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1.
Rev Sci Instrum ; 95(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38602461

RESUMO

Intelligent diagnostic algorithms based on convolutional neural networks (CNNs) have shown great potential in diagnosing various conditions. However, accurately and robustly diagnosing faults in noisy situations remains challenging. This study presents an adaptive fully convolutional network (AFCN) for identifying bearing defects in noisy environments. First, we use a novel large kernel convolution method for high-frequency noise reduction and wide-area temporal feature extraction. By utilizing a sequence of stacked residual adaptive convolution blocks, the AFCN achieves a selective emphasis on significant features and adaptive adjustment of feature weights at various convolution scales. The experimental results have shown that the AFCN achieves a diagnostic accuracy of over 90% for the faults in the CWRU dataset under the -8 dB noise and over 77% for the PU dataset in the case of -6 dB noise. The comparison results with five advanced baseline models have demonstrated the superiority of the AFCN in feature extraction, noise immunity, and robustness to the noise environment. The AFCN provides a better adaption to noise interference than conventional CNNs and other advanced adaptive networks.

2.
Antimicrob Agents Chemother ; : e0139023, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38546223

RESUMO

Dihydroartemisinin-piperaquine is efficacious for the treatment of uncomplicated malaria and its use is increasing globally. Despite the positive results in fighting malaria, inhibition of the Kv11.1 channel (hERG; encoded by the KCNH2 gene) by piperaquine has raised concerns about cardiac safety. Whether genetic factors could modulate the risk of piperaquine-mediated QT prolongations remained unclear. Here, we first profiled the genetic landscape of KCNH2 variability using data from 141,614 individuals. Overall, we found 1,007 exonic variants distributed over the entire gene body, 555 of which were missense. By optimizing the gene-specific parametrization of 16 partly orthogonal computational algorithms, we developed a KCNH2-specific ensemble classifier that identified a total of 116 putatively deleterious missense variations. To evaluate the clinical relevance of KCNH2 variability, we then sequenced 293 Malian patients with uncomplicated malaria and identified 13 variations within the voltage sensing and pore domains of Kv11.1 that directly interact with channel blockers. Cross-referencing of genetic and electrocardiographic data before and after piperaquine exposure revealed that carriers of two common variants, rs1805121 and rs41314375, experienced significantly higher QT prolongations (ΔQTc of 41.8 ms and 61 ms, respectively, vs 14.4 ms in controls) with more than 50% of carriers having increases in QTc >30 ms. Furthermore, we identified three carriers of rare population-specific variations who experienced clinically relevant delayed ventricular repolarization. Combined, our results map population-scale genetic variability of KCNH2 and identify genetic biomarkers for piperaquine-induced QT prolongation that could help to flag at-risk patients and optimize efficacy and adherence to antimalarial therapy.

3.
Circulation ; 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38314588

RESUMO

BACKGROUND: Pulmonary hypertension (PH) is a progressive cardiopulmonary disease with a high mortality rate. Although growing evidence has revealed the importance of dysregulated energetic metabolism in the pathogenesis of PH, the underlying cellular and molecular mechanisms are not fully understood. In this study, we focused on ME1 (malic enzyme 1), a key enzyme linking glycolysis to the tricarboxylic acid cycle. We aimed to determine the role and mechanistic action of ME1 in PH. METHODS: Global and endothelial-specific ME1 knockout mice were used to investigate the role of ME1 in hypoxia- and SU5416/hypoxia (SuHx)-induced PH. Small hairpin RNA and ME1 enzymatic inhibitor (ME1*) were used to study the mechanism of ME1 in pulmonary artery endothelial cells. Downstream key metabolic pathways and mediators of ME1 were identified by metabolomics analysis in vivo and ME1-mediated energetic alterations were examined by Seahorse metabolic analysis in vitro. The pharmacological effect of ME1* on PH treatment was evaluated in PH animal models induced by SuHx. RESULTS: We found that ME1 protein level and enzymatic activity were highly elevated in lung tissues of patients and mice with PH, primarily in vascular endothelial cells. Global knockout of ME1 protected mice from developing hypoxia- or SuHx-induced PH. Endothelial-specific ME1 deletion similarly attenuated pulmonary vascular remodeling and PH development in mice, suggesting a critical role of endothelial ME1 in PH. Mechanistic studies revealed that ME1 inhibition promoted downstream adenosine production and activated A2AR-mediated adenosine signaling, which leads to an increase in nitric oxide generation and a decrease in proinflammatory molecule expression in endothelial cells. ME1 inhibition activated adenosine production in an ATP-dependent manner through regulating malate-aspartate NADH (nicotinamide adenine dinucleotide plus hydrogen) shuttle and thereby balancing oxidative phosphorylation and glycolysis. Pharmacological inactivation of ME1 attenuated the progression of PH in both preventive and therapeutic settings by promoting adenosine production in vivo. CONCLUSIONS: Our findings indicate that ME1 upregulation in endothelial cells plays a causative role in PH development by negatively regulating adenosine production and subsequently dysregulating endothelial functions. Our findings also suggest that ME1 may represent as a novel pharmacological target for upregulating protective adenosine signaling in PH therapy.

4.
Expert Rev Clin Pharmacol ; 17(3): 213-223, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38247431

RESUMO

INTRODUCTION: The technological advances of sequencing methods during the past 20 years have fuelled the generation of large amounts of sequencing data that comprise common variations, as well as millions of rare and personal variants that would not be identified by conventional genotyping. While comprehensive sequencing is technically feasible, its clinical utility for guiding personalized treatment decisions remains controversial. AREAS COVERED: We discuss the opportunities and challenges of comprehensive sequencing compared to targeted genotyping for pharmacogenomic applications. Current pharmacogenomic sequencing panels are heterogeneous and clinical actionability of the included genes is not a major focus. We provide a current overview and critical discussion of how current studies utilize sequencing data either retrospectively from biobanks, databases or repurposed diagnostic sequencing, or prospectively using pharmacogenomic sequencing. EXPERT OPINION: While sequencing-based pharmacogenomics has provided important insights into genetic variations underlying the safety and efficacy of a multitude pharmacological treatments, important hurdles for the clinical implementation of pharmacogenomic sequencing remain. We identify gaps in the interpretation of pharmacogenetic variants, technical challenges pertaining to complex loci and variant phasing, as well as unclear cost-effectiveness and incomplete reimbursement. It is critical to address these challenges in order to realize the promising prospects of pharmacogenomic sequencing.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Farmacogenética , Humanos , Farmacogenética/métodos , Medicina de Precisão/métodos , Estudos Retrospectivos , Sequenciamento de Nucleotídeos em Larga Escala/métodos
5.
Vascul Pharmacol ; 154: 107278, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38262506

RESUMO

Aortic aneurysm (AA) and dissection (AD) are aortic diseases caused primarily by medial layer degeneration and perivascular inflammation. They are lethal when the rupture happens. Vascular smooth muscle cells (SMCs) play critical roles in the pathogenesis of medial degeneration, characterized by SMC loss and elastin fiber degradation. Many molecular pathways, including cyclic nucleotide signaling, have been reported in regulating vascular SMC functions, matrix remodeling, and vascular structure integrity. Intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are second messengers that mediate intracellular signaling transduction through activating effectors, such as protein kinase A (PKA) and PKG, respectively. cAMP and cGMP are synthesized by adenylyl cyclase (AC) and guanylyl cyclase (GC), respectively, and degraded by cyclic nucleotide phosphodiesterases (PDEs). In this review, we will discuss the roles and mechanisms of cAMP/cGMP signaling and PDEs in AA/AD formation and progression and the potential of PDE inhibitors in AA/AD, whether they are beneficial or detrimental. We also performed database analysis and summarized the results showing PDEs with significant expression changes under AA/AD, which should provide rationales for future research on PDEs in AA/AD.


Assuntos
Aneurisma Aórtico , Dietilestilbestrol/análogos & derivados , Guanosina Monofosfato , Humanos , Monofosfato de Adenosina , Adenosina , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Nucleotídeos Cíclicos
6.
Annu Rev Pharmacol Toxicol ; 64: 33-51, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-37506333

RESUMO

Interindividual variability in genes encoding drug-metabolizing enzymes, transporters, receptors, and human leukocyte antigens has a major impact on a patient's response to drugs with regard to efficacy and safety. Enabled by both technological and conceptual advances, the field of pharmacogenomics is developing rapidly. Major progress in omics profiling methods has enabled novel genotypic and phenotypic characterization of patients and biobanks. These developments are paralleled by advances in machine learning, which have allowed us to parse the immense wealth of data and establish novel genetic markers and polygenic models for drug selection and dosing. Pharmacogenomics has recently become more widespread in clinical practice to personalize treatment and to develop new drugs tailored to specific patient populations. In this review, we provide an overview of the latest developments in the field and discuss the way forward, including how to address the missing heritability, develop novel polygenic models, and further improve the clinical implementation of pharmacogenomics.


Assuntos
Proteínas de Membrana Transportadoras , Farmacogenética , Humanos , Tecnologia
7.
Br J Clin Pharmacol ; 2023 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-37759374

RESUMO

The rapid development of sequencing technologies during the past 20 years has provided a variety of methods and tools to interrogate human genomic variations at the population level. Pharmacogenes are well known to be highly polymorphic and a plethora of pharmacogenomic variants has been identified in population sequencing data. However, so far only a small number of these variants have been functionally characterized regarding their impact on drug efficacy and toxicity and the significance of the vast majority remains unknown. It is therefore of high importance to develop tools and frameworks to accurately infer the effects of pharmacogenomic variants and, eventually, aggregate the effect of individual variations into personalized drug response predictions. To address this challenge, we here first describe the technological advances, including sequencing methods and accompanying bioinformatic processing pipelines that have enabled reliable variant identification. Subsequently, we highlight advances in computational algorithms for pharmacogenomic variant interpretation and discuss the added value of emerging strategies, such as machine learning and the integrative use of omics techniques that have the potential to further contribute to the refinement of personalized pharmacological response predictions. Lastly, we provide an overview of experimental and clinical approaches to validate in silico predictions. We conclude that the iterative feedback between computational predictions and experimental validations is likely to rapidly improve the accuracy of pharmacogenomic prediction models, which might soon allow for an incorporation of the entire pharmacogenetic profile into personalized response predictions.

8.
NPJ Genom Med ; 8(1): 24, 2023 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-37684227

RESUMO

Genetic variants in drug targets and genes encoding factors involved in drug absorption, distribution, metabolism and excretion (ADME) can have pronounced impacts on drug pharmacokinetics, response, and toxicity. While the landscape of genetic variability at the level of single nucleotide variants (SNVs) has been extensively studied in these pharmacogenetic loci, their structural variation is only poorly understood. Thus, we systematically analyzed the genetic structural variability across 908 pharmacogenes (344 ADME genes and 564 drug targets) based on publicly available whole genome sequencing data from 10,847 unrelated individuals. Overall, we extracted 14,984 distinct structural variants (SVs) ranging in size from 50 bp to 106 Mb. Each individual harbored on average 10.3 and 1.5 SVs with putative functional effects that affected the coding regions of ADME genes and drug targets, respectively. In addition, by cross-referencing pharmacogenomic SVs with experimentally determined binding data of 224 transcription factors across 130 cell types, we identified 1276 non-coding SVs that overlapped with gene regulatory elements. Based on these data, we estimate that non-coding structural variants account for 22% of the genetically encoded pharmacogenomic variability. Combined, these analyses provide the first comprehensive map of structural variability across pharmacogenes, derive estimates for the functional impact of non-coding SVs and incentivize the incorporation of structural genomic data into personalized drug response predictions.

9.
Nat Methods ; 20(10): 1593-1604, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37770711

RESUMO

Recent proliferation and integration of tissue-clearing methods and light-sheet fluorescence microscopy has created new opportunities to achieve mesoscale three-dimensional whole-brain connectivity mapping with exceptionally high throughput. With the rapid generation of large, high-quality imaging datasets, downstream analysis is becoming the major technical bottleneck for mesoscale connectomics. Current computational solutions are labor intensive with limited applications because of the exhaustive manual annotation and heavily customized training. Meanwhile, whole-brain data analysis always requires combining multiple packages and secondary development by users. To address these challenges, we developed D-LMBmap, an end-to-end package providing an integrated workflow containing three modules based on deep-learning algorithms for whole-brain connectivity mapping: axon segmentation, brain region segmentation and whole-brain registration. D-LMBmap does not require manual annotation for axon segmentation and achieves quantitative analysis of whole-brain projectome in a single workflow with superior accuracy for multiple cell types in all of the modalities tested.


Assuntos
Aprendizado Profundo , Processamento de Imagem Assistida por Computador , Processamento de Imagem Assistida por Computador/métodos , Encéfalo , Algoritmos , Mapeamento Encefálico
10.
Sci Adv ; 9(25): eadg5332, 2023 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-37343106

RESUMO

One-step conversion of low-purity polyolefins to value-added products without pretreatments represents a great opportunity for chemical recycling of waste plastics. However, additives, contaminants, and heteroatom-linking polymers tend to be incompatible with catalysts that break down polyolefins. Here, we disclose a reusable, noble metal-free and impurity-tolerant bifunctional catalyst, MoSx-Hbeta, for hydroconversion of polyolefins into branched liquid alkanes under mild conditions. The catalyst works for a wide scope of polyolefins, including different kinds of high-molecular weight polyolefins, polyolefins mixed with various heteroatom-linking polymers, contaminated polyolefins, and postconsumer polyolefins with/without cleaning under 250°C and 20 to 30 bar H2 in 6 to 12 hours. A 96% yield of small alkanes was successfully achieved even at a temperature as low as 180°C. These results demonstrate the great potentials of hydroconversion in practical use of waste plastics as a largely untapped carbon feedstock.

11.
IEEE Trans Med Imaging ; 42(9): 2666-2677, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37030826

RESUMO

Recognition and quantitative analytics of histopathological cells are the golden standard for diagnosing multiple cancers. Despite recent advances in deep learning techniques that have been widely investigated for the automated segmentation of various types of histopathological cells, the heavy dependency on specific histopathological image types with sufficient supervised annotations, as well as the limited access to clinical data in hospitals, still pose significant challenges in the application of computer-aided diagnosis in pathology. In this paper, we focus on the model generalization of cell segmentation towards cross-tissue histopathological images. Remarkably, a novel target-specific finetuning-based self-supervised domain adaptation framework is proposed to transfer the cell segmentation model to unlabeled target datasets, without access to source datasets and annotations. When performed on the target unlabeled histopathological image set, the proposed method only needs to tune very few parameters of the pre-trained model in a self-supervised manner. Considering the morphological properties of pathological cells, we introduce two constraint terms at both local and global levels into this framework to access more reliable predictions. The proposed cross-domain framework is validated on three different types of histopathological tissues, showing promising performance in self-supervised cell segmentation. Additionally, the whole framework can be further applied to clinical tools in pathology without accessing the original training image data. The code and dataset are released at: https://github.com/NeuronXJTU/SFDA-CellSeg.


Assuntos
Diagnóstico por Computador , Processamento de Imagem Assistida por Computador , Aprendizado de Máquina Supervisionado
12.
Hum Genomics ; 17(1): 15, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36855170

RESUMO

BACKGROUND: Genetic variability in the cytochrome P450 CYP2C9 constitutes an important predictor for efficacy and safety of various commonly prescribed drugs, including coumarin anticoagulants, phenytoin and multiple non-steroidal anti-inflammatory drugs (NSAIDs). A global map of CYP2C9 variability and its inferred functional consequences has been lacking. RESULTS: Frequencies of eight functionally relevant CYP2C9 alleles (*2, *3, *5, *6, *8, *11, *13 and *14) were analyzed. In total, 108 original articles were identified that included genotype data from a total of 81,662 unrelated individuals across 70 countries and 40 unique ethnic groups. The results revealed that CYP2C9*2 was most abundant in Europe and the Middle East, whereas CYP2C9*3 was the main reason for reduced CYP2C9 activity across South Asia. Our data show extensive variation within superpopulations with up to tenfold differences between geographically adjacent populations in Malaysia, Thailand and Vietnam. Translation of genetic CYP2C9 variability into functional consequences indicates that up to 40% of patients in Southern Europe and the Middle East might benefit from warfarin and phenytoin dose reductions, while 3% of patients in Southern Europe and Israel are recommended to reduce starting doses of NSAIDs. CONCLUSIONS: This study provides a comprehensive map of the genetic and functional variability of CYP2C9 with high ethnogeographic resolution. The presented data can serve as a useful resource for CYP2C9 allele and phenotype frequencies and might guide the optimization of genotyping strategies, particularly for indigenous and founder populations with distinct genetic profiles.


Assuntos
Anti-Inflamatórios não Esteroides , Anticoagulantes , Citocromo P-450 CYP2C9 , Fenitoína , Alelos , Ásia Meridional , Citocromo P-450 CYP2C9/genética , Humanos , Genética Populacional
13.
Clin Pharmacol Ther ; 113(3): 712-723, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36629403

RESUMO

The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4-hydroxy-tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6). Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross-ancestry genome-wide association study with well-characterized patients of European, Middle-Eastern, and Asian descent (n = 497) to identify genetic factors impacting active and parent metabolite formation. Genome-wide significant variants were functionally evaluated in an independent liver cohort (n = 149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (n = 287, n = 189). Within a single 1-megabase (Mb) region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and metabolic ratio (MR) endoxifen/N-desmethyltamoxifen (minimal P = 5.4E-35 and 2.5E-65, respectively). Previously suggested other loci were not confirmed. Functional analyses revealed 66% of associated, mostly intergenic variants to be significantly correlated with hepatic CYP2D6 activity or expression (ρ = 0.35 to -0.52), and six hotspot regions in the extended 22q13 locus impacting gene regulatory function. Machine learning models based on hotspot variants (n = 12) plus CYP2D6 activity score (AS) increased the explained variability (~ 9%) compared with AS alone, explaining up to 49% (median R2 ) and 72% of the variability in endoxifen and MR endoxifen/N-desmethyltamoxifen, respectively. Our findings suggest that the extended CYP2D6 locus at 22q13 is the principal genetic determinant of endoxifen plasma concentration. Long-distance haplotypes connecting CYP2D6 with adjacent regulatory sites and nongenetic factors may account for the unexplained portion of variability.


Assuntos
Neoplasias da Mama , Citocromo P-450 CYP2D6 , Humanos , Feminino , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Estudo de Associação Genômica Ampla , Antineoplásicos Hormonais/uso terapêutico , Tamoxifeno , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Genótipo
14.
Handb Exp Pharmacol ; 280: 237-260, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35792943

RESUMO

Over the last decade, next-generation sequencing (NGS) methods have become increasingly used in various areas of human genomics. In routine clinical care, their use is already implemented in oncology to profile the mutational landscape of a tumor, as well as in rare disease diagnostics. However, its utilization in pharmacogenomics is largely lacking behind. Recent population-scale genome data has revealed that human pharmacogenes carry a plethora of rare genetic variations that are not interrogated by conventional array-based profiling methods and it is estimated that these variants could explain around 30% of the genetically encoded functional pharmacogenetic variability.To interpret the impact of such variants on drug response a multitude of computational tools have been developed, but, while there have been major advancements, it remains to be shown whether their accuracy is sufficient to improve personalized pharmacogenetic recommendations in robust trials. In addition, conventional short-read sequencing methods face difficulties in the interrogation of complex pharmacogenes and high NGS test costs require stringent evaluations of cost-effectiveness to decide about reimbursement by national healthcare programs. Here, we illustrate current challenges and discuss future directions toward the clinical implementation of NGS to inform genotype-guided decision-making.


Assuntos
Neoplasias , Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Farmacogenética/métodos , Neoplasias/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos
15.
Am J Respir Cell Mol Biol ; 68(2): 213-227, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36227848

RESUMO

Progressive fibrosing interstitial lung diseases (PF-ILDs) result in high mortality and lack effective therapies. The pathogenesis of PF-ILDs involves macrophages driving inflammation and irreversible fibrosis. Fc-γ receptors (FcγRs) regulate macrophages and inflammation, but their roles in PF-ILDs remain unclear. We characterized the expression of FcγRs and found upregulated FcγRIIB in human and mouse lungs after exposure to silica. FcγRIIB deficiency aggravated lung dysfunction, inflammation, and fibrosis in silica-exposed mice. Using single-cell transcriptomics and in vitro experiments, FcγRIIB was found in alveolar macrophages, where it regulated the expression of fibrosis-related genes Spp1 and Ctss. In mice with macrophage-specific overexpression of FcγRIIB and in mice treated with adenovirus by intratracheal instillation to upregulate FcγRIIB, silica-induced functional and histological changes were ameliorated. Our data from three genetic models and a therapeutic model suggest that FcγRIIB plays a protective role that can be enhanced by adenoviral overexpression, representing a potential therapeutic strategy for PF-ILDs.


Assuntos
Doenças Pulmonares Intersticiais , Pneumonia , Humanos , Animais , Camundongos , Adenoviridae/genética , Adenoviridae/metabolismo , Pneumonia/genética , Inflamação/genética , Inflamação/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Fibrose , Dióxido de Silício
16.
Eur Respir J ; 61(3)2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36423907

RESUMO

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease featuring pulmonary vessel remodelling and perivascular inflammation. The effect, if any, of eosinophils (EOS) on the development of PH remains unclear. METHODS: EOS infiltration and chemotaxis were investigated in peripheral blood and lung tissues from pulmonary arterial hypertension (PAH) patients without allergic history and from sugen/hypoxia-induced PH mice. The role of EOS deficiency in PH development was investigated using GATA1-deletion (ΔdblGATA) mice and anti-interleukin 5 antibody-treated mice and rats. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was conducted to identify the critical oxylipin molecule(s) produced by EOS. Culture supernatants and lysates of EOS were collected to explore the mechanisms in co-culture cell experiments. RESULTS: There was a lower percentage of EOS in peripheral blood but higher infiltration in lung tissues from PAH patients and PH mice. PAH/PH lungs showed increased EOS-related chemokine expression, mainly C-C motif chemokine ligand 11 derived from adventitial fibroblasts. EOS deficiency aggravated PH in rodents, accompanied by increased neutrophil and monocyte/macrophage infiltration. EOS highly expressed arachidonate 15-lipoxygenase (ALOX15). 14-hydroxy docosahexaenoic acid (14-HDHA) and 17-HDHA were critical downstream oxylipins produced by EOS, which showed anti-inflammatory effects on recruitment of neutrophils and monocytes/macrophages through N-formyl peptide receptor 2. They also repressed pulmonary artery smooth muscle cell (PASMC) proliferation by activating peroxisome proliferator-activated receptor γ and blunting Stat3 phosphorylation. CONCLUSIONS: In PH development without external stimuli, peripheral blood exhibits a low EOS level. EOS play a protective role by suppressing perivascular inflammation and maintaining PASMC homeostasis via 14/17-HDHA.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Ratos , Camundongos , Animais , Eosinófilos/metabolismo , Espectrometria de Massas em Tandem , Camundongos Knockout , Hipertensão Arterial Pulmonar/complicações , Artéria Pulmonar , Hipertensão Pulmonar Primária Familiar/metabolismo , Inflamação/metabolismo , Miócitos de Músculo Liso/metabolismo , Proliferação de Células , Células Cultivadas , Hipóxia/metabolismo
17.
iScience ; 25(12): 105506, 2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36425762

RESUMO

Deep learning-based cell segmentation is increasingly utilized in cell biology due to the massive accumulation of large-scale datasets and excellent progress in model architecture and instance representation. However, the development of specialist algorithms has long been hampered by a paucity of annotated training data, whereas the performance of generalist algorithms is limited without experiment-specific calibration. Here, we present Scellseg, an adaptive pipeline that utilizes a style-aware pre-trained model coupled to a contrastive fine-tuning strategy that also learns from unlabeled data. Scellseg achieves state-of-the-art transferability in average precision and Aggregated Jaccard Index on disparate datasets containing microscopy images at three biological levels, from organelle, cell to organism. Interestingly, when fine-tuning Scellseg, we show that performance plateaued after approximately eight images, implying that a specialist model can be obtained with few manual efforts. For convenient dissemination, we develop a graphical user interface that allows biologists to easily specialize their self-adaptive segmentation model.

18.
Pharmacogenomics J ; 22(5-6): 284-293, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36068297

RESUMO

Genes encoding cytochrome P450 enzymes (CYPs) are extremely polymorphic and multiple CYP variants constitute clinically relevant biomarkers for the guidance of drug selection and dosing. We previously reported the distribution of the most relevant CYP alleles using population-scale sequencing data. Here, we update these findings by making use of the increasing wealth of data, incorporating whole exome and whole genome sequencing data from 141,614 unrelated individuals across 12 human populations. We furthermore extend our previous studies by systematically considering also uncharacterized rare alleles and reveal that they contribute between 1.5% and 17.5% to the overall genetically encoded functional variability. By using established guidelines, we aggregate and translate the available sequencing data into population-specific patterns of metabolizer phenotypes. Combined, the presented data refine the worldwide landscape of ethnogeographic variability in CYP genes and aspire to provide a relevant resource for the optimization of population-specific genotyping strategies and precision public health.


Assuntos
Sistema Enzimático do Citocromo P-450 , Exoma , Humanos , Análise de Sequência de DNA , Sistema Enzimático do Citocromo P-450/genética , Alelos , Sequenciamento Completo do Genoma
19.
Biomed Pharmacother ; 154: 113644, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36063648

RESUMO

Preemptive targeted pharmacogenetic testing of candidate variations in DPYD is currently being used to limit toxicity associated with fluoropyrimidines. The use of innovative next generation sequencing (NGS) approaches could unveil additional rare (minor allele frequency <1%) genetic risk variants. However, their predictive value and management in clinical practice are still controversial, at least partly due to the challenges associated with functional analyses of rare variants. The aim of this study was to define the predictive power of rare DPYD variants burden on the risk of severe fluoropyrimidine-related toxicity. The DPYD coding sequence and untranslated regions were analyzed by NGS in 120 patients developing grade 3-5 (NCI-CTC vs3.0) fluoropyrimidine-related toxicity and 104 matched controls (no-toxicity). The functional impact of rare variants was assessed using two different in silico predictive tools (i.e., Predict2SNP and ADME Prediction Framework) and structural modeling. Plasma concentrations of uracil (U) and dihydrouracil (UH2) were quantified in carriers of the novel variants. Here, we demonstrate that the burden of rare variants was significantly higher in patients with toxicity compared to controls (p = 0.007, Mann-Whitney test). Carriers of at least one rare missense DPYD variant had a 16-fold increased risk in the first cycle and an 11-fold increased risk during the entire course of chemotherapy of developing a severe adverse event compared to controls (p = 0.013 and p = 0.0250, respectively by multinomial regression model). Quantification of plasmatic U/UH2 metabolites and in silico visualization of the encoded protein were consistent with the predicted functional effect for the novel variations. Analysis and consideration of rare variants by DPYD-sequencing could improve prevention of severe toxicity of fluoropyrimidines and improve patients' quality of life.


Assuntos
Di-Hidrouracila Desidrogenase (NADP) , Qualidade de Vida , Antimetabólitos , Antimetabólitos Antineoplásicos/efeitos adversos , Di-Hidrouracila Desidrogenase (NADP)/genética , Fluoruracila/efeitos adversos , Frequência do Gene , Genótipo , Humanos
20.
Soft Matter ; 18(35): 6618-6628, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36000279

RESUMO

The ubiquitous nature of microorganisms, especially of biofilm-forming bacteria, makes biofouling a prevalent challenge in many settings, including medical and industrial environments immersed in liquid and subjected to shear forces. Recent studies have shown that zwitterionic groups are effective in suppressing bacteria and protein adhesion as well as biofilm growth. However, the effect of zwitterionic groups on the removal of surface-bound bacteria has not been extensively studied. Here we present a microfluidic approach to evaluate the effectiveness in facilitating bacteria detachment by shear of an antifouling surface treatment using (3-(dimethyl;(3-trimethoxysilyl)propyl)ammonia propane-1-sulfonate), a sulfobetaine silane (SBS). Control studies show that SBS-functionalized surfaces greatly increase protein (bovine serum albumin) removal upon rinsing. On the same surfaces, enhanced bacteria (Pseudomonas aeruginosa) removal is observed under shear. To quantify this enhancement a microfluidic shear device is employed to investigate how SBS-functionalized surfaces promote bacteria detachment under shear. By using a microfluidic channel with five shear zones, we compare the removal of bacteria from zwitterionic and glass surfaces under different shear rates. At times of 15 min, 30 min, and 60 min, bacteria adhesion on SBS-functionalized surfaces is reduced relative to the control surface (glass) under quiescent conditions. However, surface-associated bacteria on the SBS-functionalized glass and control show similar percentages of live cells, suggesting minimal intrinsic biocidal effect from the SBS-functionalized surface. Notably, when exposed to shear rates ranging from 104 to 105 s-1, significantly fewer bacteria remain on the SBS-functionalized surfaces. These results demonstrate the potential of zwitterionic sulfobetaine as effective antifouling coatings that facilitate the removal of bacteria under shear.


Assuntos
Aderência Bacteriana , Incrustação Biológica , Bactérias , Betaína/análogos & derivados , Betaína/química , Betaína/farmacologia , Incrustação Biológica/prevenção & controle , Propriedades de Superfície
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