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1.
ACS Sens ; 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36693235

RESUMO

Genetically encoded biosensors based on Förster resonance energy transfer (FRET) are indispensable tools for monitoring biochemical changes in cells. Green and red fluorescent protein-based FRET pairs offer advantages over the classically employed cyan and yellow fluorescent protein pairs, such as better spectral separation, lower phototoxicity, and less autofluorescence. Here, we describe the development of an mScarlet-derived green fluorescent protein (designated as mWatermelon) and its use as a FRET donor to the red fluorescent protein mScarlet-I as a FRET acceptor. We tested the functionality of this FRET pair by engineering biosensors for the detection of protease activity, Ca2+, and K+. Furthermore, we described a strategy to enhance the FRET efficiency of these biosensors by modulating the intramolecular association between mWatermelon and mScarlet-I.

2.
BMC Gastroenterol ; 23(1): 3, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604612

RESUMO

AIMS: Observational studies showed that low thyroid function may perturb liver function. We aimed to evaluate the association of low thyroid function with both metabolic dysfunction-associated fatty liver disease (MAFLD) and advanced hepatic fibrosis. METHODS: Participants who underwent abdominal ultrasonography and thyroid function test in a Chinese hospital from 2015 to 2021were enrolled. Fibrosis-4 index (FIB-4) > 2.67 and/or non-alcoholic fatty liver disease fibrosis score (NFS) > 0.676 were used to define advanced fibrosis. Descriptive analyses were performed to characterize the epidemiology of MAFLD according to levels of thyroid-stimulating hormone (TSH). The logistic regression model was applied to estimate the association of low thyroid function with MAFLD and advanced fibrosis. RESULTS: A total of 19,946 participants (52.78% males, mean age: 47.31 years, 27.55% MAFLD) were included, among which 14,789 were strict-normal thyroid function, 4,328 were low-normal thyroid function, 829 were subclinical hypothyroidism. TSH levels were significantly higher in MAFLD patients with a FIB-4 > 2.67 and /or NFS > 0.676 than their counterparts. The logistic regression model adjusted for age and sex showed that low-normal thyroid function increased the risk of MAFLD (odds ratio [OR] = 1.09; 95% confidence interval [CI] 1.01-1.18). Multivariable regression model adjusted for age, sex, body mass index, type 2 diabetes, and hypertension showed low-normal thyroid function increased the risk of advanced fibrosis in patients with MAFLD (FIB-4 > 2.67: OR = 1.41, 95% CI 1.02-1.93; NFS > 0.676: OR = 1.72, 95% CI 1.08-2.72). CONCLUSION: Elevated TSH concentrations are associated with advanced hepatic fibrosis, even in the euthyroid state.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Glândula Tireoide , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Tireotropina
3.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36675319

RESUMO

KB-R7943, an isothiourea derivative, has been recognized as an inhibitor in the reverse mode of the Na+-Ca2+ exchanging process. This compound was demonstrated to prevent intracellular Na+-dependent Ca2+ uptake in intact cells; however, it is much less effective at preventing extracellular Na+-dependent Ca2+ efflux. Therefore, whether or how this compound may produce any perturbations on other types of ionic currents, particularly on voltage-gated Na+ current (INa), needs to be further studied. In this study, the whole-cell current recordings demonstrated that upon abrupt depolarization in pituitary GH3 cells, the exposure to KB-R7943 concentration-dependently depressed the transient (INa(T)) or late component (INa(L)) of INa with an IC50 value of 11 or 0.9 µM, respectively. Likewise, the dissociation constant for the KB-R7943-mediated block of INa on the basis of a minimum reaction scheme was estimated to be 0.97 µM. The presence of benzamil or amiloride could suppress the INa(L) magnitude. The instantaneous window Na+ current (INa(W)) activated by abrupt ascending ramp voltage (Vramp) was suppressed by adding KB-R7943; however, subsequent addition of deltamethrin or tefluthrin (Tef) effectively reversed KB-R7943-inhibted INa(W). With prolonged duration of depolarizing pulses, the INa(L) amplitude became exponentially decreased; moreover, KB-R7943 diminished INa(L) magnitude. The resurgent Na+ current (INa(R)) evoked by a repolarizing Vramp was also suppressed by adding this compound; moreover, subsequent addition of ranolazine or Tef further diminished or reversed, respectively, its reduction in INa(R) magnitude. The persistent Na+ current (INa(P)) activated by sinusoidal voltage waveform became enhanced by Tef; however, subsequent application of KB-R7943 counteracted Tef-stimulated INa(P). The docking prediction reflected that there seem to be molecular interactions of this molecule with the hNaV1.2 or hNaV1.7 channels. Collectively, this study highlights evidence showing that KB-R7943 has the propensity to perturb the magnitude and gating kinetics of INa (e.g., INa(T), INa(L), INa(W), INa(R), and INa(P)) and that the NaV channels appear to be important targets for the in vivo actions of KB-R7943 or other relevant compounds.


Assuntos
Trocador de Sódio e Cálcio , Tioureia , Tioureia/farmacologia
4.
Gut Microbes ; 15(1): 2155018, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36519342

RESUMO

Gut dysbiosis has been reported in chronic hepatitis B (CHB) infection, however its role in CHB progression and antiviral treatment remains to be clarified. Herein, the present study aimed to characterize gut microbiota (GM) in patients with chronic hepatitis B virus infection-associated liver diseases (HBV-CLD) by combining microbiome with metabolome analyses and to evaluate their effects on peripheral immunity. Fecal samples from HBV-CLD patients (n = 64) and healthy controls (n = 17) were collected for 16s rRNA sequencing. Fecal metabolomics was measured with untargeted liquid chromatography-mass spectrometry in subgroups of 58 subjects. Lineage changes of peripheral blood mononuclear cells (PBMCs) were determined upon exposure to bacterial extracts (BE) from HBV-CLD patients. Integrated analyses of microbiome with metabolome revealed a remarkable shift of gut microbiota and metabolites in HBV-CLD patients, and disease progression and antiviral treatment were found to be two main contributing factors for the shift. Concordant decreases in Turicibacter with 4-hydroxyretinoic acid were detected to be inversely correlated with serum AST levels through host-microbiota-metabolite interaction analysis in cirrhotic patients. Moreover, depletion of E.hallii group with elevated choline was restored in patients with 5-year antiviral treatment. PBMC exposure to BE from non-cirrhotic patients enhanced expansion of T helper 17 cells; however, BE from cirrhotics attenuated T helper 1 cell count. CHB progression and antiviral treatment are two main factors contributing to the compositional shift in microbiome and metabolome of HBV-CLD patients. Peripheral immunity might be an intermediate link in gut microbe-host interplay underlying CHB pathogenesis.


Integrated analyses of microbiome with metabolomics revealed a remarkable shift of gut microbiota and metabolites in HBV-CLD patients. Disease progression and entecavir treatment were found to be two main contributing factors for the shift. Novel host-microbiota-metabolite interplay was investigated (red, positive correlation; blue, negative correlation). Ex vivo results showed that exposure of PBMCs to BE from non-cirrhotic patients promoted expansion of T helper 17 cells whilst BE from cirrhotic patients attenuated T helper 1 cell count, suggesting peripheral immunity may be one of mechanisms by which overall bacterial products exert profibrotic effects and have an impact on prognosis of HBV-CLD patients. Our research confers new insights into the role of gut dysbiosis and metabolomics in the pathogenesis of HBV-CLD, and underscores that disrupted peripheral immunity homeostasis during the microbe-host interplay may contribute to fibrosis progression in HBV-CLD. CHB, chronic hepatitis B (treatment-naive); Crrh, cirrhosis; ETV, entecavir; HBV-CLD, chronic hepatitis B virus infection-associated liver diseases; HCs, healthy controls; MCFAs, medium chain fatty acids; NC, non-cirrhosis; Th1, T helper 1; Th17, T helper 17.Abbreviations: ALB, albumin; ALP, alkaline phosphatase; ANOISM, analysis of similarities; AST, aspartate aminotransferase; BE, bacterial extracts; BMI, body mass index; CC, compensated cirrhosis; CHB, chronic hepatitis B; DB, direct bilirubin; DC, decompensated cirrhosis; DCA, deoxycholic acid; ETV, entecavir; FDR, false discovery rate; GGT, γ-glutamyl transpeptidase; GM, gut microbiota; HBV, hepatitis B virus; HBV-CLD, chronic hepatitis B virus infection-associated liver diseases; HCs, healthy controls; HCC, hepatocellular carcinoma; LC-MS, liquid chromatography-mass spectrometry; LRE, liver-related events; LS, liver stiffness; ImP, imidazole propionate; IQR, interquartile range; MCFAs, medium chain fatty acids; OCT, organic cation transporter; OPLS-DA, orthogonal partial least square discriminant analysis; PBMCs, peripheral blood mononuclear cells; PERMANOVA, permutational multivariate analysis of variance; PLS-DA, partial least square discriminant analysis; PCA, principal component analysis; PcoA, principal coordinates analysis; PT, prolonged prothrombin time; SDs, standard deviations; TB, total bilirubin; Tregs, regulatory T cells; Th1, T helper 1; Th17, T helper 17.


Assuntos
Microbioma Gastrointestinal , Hepatite B Crônica , Humanos , Hepatite B Crônica/complicações , Vírus da Hepatite B/fisiologia , Leucócitos Mononucleares/metabolismo , RNA Ribossômico 16S/genética , Antivirais/uso terapêutico , Imunidade , Cirrose Hepática/patologia
5.
Comput Biol Med ; 152: 106375, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36502693

RESUMO

Metazoa gene expression is controlled by modular DNA segments called cis-regulatory modules (CRMs). CRMs can convey promoter/enhancer/insulator roles, generating additional regulation layers in transcription. Experiments for understanding CRM roles are low-throughput and costly. Large-scale CRM function investigation still depends on computational methods. However, existing in silico tools only recognize enhancers or promoters exclusively, thus accumulating errors when considering CRM promoter/enhancer/insulator roles altogether. Currently, no algorithm can concurrently consider these CRM roles. In this research, we developed the CRM Function Annotator (CFA) model. CFA provides complete CRM transcriptional role labeling based on epigenetic profiling interpretation. We demonstrated that CFA achieves high performance (test macro auROC/auPRC = 94.1%/90.3%) and outperforms existing tools in promoter/enhancer/insulator identification. CFA is also inspected to recognize explainable epigenetic codes consistent with previous findings when labeling CRM roles. By considering the higher-order combinations of the epigenetic codes, CFA significantly reduces false-positive rates in CRM transcriptional role annotation. CFA is available at https://github.com/cobisLab/CFA/.


Assuntos
Aprendizado Profundo , Regiões Promotoras Genéticas/genética , Epigênese Genética/genética
6.
Zhongguo Zhong Yao Za Zhi ; 47(21): 5849-5854, 2022 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-36472003

RESUMO

Eight terpenoids were isolated from the fruits of Amomum villosum by silica gel, Sephadex LH-20, Rp-C_(18), MCI GEL CHP20 P column chromatography, preparative TLC, and HPLC. Their structures were identified by HR-ESI-MS, ~1H and ~(13)C-NMR, IR, UV, [α]_D, and ECD spectroscopic data as kravanhin A 3-O-ß-D-glucopyranoside(1), kravanhin B(2), 6-eudesmene-1ß,4ß-diol(3), oplodiol(4), vicodiol(5),(1R,2S,4R,7S)-vicodiol 9-O-ß-D-glucopyranoside(6),(1R,2S,4S,5R)-angelicoidenol 2-O-ß-D-glucopyranoside(7), and(1S,2S,4R,6S)-bornane-2,6-diol 2-O-ß-D-glucopyranoside(8). Compound 1 was a new compound, and compounds 2-5 were isolated from A. villosum for the first time. Their hypoglycemic activity was tested based on STC-1 cell model and two enzymatic models(GPa and PTP1 B). The results showed that compounds 1, 7, and 8 could stimulate GLP-1 with the secretion rates of 692.8%, 398.6%, and 483.3% at 25.0 µmol·L~(-1), and compound 6 showed inhibitory activity against GPa with an IC_(50) value of 78.6 µmol·L~(-1).


Assuntos
Amomum , Frutas , Frutas/química , Terpenos/análise , Hipoglicemiantes/farmacologia , Hipoglicemiantes/análise , Cromatografia Líquida de Alta Pressão
7.
Zhen Ci Yan Jiu ; 47(11): 962-8, 2022 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-36453672

RESUMO

OBJECTIVE: To explore the effects of electroacupuncture(EA) on metabolic patterns of the prefrontal cortex in rats with acute myocardial ischemia. METHODS: Eighteen SD rats were randomly divided into sham group, model group and EA group, with 6 rats in each group. Rats in the model and EA groups were subject to acute myocardial ischemia by ligation of the left anterior descending coronary artery. For the EA group, EA stimulation (1 mA, 2 Hz/15 Hz, 30 min) was applied to "Shenmen"(HT7) -"Tongli"(HT5) once a day for 3 consecutive days. The histopathological changes of myocardial tissue and levels of ischemia modified albumin (IMA) in serum were determined by HE staining and ELISA, respectively. The LC-MS/MS technique was used to characterize the metabolic profiling of the prefrontal cortex. The differentially expressed metabolites were screened by principal component analysis(PCA) and partial least squares-linear discriminant analysis (PLS-LDA), and subsequently Kyoto encyclopedia of genes and genomes (KEGG) metabolic pathway enrichment analysis was performed. RESULTS: Compared with the sham group, the myocardial fibers were disordered and fractured, and content of serum IMA was significantly increased in the model group (P<0.01), which, however, were significantly decreased in the EA group (P<0.01). With PCA and PLS-LDA, there were 18 differential metabolites between the model and sham groups. Forty-eight differential metabolites were emerged between the EA and model groups. Three metabolites associated to the sphingolipid metabolism were reversed by EA stimulation, as indicated by KEGG. CONCLUSION: The molecular mechanism of EA against myocardial ischemia is partially mediated by regulating sphingolipid-related metabolites in the prefrontal cortex.


Assuntos
Eletroacupuntura , Isquemia Miocárdica , Ratos , Animais , Ratos Sprague-Dawley , Biomarcadores , Cromatografia Líquida , Albumina Sérica , Espectrometria de Massas em Tandem , Isquemia Miocárdica/genética , Isquemia Miocárdica/terapia , Metabolômica , Córtex Pré-Frontal , Esfingolipídeos
8.
Nanomaterials (Basel) ; 12(23)2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36500944

RESUMO

We report the superconducting properties between a conventional strong-coupled Pb and weak-coupled Sn superconductor. A series of SnrPb1-r nanoalloys with various compositions r were synthesized, and their superconducting properties were measured using superconducting quantum interference devices (SQUIDs) magnetometer. Our results reveal a superconducting proximity effect (SPE) between immiscible Sn and Pb granules in the range of r = 0.2~0.9, as a weak superconducting coupling can be established with the coexistence of phonon hardening and increased Ginzburg-Landau coherence length. Furthermore, our results provide new insights into improving the study of the superconducting proximity effect introduced by Sn doping.

9.
Int J Mol Sci ; 23(24)2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36555538

RESUMO

Muscle loss and weakness after a burn injury are typically the consequences of neuronal dysregulation and metabolic change. Hypermetabolism has been noted to cause muscle atrophy. However, the mechanism underlying the development of burn-induced motor neuropathy and its contribution to muscle atrophy warrant elucidation. Current therapeutic interventions for burn-induced motor neuropathy demonstrate moderate efficacy and have side effects, which limit their usage. We previously used a third-degree burn injury rodent model and found that irisin-an exercise-induced myokine-exerts a protective effect against burn injury-induced sensory and motor neuropathy by attenuating neuronal damage in the spinal cord. In the current study, spinal irisin gene delivery was noted to attenuate burn injury-induced sciatic nerve demyelination and reduction of neuromuscular junction innervation. Spinal overexpression of irisin leads to myelination rehabilitation and muscular innervation through the modulation of brain-derived neurotrophic factor and glial-cell-line-derived neurotrophic factor expression along the sciatic nerve to the muscle tissues and thereby modulates the Akt/mTOR pathway and metabolic derangement and prevents muscle atrophy.


Assuntos
Queimaduras , Atrofia Muscular Espinal , Traumatismos dos Nervos Periféricos , Neuropatia Ciática , Axônios/metabolismo , Queimaduras/complicações , Queimaduras/terapia , Queimaduras/patologia , Fibronectinas/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/prevenção & controle , Atrofia Muscular Espinal/patologia , Junção Neuromuscular/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Neuropatia Ciática/patologia , Animais
11.
Front Neurol ; 13: 1038735, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36530623

RESUMO

Objectives: Obstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD). However, potential associations among sleep-disordered breathing, hypoxia, and OSA-induced arousal responses should be investigated. This study determined differences in sleep parameters and investigated the relationship between such parameters and the risk of AD. Methods: Patients with suspected OSA were recruited and underwent in-lab polysomnography (PSG). Subsequently, blood samples were collected from participants. Patients' plasma levels of total tau (T-Tau) and amyloid beta-peptide 42 (Aß42) were measured using an ultrasensitive immunomagnetic reduction assay. Next, the participants were categorized into low- and high-risk groups on the basis of the computed product (Aß42 × T-Tau, the cutoff for AD risk). PSG parameters were analyzed and compared. Results: We included 36 patients in this study, of whom 18 and 18 were assigned to the low- and high-risk groups, respectively. The average apnea-hypopnea index (AHI), apnea, hypopnea index [during rapid eye movement (REM) and non-REM (NREM) sleep], and oxygen desaturation index (≥3%, ODI-3%) values of the high-risk group were significantly higher than those of the low-risk group. Similarly, the mean arousal index and respiratory arousal index (R-ArI) of the high-risk group were significantly higher than those of the low-risk group. Sleep-disordered breathing indices, oxygen desaturation, and arousal responses were significantly associated with an increased risk of AD. Positive associations were observed among the AHI, ODI-3%, R-ArI, and computed product. Conclusions: Recurrent sleep-disordered breathing, intermittent hypoxia, and arousal responses, including those occurring during the NREM stage, were associated with AD risk. However, a longitudinal study should be conducted to investigate the causal relationships among these factors.

12.
Front Plant Sci ; 13: 1063056, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36531364

RESUMO

The spatial morphological structure of plant leaves is an important index to evaluate crop ideotype. In this study, we characterized the three-dimensional (3D) data of the ear leaf midrib of maize at the grain-filling stage using the 3D digitization technology and obtained the phenotypic values of 15 traits covering four different dimensions of the ear leaf midrib, of which 13 phenotypic traits were firstly proposed for featuring plant leaf spatial structure. Cluster analysis results showed that the 13 traits could be divided into four groups, Group I, -II, -III and -IV. Group I contains HorizontalLength, OutwardGrowthMeasure, LeafAngle and DeviationTip; Group II contains DeviationAngle, MaxCurvature and CurvaturePos; Group III contains LeafLength and ProjectionArea; Group IV contains TipTop, VerticalHeight, UpwardGrowthMeasure, and CurvatureRatio. To investigate the genetic basis of the ear leaf midrib curve, 13 traits with high repeatability were subjected to genome-wide association study (GWAS) analysis. A total of 828 significantly related SNPs were identified and 1365 candidate genes were annotated. Among these, 29 candidate genes with the highest significant and multi-method validation were regarded as the key findings. In addition, pathway enrichment analysis was performed on the candidate genes of traits to explore the potential genetic mechanism of leaf midrib curve phenotype formation. These results not only contribute to further understanding of maize leaf spatial structure traits but also provide new genetic loci for maize leaf spatial structure to improve the plant type of maize varieties.

13.
Int J Mol Sci ; 23(23)2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36499059

RESUMO

Deltamethrin (DLT) is a type-II pyrethroid ester insecticide used in agricultural and domestic applications as well as in public health. However, transmembrane ionic channels perturbed by this compound remain largely unclear, although the agent is thought to alter the gating characteristics of voltage-gated Na+ (NaV) channel current. In this study, we reappraised whether and how it and other related compounds can make any further modifications on voltage-gated Na+ current (INa) in pituitary tumor (GH3) cells. Cell exposure to DLT produced a differential and dose-dependent stimulation of peak (transient, INa(T)) or sustained (late, INa(L)) INa; consequently, the EC50 value required for DLT-stimulated INa(T) or INa(L) was determined to be 11.2 or 2.5 µM, respectively. However, neither the fast nor slow component in the inactivation time constant of INa(T) activated by short depolarizing pulse was changed with the DLT presence; conversely, tefluthrin (Tef), a type-I pyrethroid insecticide, can accentuate INa with a slowing in inactivation time course of the current. The INa(L) augmented by DLT was attenuated by further application of either dapagliflozin (Dapa) or amiloride, but not by chlorotoxin. During pulse train (PT) stimulation, with the Tef or DLT presence, the cumulative inhibition of INa(T) became slowed; moreover, following PT stimuli, a large tail current with a slowly recovering process was observed. Alternatively, during rapid depolarizing pulse, the amplitude of INa(L) and tail INa (INa(Tail)) for each depolarizing pulse became progressively increased by adding DLT, not by Tef. The recovery time constant following PT stimulation with continued presence of Tef or DLT was shortened by further addition of Dapa. The voltage-dependent hysteresis (Hys(V)) of persistent INa was differentially augmented by Tef or DLT. Taken together, the magnitude, gating, frequency dependence, as well as Hys(V) behavior of INa exerted by the presence of DLT or Tef might exert a synergistic impact on varying functional activities of excitable cells in culture or in vivo.


Assuntos
Piretrinas , Piretrinas/farmacologia , Ciclopropanos , Sódio , Hidrocarbonetos Fluorados
14.
Int J Mol Sci ; 23(23)2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36499454

RESUMO

The cadmium tungstate rods have been given much attention due to their potential for usage in numerous luminescent applications. We have prepared single crystalline Sn-doped Cd1-xSnxWO4 (where x = 0, 1, 3, and 5%) nanorods (NRDs) and characterized them using refined X-ray diffraction and TEM analysis, revealing a monoclinic phase and a crystallite size that decreased from 62 to 38 nm as Sn concentration increased. Precise Sn doping modulation in CdWO4 NRDs causes surface recombination of electrons and holes, which causes the PL intensity to decrease as the Sn content rises. The chromaticity diagram shows that an increase in the Sn content caused a change in the emission color from sky blue to light green, which was attributed to the increased defect density. The photoluminescence time decay curve of all samples fit well with double-order exponential decay, and the average decay lifetime was found to be 1.11, 0.93, and 1.16 ns for Cd1-xSnxWO4, x = 0, 1, and 5%, respectively. This work provides an understanding of the behavior of Sn-doped CdWO4 NRDs during electron transitions and the physical nature of emission that could be used in bio-imaging, light sources, displays, and other applications.


Assuntos
Cádmio , Nanotubos , Luminescência , Difração de Raios X
15.
PLoS One ; 17(11): e0278123, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36445863

RESUMO

OBJECTIVE: To explore if random forest (RF) model can predict the prognosis of hospital-acquired Klebsiella pneumoniae infection as well as traditional logistic regression(LR) model. METHODS: A total of 254 cases of hospital-acquired Klebsiella pneumoniae infection in a tertiary hospital in Beijing from January 2016 to December 2020 were retrospectively collected. Appropriate influencing factors were selected by referring to relevant articles from the aspects of basic clinical information and contact history before infection, and divided into a training set and a test set. Both the RF and LR models were trained by the training set, and using testing set to compare these two models. RESULTS: The prediction accuracy of the LR model was 87.0%, the true positive rate of the LR model was 94.7%; the false negative rate of the LR model was 5.3%; the false positive rate of the LR model was 35%; the true negative rate of the LR model was 65%; the sensitivity of the LR model for the prognosis prediction of hospital-acquired Klebsiella pneumoniae infection was 94.7%; and the specificity was 65%. The prediction accuracy of the RF model was 89.6%; the true positive rate of the RF model was 92.1%; the false negative rate of the RF model was 7.9%; the false positive rate of the RF model was 21.4%; the true negative rate of the RF model was 78.6%; the sensitivity of the RF model for the prognosis prediction of hospital-acquired Klebsiella pneumoniae infection was 92.1%; and the specificity was 78.6%. ROC curve shows that the area under curve(AUC) of the LR model was 0.91, and that of the RF model was 0.95. CONCLUSION: The RF model has higher specificity, sensitivity, and accuracy for the prognostic prediction of hospital-acquired Klebsiella pneumoniae infection than the LR model and has greater clinical application prospects.


Assuntos
Infecção Hospitalar , Klebsiella pneumoniae , Humanos , Modelos Logísticos , Estudos Retrospectivos , Infecção Hospitalar/diagnóstico , Prognóstico , Centros de Atenção Terciária
16.
Front Oncol ; 12: 963896, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36439487

RESUMO

Background: The interactions between tumor cells and the host immune system play a crucial role in lung cancer progression and resistance to treatment. The alterations of EGFR signaling have the potential to produce an ineffective tumor-associated immune microenvironment by upregulating a series of immune suppressors, including inhibitory immune checkpoints, immunosuppressive cells, and cytokines. Elevated Heparin-binding EGF-like growth factor (HB-EGF) expression, one EGFR ligand correlated with higher histology grading, worse patient prognosis, and lower overall survival rate, acts as a chemotactic factor. However, the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the accumulation of immune cells in the tumor microenvironment remains unclear. Methods: The clinical association of HB-EGF expression in lung cancer was examined using the Gene Expression Omnibus (GEO) repository. HB-EGF expression in different cell types was determined using single-cell RNA sequencing (scRNA-seq) dataset. The correlation between HB-EGF expression and cancer-immune infiltrated cells was investigated by performing TIMER and ClueGo pathways analysis from TCGA database. The chemotaxis of HB-EGF and macrophage infiltration was investigated using migration and immunohistochemical staining. Results: The high HB-EGF expression was significantly correlated with poor overall survival in patients with lung adenocarcinoma (LUAD) but not lung squamous cell carcinoma (LUSC). Moreover, HB-EGF expression was correlated with the infiltration of monocytes, macrophages, neutrophils, and dendritic cells in LUAD but not in LUSC. Analysis of scRNA-seq data revealed high HB-EGF expression in lung cancer cells and myeloid cells. Results from the pathway analysis and cell-based experiment indicated that elevated HB-EGF expression was associated with the presence of macrophage and lung cancer cell migration. HB-EGF was highly expressed in tumors and correlated with M2 macrophage infiltration in LUAD. Conclusions: HB-EGF is a potential prognostic marker and therapeutic target for lung cancer progression, particularly in LUAD.

17.
Int J Mol Sci ; 23(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36430153

RESUMO

Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH3 lactotrophs. RFM increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) in pituitary GH3 lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca2+-activated K+ channels (BKCa channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BKCa channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na+ current (INa) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of KCa1.1 channels with amino acid residues, thereby functionally affecting BKCa channels' activity. This study is the first to present evidence that, in addition to inhibiting the INa, RFM effectively modifies the IK(Ca), which suggests that it has an impact on neuronal function and excitability.


Assuntos
Anticonvulsivantes , Triazóis , Anticonvulsivantes/farmacologia , Simulação de Acoplamento Molecular , Triazóis/farmacologia , Íons
18.
BMC Urol ; 22(1): 185, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36384495

RESUMO

BACKGROUND: The American Joint Committee on Cancer (AJCC) 8th staging system of prostate cancer may be insufficient in predicting the prognosis of some staged patients. This study aimed to modify the AJCC 8th staging system in patients with advanced prostate cancer. METHODS: Data of patients with advanced prostate cancer from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016 were enrolled in this cohort study. All patients were divided into the training set and the testing set with a ratio of 6:4. Multivariate Cox survival model was utilized to obtain the nomogram score for each stage variable. The modified staging system was based on the total nomogram score. The C-index and Kaplan-Meier (K-M) curves were used to show the prognostic prediction effect of patients with different staging systems. RESULTS: A total of 28,006 patients were included for analysis. T stage, N stage, M stage, primary Gleason pattern score, secondary Gleason pattern score, and PSA level were included as stage variables. Patients with AJCC stage III C [hazard ratio (HR) = 4.17, 95% confidence interval (CI), 3.39-5.13] and AJCC stage IV B (HR = 3.19, 95%CI, 1.79-5.69) were associated with worse prognosis compared with those of AJCC stage III B, while no statistical significance was found in patients with stage IV A (P > 0.05). In terms of the modified staging system, patients with modified stage III C (HR = 2.06, 95%CI, 1.46-2.92), modified stage IV A (HR = 6.91, 95%CI, 4.81-9.94), and modified stage IV B (HR = 21.89, 95%CI, 14.76-32.46) were associated with a poorer prognosis compared with patients with modified stage III B. The prognostic ability (C-index) of the modified staging system (0.789; 95%CI, 0.777-0.801) was better than that of the AJCC 8th edition system (0.762; 95%CI, 0.748-0.776) (0.789 vs. 0.762, P = 0.004). The K-M curves indicated that the modified staging system may be distinguished prognostic differences in patients with different stages. CONCLUSION: Modified staging system may be better than AJCC 8th staging system for predicting prognosis in prostate cancer patients. The AJCC 8th staging system should be further optimized.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Programa de SEER , Estadiamento de Neoplasias , Estudos de Coortes , Prognóstico
19.
Biomed Pharmacother ; 157: 113962, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36370523

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) patients suffer varying degrees of heart dysfunction after tyrosine kinase inhibitor (TKI) treatment. Interestingly, HCC patients often have higher levels of pentraxin 3 (PTX3), and PTX3 inhibition was found to improve left ventricular dysfunction in animal models. OBJECTIVES: We sought to assess the therapeutic potential of PTX3 inhibition on TKI-associated cardiotoxicity. METHODS: We used a human embryonic stem cell line, RUES2, to generate cardiomyocyte cultures (RUES2-CM) for functional testing. We also assessed heart function and PTX3 expression levels in 16 HCC patients who received TKI treatment, 3 HCC patients who did not receive TKIs, and 7 healthy volunteers. RESULTS: Significantly higher PTX3 expression was noted in HCC patients with TKI treatment versus those without, and 38% of male and 33% of female patients had QTc prolongation after TKI treatment. Treatment of cardiomyocyte cultures with sorafenib also increased PTX3 expression and induced cytoskeletal remodelling, contraction reduction, sodium current inhibition, and mitochondrial respiratory dysfunction. PTX3 colocalised with CD44 in cardiomyocytes, and cardiomyocyte contraction, mitochondrial respiratory function, and regular cytoskeletal and apoptotic protein expression were restored with PTX3 inhibition. CD44 knockdown confirmed PTX3/CD44 signalling. These results suggest a possible mechanism in which sorafenib treatment increases PTX3 expression, thereby resulting in reduced extracellular signal-regulated kinase (ERK) 1/2 expression that affects cardiomyocyte contraction, while also activating c-Jun N-terminal kinase (JNK) downstream pathways to disrupt mitochondrial respiration and trigger apoptosis. CONCLUSIONS: TKI-induced cardiotoxicity may be partly mediated by the upregulation of PTX3, and thus PTX3 inhibition has potential as a therapeutic strategy.

20.
Mar Genomics ; 66: 100996, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36400547

RESUMO

Stutzerimonas kunmingensis 7850S is a piezotolerant bacterium isolated from the sediment of the Mariana trench. Here, we described the complete genome of strain 7850S, which contains a single circular chromosome of 4,775,870 base pairs with 62.66% G + C content, and harbors 4494 protein-coding genes, 65 transfer RNA genes, and 12 ribosomal RNA genes. The experimental results showed that strain 7850S could grow under hydrostatic pressure of 0.1-70 MPa. Genomic analyses led to identifications of numbers of high hydrostatic pressure-associated genes, such as the ones associated with unsaturated fatty acids, betaine, and ectoine. A complete set of denitrification genes and some heavy metal detoxification genes were also found in this strain. The presence of these genes suggests metabolic characteristics for adaption to hadal environments and provides insights to further understand adaption strategies and ecological roles of Stutzerimonas in hadal environments.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Metais Pesados , Análise de Sequência de DNA , Bactérias , Composição de Bases
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