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1.
Artigo em Inglês | MEDLINE | ID: mdl-33813702

RESUMO

Harmful algal blooms caused by Karlodinium veneficum recently occurred with high incidence, posing a serious threat to the marine ecological environment, public health, and mariculture. It is therefore rather vital to establish a method for rapid detection of K. veneficum. In this study, the D1-D2 region of the large subunit rDNA (LSU rDNA D1-D2) of K. veneficum was cloned and sequenced to design the specific probes and primers. A novel method referred to as double-nick rolling circle amplification (dn-RCA) based on the designed probes and primers was initially established. The optimal reaction conditions for dn-RCA were as follows: probe concentration, 200 pM; ligation temperature, 57 °C; ligation time, 50 min; amplification temperature, 60 °C; and amplification time, 60 min. Furthermore, lateral flow dipstick (LFD) was employed instead of agarose gel electrophoresis to analyze dn-RCA products, which can simplify the detection procedure and reduce the operation time. The sensitivity of dn-RCA-LFD was tested with the genomic DNA, the recombinant plasmid containing the inserted LSU rDNA D1-D2, and the DNA crude extract of K. veneficum. The results showed that the sensitivity of dn-RCA-LFD was 10 times higher than that of conventional PCR; the detection limit of dn-RCA-LFD was 1.1 × 10-4 ng µL-1 for the genomic DNA, 360 copies µL-1 for the recombinant plasmid, and 5.3 cells mL-1 for DNA crude extract. The results of the cross-reactivity test with 22 control microalgal species showed that the dn-RCA-LFD had high specificity for K. veneficum. The stability of dn-RCA-LFD was tested by mixing the interfering genomic DNA with the target genomic DNA, which can be expected to simulate the natural samples containing different ratios of interfering cells to target cells. The results indicated that the performance of dn-RCA-LFD was immune to the DNA concentration of the interfering species. Finally, the practicability of dn-RCA-LFD was further confirmed by the test with field samples collected from the East China Sea. In conclusion, the established dn-RCA-LFD has advantages of high sensitivity, strong specificity, and stable performance, and is therefore promising for rapid detection of K. veneficum.

2.
J Nutr ; 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33830211

RESUMO

BACKGROUND: Obesity, a major public health problem worldwide, is associated with dysfunction of the intestinal barrier. Glycine (Gly) has been reported to enhance the expression of tight-junction proteins in porcine enterocytes. It is unknown whether Gly can improve intestinal barrier integrity in obese mice. OBJECTIVES: This study tested the hypothesis that Gly enhances the intestinal epithelial barrier by regulating endoplasmic reticulum (ER) stress-related signaling and mitigating inflammation in high-fat diet (HFD)-induced obese mice. METHODS: Five-week-old male C57BL/6J mice were fed a normal-fat diet (ND; fat = 10% energy) or an HFD (fat = 60% energy) and received drinking water supplemented with 2% Gly or 2.37% l-alanine (Ala; isonitrogenous control) daily for 12 wk. Body weight gain and tissue weights, glucose tolerance and the activation of immune cells, as well as the abundances of tight-junction proteins, ER stress proteins, and apoptosis-related proteins in the jejunum and colon were determined. In addition, the body weights of naïve ND and HFD groups (nND and nHFD, respectively) were also recorded for comparison. Differences were analyzed statistically by ANOVA followed by the Duncan multiple-comparison test using SAS software. RESULTS: Compared with ND-Ala, HFD-feeding resulted in enhanced macrophage (CD11b+ and F4/80+) infiltration and immune cell activation by 1.9- to 5.4-fold (P < 0.05), as well as the upregulation of ER stress sensor proteins (including phospho-inositol-requiring enzyme 1α and binding immunoglobulin protein) by 2.5- to 4.5-fold, the induction of apoptotic proteins by 1.5- to 3.2-fold, and decreased abundances of tight-junction proteins by 35%-65% (P < 0.05) in the intestine. These HFD-induced abnormalities were significantly ameliorated by Gly supplementation in the HFD-Gly group (P < 0.05). Importantly, Gly supplementation also significantly enhanced glucose tolerance (P < 0.05) by 1.5-fold without affecting the fat accumulation of HFD-induced obese mice. CONCLUSIONS: Gly supplementation enhanced the intestinal barrier and ameliorated inflammation and insulin resistance in HFD-fed mice. These effects of Gly were associated with reduced ER stress-related apoptosis in the intestine of obese mice.

3.
J Biomed Sci ; 28(1): 24, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33827580

RESUMO

Thyroid hormone analogues-particularly, L-thyroxine (T4) has been shown to be relevant to the functions of a variety of cancers. Integrin αvß3 is a plasma membrane structural protein linked to signal transduction pathways that are critical to cancer cell proliferation and metastasis. Thyroid hormones, T4 and to a less extend T3 bind cell surface integrin αvß3, to stimulate the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway to stimulate cancer cell growth. Thyroid hormone analogues also engage in crosstalk with the epidermal growth factor receptor (EGFR)-Ras pathway. EGFR signal generation and, downstream, transduction of Ras/Raf pathway signals contribute importantly to tumor cell progression. Mutated Ras oncogenes contribute to chemoresistance in colorectal carcinoma (CRC); chemoresistance may depend in part on the activity of ERK1/2 pathway. In this review, we evaluate the contribution of thyroxine interacting with integrin αvß3 and crosstalking with EGFR/Ras signaling pathway non-genomically in CRC proliferation. Tetraiodothyroacetic acid (tetrac), the deaminated analogue of T4, and its nano-derivative, NDAT, have anticancer functions, with effectiveness against CRC and other tumors. In Ras-mutant CRC cells, tetrac derivatives may overcome chemoresistance to other drugs via actions initiated at integrin αvß3 and involving, downstream, the EGFR-Ras signaling pathways.

4.
Brief Bioinform ; 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33839756

RESUMO

Batch effect correction is an essential step in the integrative analysis of multiple single-cell RNA-sequencing (scRNA-seq) data. One state-of-the-art strategy for batch effect correction is via unsupervised or supervised detection of mutual nearest neighbors (MNNs). However, both types of methods only detect MNNs across batches of uncorrected data, where the large batch effects may affect the MNN search. To address this issue, we presented a batch effect correction approach via iterative supervised MNN (iSMNN) refinement across data after correction. Our benchmarking on both simulation and real datasets showed the advantages of the iterative refinement of MNNs on the performance of correction. Compared to popular alternative methods, our iSMNN is able to better mix the cells of the same cell type across batches. In addition, iSMNN can also facilitate the identification of differentially expressed genes (DEGs) that are relevant to the biological function of certain cell types. These results indicated that iSMNN will be a valuable method for integrating multiple scRNA-seq datasets that can facilitate biological and medical studies at single-cell level.

5.
Cardiovasc Res ; 2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33839759

RESUMO

AIMS: The precise cellular identity and molecular features of non-myocytes (nonCM) in a mammalian heart at a single cell level remain elusive. Depiction of epigenetic landscape with transcriptomic signatures using the latest single-cell multi-omics has the potential to unravel the molecular programs underlying the cellular diversity of cardiac non-myocytes. Here, we characterized the molecular and cellular features of cardiac nonCM populations in the adult murine heart at the single cell level. METHODS AND RESULTS: Through single-cell dual omics analysis, we mapped the epigenetic landscapes, characterized the transcriptomic profiles and delineated the molecular signatures of cardiac nonCMs in the adult murine heart. Distinct cis-regulatory elements and trans-acting factors for the individual major nonCM cell types (endothelial cells, fibroblast, pericytes and immune cells) were identified. In particular, unbiased sub-clustering and functional annotation of cardiac fibroblasts (FB) revealed extensive FB heterogeneity and identified FB subtypes with functional states related to cellular response to stimuli, cytoskeleton organization and immune regulation, respectively. We further explored the function of marker genes Hsd11b1 and Gfpt2 that label major FB sub-populations and determined the distribution of Hsd11b1+ and Gfp2+ FBs in murine healthy and diseased hearts. CONCLUSIONS: In summary, we characterized the nonCM cellular identity at the transcriptome and epigenome levels using single-cell omics approaches and discovered previously unrecognized cardiac fibroblast subpopulations with unique functional states. TRANSLATIONAL PERSPECTIVE: Our research identified discrete cell types of nonCM in the heart and differentially expressed genes with regulatory factors. Unveiling the heterogeneity of nonCMs and molecular signatures of each cell type or subtypes allows for study, precise capture and manipulation of specific cell type(s) in heart and will provide insights into the development of therapeutics for cardiovascular diseases.

6.
Med (N Y) ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33870241

RESUMO

Sexual dimorphisms in immune responses contribute to coronavirus disease 2019 (COVID-19) outcomes, yet the mechanisms governing this disparity remain incompletely understood. We carried out sex-balanced sampling of peripheral blood mononuclear cells from confirmed COVID-19 inpatients and outpatients, uninfected close contacts, and healthy controls for 36-color flow cytometry and single cell RNA-sequencing. Our results revealed a pronounced reduction of circulating mucosal associated invariant T (MAIT) cells in infected females. Integration of published COVID-19 airway tissue datasets implicate that this reduction represented a major wave of MAIT cell extravasation during early infection in females. Moreover, female MAIT cells possessed an immunologically active gene signature, whereas male counterparts were pro-apoptotic. Collectively, our findings uncover a female-specific protective MAIT profile, potentially shedding light on reduced COVID-19 susceptibility in females.

7.
Biomed Pharmacother ; 138: 111485, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33740521

RESUMO

Aberrant alteration of epigenetic information disturbs chromatin structure and gene function, thereby facilitating cancer development. Several drugs targeting histone deacetylases (HDACs), a group of epigenetic enzymes, have been approved for treating hematologic malignancies in the clinic. However, patients who suffer from solid tumors often respond poorly to these drugs. In this study, we report a selective entinostat derivative, MPT0L184, with potent cancer-killing activity in both cell-based and mouse xenograft models. A time-course analysis of cell-cycle progression revealed that MPT0L184 treatment elicited an early onset of mitosis but prevented the division of cells with duplicated chromosomes. We show that MPT0L184 possessed potent inhibitory activity toward HDAC1 and 2, and its HDAC-inhibitory activity was required for initiating premature mitotic signaling. HDAC inhibition by MPT0L184 reduced WEE1 expression at the transcription level. In addition, MPT0L184 treatment also downregulated ATR-mediated CHK1 phosphorylation independent of HDAC inhibition. Furthermore, gastric cancer cells resistant to HDAC inhibitors were vulnerable to MPT0L184. Taken together, our study discovers MPT0L184 as a novel HDAC inhibitor that can trigger premature mitosis and potentially counteract drug resistance of cancers.

8.
Neonatology ; : 106-116, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33677454

RESUMO

BACKGROUND: Preclinical studies have demonstrated that hyperoxia disrupts the intestinal barrier, changes the intestinal bacterial composition, and injures the lungs of newborn animals. OBJECTIVES: The aim of the study was to investigate the effects of hyperoxia on the lung and intestinal microbiota and the communication between intestinal and lung microbiota and to develop a predictive model for the identification of hyperoxia-induced lung injury from intestinal and lung microbiota based on machine learning algorithms in neonatal mice. METHODS: Neonatal C57BL/6N mice were reared in either room air or hyperoxia (85% O2) from postnatal days 1-7. On postnatal day 7, lung and intestinal microbiota were sampled from the left lung and lower gastrointestinal tract for 16S ribosomal RNA gene sequencing. Tissue from the right lung and terminal ileum were harvested for Western blot and histology analysis. RESULTS: Hyperoxia induced intestinal injury, decreased intestinal tight junction expression, and impaired lung alveolarization and angiogenesis in neonatal mice. Hyperoxia also altered intestinal and lung microbiota and promoted bacterial translocation from the intestine to the lung as evidenced by the presence of intestinal bacteria in the lungs of hyperoxia-exposed neonatal mice. The relative abundance of these bacterial taxa was significantly positively correlated with the increased lung cytokines. CONCLUSIONS: Neonatal hyperoxia induced intestinal and lung dysbiosis and promoted bacterial translocation from the intestine to the lung. Further studies are needed to clarify the pathophysiology of bacterial translocation to the lung.

9.
J Dairy Sci ; 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33715853

RESUMO

Ketosis is a common metabolic disorder in high-producing dairy cows during the peripartal period. Negative energy balance leads to increased circulating levels of nonesterified fatty acids (NEFA) and ß-hydroxybutyrate (BHB), consequently increasing the risk of ketosis. It is well-known that NEFA and BHB can induce lipotoxicity and oxidative stress in bovine tissues/organs including the liver and adipose tissue. Although the mammary gland is one important site for NEFA and BHB metabolism, whether an overload in their concentrations within mammary cells causes oxidative stress during ketosis remains unclear. Thus, the present study compared oxidative stress status and mitochondrial function in mammary tissues harvested by biopsy from healthy (n = 15) and clinically ketotic (n = 15) dairy cows within 2 to 3 wk postpartum. Compared with healthy cows, ketotic cows had depressed daily milk yield (median: 28.92 vs. 21.56 kg) and dry matter intake (median: 22.36 vs. 19.92 kg/d), accompanied by elevated plasma NEFA (median: 0.32 vs. 1.26 mM), BHB (median: 0.52 vs. 3.69 mM), and lower plasma glucose (median: 4.55 vs. 2.13 mM). As detected by a commercial kit, a greater level of reactive oxygen species in mammary epithelial cells of ketotic cows, and greater oxidant indices including hydrogen peroxide and malondialdehyde coupled with lower antioxidant indices including glutathione peroxidase, catalase, and superoxide dismutase activities as detected by the respective biochemical kits in the homogenate of mammary tissue of ketotic cows indicated increased oxidative stress status. Lower citrate synthase activity and ATP production as detected by the respective commercial kits coupled with lower mRNA and protein abundance of mitochondrial respiratory chain oxidative phosphorylation complexes I-V (CO I-V) in ketotic cows suggested an impairment of mitochondrial function. This was supported by lower mRNA and protein abundance of nucleus-derived mitochondrial function regulators including peroxisome proliferator activated receptor gamma coactivator 1 α, mitofusin 2, nuclear respiratory factor 1, and mitochondrial transcription factor A. Lower mitochondrial membrane potential evaluated via the tetraethylbenzimidazolylcarbocyanine iodide (JC-1) labeling method and swollen mitochondria in mammary epithelial cells of ketotic cows suggested the existence of mitochondrial damage. Overall, the present study revealed extensive mitochondrial dysfunction and oxidative stress in the mammary gland of clinically ketotic cows. As such, data suggest that reduced milk yield in cows with ketosis is partly due to enhanced oxidative stress along with mitochondrial dysregulation in the mammary gland.

10.
J Biol Chem ; : 100581, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33771559

RESUMO

The formation of UV-induced DNA damage and its repair are influenced by many factors that modulate lesion formation and the accessibility of repair machinery. However, it remains unknown which genomic sites are prioritized for immediate repair after UV damage induction, and whether these prioritized sites overlap with hotspots of UV damage. We identified the super-hotspots subject to the earliest repair for (6-4) pyrimidine-pyrimidone photoproduct [(6-4)PP] by using the eXcision Repair-sequencing (XR-seq) method. We further identified super-coldspots for (6-4)PP repair and super-hotspots for cyclobutane pyrimidine dimer (CPD) repair by analyzing available XR-seq time-course data. By integrating datasets of XR-seq, Damage-seq, adductSeq, and CPD-seq, we show that neither repair super-hotspots nor -coldspots overlap hotspots of UV damage. Furthermore, we demonstrate that repair super-hotspots are significantly enriched in frequently interacting regions (FIREs) and super-enhancers. Finally, we report our discovery of an enrichment of cytosine in repair super-hotspots and -coldspots. These findings suggest that local DNA features together with large-scale chromatin features contribute to the orders of magnitude variability in the rates of UV damage repair.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33619373

RESUMO

The reprogramming of somatic cells with defined factors, which converts cells from one lineage into cells of another, has greatly reshaped our traditional views on cell identity and cell fate determination. Direct reprogramming (also known as transdifferentiation) refers to cell fate conversion without transitioning through an intermediary pluripotent state. Given that the number of cell types that can be generated by direct reprogramming is rapidly increasing, it has become a promising strategy to produce functional cells for therapeutic purposes. This Review discusses the evolution of direct reprogramming from a transcription factor-based method to a small-molecule-driven approach, the recent progress in enhancing reprogrammed cell maturation, and the challenges associated with in vivo direct reprogramming for translational applications. It also describes our current understanding of the molecular mechanisms underlying direct reprogramming, including the role of transcription factors, epigenetic modifications, non-coding RNAs, and the function of metabolic reprogramming, and highlights novel insights gained from single-cell omics studies.

12.
Am J Hum Genet ; 108(2): 257-268, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33545029

RESUMO

Genome-wide chromatin conformation capture technologies such as Hi-C are commonly employed to study chromatin spatial organization. In particular, to identify statistically significant long-range chromatin interactions from Hi-C data, most existing methods such as Fit-Hi-C/FitHiC2 and HiCCUPS assume that all chromatin interactions are statistically independent. Such an independence assumption is reasonable at low resolution (e.g., 40 kb bin) but is invalid at high resolution (e.g., 5 or 10 kb bins) because spatial dependency of neighboring chromatin interactions is non-negligible at high resolution. Our previous hidden Markov random field-based methods accommodate spatial dependency but are computationally intensive. It is urgent to develop approaches that can model spatial dependence in a computationally efficient and scalable manner. Here, we develop HiC-ACT, an aggregated Cauchy test (ACT)-based approach, to improve the detection of chromatin interactions by post-processing results from methods assuming independence. To benchmark the performance of HiC-ACT, we re-analyzed deeply sequenced Hi-C data from a human lymphoblastoid cell line, GM12878, and mouse embryonic stem cells (mESCs). Our results demonstrate advantages of HiC-ACT in improving sensitivity with controlled type I error. By leveraging information from neighboring chromatin interactions, HiC-ACT enhances the power to detect interactions with lower signal-to-noise ratio and similar (if not stronger) epigenetic signatures that suggest regulatory roles. We further demonstrate that HiC-ACT peaks show higher overlap with known enhancers than Fit-Hi-C/FitHiC2 peaks in both GM12878 and mESCs. HiC-ACT, effectively a summary statistics-based approach, is computationally efficient (∼6 min and ∼2 GB memory to process 25,000 pairwise interactions).


Assuntos
Cromatina/genética , Cromatina/metabolismo , Genômica/métodos , Animais , Linhagem Celular , Cromatina/química , Simulação por Computador , Células-Tronco Embrionárias , Elementos Facilitadores Genéticos , Humanos , Camundongos , Conformação Molecular , Regiões Promotoras Genéticas , Sequências Reguladoras de Ácido Nucleico , Análise de Sequência de DNA
13.
PLoS Pathog ; 17(2): e1009285, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33524073

RESUMO

Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that activate the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18. We found that mice deficient in the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), had significantly improved survival and lower levels of IL-1ß and IL-18 in the brain. Importantly, this difference in survival was independent of viral replication in the central nervous system (CNS). We found that microglia, the resident macrophages of the CNS, are the primary mediators of the ASC-dependent inflammasome response during infection. Using in vitro glial infections and a murine HSE model, we demonstrate that inflammasome activation contributes to the expression of chemokine (C-C motif) ligand 6 (CCL6), a leukocyte chemoattractant. The lower concentration of CCL6 in the brains of ASC-/- mice correlated with lower numbers of infiltrating macrophages during infection. Together, these data suggest that inflammasomes contribute to pathogenic inflammation in HSE and provide a mechanistic link between glial inflammasome activation and leukocyte infiltration. The contribution of inflammasomes to survival was independent of viral replication in our study, suggesting a promising new target in combating harmful inflammation in HSE.

14.
Pediatr Res ; 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33469177

RESUMO

BACKGROUND: Perinatal antibiotic treatment alters intestinal microbiota and augments hyperoxia-induced lung injury in mice offspring. The effect of maternal antibiotic treatment (MAT) during pregnancy on the lung microbiota and its relationship with lung injury remains unknown. METHODS: We fed timed-pregnant C57BL/6N mice sterile drinking water containing antibiotics from gestational day 15 to delivery. Neonatal mice were reared in either room air (RA) or hyperoxia (85% O2) from postnatal days 1 to 7. Four study groups were obtained: control + RA, control + O2, MAT + RA, and MAT + O2. On postnatal day 7, lung and intestinal microbiota were sampled from the left lung and lower gastrointestinal tract. The right lung was harvested for histology and cytokine analysis. RESULTS: MAT during pregnancy significantly reduced the total number of commensal bacteria in the intestine and birth body weight of newborn mice compared with control newborn mice. Neonatal hyperoxia exposure impaired alveolarization and angiogenesis, which was exacerbated by MAT. Neonatal hyperoxia altered the composition and diversity of intestinal and lung microbiota and MAT further exacerbated neonatal hyperoxia-induced intestinal and lung dysbiosis. CONCLUSIONS: MAT during pregnancy exacerbates hyperoxia-induced lung injury probably through the modulation of intestinal and lung microbiota in neonatal mice. IMPACT: MAT during pregnancy reduced the total number of commensal bacteria in the intestine. Neonatal hyperoxia altered the composition and diversity of intestinal and lung microbiota. MAT exacerbated neonatal hyperoxia-induced intestinal and lung dysbiosis. Neonatal hyperoxia exposure impaired alveolarization and angiogenesis, which was exacerbated by MAT. Avoiding and carefully using antibiotics during pregnancy is a potential therapeutic target for preventing lung injury in hyperoxia-exposed infants.

15.
Mediators Inflamm ; 2020: 9694012, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376453

RESUMO

The activation of microglial cells plays an important role in the cascade of events leading to inflammation-mediated neurodegenerative disorders. Precision therapeutics require that adjunctively feasible drugs be found to prevent microglial cell activation and prevent inflammation-mediated neuronal injury. Dextromethorphan (DM) has been reported to possess neuroprotective effects in lipopolysaccharide- (LPS-) stimulated animals; however, it remains unclear whether epigenetic regulatory mechanisms in microglial cells are involved in such DM-mediated neuroprotective effects. In this study, DM simultaneously suppressed LPS-induced activation of tumor necrosis factor- (TNF-) α expression and subsequent caspase-3 signaling in primary microglial cells associated with notable morphological changes. Furthermore, therapeutic action sites of DM involved differential enhanced trimethylation of H3K4 modifications in the promoter region of tnf-α gene locus in primary microglial cells. In summary, DM may exert neuroprotective and anti-inflammatory effects through differential epigenetic histone modifications of TNF-α expression in microglial cells and might therefore raise the possibility of providing an adjunctively beneficial role for a tentative therapeutic strategy in neurodegenerative diseases resulting from inflammation.

16.
Ann Surg Treat Res ; 99(5): 268-274, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33163456

RESUMO

Purpose: Spontaneous rupture is a potentially serious complication of liver cancer. A risk score was developed and validated for predicting spontaneous rupture based on a retrospective study. Methods: Multiple logistic regression analysis was used to study the relationship between clinical variables and spontaneous rupture. The independent rupture predictors were converted into a score based on the odds ratio. Predicted attributes of the developed scores were then verified using a dataset in 2019. Results: The incidence of spontaneous rupture was 5.5% from 2002 to 2019. A 10-point score (α-FP of ≥400 µg/L, 1; protrusion from liver surface, 2; ascites, 3; tumor size of >5 cm, 4) was derived for prediction of rupture and area under the receiver-operating characteristic curve was 0.9 (95% confidence interval, 0.87-0.92). When applying a cutoff value of 5 points or more, the specificity was 0.87 and the sensitivity was 0.84. A validation cohort consisting of 202 hepatocellular carcinoma patients reproduces the predictive, identification, and calibration characteristics. The observed rate of spontaneous rupture according to risk stratification of the score was 0.6% for those with a score of 0-4, 21.6% for a score of 5-7, and 36.4% for a score of 8-10 in the validation cohort. Conclusion: Here, based on routine clinical data, we determine the factors that affect prognosis and propose an effective tool for predicting spontaneous rupture, which may be useful in guiding priority treatment of high-risk patients or clinical routine preventive treatment.

17.
Stat Med ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33169416

RESUMO

A cross sectional population is defined as a population of living individuals at the sampling or observational time. Cross-sectionally sampled data with binary disease outcome are commonly analyzed in observational studies for identifying how covariates correlate with disease occurrence. It is generally understood that cross-sectional binary outcome is not as informative as longitudinally collected time-to-event data, but there is insufficient understanding as to whether bias can possibly exist in cross-sectional data and how the bias is related to the population risk of interest. As the progression of a disease typically involves both time and disease status, we consider how the binary disease outcome from the cross-sectional population is connected to birth-illness-death process in the target population. We argue that the distribution of cross-sectional binary outcome is different from the risk distribution from the target population and that bias would typically arise when using cross-sectional data to draw inference for population risk. In general, the cross-sectional risk probability is determined jointly by the population risk probability and the ratio of duration of diseased state to the duration of disease-free state. Through explicit formulas we conclude that bias can almost never be avoided from cross-sectional data. We present age-specific risk probability (ARP) and argue that models based on ARP offers a compromised but still biased approach to understand the population risk. An analysis based on Alzheimer's disease data is presented to illustrate the ARP model and possible critiques for the analysis results.

18.
Sci Transl Med ; 12(566)2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087505

RESUMO

Direct reprogramming of fibroblasts to alternative cell fates by forced expression of transcription factors offers a platform to explore fundamental molecular events governing cell fate identity. The discovery and study of induced cardiomyocytes (iCMs) not only provides alternative therapeutic strategies for heart disease but also sheds lights on basic biology underlying CM fate determination. The iCM field has primarily focused on early transcriptome and epigenome repatterning, whereas little is known about how reprogramming iCMs remodel, erase, and exit the initial fibroblast lineage to acquire final cell identity. Here, we show that autophagy-related 5 (Atg5)-dependent autophagy, an evolutionarily conserved self-digestion process, was induced and required for iCM reprogramming. Unexpectedly, the autophagic factor Beclin1 (Becn1) was found to suppress iCM induction in an autophagy-independent manner. Depletion of Becn1 resulted in improved iCM induction from both murine and human fibroblasts. In a mouse genetic model, Becn1 haploinsufficiency further enhanced reprogramming factor-mediated heart function recovery and scar size reduction after myocardial infarction. Mechanistically, loss of Becn1 up-regulated Lef1 and down-regulated Wnt inhibitors, leading to activation of the canonical Wnt/ß-catenin signaling pathway. In addition, Becn1 physically interacts with other classical class III phosphatidylinositol 3-kinase (PI3K III) complex components, the knockdown of which phenocopied Becn1 depletion in cardiac reprogramming. Collectively, our study revealed an inductive role of Atg5-dependent autophagy as well as a previously unrecognized autophagy-independent inhibitory function of Becn1 in iCM reprogramming.

19.
Plant Physiol Biochem ; 157: 211-218, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33120112

RESUMO

Pomegranate (Punica granatum L.), a fruit tree of great economic and nutritional importance, is sensitive to drought stress, which largely affects its transplantation survival rate, fruit yield and quality. Abscisic acid (ABA) treatment can reduce the drought-induced adverse impacts on plants. However, our knowledge on the molecular mechanisms behind ABA-mediated drought tolerance in pomegranates is still limited. In this study, we treated the pomegranates under drought stress with exogenous ABA of different concentrations (30, 60 and 90 µM) and found that, compared to those without treatment, ABA can improve pomegranate's growth condition and related physiological responding processes. We also performed comparative transcriptome analysis between the ABA-treated and untreated pomegranates to reveal the ABA-induced mechanisms in response to drought-stress. Our results showed that exogenous ABA application substantially enhanced pomegranate drought resistance by strengthening some metabolic pathways, such as brassinosteroid synthesis, peroxisome biogenesis, photosynthesis and hemicelluloses synthesis. Furthermore, the over-dose treatment of exogenous ABA was found to trigger ABA degradation process and a feedback loop in pomegranate to balances the ABA accumulation that exceeds the optimal ABA requirement, at the cost of suppressed growth process and stress resistance. Our findings provide new insights into the molecular regulation mechanisms underlying the ABA-mediated drought-stress resistance in pomegranates.

20.
Int J Biol Macromol ; 165(Pt A): 1519-1528, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33058973

RESUMO

This study investigated the gastroprotective effect of Lycium barbarum polysaccharides (LBP) and C-phycocyanin (C-PC) in rats with ethanol-induced gastric ulcer. Rats were divided into 5 groups: normal, ulcer, ulcer treated with 100 mg/kg bw LBP, ulcer treated with 50 mg/kg bw C-PC, and ulcer treated with 50 mg/kg bw LBP and 25 mg/kg bw C-PC. Pretreatment with LBP and/or C-PC was given a week before ulcer induction. Ulcer induction was produced by 50% ethanol administration orally every other day for 4 weeks. After 5-week treatment, the histopathological observation showed that LBP or C-PC attenuated the severity of gastric mucosal damage. LBP decreased serum malondialdehyde (MDA) levels and gastric interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) levels, and myeloperoxidase (MPO) activity. C-PC decreased serum MDA levels and gastric tumor necrosis factor-α (TNF-α), IL-1ß, IL-6, ICAM-1 levels, and MPO activity. Combined LBP and C-PC decreased serum MDA levels and gastric TNF-α, IL-1ß, IL-6, and ICAM-1 levels. LBP and/or C-PC increased gastric heat shock protein 70 and non-protein sulfhydryl compounds. Rats with ulcer and treatment had enriched with the family Bacillaceae. Therefore, pretreatment with LBP and/or C-PC attenuated ethanol-induced gastric ulcer in rats via suppressing oxidation and inflammation and increasing gastroprotection.

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