groups (9.103 s, 7.430~10.776, p < 0.001) showed a greater change than that of ShEx group (1.727 s, 0.684~2.770). The increment of VC (273.049 mL, 199.510~346.587, p < 0.001) and SU (2.537 times/min, 0.639~4.435, p = 0.017) was higher in HiInEx group, whereas the accrual in SLJ was larger in HiExVi (7.488 cm, 4.936~10.040, p = 0.007) compared with ShEx group (58.902 mL, 7.990~109.814; -0.463 times/min, -2.003~1.077; 1.488 cm, -0.654~3.630). CONCLUSION: The brief school-based exercises were effective in improving schoolchildren's health, but they showed different effects, with HiEx mostly improving bone health, HiInEx largely benefiting physical fitness function, and HiExVi enhancing both bone and physical fitness.


Assuntos
Densidade Óssea , Aptidão Física , Criança , Exercício Físico , Feminino , Humanos , Masculino , Instituições Acadêmicas , Posição Ortostática
10.
World J Emerg Med ; 12(4): 281-286, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512824

RESUMO

BACKGROUND: To investigate the clinical characteristics and risk factors of human immunodeficiency virus (HIV)-negative patients with Talaromyces marneffei (T. marneffei) infection. METHODS: We retrospectively collected the clinical information of HIV-negative patients with T. marneffei infection from January 1, 2010 to June 30, 2019, and analyzed the related risk factors of poor prognosis. RESULTS: Twenty-five cases aging 22 to 79 years were included. Manifestations of T. marneffei infection included fever, cough, dyspnea, chest pain or distress, lymphadenopathy, ear, nose, and throat (ENT) and/or skin lesions, bone or joint pain, edema and pain in the lower extremities, digestive symptoms, icterus, malaise, and hoarseness. Two cases had no comorbidity, while 23 cases suffered from autoimmune disease, pulmonary disease, cancer, and other chronic diseases. Sixteen cases had a medication history of glucocorticoids, chemotherapy or immunosuppressors. Pulmonary lesions included interstitial infiltration, nodules, atelectasis, cavitary lesions, pleural effusion or hydropneumothorax, bronchiectasis, pulmonary fibrosis, pulmonary edema, and consolidation. The incidence of osteolytic lesions was 20%. Eight patients received antifungal monotherapy, and 11 patients received combined antifungal agents. Fifteen patients survived and ten patients were dead. The Cox regression analysis showed that reduced eosinophil counts, higher levels of blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactic dehydrogenase (LDH), myoglobin (Mb), procalcitonin (PCT), and galactomannan were related to poor prognosis (hazard ratio [HR]>1, P<0.05). CONCLUSIONS: Bone destruction is common in HIV-negative patients with T. marneffei infection. Defective cell-mediated immunity, active infection, multiple system, and organ damage can be the risk factors of poor prognosis.

12.
Chem Commun (Camb) ; 57(70): 8798-8801, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34382624

RESUMO

An Ir/CeO2 composite catalyst with Ir nanorods (NRs) on amorphous CeO2 was synthesized through a facile one-pot hydrothermal method, which shows excellent activity towards hydrogen evolution and oxygen evolution in alkaline media, even superior to the performance of commercial Pt/C, IrO2 and RuO2 catalysts. The enhanced performance could be attributed to the interfacial electron synergistic effect between Ir and CeO2.

13.
Front Oncol ; 11: 611738, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34221954

RESUMO

Introduction: Hepatic sarcomatoid carcinoma (HSC) is a rare type of liver cancer with a high malignant grade and poor prognosis. This study compared the clinical characteristics and magnetic resonance imaging (MRI) features of HSCs with those of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), aiming to identify valuable features for HSC diagnosis. Methods: In total, 17 pathologically confirmed HSC cases, 50 HCC cases and 50 common ICC cases were enrolled from two hospitals. The clinical characteristics and MRI features of all cases were summarized and statistically analyzed. Results: On the one hand, the incidence rates of elevated carbohydrate antigen (CA) 19-9 and elevated carcinoembryonic antigen (CEA) were significantly higher in the HSC cases than in the HCC cases (29.4% vs. 0%; 17.6% vs. 0%). The HSC enhancement patterns, primarily including progressive enhancement, were also significantly different from HCC cases. The incidence rates of heterogeneous signals on T2-weighted imaging and during the arterial phase were significantly higher in the HSC cases than in the HCC cases (94.1% vs. 66.0%; 100.0% vs. 72.0%). The diameter of HSCs was significantly larger than that in the HCC cases (6.12 cm vs. 4.21 cm), and the incidence rates of adjacent cholangiectasis, intrahepatic metastasis and lymph node enlargement were considerably higher in the HSC cases than in the HCC cases (52.9% vs. 6.0%; 47.1% vs. 12.0%; 41.2% vs. 2.0%). On the other hand, the incidence rate of elevated CA199 was significantly lower in the HSC cases than in the ICC cases (29.4% vs. 60.0%). The incidence rates of intratumoral necrosis and pseudocapsules were significantly higher in the HSC cases than in the HCC cases (35.3% vs. 8.0%; 47.1% vs. 12.0%). However, the incidence rates of target signs were significantly lower in the HSC cases than in the HCC cases (11.8% vs. 42.0%). In addition, there was no significant difference in the enhancement patterns between HSC cases and ICC cases. Conclusions: HSCs were frequently seen in elderly men with clinical symptoms and elevated CA199 levels. The MRI features, including large size, obvious heterogeneity, hemorrhage, progressive enhancement, pseudocapsule and lymph node enlargement, contributed to the diagnosis of HSC.

14.
Biomark Med ; 15(13): 1097-1109, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34128691

RESUMO

Aim: To explore the expression profiles of long noncoding RNAs (lncRNAs) and identify novel lncRNAs as biomarkers for early diagnosis and therapy of hepatocellular carcinoma (HCC). Materials & methods: Expression profiles of lncRNAs and mRNAs in five paired HCC and adjacent normal tissues were obtained by RNA sequencing. Eight lncRNAs, including two novel liver-specific lncRNAs (NONHSAT059247.2 and NONHSAT013897.2), were validated in another 74 pairs of HCC and adjacent normal tissues by quantitative reverse transcription PCR. Results: The results of quantitative reverse transcription PCR showed that NONHSAT252133.1, NONHSAT112116.2 and NONHSAT242657.1 were significantly upregulated in HCC tissues, whereas NONHSAT169790.1, NONHSAT059247.2 and NONHSAT013897.2 were significantly downregulated. Two liver-specific lncRNAs demonstrated excellent diagnostic performance: NONHSAT059247.2 (area under the curve = 0.941, 95% CI: 0.902-0.979, p < 0.0001), NONHSAT013897.2 (area under the curve = 0.944, 95% CI: 0.906-0.983, p < 0.0001). Conclusion: The liver-specific lncRNAs NONHSAT059247.2 and NONHSAT013897.2, may provide new biomarkers for the future study on diagnosis, therapy and mechanisms of HCC.

15.
Exp Ther Med ; 21(6): 656, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33968186

RESUMO

Ventricular arrhythmia (VA) is a highly fatal arrhythmia that involves multiple ion channels. Of all sudden cardiac death events, ~85% result from VAs, including ventricular tachycardia and ventricular fibrillation. Calcium/calmodulin-dependent pro-tein kinase II (CaMKII) is an important ion channel regulator that participates in the excitation-contraction coupling of the heart, and as such is important for regulating its electrophysiological function. CaMKII can be activated in a Ca2+/calmodulin (CaM)-dependent or Ca2+/CaM-independent manner, serving a key role in the occurrence and development of VA. The present review aimed to determine whether activated CaMKII induces early afterdepolarizations and delayed afterdepolarizations that result in VA by regulating sodium, potassium and calcium ions. Assessing VA mechanisms based on the CaMKII pathway is of great significance to the clinical treatment of VA and the de-velopment of effective drugs for use in clinical practice.

16.
Epigenomics ; 13(7): 513-530, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33683141

RESUMO

Aim: To explore the expression profiles and functions of circRNAs in hepatocellular carcinoma (HCC). Materials & methods: We obtained circRNA expression profiles through RNA sequencing. Expression levels of circRNAs were confirmed by quantitative real-time PCR. The effects on HCC progression were determined using Cell Counting Kit 8, clone formation and transwell assays. Results: We identified 114 upregulated and 144 downregulated circRNAs in HCC tissues. The results of quantitative real-time PCR showed that circGNAO1, circRNF180 and circMERTK were significantly downregulated in HCC tissues, whereas circSNX6 was significantly upregulated. CircRNF180 was associated with microvascular invasion. Overexpression of circRNF180 inhibits the proliferation, colony formation, migration and invasion of HCC cells. Conclusion: CircRNF180 may function as a tumor suppressor and could serve as a potential biomarker and therapeutic target in HCC.

18.
Nat Commun ; 12(1): 1566, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692347

RESUMO

The Kondo effect offers an important paradigm to understand strongly correlated many-body physics. Although under intensive study, some of the important properties of the Kondo effect, in systems where both itinerant coupling and localized coupling play significant roles, are still elusive. Here we report the evolution and universality of the two-stage Kondo effect, the simplest form where both couplings are important using single molecule transistor devices incorporating Manganese phthalocyanine molecules. The Kondo temperature T* of the two-stage Kondo effect evolves linearly against effective interaction of involved two spins. Observed Kondo resonance shows universal quadratic dependence with all adjustable parameters: temperature, magnetic field and biased voltages. The difference in nonequilibrium conductance of two-stage Kondo effect to spin 1/2 Kondo effect is also identified. Messages learned in this study fill in directive experimental evidence of the evolution of two-stage Kondo resonance near a quantum phase transition point, and help in understanding sophisticated molecular electron spectroscopy in a strong correlation regime.

20.
Gastroenterology ; 2021 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-34973295

RESUMO

OBJECTIVE: Alteration of the gut microbiota is implicated in the development of autoimmune type 1 diabetes (T1D), as shown in humans and the non-obese diabetic (NOD) mouse model. However, how gut dysbiosis arises and promotes the autoimmune response remains an open question. We investigated whether early events affecting the intestinal homeostasis in newborn NOD mice may explain the development of the autoimmune response in the adult pancreas. DESIGN: We profiled the transcriptome and the microbiota in the colon between newborn NOD mice and non-autoimmune strains. We identified a seminal defect in the intestinal homeostasis of newborn NOD mice and deciphered the mechanism linking this defect to the diabetogenic response in the adult. RESULTS: We determined that the cathelicidin-related antimicrobial peptide (CRAMP) expression was defective in the colon of newborn NOD mice allowing inducing dysbiosis. Dysbiosis stimulated the colonic epithelial cells to produce type I IFNs that pathologically imprinted the local neonatal immune system. This pathological immune imprinting later promoted the pancreatic autoimmune response in the adult and the development of diabetes. Increasing colonic CRAMP expression in newborn NOD mice, by local CRAMP treatment or CRAMP-expressing probiotic, restored colonic homeostasis, and halted the diabetogenic response preventing autoimmune diabetes. CONCLUSION: We identified whether a defective colonic expression in the CRAMP antimicrobial peptide induces dysbiosis contributing to autoimmunity in the pancreas. Hence, the manipulation of intestinal antimicrobial peptides may be considered a relevant therapeutic approach to prevent autoimmune diabetes in at-risk children.

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