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1.
Crit Rev Food Sci Nutr ; : 1-24, 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34852703

RESUMO

Excessive use of pesticides can cause contamination of the environment and agricultural products that are directly threatening human life and health. Therefore, in the process of food safety supervision, it is crucial to conduct sensitive and rapid detection of pesticide residues. The recognition element is the vital component of sensors and methods for fast testing pesticide residues in food. Improper recognition elements may lead to defects of testing methods, such as poor stability, low sensitivity, high economic costs, and waste of time. We can use the molecular biological technique to address these challenges as a good strategy for recognition element production and modification. Herein, we review the molecular biological methods of five specific recognition elements, including aptamers, genetic engineering antibodies, DNAzymes, genetically engineered enzymes, and whole-cell-based biosensors. In addition, the application of these identification elements combined with biosensor and immunoassay methods in actual detection was also discussed. The purpose of this review was to provide a valuable reference for further development of rapid detection methods for pesticide residues.

2.
Math Biosci Eng ; 18(6): 7440-7463, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34814257

RESUMO

BACKGROUND: Brain network can be well used in emotion analysis to analyze the brain state of subjects. A novel dynamic brain network in arousal is proposed to analyze brain states and emotion with Electroencephalography (EEG) signals. New Method: Time factors is integrated to construct a dynamic brain network under high and low arousal conditions. The transfer entropy is adopted in the dynamic brain network. In order to ensure the authenticity of dynamics and connections, surrogate data are used for testing and analysis. Channel norm information features are proposed to optimize the data and evaluate the level of activity of the brain. RESULTS: The frontal lobe, temporal lobe, and parietal lobe provide the most information about emotion arousal. The corresponding stimulation state is not maintained at all times. The number of active brain networks under high arousal conditions is generally higher than those under low arousal conditions. More consecutive networks show high activity under high arousal conditions among these active brain networks. The results of the significance analysis of the features indicates that there is a significant difference between high and low arousal. Comparison with Existing Method(s): Compared with traditional methods, the method proposed in this paper can analyze the changes of subjects' brain state over time in more detail. The proposed features can be used to quantify the brain network for accurate analysis. CONCLUSIONS: The proposed dynamic brain network bridges the research gaps in lacking time resolution and arousal conditions in emotion analysis. We can clearly get the dynamic changes of the overall and local details of the brain under high and low arousal conditions. Furthermore, the active segments and brain regions of the subjects were quantified and evaluated by channel norm information.This method can be used to realize the feature extraction and dynamic analysis of the arousal dimension of emotional EEG, further explore the emotional dimension model, and also play an auxiliary role in emotional analysis.

3.
Cancer Res ; 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34764205

RESUMO

Metabolic reprogramming by oncogenic signaling is a hallmark of cancer. Hyperactivation of Wnt/ß-catenin signaling has been reported in hepatocellular carcinoma (HCC). However, the mechanisms inducing hyperactivation of Wnt/ß-catenin signaling and strategies for targeting this pathway are incompletely understood. In this study, we find nucleoside diphosphate kinase 7 (NME7) to be a positive regulator of Wnt/ß-catenin signaling. Upregulation of NME7 positively correlated with the clinical features of HCC. Knockdown of NME7 inhibited HCC growth in vitro and in vivo, while overexpression of NME7 cooperated with c-Myc to drive tumorigenesis in a mouse model and promote the growth of tumor-derived organoids. Mechanistically, NME7 bound and phosphorylated serine 9 of GSK3ß to promote ß-catenin activation. Furthermore, MTHFD2, the key enzyme in one-carbon metabolism, was a target gene of ß-catenin and mediated the effects of NME7. Tumor-derived organoids with NME7 overexpression exhibited increased sensitivity to MTHFD2 inhibition. Additionally, expression levels of NME7, ß-catenin and MTHFD2 correlated with each other and with poor prognosis in HCC patients. Collectively, this study emphasizes the crucial roles of NME7 protein kinase activity in promoting Wnt/ß-catenin signaling and one-carbon metabolism, suggesting NME7 and MTHFD2 as potential therapeutic targets for HCC.

4.
Front Cardiovasc Med ; 8: 699175, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722652

RESUMO

Background: Clinical studies have shown that exosomes are associated with atrial fibrillation (AF). However, the roles and underlying mechanisms remain unclear. Hence, this study aimed to investigate the function of exosomes in AF development. Methods: Twenty beagles were randomly divided into the sham group (n = 6), the pacing group (n = 7), and the pacing + GW4869 group (n = 7). The pacing and GW4869 groups underwent rapid atrial pacing (450 beats/min) for 7 days. The GW4869 group received intravenous GW4869 injection (an inhibitor of exosome biogenesis/release, 0.3 mg/kg, once a day) during pacing. Electrophysiological measurements, transmission electron microscopy, nanoparticle tracking analysis, western blotting, RT-PCR, Masson's staining, and immunohistochemistry were performed in this study. Results: Rapid atrial pacing increased the release of plasma and atrial exosomes. GW4869 treatment markedly suppressed AF inducibility and reduced the release of exosomes. After 7 days of pacing, the expression of transforming growth factor-ß1 (TGF-ß1), collagen I/III, and matrix metalloproteinases was enhanced in the atrium, and the levels of microRNA-21-5p (miR-21-5p) were upregulated in both plasma exosomes and the atrium, while the tissue inhibitor of metalloproteinase 3 (TIMP3), a target of miR-21-5p, showed a lower expression in the atrium. The administration of GW4869 abolished these effects. Conclusions: The blockade of exosome release with GW4869 suppressed AF by alleviating atrial fibrosis in a canine model, which was probably related to profibrotic miR-21-5p enriched in exosomes and its downstream TIMP3/TGF-ß1 pathway.

5.
Open Life Sci ; 16(1): 1141-1150, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722886

RESUMO

Vascular hyporesponsiveness in the shock decompensation period is an important factor leading to death. Myosin light chain 20 (MLC20) is the main effector protein that regulates vascular reactivity. However, whether the change in semicarbazide-sensitive amine oxidase (SSAO) expression during hypoxia can change the MLC20 phosphorylation level, and its underlying mechanism were not clear. The amine oxidase copper containing 3 (AOC3) overexpressing adenovirus vector was constructed and transfected into rat intestinal microvascular endothelial cells (RIMECs) to overexpress SSAO, and the RIMECs were co-cultured with rat intestinal microvascular smooth muscle cells (RIMSCs). The changes in SSAO/inducible nitric oxide synthase (iNOS)/Rho associate coiled-coil containing protein kinase 1 (ROCK1) expression levels and MLC20 phosphorylation level were detected. Here we found that the increased SSAO by AOC3 overexpression can decrease the iNOS expression level and its activity after hypoxia. In addition, RIMSCs co-cultured with RIMECs overexpressed with AOC3 gene had significantly higher ROCK1 protein level and MLC20 phosphorylation level than RIMSCs co-cultured with normal RIMECs. Our study demonstrated that SSAO overexpression can significantly inhibit iNOS activity, promote RhoA/ROCK pathway activation, and increase the phosphorylation level of MLC20, which might be the potential mechanism in relieving the vascular hyporesponsiveness during shock decompensation.

6.
Poult Sci ; 100(12): 101485, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34695626

RESUMO

Livestock farms are generally considered to be the important source of antibiotic resistance genes (ARGs). It is important to explore the spread of ARGs to reduce their harm. This study analyzed 13 resistance genes belonging to 7 types in 68 samples of layer manure including different stages of layer breeding, layer manure fertilizer, and soil from 9 laying hen farms in Guangdong Province. The detection rate of antibiotic resistance genes was extremely high at the layer farm in manure (100%), layer manure fertilizer (100%), and soil (> 95%). The log counts of antibiotic resistance genes in layer manure (3.34-11.83 log copies/g) were significantly higher than those in layer manure fertilizer (3.45-9.80 log copies/g) and soil (0-7.69 log copies/g). In layer manure, ermB was the most abundant antibiotic resistance gene, with a concentration of 3.19 × 109- 6.82 × 1011 copies/g. The average abundances of 5 antibiotic resistance genes were above 1010 copies/g in the descending order ermB, sul2, tetA, sul1, and strB. The relative abundances of ARGs in layer manure samples from different breeding stages ranked as follows: brooding period (BP), late laying period (LL), growing period (GP), early laying period (EL), and peak laying period (PL). There was no significant correlation between the farm scale and the abundance of antibiotic resistance genes. Moreover, the farther away from the layer farm, the lower the abundance of antibiotic resistance genes in the soil. We also found that compost increases the correlation between antibiotic resistance genes, and the antibiotic resistance genes in soil may be directly derived from layer manure fertilizer instead of manure. Therefore, when applying layer manure fertilizer to cultivated land, the risk of antibiotic resistance genes pollution should be acknowledged, and in-depth research should be conducted on how to remove antibiotic resistance genes from layer manure fertilizer to control the spread of antibiotic resistance genes.


Assuntos
Antibacterianos , Galinhas , Animais , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos/genética , Fazendas , Feminino , Genes Bacterianos , Esterco , Microbiologia do Solo
7.
Syst Biol ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34605924

RESUMO

Phylogenetic networks provide a powerful framework for modeling and analyzing reticulate evolutionary histories. While polyploidy has been shown to be prevalent not only in plants but also in other groups of eukaryotic species, most work done thus far on phylogenetic network inference assumes diploid hybridization. These inference methods have been applied, with varying degrees of success, to data sets with polyploid species, even though polyploidy violates the mathematical assumptions underlying these methods. Statistical methods were developed recently for handling specific types of polyploids and so were parsimony methods that could handle polyploidy more generally yet while excluding processes such as incomplete lineage sorting. In this paper, we introduce a new method for inferring most parsimonious phylogenetic networks on data that include polyploid species. Taking gene tree topologies as input, the method seeks a phylogenetic network that minimizes deep coalescences while accounting for polyploidy. We demonstrate the performance of the method on both simulated and biological data. The inference method as well as a method for evaluating evolutionary hypotheses in the form of phylogenetic networks are implemented and publicly available in the PhyloNet software package.

8.
Brief Bioinform ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34643213

RESUMO

Understanding the impact of non-coding sequence variants on complex diseases is an essential problem. We present a novel ensemble learning framework-CASAVA, to predict genomic loci in terms of disease category-specific risk. Using disease-associated variants identified by GWAS as training data, and diverse sequencing-based genomics and epigenomics profiles as features, CASAVA provides risk prediction of 24 major categories of diseases throughout the human genome. Our studies showed that CASAVA scores at a genomic locus provide a reasonable prediction of the disease-specific and disease category-specific risk prediction for non-coding variants located within the locus. Taking MHC2TA and immune system diseases as an example, we demonstrate the potential of CASAVA in revealing variant-disease associations. A website (http://zhanglabtools.org/CASAVA) has been built to facilitate easily access to CASAVA scores.

9.
Life Sci ; 285: 119995, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34592228

RESUMO

3-Epipachysamine B is a natural steroidal alkaloid isolated from Pachysandra terminalis Sieb. et Zucc. (known locally as Kunxianqi). Kunxianqi contains numerous compounds with demonstrated activity against breast cancer (BRCA). However, it is unknown whether 3-epipachysamine B also has anti-BRCA efficacy. In the present study, we employed network pharmacology technology to search and find potential molecular targets of 3-epipachysamine B. We applied cell proliferation, apoptosis, and western blotting assays to test the predicted key targets and the effects of 3-epipachysamine B against BRCA. Network pharmacology disclosed 80 potential BRCA-related targets of 3-epipachysamine B and assigned them to 75 signaling pathways. Of these, the most highly enriched was the PI3K/AKT signaling pathway. PIK3R1, AKT1, and mTOR had high degrees and betweenness centrality in protein-protein interaction network and are associated with PI3K/AKT signaling. Molecular docking and molecular dynamics simulation indicated strong binding between 3-epipachysamine B and PIK3R1, AKT1, and mTOR. 3-Epipachysamine B repressed the proliferation and induced the apoptosis of BRCA cells, as well as downregulated P-AKT/AKT, P-mTOR/mTOR, and P-PI3K/PI3K in the cells. The PI3K inhibitor LY294002 augmented these changes. Hence, 3-epipachysamine could also prove effective as an anticancer agent in future animal tumor model and human clinical breast cancer trials. Successful validation results could lead to a safe and effective new breast cancer treatment that improves patient prognosis and quality of life.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/enzimologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Feminino , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
10.
Quant Imaging Med Surg ; 11(9): 4074-4096, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34476190

RESUMO

Background: Subjective cognitive decline plus could be an extremely early phase of Alzheimer's disease; however, changes of N-acetylaspartate, myoinositol, and N-acetylaspartate/myoinositol is still unknown at this stage. This study aimed to explore brain neurometabolic alterations in patients with subjective cognitive decline plus using quantitative single-voxel and multi-voxel 1H-magnetic resonance spectroscopy. Methods: A total of 91 participants were enrolled and underwent a GE 3.0-T magnetic resonance imaging, including 33 elderly controls, 27 patients with subjective cognitive decline plus, and 31 patients with amnestic mild cognitive impairment (MCI). Single-voxel and multi-voxel 1H-magnetic resonance spectroscopy were used to investigate the differences in neurometabolite levels among the three groups. Results: Compared with elderly controls, patients with subjective cognitive decline plus showed significant decline in N-acetylaspartate and N-acetylaspartate/myoinositol values in multiple regions, and amnestic MCI participants demonstrated more significant decreased N-acetylaspartate and N-acetylaspartate/myoinositol levels in multiple regions. The combined concentrations of N-acetylaspartate with myoinositol showed an excellent discrimination between those with subjective cognitive decline plus and elderly controls as compared to that obtained using N-acetylaspartate/myoinositol ratios with the area under the receiver operating characteristic curve of 0.895 and 0.860, respectively. Likewise, the combined area under the curve for differentiating patients with subjective cognitive decline plus from amnestic MCI was obtained using the combined levels of N-acetylaspartate with myoinositol was 0.892. This was also higher than the combined area under the curve of 0.836 obtained using N-acetylaspartate/myoinositol ratios. Moreover, N-acetylaspartate levels in the left hippocampus and left posterior cingulate cortex (PCC) was positively related to the Auditory Verbal Learning Test delayed recall scores in patients with subjective cognitive decline plus, whereas only the N-acetylaspartate/myoinositol ratio was positively related to this scale scores in the left hippocampus. Conclusions: Quantitative single-voxel and multi-voxel 1H-magnetic resonance spectroscopy can provide valuable information to detect alterative brain neurometabolites characteristics in patients with subjective cognitive decline plus. N-acetylaspartate concentrations may be used as one of the earliest neuroimaging markers at this stage, while N-acetylaspartate/myoinositol ratio could be more suitable for monitoring Alzheimer's disease progression.

11.
Microsyst Nanoeng ; 7: 65, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34567777

RESUMO

Here, we present integrated nanorod arrays on microfluidic chips for fast and sensitive flow-through immunoassays of physiologically relevant macromolecules. Dense arrays of Au nanorods are easily fabricated through one-step oblique angle deposition, which eliminates the requirement of advanced lithography methods. We report the utility of this plasmonic structure to improve the detection limit of the cardiac troponin I (cTnI) assay by over 6 × 105-fold, reaching down to 33.9 fg mL-1 (~1.4 fM), compared with an identical assay on glass substrates. Through monolithic integration with microfluidic elements, the device enables a flow-through assay for quantitative detection of cTnI in the serum with a detection sensitivity of 6.9 pg mL-1 (~0.3 pM) in <6 min, which was 4000 times lower than conventional glass devices. This ultrasensitive detection arises from the large surface area for antibody conjugation and metal-enhanced fluorescent signals through plasmonic nanostructures. Moreover, due to the parallel arrangement of flow paths, simultaneous detection of multiple cancer biomarkers, including prostate-specific antigen and carcinoembryonic antigen, has been fulfilled with increased signal-to-background ratios. Given the high performance of this assay, together with its simple fabrication process that is compatible with standard mass manufacturing techniques, we expect that the prepared integrated nanorod device can bring on-site point-of-care diagnosis closer to reality.

12.
Ecotoxicol Environ Saf ; 225: 112815, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34562788

RESUMO

The application of manure compost may cause the transmission of antibiotic resistance genes (ARGs) in agroecological environment, which poses a global threat to public health. However, the driving factors for the transmission of ARGs from animal manure to agroecological systems remains poorly understood. Here, we explored the spatiotemporal variation in ARG abundance and bacterial community composition as well as relative driving factors in a soil-lettuce system amended with swine manure compost. The results showed that ARGs abundance had different variation trends in soil, lettuce phylloplane and endophyere after the application of swine manure compost. The temporal variations of total ARGs abundance had no significant different in soil and lettuce phylloplane, while lettuce endosphere enriched half of ARGs to the highest level at harvest. There was a significant linear correlation between ARGs and integrase genes (IGs). In contrast to the ARGs variation trend, the alpha diversity of soil and phylloplane bacteria showed increasing trends over planting time, and endosphere bacteria remained stable. Correlation analysis showed no identical ARG-related genera in the three parts, but the shared Proteobacteria, Pseudomonas, Halomonas and Chelativorans, from manure compost dominated ARG profile in the soil-lettuce system. Moreover, redundancy analysis and structural equation modelling showed the variations of ARGs may have resulted from the combination of multiple driving factors in soil-lettuce system. ARGs in soil were more affected by the IGs, antibiotic and heavy metals, and bacterial community structure and IGs were the major influencing factors of ARG profiles in the lettuce. The study provided insight into the multiple driving factors contribute to the variations of typical ARGs in different parts of soil-lettuce system, which was conducive to the risk assessment of ARGs in agroecosystem and the development of effective prevention and control measures for ARGs spread in the environment.


Assuntos
Alface , Solo , Animais , Antibacterianos , Resistência Microbiana a Medicamentos , Esterco , Suínos
13.
Ecotoxicol Environ Saf ; 226: 112827, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34571416

RESUMO

Reducing the production of odor during swine breeding has attracted attention. Ammonia (NH3) and hydrogen sulfide (H2S) contributed to the odor emissions from swine breeding because NH3 emissions are high and hydrogen sulfide (H2S) has a low odor threshold. Sodium butyrate reduces the odor emissions caused by NH3 and H2S, but the corresponding mechanism is unclear. After mixing the feces of six fattening pigs, the mixture was used to process in vitro fermentation experiment. The purpose was researching the effect of sodium butyrate reduced NH3 and H2S emissions in swine cecal contents. The control group was denoted CK, and the treatment groups with different sodium butyrate concentrations (0.015%, 0.030% and 0.150%) were denoted L, M and H. The NH3, H2S, total gas production and physicochemical indexes were measured, and the bacterial communities in the fermented product were analyzed by 16 S rDNA sequencing. The results showed that group M reduced NH3, H2S and total gas production by 17.96%, 12.26% and 30.30%, respectively. Sodium butyrate promoted SO42- accumulation and lowered the pH. Importantly, sodium butyrate decreased the relative abundance of bacteria positively correlated with NH3 and H2S production, but increased the negatively correlated ones. Proteobacteria made a greater contribution to reducing emissions than did other bacterial phyla. Our results showed that adding 0.030% sodium butyrate can significantly reduce NH3 and H2S production, which occurred via alterations in the physicochemical indicators to adjust the abundance of the bacteria related to odor production, including Proteobacteria.


Assuntos
Amônia , Sulfeto de Hidrogênio , Animais , Bactérias , Ácido Butírico , Ceco , Suínos
14.
J Agric Food Chem ; 69(37): 11131-11141, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34494438

RESUMO

A bio-barcode immunoassay based on droplet digital polymerase chain reaction (ddPCR) was developed to simultaneously quantify triazophos, parathion, and chlorpyrifos in apple, cucumber, cabbage, and pear. Three gold nanoparticle (AuNP) probes and magnetic nanoparticle (MNP) probes were prepared, binding through their antibodies with the three pesticides in the same tube. Three groups of primers, probes, templates, and three antibodies were designed to ensure the specificity of the method. Under the optimal conditions, the detection limits (expressed as IC10) of triazophos, parathion, and chlorpyrifos were 0.22, 0.45, and 4.49 ng mL-1, respectively. The linear ranges were 0.01-20, 0.1-100, and 0.1-500 ng mL-1, and the correlation coefficients (R2) were 0.9661, 0.9834, and 0.9612, respectively. The recoveries and relative standard deviations (RSDs) were in the ranges of 75.5-98.9 and 8.3-16.7%. This study provides the first insights into the ddPCR for the determination of organophosphate pesticides. It also laid the foundation for high-throughput detection of other small molecules.


Assuntos
Nanopartículas Metálicas , Praguicidas , Ouro , Imunoensaio , Limite de Detecção , Praguicidas/análise , Reação em Cadeia da Polimerase
15.
Adv Mater ; 33(43): e2102964, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34510582

RESUMO

High-voltage lithium-ion batteries (LIBs) enabled by high-voltage electrolytes can effectively boost energy density and power density, which are critical requirements to achieve long travel distances, fast-charging, and reliable safety performance for electric vehicles. However, operating these batteries beyond the typical conditions of LIBs (4.3 V vs Li/Li+ ) leads to severe electrolyte decomposition, while interfacial side reactions remain elusive. These critical issues have become a bottleneck for developing electrolytes for applications in extreme conditions. Herein, an additive-free electrolyte is presented that affords high stability at high voltage (4.5 V vs Li/Li+ ), lithium-dendrite-free features upon fast-charging operations (e.g., 162 mAh g-1 at 3 C), and superior long-term battery performance at low temperature. More importantly, a new solvation structure-related interfacial model is presented, incorporating molecular-scale interactions between the lithium-ion, anion, and solvents at the electrolyte-electrode interfaces to help interpret battery performance. This report is a pioneering study that explores the dynamic mutual-interaction interfacial behaviors on the lithium layered oxide cathode and graphite anode simultaneously in the battery. This interfacial model enables new insights into electrode performances that differ from the known solid electrolyte interphase approach to be revealed, and sets new guidelines for the design of versatile electrolytes for metal-ion batteries.

16.
PLoS Genet ; 17(8): e1009701, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34407067

RESUMO

Trait evolution among a set of species-a central theme in evolutionary biology-has long been understood and analyzed with respect to a species tree. However, the field of phylogenomics, which has been propelled by advances in sequencing technologies, has ushered in the era of species/gene tree incongruence and, consequently, a more nuanced understanding of trait evolution. For a trait whose states are incongruent with the branching patterns in the species tree, the same state could have arisen independently in different species (homoplasy) or followed the branching patterns of gene trees, incongruent with the species tree (hemiplasy). Another evolutionary process whose extent and significance are better revealed by phylogenomic studies is gene flow between different species. In this work, we present a phylogenomic method for assessing the role of hybridization and introgression in the evolution of polymorphic or monomorphic binary traits. We apply the method to simulated evolutionary scenarios to demonstrate the interplay between the parameters of the evolutionary history and the role of introgression in a binary trait's evolution (which we call xenoplasy). Very importantly, we demonstrate, including on a biological data set, that inferring a species tree and using it for trait evolution analysis in the presence of gene flow could lead to misleading hypotheses about trait evolution.


Assuntos
Biologia Computacional/métodos , Introgressão Genética/genética , Locos de Características Quantitativas , Evolução Molecular , Especiação Genética , Modelos Genéticos , Fenótipo , Filogenia
17.
Proc Natl Acad Sci U S A ; 118(32)2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34353917

RESUMO

The increasing complexity of different cell types revealed by single-cell analysis of tissues presents challenges in efficiently elucidating their functions. Here we show, using prostate as a model tissue, that primary organoids and freshly isolated epithelial cells can be CRISPR edited ex vivo using Cas9-sgRNA (guide RNA) ribotnucleoprotein complex technology, then orthotopically transferred in vivo into immunocompetent or immunodeficient mice to generate cancer models with phenotypes resembling those seen in traditional genetically engineered mouse models. Large intrachromosomal (∼2 Mb) or multigenic deletions can be engineered efficiently without the need for selection, including in isolated subpopulations to address cell-of-origin questions.

19.
Artigo em Inglês | MEDLINE | ID: mdl-34453203

RESUMO

PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising target for prostate cancer imaging and therapy. The most commonly used scaffold incorporates a glutamate-urea (Glu-Urea) function. We recently developed oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA ligands in an attempt to improve upon the pharmacokinetic properties of existing agents. Here, we report the synthesis of an optimized 68Ga-labeled ODAP-Urea-based ligand, [68Ga]Ga-P137, and first-in-human results. METHODS: Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with 68Ga in high radiochemical yield and purity. Their PSMA inhibitory capacities were determined using the NAALADase assay. Radioligands were evaluated in mice-bearing 22Rv1 prostate tumors by microPET. Lead compound [68Ga]Ga-P137 was evaluated for stability, cell uptake, and biodistribution. PET imaging of [68Ga]Ga-P137 was performed in three patients head-to-head compared to [68Ga]Ga-PSMA-617. RESULTS: Ligands were synthesized in 11.1-44.4% yield and > 95% purity. They have high affinity to PSMA (Ki of 0.13 to 5.47 nM). [68Ga]Ga-P137 was stable and hydrophilic. [68Ga]Ga-P137 showed higher uptake than [68Ga]Ga-PSMA-617 in tumor-bearing mice at 6.43 ± 0.98%IA/g vs 3.41 ± 1.31%IA/g at 60-min post-injection. In human studies, the normal organ biodistribution of [68Ga]Ga-P137 was grossly equivalent to that of [68Ga]Ga-PSMA-617 except for within the urinary tract, in which [68Ga]Ga-P137 demonstrated lower uptake. CONCLUSION: The optimized ODAP-Urea-based ligand [68Ga]Ga-P137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [68Ga]Ga-PSMA-617, in a preliminary, first-in-human study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04560725, Registered 23 September 2020. https://clinicaltrials.gov/ct2/show/NCT04560725.

20.
Hematology ; 26(1): 543-551, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34348586

RESUMO

Objectives: Chronic myeloid leukemia (CML) is a malignant tumor of the blood system. Gö6976, as a type of indolocarbazole and shows strong antitumor effects, but there have been no reports on the effect of Gö6976 on CML. The objectives of this research were: (1) to explore the impact of Gö6976 on CML in vitro and in vivo; and (2) to explore the drug toxicity of Gö6976 to normal cells and animals.Methods:K562 cells and CML mice were used to explore the effect of Gö6976 on CML. Peripheral blood mononuclear cells (PBMCs), CD34+ cells, and healthy mice were used to explore the drug toxicity of Gö6976.Results: Cell experiments showed that Gö6976 could inhibit the proliferation of K562 cells and enhance the inhibitory effects of imatinib at 5 µM and 10 µM, but it had little effect on CD34+ cells or PBMCs at concentrations less than 5 µM. Animal experiments showed that 2.5 mg/kg Gö6976 could effectively inhibit the development of CML in mice, and it had almost no effects on healthy mice at 2.5 mg/kg and 10 mg/kg.Discussion: Because of the direct inhibitory effect of Gö6976 on CML and its pharmacological enhancement effect on imatinib, it is foreseeable that Gö6976 could become a new type of anti-CML medicine. And the further research is needed.Conclusion: Our findings verified that Gö6976 could effectively inhibit CML in vitro and in vivo, and it is almost nontoxic to hematopoietic cells, immune cells, and healthy mice.


Assuntos
Carbazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Animais , Carbazóis/agonistas , Agonismo de Drogas , Humanos , Mesilato de Imatinib/agonistas , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Ensaios Antitumorais Modelo de Xenoenxerto
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