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1.
Proc Natl Acad Sci U S A ; 120(6): e2216906120, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36730193

RESUMO

The human estrogen receptor α (hERα) is involved in the regulation of growth, development, and tissue homeostasis. Agonists that bind to the receptor's ligand-binding domain (LBD) lead to recruitment of coactivators and the enhancement of gene expression. In contrast, antagonists bind to the LBD and block the binding of coactivators thus decreasing gene expressions. In this work, we carry out simulations using the AWSEM (Associative memory, Water mediated, Structure and Energy Model)-Suite force field along with the 3SPN.2C force field for DNA to predict the structure of hERα and study its dynamics when binding to DNA and coactivators. Using simulations of antagonist-bound hERα and agonist-bound hERα by themselves and also along with bound DNA and coactivators, principal component analyses and free energy landscape analyses capture the pathway of domain-domain communication for agonist-bound hERα. This communication is mediated through the hinge domains that are ordinarily intrinsically disordered. These disordered segments manipulate the hinge domains much like the strings of a marionette as they twist in different ways when antagonists or agonists are bound to the ligand-binding domain.


Assuntos
Receptor alfa de Estrogênio , Receptores de Estrogênio , Humanos , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Ligantes , Sítios de Ligação , DNA/metabolismo , Comunicação , Ligação Proteica
2.
Bioinformatics ; 40(4)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38597887

RESUMO

MOTIVATION: Discovering disease causative pathogens, particularly viruses without reference genomes, poses a technical challenge as they are often unidentifiable through sequence alignment. Machine learning prediction of patient high-throughput sequences unmappable to human and pathogen genomes may reveal sequences originating from uncharacterized viruses. Currently, there is a lack of software specifically designed for accurately predicting such viral sequences in human data. RESULTS: We developed a fast XGBoost method and software VirusPredictor leveraging an in-house viral genome database. Our two-step XGBoost models first classify each query sequence into one of three groups: infectious virus, endogenous retrovirus (ERV) or non-ERV human. The prediction accuracies increased as the sequences became longer, i.e. 0.76, 0.93, and 0.98 for 150-350 (Illumina short reads), 850-950 (Sanger sequencing data), and 2000-5000 bp sequences, respectively. Then, sequences predicted to be from infectious viruses are further classified into one of six virus taxonomic subgroups, and the accuracies increased from 0.92 to >0.98 when query sequences increased from 150-350 to >850 bp. The results suggest that Illumina short reads should be de novo assembled into contigs (e.g. ∼1000 bp or longer) before prediction whenever possible. We applied VirusPredictor to multiple real genomic and metagenomic datasets and obtained high accuracies. VirusPredictor, a user-friendly open-source Python software, is useful for predicting the origins of patients' unmappable sequences. This study is the first to classify ERVs in infectious viral sequence prediction. This is also the first study combining virus sub-group predictions. AVAILABILITY AND IMPLEMENTATION: www.dllab.org/software/VirusPredictor.html.


Assuntos
Genoma Viral , Software , Humanos , Vírus/genética , Análise de Sequência de DNA/métodos , Alinhamento de Sequência/métodos , Aprendizado de Máquina
3.
Circ Res ; 133(4): 333-349, 2023 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-37462027

RESUMO

BACKGROUND: Lymphatic vessels are responsible for tissue drainage, and their malfunction is associated with chronic diseases. Lymph uptake occurs via specialized open cell-cell junctions between capillary lymphatic endothelial cells (LECs), whereas closed junctions in collecting LECs prevent lymph leakage. LEC junctions are known to dynamically remodel in development and disease, but how lymphatic permeability is regulated remains poorly understood. METHODS: We used various genetically engineered mouse models in combination with cellular, biochemical, and molecular biology approaches to elucidate the signaling pathways regulating junction morphology and function in lymphatic capillaries. RESULTS: By studying the permeability of intestinal lacteal capillaries to lipoprotein particles known as chylomicrons, we show that ROCK (Rho-associated kinase)-dependent cytoskeletal contractility is a fundamental mechanism of LEC permeability regulation. We show that chylomicron-derived lipids trigger neonatal lacteal junction opening via ROCK-dependent contraction of junction-anchored stress fibers. LEC-specific ROCK deletion abolished junction opening and plasma lipid uptake. Chylomicrons additionally inhibited VEGF (vascular endothelial growth factor)-A signaling. We show that VEGF-A antagonizes LEC junction opening via VEGFR (VEGF receptor) 2 and VEGFR3-dependent PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) activation of the small GTPase RAC1 (Rac family small GTPase 1), thereby restricting RhoA (Ras homolog family member A)/ROCK-mediated cytoskeleton contraction. CONCLUSIONS: Our results reveal that antagonistic inputs into ROCK-dependent cytoskeleton contractions regulate the interconversion of lymphatic junctions in the intestine and in other tissues, providing a tunable mechanism to control the lymphatic barrier.


Assuntos
Vasos Linfáticos , Proteínas Monoméricas de Ligação ao GTP , Camundongos , Animais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Quilomícrons/metabolismo , Vasos Linfáticos/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Permeabilidade Capilar
4.
Proc Natl Acad Sci U S A ; 119(32): e2202239119, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35914145

RESUMO

Bacteriophage T7 gp4 helicase has served as a model system for understanding mechanisms of hexameric replicative helicase translocation. The mechanistic basis of how nucleoside 5'-triphosphate hydrolysis and translocation of gp4 helicase are coupled is not fully resolved. Here, we used a thermodynamically benchmarked coarse-grained protein force field, Associative memory, Water mediated, Structure and Energy Model (AWSEM), with the single-stranded DNA (ssDNA) force field 3SPN.2C to investigate gp4 translocation. We found that the adenosine 5'-triphosphate (ATP) at the subunit interface stabilizes the subunit-subunit interaction and inhibits subunit translocation. Hydrolysis of ATP to adenosine 5'-diphosphate enables the translocation of one subunit, and new ATP binding at the new subunit interface finalizes the subunit translocation. The LoopD2 and the N-terminal primase domain provide transient protein-protein and protein-DNA interactions that facilitate the large-scale subunit movement. The simulations of gp4 helicase both validate our coarse-grained protein-ssDNA force field and elucidate the molecular basis of replicative helicase translocation.


Assuntos
Bacteriófago T7 , DNA Helicases , DNA de Cadeia Simples , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Bacteriófago T7/enzimologia , Bacteriófago T7/genética , DNA Helicases/metabolismo , DNA Primase/metabolismo , Conformação Proteica
5.
Curr Opin Neurol ; 37(4): 369-380, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38804205

RESUMO

PURPOSE OF REVIEW: Human brain parcellation based on functional magnetic resonance imaging (fMRI) plays an essential role in neuroscience research. By segmenting vast and intricate fMRI data into functionally similar units, researchers can better decipher the brain's structure in both healthy and diseased states. This article reviews current methodologies and ideas in this field, while also outlining the obstacles and directions for future research. RECENT FINDINGS: Traditional brain parcellation techniques, which often rely on cytoarchitectonic criteria, overlook the functional and temporal information accessible through fMRI. The adoption of machine learning techniques, notably deep learning, offers the potential to harness both spatial and temporal information for more nuanced brain segmentation. However, the search for a one-size-fits-all solution to brain segmentation is impractical, with the choice between group-level or individual-level models and the intended downstream analysis influencing the optimal parcellation strategy. Additionally, evaluating these models is complicated by our incomplete understanding of brain function and the absence of a definitive "ground truth". SUMMARY: While recent methodological advancements have significantly enhanced our grasp of the brain's spatial and temporal dynamics, challenges persist in advancing fMRI-based spatio-temporal representations. Future efforts will likely focus on refining model evaluation and selection as well as developing methods that offer clear interpretability for clinical usage, thereby facilitating further breakthroughs in our comprehension of the brain.


Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Processamento de Imagem Assistida por Computador/métodos
6.
Anal Chem ; 96(23): 9353-9361, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38810149

RESUMO

The retroperitoneal liposarcoma (RLPS) is a rare malignancy whose only curative therapy is surgical resection. However, well-differentiated liposarcomas (WDLPSs), one of its most common types, can hardly be distinguished from normal fat during operation without an effective margin assessment method, jeopardizing the prognosis severely with a high recurrence risk. Here, we combined dual label-free nonlinear optical modalities, stimulated Raman scattering (SRS) microscopy and second harmonic generation (SHG) microscopy, to image two predominant tissue biomolecules, lipids and collagen fibers, in 35 RLPSs and 34 normal fat samples collected from 35 patients. The produced dual-modal tissue images were used for RLPS diagnosis based on deep learning. Dramatically decreasing lipids and increasing collagen fibers during tumor progression were reflected. A ResNeXt101-based model achieved 94.7% overall accuracy and 0.987 mean area under the ROC curve (AUC) in differentiating among normal fat, WDLPSs, and dedifferentiated liposarcomas (DDLPSs). In particular, WDLPSs were detected with 94.1% precision and 84.6% sensitivity superior to existing methods. The ablation experiment showed that such performance was attributed to both SRS and SHG microscopies, which increased the sensitivity of recognizing WDLPS by 16.0 and 3.6%, respectively. Furthermore, we utilized this model on RLPS margins to identify the tumor infiltration. Our method holds great potential for accurate intraoperative liposarcoma detection.


Assuntos
Aprendizado Profundo , Lipossarcoma , Neoplasias Retroperitoneais , Humanos , Lipossarcoma/diagnóstico por imagem , Lipossarcoma/patologia , Lipossarcoma/diagnóstico , Neoplasias Retroperitoneais/diagnóstico por imagem , Neoplasias Retroperitoneais/patologia , Neoplasias Retroperitoneais/diagnóstico , Análise Espectral Raman/métodos , Microscopia/métodos , Microscopia de Geração do Segundo Harmônico
7.
Anal Chem ; 96(16): 6158-6169, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38602477

RESUMO

Raman spectroscopy has been widely used for label-free biomolecular analysis of cells and tissues for pathological diagnosis in vitro and in vivo. AI technology facilitates disease diagnosis based on Raman spectroscopy, including machine learning (PCA and SVM), manifold learning (UMAP), and deep learning (ResNet and AlexNet). However, it is not clear how to optimize the appropriate AI classification model for different types of Raman spectral data. Here, we selected five representative Raman spectral data sets, including endometrial carcinoma, hepatoma extracellular vesicles, bacteria, melanoma cell, diabetic skin, with different characteristics regarding sample size, spectral data size, Raman shift range, tissue sites, Kullback-Leibler (KL) divergence, and significant Raman shifts (i.e., wavenumbers with significant differences between groups), to explore the performance of different AI models (e.g., PCA-SVM, SVM, UMAP-SVM, ResNet or AlexNet). For data set of large spectral data size, Resnet performed better than PCA-SVM and UMAP. By building data characteristic-assisted AI classification model, we optimized the network parameters (e.g., principal components, activation function, and loss function) of AI model based on data size and KL divergence etc. The accuracy improved from 85.1 to 94.6% for endometrial carcinoma grading, from 77.1 to 90.7% for hepatoma extracellular vesicles detection, from 89.3 to 99.7% for melanoma cell detection, from 88.1 to 97.9% for bacterial identification, from 53.7 to 85.5% for diabetic skin screening, and mean time expense of 5 s.


Assuntos
Análise Espectral Raman , Análise Espectral Raman/métodos , Humanos , Feminino , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/química , Aprendizado de Máquina , Melanoma/patologia , Melanoma/diagnóstico , Melanoma/classificação , Vesículas Extracelulares/química , Máquina de Vetores de Suporte , Bactérias/classificação , Bactérias/isolamento & purificação , Inteligência Artificial
8.
Cytokine ; 173: 156436, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37979214

RESUMO

Failure of bone healing after fracture often results in nonunion, but the underlying mechanism of nonunion pathogenesis is poorly understood. Herein, we provide evidence to clarify that the inflammatory microenvironment of atrophic nonunion (AN) mice suppresses the expression levels of DNA methyltransferases 2 (DNMT2) and 3A (DNMT3a), preventing the methylation of CpG islands on the promoters of C-terminal binding protein 1/2 (CtBP1/2) and resulting in their overexpression. Increased CtBP1/2 acts as transcriptional corepressors that, along with histone acetyltransferase p300 and Runt-related transcription factor 2 (Runx2), suppress the expression levels of six genes involved in bone healing: BGLAP (bone gamma-carboxyglutamate protein), ALPL (alkaline phosphatase), SPP1 (secreted phosphoprotein 1), COL1A1 (collagen 1a1), IBSP (integrin binding sialoprotein), and MMP13 (matrix metallopeptidase 13). We also observe a similar phenomenon in osteoblast cells treated with proinflammatory cytokines or treated with a DNMT inhibitor (5-azacytidine). Forced expression of DNMT2/3a or blockage of CtBP1/2 with their inhibitors can reverse the expression levels of BGLAP/ALPL/SPP1/COL1A1/IBSP/MMP13 in the presence of proinflammatory cytokines. Administration of CtBP1/2 inhibitors in fractured mice can prevent the incidence of AN. Thus, we demonstrate that the downregulation of bone healing genes dependent on proinflammatory cytokines/DNMT2/3a/CtBP1/2-p300-Runx2 axis signaling plays a critical role in the pathogenesis of AN. Disruption of this signaling may represent a new therapeutic strategy to prevent AN incidence after bone fracture.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core , Citocinas , DNA (Citosina-5-)-Metiltransferases , DNA Metiltransferase 3A , Consolidação da Fratura , Animais , Camundongos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Citocinas/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Metiltransferases/metabolismo , Osteoblastos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Consolidação da Fratura/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA Metiltransferase 3A/genética , DNA Metiltransferase 3A/metabolismo
9.
Phys Rev Lett ; 132(15): 152502, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38682998

RESUMO

^{134}Xe is a candidate isotope for neutrinoless double beta decay (0νßß) search. In addition, the two-neutrino case (2νßß) allowed by the standard model of particle physics has not yet been observed. With the 656-kg natural xenon in the fiducial volume of the PandaX-4T detector, which contains 10.4% of ^{134}Xe, and its initial 94.9-day exposure, we have established the most stringent constraints on 2νßß and 0νßß of ^{134}Xe half-lives, with limits of 2.8×10^{22} yr and 3.0×10^{23} yr at 90% confidence level, respectively. The 2νßß (0νßß) limit surpasses the previously reported best result by a factor of 32 (2.7), highlighting the potential of large monolithic natural xenon detectors for double beta decay searches.

10.
J Org Chem ; 89(9): 6169-6179, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38654590

RESUMO

An efficient 2,2,6,6-tetramethylpiperidinooxy (TEMPO)-mediated hydroxyfluoroalkylation of arylamines with polyfluorinated alcohols via a radical-triggered C(sp2)-H/C(sp3)-H dehydrogenative cross-coupling process was developed. This transformation features simple operation, high atom economy, broad substrate compatibility, and excellent regioselectivity, leading to a series of hydroxyfluoroalkylated arylamine derivatives. Importantly, these synthetic products were further used to evaluate the antitumor activity in cancer cell lines by Cell Counting Kit-8 assay and the outcomes indicated that some compounds show a potent antiproliferative effect.

11.
Environ Sci Technol ; 58(14): 6258-6273, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38450439

RESUMO

Contamination of small-sized plastics is recognized as a factor of global change. Nanoplastics (NPs) can readily enter organisms and pose significant ecological risks. Arbuscular mycorrhizal (AM) fungi are the most ubiquitous and impactful plant symbiotic fungi, regulating essential ecological functions. Here, we first found that an AM fungus, Rhizophagus irregularis, increased lettuce shoot biomass by 25-100% when exposed to positively and negatively charged NPs vs control, although it did not increase that grown without NPs. The stress alleviation was attributed to the upregulation of gene expressions involving phytohormone signaling, cell wall metabolism, and oxidant scavenging. Using a root organ-fungus axenic growth system treated with fluorescence-labeled NPs, we subsequently revealed that the hyphae captured NPs and further delivered them to roots. NPs were observed at the hyphal cell walls, membranes, and spore walls. NPs mediated by the hyphae were localized at the root epidermis, cortex, and stele. Hyphal exudates aggregated positively charged NPs, thereby reducing their uptake due to NP aggregate formation (up to 5000 nm). This work demonstrates the critical roles of AM fungus in regulating NP behaviors and provides a potential strategy for NP risk mitigation in terrestrial ecosystems. Consequent NP-induced ecological impacts due to the affected AM fungi require further attention.


Assuntos
Micorrizas , Micorrizas/metabolismo , Microplásticos , Raízes de Plantas/metabolismo , Raízes de Plantas/microbiologia , Hifas , Ecossistema , Expressão Gênica
12.
Exp Cell Res ; 432(1): 113765, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37696386

RESUMO

Atrophic nonunion (AN) is a complex and poorly understood pathological condition resulting from impaired fracture healing. Advanced glycation end products (AGEs) have been implicated in the pathogenesis of several bone disorders, including osteoporosis and osteoarthritis. However, the role of AGEs in the development of AN remains unclear. This study found that mice fed a high-AGE diet had a higher incidence of atrophic nonunion (AN) compared to mice fed a normal diet following tibial fractures. AGEs induced two C-terminal binding proteins (CtBPs), CtBP1 and CtBP2, which were necessary for the development of AN in response to AGE accumulation. Feeding a high-AGE diet after fracture surgery in CtBP1/2-/- and RAGE-/- (receptor of AGE) mice did not result in a significant occurrence of AN. Molecular investigation revealed that CtBP1 and CtBP2 formed a heterodimer that was recruited by histone deacetylase 1 (HDAC1) and runt-related transcription factor 2 (Runx2) to assemble a complex. The CtBP1/2-HDAC1-Runx2 complex was responsible for the downregulation of two classes of bone development and differentiation genes, including bone morphogenic proteins (BMPs) and matrix metalloproteinases (MMPs). These findings demonstrate that AGE accumulation promotes the incidence of AN in a CtBP1/2-dependent manner, possibly by modulating genes related to bone development and fracture healing. These results provide new insights into the pathogenesis of AN and suggest new therapeutic targets for its prevention and treatment.


Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core , Fatores de Transcrição , Camundongos , Animais , Incidência , Produtos Finais de Glicação Avançada , Receptor para Produtos Finais de Glicação Avançada
13.
Artigo em Inglês | MEDLINE | ID: mdl-38551440

RESUMO

Objective: This is a meta-analysis comparing the efficacy of Tenofovir disoproxil fumarate (TDF) and Tenofovir alafenamide (TAF) in the treatment of chronic hepatitis B (CHB) so as to provide a reference for clinical medication. Methods: Relevant literature about TDF and TAF in the treatment of CHB was searched in the literature databases, and two researchers two researchers conducted independent cross-screening conducted independent cross-screening according to the inclusion and exclusion criteria. The authors, publication time, research subjects. The literature quality was evaluated by, and outcome measures of the selected literature were extracted. The literature quality was evaluated using the Jadad scale and Cochrane risk-of-bias tool. Meta-analysis was conducted using the RevMan 5.3 software. Results: After screening, 5 references were included, with a total of 5324 subjects. Patients who were treated with TDF and TAF were included in the TDF group and TAF group, respectively. The meta-analysis showed no significant difference in viral suppression between groups after 12 months of treatment (P > .05). Still, the alanine transaminase (ALT) normalization rate was higher, and the incidence of adverse reactions was lower in TAF group versus TDF group at 12 months after treatment (P < .05). Conclusions: Both TAF and TDF are effective in the treatment of CHB, but the former is preferred due to its higher safety profile.

14.
Ecotoxicol Environ Saf ; 269: 115745, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38029583

RESUMO

Magnetic graphene oxide nanocomposites (MGO NPs) have been widely studied in biomedical applications. However, their cytotoxicity and underlying mechanisms remain unclear. In this study, the biosafety of MGO NPs was investigated, and the mechanism involved in ferroptosis was further explored. MGO can produce cytotoxicity in ADSCs, which is dependent on their concentration. Ferroptosis was involved in MGO NP-induced ADSC survival inhibition by increasing total ROS and lipid ROS accumulation as well as regulating the expression levels of ferroptosis-related genes and proteins. GPX4 played a critical role in the MGO NP-induced ADSC ferroptosis process, and overexpressing GPX4 suppressed ferroptosis to increase cell survival. This study provides a theoretical basis for the biosafety management of MGO NPs used in the field of biomedical treatment.


Assuntos
Ferroptose , Grafite , Nanocompostos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Ferroptose/genética , Grafite/toxicidade , Óxido de Magnésio , Fenômenos Magnéticos , Nanocompostos/toxicidade , Espécies Reativas de Oxigênio , Animais , Ratos , Células-Tronco Mesenquimais/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo
15.
Int Wound J ; 21(4): e14621, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38531355

RESUMO

Hyperbaric oxygen therapy (HBOT) has been used in patients with diabetic foot ulcers (DFU) for many years, but its clinical efficacy is still controversial. Therefore, this study explored the efficacy of HBOT applied to DFU by means of meta-analysis. PubMed, Cochrane Library, Embase, CNKI and Wanfang databases were searched, from database inception to October 2023, and published randomised controlled trials (RCTs) of HBOT in DFU were collected. Two investigators independently screened the collected literature, extracted relevant data and assessed the quality of the literature. Review Manager 5.4 software was applied for data analysis. Twenty-nine RCTs with 1764 patients were included. According to the combined results, when compared with conventional treatment, HBOT significantly increased the complete healing rate of DFUs (46.76% vs. 24.46%, odds ratio [OR]: 2.83, 95% CI: 2.29-3.51, p < 0.00001) and decreased the amputation rate (26.03% vs. 45.00%, OR: 0.41, 95% CI: 0.18-0.95, p = 0.04), but the incidence of adverse events was significantly higher in patients (17.37% vs. 8.27%, OR: 2.49, 95% CI: 1.35-4.57, p = 0.003), whereas there was no significant difference in the mortality (6.96% vs. 12.71%, OR: 0.52, 95% CI: 0.21-1.28, p = 0.16). Our results suggest that HBOT is effective in increasing the complete healing rate and decreasing the amputation rate in patients with DFUs, but increases the incidence of adverse events, while it has no significant effect on mortality.


Assuntos
Diabetes Mellitus , Pé Diabético , Oxigenoterapia Hiperbárica , Humanos , Oxigenoterapia Hiperbárica/métodos , Pé Diabético/terapia , Resultado do Tratamento , Cicatrização , Amputação Cirúrgica
16.
Circulation ; 146(24): 1855-1881, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36384284

RESUMO

BACKGROUND: Pulmonary hypertension (PH) is associated with increased expression of VEGF-A (vascular endothelial growth factor A) and its receptor, VEGFR2 (vascular endothelial growth factor 2), but whether and how activation of VEGF-A signal participates in the pathogenesis of PH is unclear. METHODS: VEGF-A/VEGFR2 signal activation and VEGFR2 Y949-dependent vascular leak were investigated in lung samples from patients with PH and mice exposed to hypoxia. To study their mechanistic roles in hypoxic PH, we examined right ventricle systolic pressure, right ventricular hypertrophy, and pulmonary vasculopathy in mutant mice carrying knock-in of phenylalanine that replaced the tyrosine at residual 949 of VEGFR2 (Vefgr2Y949F) and mice with conditional endothelial deletion of Vegfr2 after chronic hypoxia exposure. RESULTS: We show that PH leads to excessive pulmonary vascular leak in both patients and hypoxic mice, and this is because of an overactivated VEGF-A/VEGFR2 Y949 signaling axis. In the context of hypoxic PH, activation of Yes1 and c-Src and subsequent VE-cadherin phosphorylation in endothelial cells are involved in VEGFR2 Y949-induced vascular permeability. Abolishing VEGFR2 Y949 signaling by Vefgr2Y949F point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure, thereby leading to alleviated PH manifestations, including muscularization of distal pulmonary arterioles, elevated right ventricle systolic pressure, and right ventricular hypertrophy. It is important that we found that VEGFR2 Y949 signaling in myeloid cells including macrophages was trivial and dispensable for hypoxia-induced vascular abnormalities and PH. In contrast with selective blockage of VEGFR2 Y949 signaling, disruption of the entire VEGFR2 signaling by conditional endothelial deletion of Vegfr2 promotes the development of PH. CONCLUSIONS: Our results support the notion that VEGF-A/VEGFR2 Y949-dependent vascular permeability is an important determinant in the pathogenesis of PH and might serve as an attractive therapeutic target pathway for this disease.


Assuntos
Permeabilidade Capilar , Hipertensão Pulmonar , Fator A de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Animais , Camundongos , Permeabilidade Capilar/fisiologia , Células Endoteliais/metabolismo , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/etiologia , Hipóxia/complicações , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
Neuroimage ; 270: 119997, 2023 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-36868393

RESUMO

The brain functions as an accurate circuit that regulates information to be sequentially propagated and processed in a hierarchical manner. However, it is still unknown how the brain is hierarchically organized and how information is dynamically propagated during high-level cognition. In this study, we developed a new scheme for quantifying the information transmission velocity (ITV) by combining electroencephalogram (EEG) and diffusion tensor imaging (DTI), and then mapped the cortical ITV network (ITVN) to explore the information transmission mechanism of the human brain. The application in MRI-EEG data of P300 revealed bottom-up and top-down ITVN interactions subserving P300 generation, which was comprised of four hierarchical modules. Among these four modules, information exchange between visual- and attention-activated regions occurred at a high velocity, related cognitive processes could thus be efficiently accomplished due to the heavy myelination of these regions. Moreover, inter-individual variability in P300 was probed to be attributed to the difference in information transmission efficiency of the brain, which may provide new insight into the cognitive degenerations in clinical neurodegenerative disorders, such as Alzheimer's disease, from the transmission velocity perspective. Together, these findings confirm the capacity of ITV to effectively determine the efficiency of information propagation in the brain.


Assuntos
Encéfalo , Imagem de Tensor de Difusão , Humanos , Encéfalo/fisiologia , Cognição/fisiologia , Eletroencefalografia/métodos , Mapeamento Encefálico/métodos
18.
J Med Virol ; 95(10): e29187, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37877809

RESUMO

Chronic infection of hepatitis B virus (HBV) is the major cause of hepatocellular carcinoma (HCC). Notably, 90% of HBV-positive HCC cases exhibit detectable HBV integrations, hinting at the potential early entanglement of these viral integrations in tumorigenesis and their subsequent oncogenic implications. Nevertheless, the precise chronology of integration events during HCC tumorigenesis, alongside their sequential structural patterns, has remained elusive thus far. In this study, we applied whole-genome sequencing to multiple biopsies extracted from six HBV-positive HCC cases. Through this approach, we identified point mutations and viral integrations, offering a blueprint for the intricate tumor phylogeny of these samples. The emergent narrative paints a rich tapestry of diverse evolutionary trajectories characterizing the analyzed tumors. We uncovered oncogenic integration events in some samples that appear to happen before and during the initiation stage of tumor development based on their locations in reconstituted trajectories. Furthermore, we conducted additional long-read sequencing of selected samples and unveiled integration-bridged chromosome rearrangements and tandem repeats of the HBV sequence within integrations. In summary, this study revealed premalignant oncogenic and sequential complex integrations and highlighted the contributions of HBV integrations to HCC development and genome instability.


Assuntos
Carcinoma Hepatocelular , Hepatite B , Neoplasias Hepáticas , Humanos , Vírus da Hepatite B/genética , Carcinogênese , Transformação Celular Neoplásica
19.
Opt Express ; 31(24): 40285-40292, 2023 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-38041333

RESUMO

Pre-pulses caused by the post-pulses in the optical parametric chirped-pulse amplifier were comprehensively studied for the first time, including the underlying mechanism for the delay-shift of pre-pulses, the intensity variation of pre-pulses affected by the initial delay of post-pulses and the pump energy, and also the nonlinear beat noise. The simulation and measurement confirmed that the high-order dispersion of the pulse stretcher was the main cause for the delay-shift of pre-pulses, which should be similar with the chirped-pulse amplifiers. The intensity of pre-pulses would decrease significantly as the initial delay of post-pulses increased, but would increase with the growth of pump energy. Moreover, the temporal position of the nonlinear beat noise in the experiment was successfully predicted by our simulation. This work could help us better understand the pre-pulses in OPCPA and provide helpful guidance for designing high-contrast laser systems.

20.
Phys Rev Lett ; 130(26): 261001, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37450819

RESUMO

We report the search results of light dark matter through its interactions with shell electrons and nuclei, using the commissioning data from the PandaX-4T liquid xenon detector. Low energy events are selected to have an ionization-only signal between 60 to 200 photoelectrons, corresponding to a mean nuclear recoil energy from 0.77 to 2.54 keV and electronic recoil energy from 0.07 to 0.23 keV. With an effective exposure of 0.55 tonne·year, we set the most stringent limits within a mass range from 40 MeV/c^{2} to 10 GeV/c^{2} for pointlike dark matter-electron interaction, 100 MeV/c^{2} to 10 GeV/c^{2} for dark matter-electron interaction via a light mediator, and 3.2 to 4 GeV/c^{2} for dark matter-nucleon spin-independent interaction. For DM interaction with electrons, our limits are closing in on the parameter space predicted by the freeze-in and freeze-out mechanisms in the early Universe.


Assuntos
Núcleo Celular , Elétrons
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