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1.
Cancer Immunol Immunother ; 73(5): 91, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38554157

RESUMEN

BACKGROUND: Accumulation studies found that tumor-associated macrophages (TAMs) are a predominant cell in tumor microenvironment (TME), which function essentially during tumor progression. By releasing bioactive molecules, including circRNA, small extracellular vesicles (sEV) modulate immune cell functions in the TME, thereby affecting non-small cell lung cancer (NSCLC) progression. Nevertheless, biology functions and molecular mechanisms of M2 macrophage-derived sEV circRNAs in NSCLC are unclear. METHODS: Cellular experiments were conducted to verify the M2 macrophage-derived sEV (M2-EV) roles in NSCLC. Differential circRNA expression in M0 and M2-EV was validated by RNA sequencing. circFTO expression in NSCLC patients and cells was investigated via real-time PCR and FISH. The biological mechanism of circFTO in NSCLC was validated by experiments. Our team isolated sEV from M2 macrophages (M2Ms) and found that M2-EV treatment promoted NSCLC CP, migration, and glycolysis. RESULTS: High-throughput sequencing found that circFTO was highly enriched in M2-EV. FISH and RT-qPCR confirmed that circFTO expression incremented in NSCLC tissues and cell lines. Clinical studies confirmed that high circFTO expression correlated negatively with NSCLC patient survival. Luciferase reporter analysis confirmed that miR-148a-3p and PDK4 were downstream targets of circFTO. circFTO knockdown inhibited NSCLC cell growth and metastasis in in vivo experiments. Downregulating miR-148a-3p or overexpressing PDK4 restored the malignancy of NSCLC, including proliferation, migration, and aerobic glycolysis after circFTO silencing. CONCLUSION: The study found that circFTO from M2-EV promoted NSCLC cell progression and glycolysis through miR-148a-3p/PDK4 axis. circFTO is a promising prognostic and diagnostic NSCLC biomarker and has the potential to be a candidate NSCLC therapy target.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Vesículas Extracelulares , Neoplasias Pulmonares , MicroARNs , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/patología , Neoplasias Pulmonares/patología , Macrófagos/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Microambiente Tumoral
2.
Int J Gynecol Pathol ; 43(6): 646-651, 2024 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-39418588

RESUMEN

SMARCB1/SMARCA4-deficient malignancies of the female genital tract are rare entities, characterized by similar histologic features, such as sheet-like growth patterns and rhabdoid cells. Previous studies have shown mutually exclusive loss of SMARCA4/BRG1 and SMARCB1/INI1. Herein, we describe a unique cervical mixed carcinoma in a 77-year-old patient. The tumor consisted of 3 components, gastric-type adenocarcinoma, squamous carcinoma, and undifferentiated carcinoma. While the undifferentiated carcinoma was negtive for CK7, CK5/6 and p63, it was positive for pan-CK. DNA-based next-generation sequencing revealed a nonsense mutation in SMARCA4, copy number loss in SMARCB1, and a nonsense mutation in ARID1A. Different molecular alterations of the switch/sucrose nonfermenting complex subunits in the present case may provide further insights into the functions of the switch/sucrose nonfermenting complex in the progression of tumors.


Asunto(s)
ADN Helicasas , Proteínas de Unión al ADN , Proteínas Nucleares , Proteína SMARCB1 , Factores de Transcripción , Neoplasias del Cuello Uterino , Humanos , Femenino , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Anciano , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , ADN Helicasas/genética , ADN Helicasas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Codón sin Sentido , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/genética , Adenocarcinoma/metabolismo
3.
J Chem Phys ; 160(7)2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38380747

RESUMEN

The molecular dynamics with electronic friction (MDEF) approach can accurately describe nonadiabatic effects at metal surfaces in the weakly nonadiabatic limit. That being said, the MDEF approach treats nuclear motion classically such that the nuclear quantum effects are completely missing in the approach. To address this limitation, we combine Electronic Friction with Ring Polymer Molecular Dynamics (EF-RPMD). In particular, we apply the averaged electronic friction from the metal surface to the centroid mode of the ring polymer. We benchmark our approach against quantum dynamics to show that EF-RPMD can accurately capture zero-point energy as well as transition dynamics. In addition, we show that EF-RPMD can correctly predict the electronic transfer rate near metal surfaces in the tunneling limit as well as the barrier crossing limit. We expect that our approach will be very useful to study nonadiabatic dynamics near metal surfaces when nuclear quantum effects become essential.

4.
J Chem Phys ; 161(2)2024 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-38984964

RESUMEN

Fermi's golden rule (FGR) offers an empirical framework for understanding the dynamics of spin-lattice relaxation in magnetic molecules, encompassing mechanisms like direct (one-phonon) and Raman (two-phonon) processes. These principles effectively model experimental longitudinal relaxation rates, denoted as T1-1. However, under scenarios of increased coupling strength and nonlinear spin-lattice interactions, FGR's applicability may diminish. This paper numerically evaluates the exact spin-lattice relaxation rate kernels, employing the extended dissipaton equation of motion formalism. Our calculations reveal that when quadratic spin-lattice coupling is considered, the rate kernels exhibit a free induction decay-like feature, and the damping rates depend on the interaction strength. We observe that the temperature dependence predicted by FGR significantly deviates from the exact results since FGR ignores the higher order effects and the non-Markovian nature of spin-lattice relaxation. Our methods can be easily extended to study other systems with nonlinear spin-lattice interactions and provide valuable insights into the temperature dependence of T1 in molecular qubits when the coupling is strong.

5.
Environ Toxicol ; 39(2): 529-538, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37341073

RESUMEN

Ferroptosis is a novel form of programmed cell death triggered by iron-dependent lipid peroxidation and has been associated with various diseases, including cancer. Erastin, an inhibitor of system Xc-, which plays a critical role in regulating ferroptosis, has been identified as an inducer of ferroptosis in cancer cells. In this study, we investigated the impact of butyrate, a short-chain fatty acid produced by gut microbiota, on erastin-induced ferroptosis in lung cancer cells. Our results demonstrated that butyrate significantly enhanced erastin-induced ferroptosis in lung cancer cells, as evidenced by increased lipid peroxidation and reduced expression of glutathione peroxidase 4 (GPX4). Mechanistically, we found that butyrate modulated the pathway involving activating transcription factor 3 (ATF3) and solute carrier family 7 member 11 (SLC7A11), leading to enhanced erastin-induced ferroptosis. Furthermore, partial reversal of the effect of butyrate on ferroptosis was observed upon knockdown of ATF3 or SLC7A11. Collectively, our findings indicate that butyrate enhances erastin-induced ferroptosis in lung cancer cells by modulating the ATF3/SLC7A11 pathway, suggesting its potential as a therapeutic agent for cancer treatment.


Asunto(s)
Ferroptosis , Neoplasias Pulmonares , Humanos , Factor de Transcripción Activador 3/metabolismo , Butiratos/farmacología , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/metabolismo
6.
Mod Pathol ; 36(12): 100316, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37634868

RESUMEN

We developed a deep learning framework to accurately predict the lymph node status of patients with cervical cancer based on hematoxylin and eosin-stained pathological sections of the primary tumor. In total, 1524 hematoxylin and eosin-stained whole slide images (WSIs) of primary cervical tumors from 564 patients were used in this retrospective, proof-of-concept study. Primary tumor sections (1161 WSIs) were obtained from 405 patients who underwent radical cervical cancer surgery at the Fudan University Shanghai Cancer Center (FUSCC) between 2008 and 2014; 165 and 240 patients were negative and positive for lymph node metastasis, respectively (including 166 with positive pelvic lymph nodes alone and 74 with positive pelvic and para-aortic lymph nodes). We constructed and trained a multi-instance deep convolutional neural network based on a multiscale attention mechanism, in which an internal independent test set (100 patients, 228 WSIs) from the FUSCC cohort and an external independent test set (159 patients, 363 WSIs) from the Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma cohort of the Cancer Genome Atlas program database were used to evaluate the predictive performance of the network. In predicting the occurrence of lymph node metastasis, our network achieved areas under the receiver operating characteristic curve of 0.87 in the cross-validation set, 0.84 in the internal independent test set of the FUSCC cohort, and 0.75 in the external test set of the Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma cohort of the Cancer Genome Atlas program. For patients with positive pelvic lymph node metastases, we retrained the network to predict whether they also had para-aortic lymph node metastases. Our network achieved areas under the receiver operating characteristic curve of 0.91 in the cross-validation set and 0.88 in the test set of the FUSCC cohort. Deep learning analysis based on pathological images of primary foci is very likely to provide new ideas for preoperatively assessing cervical cancer lymph node status; its true value must be validated with cervical biopsy specimens and large multicenter datasets.


Asunto(s)
Adenocarcinoma , Carcinoma de Células Escamosas , Aprendizaje Profundo , Neoplasias del Cuello Uterino , Femenino , Humanos , Carcinoma de Células Escamosas/patología , Neoplasias del Cuello Uterino/patología , Metástasis Linfática/patología , Estudios Retrospectivos , Eosina Amarillenta-(YS) , Hematoxilina , China , Ganglios Linfáticos/patología , Adenocarcinoma/patología
7.
J Pathol ; 257(5): 635-649, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35411948

RESUMEN

Clear cell carcinoma (CCC) of the cervix (cCCC) is a rare and aggressive type of human papillomavirus (HPV)-negative cervical cancer with limited effective treatment options for recurrent or metastatic disease. Historically, CCCs of the lower genital tract were associated with in utero diethylstilbestrol exposure; however, the genetic landscape of sporadic cCCCs remains unknown. Here we sought to define the molecular underpinning of cCCCs. Using a combination of whole-exome, targeted capture, and RNA-sequencing, we identified pathogenic genetic alterations in the Hippo signaling pathway in 50% (10/20) of cCCCs, including recurrent WWTR1 S89W somatic mutations in 40% (4/10) of the cases harboring mutations in the Hippo pathway. Irrespective of the presence or absence of Hippo pathway genetic alterations, however, all primary cCCCs analyzed in this study (n = 20) harbored features of Hippo pathway deregulation at the transcriptomic and protein levels. In vitro functional analysis revealed that expression of the WWTR1 S89W mutation leads to reduced binding of TAZ to 14-3-3, promoting constitutive nuclear translocation of TAZ and Hippo pathway repression. WWTR1 S89W expression was found to lead to acquisition of oncogenic behavior, including increased proliferation, migration, and colony formation in vitro as well as increased tumorigenesis in vivo, which could be reversed by targeted inhibition of the TAZ/YAP1 complex with verteporfin. Finally, xenografts expressing WWTR1 S89W displayed a shift in tumor phenotype, becoming more infiltrative as well as less differentiated, and were found to be composed of cells with conspicuous cytoplasmic clearing as compared to controls. Our results demonstrate that Hippo pathway alterations are likely drivers of cCCCs and likely contribute to the clear cell phenotype. Therapies targeting this pathway may constitute a new class of treatment for these rare, aggressive tumors. © 2022 The Pathological Society of Great Britain and Ireland.


Asunto(s)
Vía de Señalización Hippo , Transactivadores , Carcinogénesis/genética , Cuello del Útero , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Mutación , Transducción de Señal/fisiología , Transactivadores/genética , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ
8.
Clin Oral Investig ; 27(3): 1035-1042, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35953564

RESUMEN

OBJECTIVES: This study aimed to find out the correlation between different anatomical parameters of the mandible and the occurrence of a bad split in patients who had undergone bilateral split sagittal ramus osteotomy (BSSRO). MATERIALS AND METHOD: At both the distal roots of the first molar (1) and the retromolar area (2), we measured the distance from the buccal margin of the inferior dental canal (IDC) to the buccal margin of the cortical bone (MCBC), the thickness of both buccal cortical (WBCB) and cancellous bone (WBCA), distance from the superior border of IDC to the alveolar crest (MCAC), buccolingual thickness (BLT), and thickness of cancellous bone (WCA). At the ramus, the distances between the sigmoid notch to the upper part of the lingula (SL) and the inferior border of the mandible (SIBM), the thickness of the ramus at the level of the lingula (BLTR), and the anteroposterior width of the ramus (APWR) were measured. The paired and independent t-tests were used when applicable, and a P-value < 0.05 was considered significant. RESULTS: MCBC1 showed a significant difference between bad and non-bad split sides (P = 0.037). Both WBCA1 and WBCA2 show the same significant difference (P = 0.023, 0.024). Similarly, WCA1 and WCA2 showed a statistical difference between the bad and non-bad split sides (P = 0.027, 0.036). There were no statistically significant differences between the compared sides of WBCB1, WBCB2, MCAC1, MCAC2, SIBM, APWR, SL, and BLTR. CONCLUSION: Narrow space between IDC and the buccal cortical margin, along with the decrease in the thickness of both buccal cancellous bone and total cancellous bone at the inferior border of the mandible along the course of SSRO, has been implicated in the occurrence of bad split intraoperatively.


Asunto(s)
Mandíbula , Osteotomía Sagital de Rama Mandibular , Humanos , Osteotomía Sagital de Rama Mandibular/métodos , Mandíbula/cirugía , Hueso Cortical/anatomía & histología , Diente Molar , Raíz del Diente , Polímeros
9.
Clin Oral Investig ; 27(9): 5121-5130, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37474831

RESUMEN

OBJECTIVE: To evaluate 3D condylar displacement and long-term remodeling following the correction of bimaxillary protrusion by anterior segment osteotomy (ASO) with and without Le Fort I surgery. MATERIALS AND METHOD: This retrospective study included 32 adults with bimaxillary protrusion who underwent ASO alone (group 1) or with concomitant Le Fort I osteotomy (group 2). Subject's computed tomography scans at basic (T0), immediate postoperatively (T1), and at 1 year or more follow-up (T2) were collected. The condyle displacement was measured at superior-inferior, lateromedially, and anteroposterior surfaces, while condyle remodeling was measured at the superior, lateral, anterior, medial, and posterior surfaces. All 3D analyses were performed using 3D Slicer software (4.11.2). RESULTS: At T1, 52.7%, 86.7%, and 94.4% of condyles in group 1 were displaced inferiorly, laterally, and posteriorly, respectively, as well as 75%, 89.2%, and 53.5% of condyles in group 2, which had not fully returned to the original preoperative positions at T2. Condylar remodeling was observed in both groups at T2, and no significant difference was found in the overall condylar volume between T1 and T2 in both groups. Patients in group 2 exhibited significant bone resorption at both lateral and anterior surfaces compared to group 1 (P = 0.000 and 0.01, respectively). CONCLUSION: This study's results demonstrated that ASO is associated with a degree of condylar changes even if the posterior mandible is not osteomized. The positional changes vary between bimaxillary ASO alone and those with simultaneous Le Fort I osteotomy. However, both groups' condyle volume remained stable at the long-term follow-up.


Asunto(s)
Cóndilo Mandibular , Procedimientos Quirúrgicos Ortognáticos , Adulto , Humanos , Cóndilo Mandibular/diagnóstico por imagen , Cóndilo Mandibular/cirugía , Procedimientos Quirúrgicos Ortognáticos/métodos , Estudios Retrospectivos , Osteotomía Le Fort/métodos , Osteotomía Sagital de Rama Mandibular/métodos , Mandíbula/cirugía , Cefalometría/métodos
10.
Oncologist ; 27(1): e53-e63, 2022 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-35305100

RESUMEN

OBJECTIVE: The objective of this study was to retrospectively explore the clinical implications of simultaneous intensity-modulated radiotherapy (IMRT) boost to the tumor bed in cervical cancer with full-thickness stromal invasion (FTSI). PATIENTS AND METHODS: Patients diagnosed with the International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB and IIA cervical cancer with confirmed FTSI were included. Patients received pelvic IMRT from a dose of 50.4 Gy in 28 fractions with (or without) a simultaneous integrated boost (SIB) to 58.8 Gy in 28 fractions for the tumor bed. The progression-free survival (PFS), overall survival (OS), and pelvic-PFS (p-PFS) were analyzed using the Kaplan-Meier method, and independent prognostic factors were explored by Cox regression analyses. RESULTS: Patients without a tumor bed boost had a poor prognosis. The 5-year OS was 81.3% versus 58.3% and the 5-year PFS rates were 75.0% versus 57.6% (boost vs non-boost). The FIGO stage, pathology, adjuvant chemotherapy, and tumor bed boost were independent factors affecting both the 5-year OS and PFS. Subgroup analysis showed that the SIB group had a higher 5-year OS, PFS, and p-PFS for different stages, lymph node status, and risk groups than the non-SIB group. Recurrence occurred in 268 of 910 (29.5%) patients without SIB and 49 of 293 (16.7%) with SIB. Among patients with recurrence, 113 of 282 (40.1%) in the non-boost group compared with 14 of 51 (23.0%) patients in the boost group had a pelvic recurrence. Tumor bed boost resulted in an increase in the mean radiation dose to the intestine, rectum, and bladder, although there were no differences in the rates of acute and late toxicities between the 2 groups. CONCLUSION: Tumor bed boost by external beam radiotherapy (EBRT) is an effective and safe method for patients with FTSI and risk factors. Compared with the standard prophylactic radiation, tumor bed boost by EBRT was not associated with increased acute and late toxicities.


Asunto(s)
Radioterapia de Intensidad Modulada , Neoplasias del Cuello Uterino , Quimioterapia Adyuvante , Femenino , Humanos , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia de Intensidad Modulada/efectos adversos , Estudios Retrospectivos , Neoplasias del Cuello Uterino/patología
11.
J Transl Med ; 20(1): 318, 2022 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-35842667

RESUMEN

Circular RNAs (circRNAs) belong to a novel class of noncoding RNA that gained more attention in human cancer pathogenesis. The role of circRNA in esophageal squamous cell carcinoma (ESCC) is largely unclear. Present investigation was to characterize new circRNAs regulating ESCC progression and explore the regulatory mechanisms in ESCC. In this study, circRNAs differentially expressed in ESCC and adjacent normal tissues were characterized via high-throughput sequencing. Then the differentially expressed circRNA between ESCC and adjacent normal tissues were investigated using Rt-qPCR. The role of circ-ARAP2 expression on tumor progression were detected in both in vivo and in vitro. Luciferase reporter assays were used to identify the relationships among circ-ARAP2, microRNA (miR)-761 and the cell cycle regulator Forkhead Box M1 (FOXM1). The result of the expression profile analyses regarding human circRNAs in ESCC demonstrated that circ-ARAP2 was up-regulated significantly in both ESCC tissues and cell lines. Downregulation circ-ARAP2 suppressed ESCC proliferation, tumor growth and metastasis in both in vivo and in vitro. The data also suggested that miR-761 and FOXM1 were circ-ARAP2 downstream targets which were confirmed through luciferase reporter analysis. Overexpression of FOXM1 or inhibiting miR-761 restored ESCC cell proliferation and invasion ability after silencing circ-ARAP2. The study also found that circ-ARAP2 influenced the endothelial-mesenchymal transition (EMT) and cancer stem cells differently by regulating miR-761/FOXM1. In one word, the results demonstrated that abnormal circ-ARAP2 expression promoted ESCC progression by regulating miR-761/FOXM1 axis-mediated stemness and EMT.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , MicroARNs , Proteínas Portadoras/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Proteína Forkhead Box M1/genética , Proteínas Activadoras de GTPasa/genética , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , ARN Circular/genética
12.
Histopathology ; 81(4): 477-485, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35852178

RESUMEN

AIMS: In 2017, a subset of cellular variants of myofibroma and myopericytoma with a smooth muscle-like immunophenotype and harbouring recurrent SRF::RELA gene fusions was reported. Although the anatomical distribution was found to be quite broad, no tumours with these gene fusions in the female reproductive system have been illustrated to date. METHODS AND RESULTS: Herein, we report the histological and immunophenotypical features of three uterine tumours with SRF::RELA gene fusions. Microscopically, all three tumours were composed of cellular oval to spindle cells arranged in intersecting fascicles with variable amounts of collagen and a rich capillary network. Mitotic figures were scant. Regarding immunohistochemistry, diffuse staining for desmin, oestrogen receptor and progesterone receptor was observed in all three cases. The first case exhibited focal staining for h-caldesmon, whereas the latter two cases had diffuse staining. Furthermore, SRF::RELA rearrangement was observed in all three cases by using next-generation sequencing (NGS). Follow-up, ranging from 11 to 15 months, was available for these three patients, all of whom were well without evidence of disease. CONCLUSIONS: In conclusion, we reported a special group of uterine neoplasms with myogenic differentiation harbouring SRF::RELA rearrangement. Although the follow-up time was limited, morphological characteristics and other studies with follow-up data supported that this type of uterine neoplasm appeared to behave in a benign manner. Further studies with longer follow-up are needed to clarify the biological nature of this particular type of uterine tumour.


Asunto(s)
Miofibroma , Proteínas de Fusión Oncogénica , Factor de Respuesta Sérica , Factor de Transcripción ReIA , Neoplasias Uterinas , Biomarcadores de Tumor/genética , Femenino , Fusión Génica , Humanos , Inmunohistoquímica , Miofibroma/patología , Proteínas de Fusión Oncogénica/genética , Factor de Respuesta Sérica/genética , Factor de Transcripción ReIA/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología
13.
J Immunol ; 205(12): 3419-3428, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33188074

RESUMEN

Melanoma differentiation-associated gene 5 (MDA5) is a key cytoplasmic dsRNA sensor. Upon binding to invading viral RNA, activated MDA5 is recruited to mitochondria and interacts with mitochondrial antiviral signaling gene (MAVS) to initiate innate antiviral immune responses. The elegant regulation of this process remains elusive. In this study, using the Chinese tree shrew (Tupaia belangeri chinensis), which is genetically close to primates, we identified the Tupaia oligoadenylate synthetases-like 1 (tOASL1) as a positive regulator of the Tupaia MDA5 (tMDA5) and Tupaia MAVS (tMAVS)-mediated IFN signaling. Overexpression of tOASL1 significantly potentiated the RNA virus-triggered induction of the type I IFNs and downstream antiviral genes. Conversely, knockdown of tOASL1 had an impaired antiviral immune response. Mechanistically, tOASL1 was associated with mitochondria and directly interacted with tMDA5 and tMAVS. Upon RNA virus infection, tOASL1 enhanced the interaction between tMDA5 and tMAVS via its OAS and UBL domains. Our results revealed a novel mechanism by which tOASL1 contributes to host antiviral responses via enhancing tMDA5 and tMAVS interaction.


Asunto(s)
2',5'-Oligoadenilato Sintetasa/inmunología , Proteínas Adaptadoras Transductoras de Señales/inmunología , Inmunidad Innata , Helicasa Inducida por Interferón IFIH1/inmunología , Infecciones por Virus ARN/inmunología , Virus ARN/inmunología , ARN Bicatenario/inmunología , ARN Viral/inmunología , Animales , Tupaia
14.
J Chem Phys ; 157(16): 164701, 2022 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-36319401

RESUMEN

Aqueous rutile TiO2(110) is the most widely studied water-oxide interface, and yet questions about water dissociation are still controversial. Theoretical studies have systematically investigated the influence of the slab thickness on water dissociation energy (Ediss) at 1 monolayer coverage using static density functional theory calculation and found that Ediss exhibits odd-even oscillation with respect to the TiO2 slab thickness. However, less studies have accounted for the full solvation of an aqueous phase using ab initio molecular dynamics due to high computational costs in which only three, four, and five trilayer models of rutile(110)-water interfaces have been simulated. Here, we report Machine Learning accelerated Molecular Dynamics (MLMD) simulations of defect-free rutile(110)-water interfaces, which allows for a systematic study of the slab thickness ranging from 3 to 17 trilayers with much lower costs while keeping ab initio accuracy. Our MLMD simulations show that the dissociation degree of surface water (α) oscillates with the slab thickness and converges to ∼2% as the TiO2 slab becomes thicker. Converting α into dissociation free energy (ΔAdiss) and comparing with dissociation total energy Ediss calculated with a single monolayer of water, we find that the full solvation of the interfaces suppresses surface water from dissociating. It is interesting to note that the machine learning potential trained from the dataset containing exclusively the five trilayer TiO2 model exhibits excellent transferability to other slab thicknesses and further captures the oscillating behavior of surface water dissociation. Detailed analyses indicate that the central plane in odd trilayer slabs modulates the interaction between double trilayers and, thus, the bonding strength between terminal Ti and water, which affects pKa of surface water and water dissociation degree.

15.
Pestic Biochem Physiol ; 188: 105264, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36464369

RESUMEN

The ATP-binding cassette (ABC) transporters C and G subfamilies have been reported to be involved in insecticide detoxification, with most studies showing increased gene transcript levels in response to insecticide exposure. Our previous studies have suggested that ABCC and G transporters participate in cyantraniliprole and thiamethoxam resistance of Aphis gossypii. In this study, we focused on the potential roles of the ABCC and G transporters of an A. gossypii field population (SDR) in neonicotinoid detoxification. The results of leaf dip bioassays showed 629.17- and 346.82-fold greater resistance to thiamethoxam and imidacloprid in the SDR strain, respectively, than in the susceptible strain (SS). Verapamil, an ABC inhibitor, was used for synergism bioassays, and the results showed synergistic effects with thiamethoxam, with synergistic ratios (SRs) of 2.07 and 6.68 in the SS and SDR strains, respectively. In addition to thiamethoxam, verapamil increased imidacloprid toxicity by 1.68- and 1.62-fold in the SS and SDR strains respectively. Then, the expression levels of several ABCC and G transporters were analyzed in different treatments. We found that the transcript levels of AgABCG4, AgABCG17, AgABCG26, AgMRP8 and AgMRP12 were higher in the SDR strain than in the SS strain. The mRNA expression of AgABCG4, AgABCG7, AgABCG13, AgABCG17, AgABCG26, AgMRP8 and AgMRP12 in the SDR strain was increased after thiamethoxam and imidacloprid exposure. The results of transgenic Drosophila melanogaster bioassays suggested that overexpression of AgABCG4, AgABCG7, AgABCG13, AgABCG17, AgABCG26, AgMRP8 and AgMRP12 in transgenic flies was sufficient to confer thiamethoxam and imidacloprid resistance, and AgABCG4, AgABCG7, AgABCG13, AgABCG26 and AgMRP12 may be related to α-cypermethrin cross-resistance with weak effects. In addition, the knockdown of AgABCG4, AgABCG13, AgABCG26, AgMRP8 and AgMRP12, and the knockdown of AgABCG7 and AgABCG26 increased thiamethoxam and imidacloprid mortality in the SDR strain, respectively. Our results suggest that changes in the expression levels of ABCC and G transporters may contribute to neonicotinoid detoxification in the SDR strain, and provide a foundation for clarify the potential roles of ABCC and G transporters in insecticide resistance.


Asunto(s)
Áfidos , Insecticidas , Animales , Tiametoxam , Transportadoras de Casetes de Unión a ATP/genética , Insecticidas/toxicidad , Drosophila melanogaster/genética , Neonicotinoides/farmacología , Verapamilo/farmacología
16.
Sensors (Basel) ; 22(17)2022 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-36080846

RESUMEN

This work aimed to detect the vegetation coverage and evaluate the benefits of afforestation and ecological protection. Unmanned aerial vehicle (UAV) aerial survey was adopted to obtain the images of tailings area at Ma'anshan near the Dianchi Lake estuary, so as to construct a high-resolution Digital Orthophoto Map (DOM) and high-density Dense Image Matching (DIM) point cloud. Firstly, the optimal scale was selected for segmentation by considering the terrain. Secondly, the visible-band difference vegetation index (VDVI) of the classified vegetation information of the tail mining area was determined from the index gray histogram, ground class error analysis, and the qualitative and quantitative analysis of the bimodal index. Then, the vegetation information was extracted by combining the random forest (RF) classification algorithm. Finally, the extracted two-dimensional (2D) vegetation information was mapped to the three-dimensional (3D) point cloud, and the redundant data was eliminated. Fractional vegetation cover (FVC) was counted in the way of surface to point and human-machine combination. The experimental results showed that the vegetation information extracted from the 2D image was mapped to the 3D point cloud in the form of surface to point, and the redundant bare ground information was eliminated. The statistical FVC was 36.06%. The field survey suggested that the vegetation information in the turf dam area adjacent to the open phosphate deposit accumulation area research area was sparse. Relevant measures should be taken in the subsequent mining to avoid ecological damage caused by expanded phosphate mining. In general, applying UAV measurement technology and related 2D and 3D products to detect the vegetation coverage in an open phosphate mine area was of practical significance and unique technical advantages.


Asunto(s)
Lagos , Tecnología de Sensores Remotos , Humanos , Minería , Fosfatos
17.
Int J Mol Sci ; 23(18)2022 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-36142822

RESUMEN

The soybean pod borer (Leguminivora glycinivorella) (SPB) is a major cause of soybean (Glycine max L.) yield losses in northeast Asia, thus it is desirable to elucidate the resistance mechanisms involved in soybean response to the SPB. However, few studies have mapped SPB-resistant quantitative trait loci (QTLs) and deciphered the response mechanism in soybean. Here, we selected two soybean varieties, JY93 (SPB-resistant) and K6 (SPB-sensitive), to construct F2 and F2:3 populations for QTL mapping and collected pod shells before and after SPB larvae chewed on the two parents to perform RNA-Seq, which can identify stable QTLs and explore the response mechanism of soybean to the SPB. The results show that four QTLs underlying SPB damage to seeds were detected on chromosomes 4, 9, 13, and 15. Among them, qESP-9-1 was scanned in all environments, hence it can be considered a stable QTL. All QTLs explained 0.79 to 6.09% of the phenotypic variation. Meanwhile, 2298 and 3509 DEGs were identified for JY93 and K6, respectively, after the SPB attack, and most of these genes were upregulated. Gene Ontology enrichment results indicated that the SPB-induced and differently expressed genes in both parents are involved in biological processes such as wound response, signal transduction, immune response, and phytohormone pathways. Interestingly, secondary metabolic processes such as flavonoid synthesis were only significantly enriched in the upregulated genes of JY93 after SPB chewing compared with K6. Finally, we identified 18 candidate genes related to soybean pod borer resistance through the integration of QTL mapping and RNA-Seq analysis. Seven of these genes had similar expression patterns to the mapping parents in four additional soybean germplasm after feeding by the SPB. These results provide additional knowledge of the early response and induced defense mechanisms against the SPB in soybean, which could help in breeding SPB-resistant soybean accessions.


Asunto(s)
Mariposas Nocturnas , Sitios de Carácter Cuantitativo , Animales , Mapeo Cromosómico/métodos , Flavonoides/metabolismo , Mariposas Nocturnas/genética , Fenotipo , Fitomejoramiento , Reguladores del Crecimiento de las Plantas/metabolismo , RNA-Seq , Semillas/genética , Glycine max/genética , Glycine max/metabolismo
18.
Am J Hum Genet ; 102(5): 794-805, 2018 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-29706348

RESUMEN

Genome-wide association studies (GWASs) and genome-wide linkage studies (GWLSs) have identified numerous risk genes affecting the susceptibility to leprosy. However, most of the reported GWAS hits are noncoding variants and account for only part of the estimated heritability for this disease. In order to identify additional risk genes and map the potentially functional variants within the GWAS loci, we performed a three-stage study combining whole-exome sequencing (WES; discovery stage), targeted next-generation sequencing (NGS; screening stage), and refined validation of risk missense variants in 1,433 individuals with leprosy and 1,625 healthy control individuals from Yunnan Province, Southwest China. We identified and validated a rare damaging variant, rs142179458 (c.1045G>A [p.Asp349Asn]) in HIF1A, as contributing to leprosy risk (p = 4.95 × 10-9, odds ratio [OR] = 2.266). We were able to show that affected individuals harboring the risk allele presented with multibacillary leprosy at an earlier age (p = 0.025). We also confirmed the association between missense variant rs3764147 (c.760A>G [p.Ile254Val]) in the GWAS hit LACC1 (formerly C13orf31) and leprosy (p = 6.11 × 10-18, OR = 1.605). By using the population attributable fraction, we have shown that HIF1A and LACC1 are the major genes with missense variants contributing to leprosy risk in our study groups. Consistently, mRNA expression levels of both HIF1A and LACC1 were upregulated in the skin lesions of individuals with leprosy and in Mycobacterium leprae-stimulated cells, indicating an active role of HIF1A and LACC1 in leprosy pathogenesis.


Asunto(s)
Pueblo Asiatico/genética , Etnicidad/genética , Predisposición Genética a la Enfermedad , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Lepra/genética , Mutación Missense/genética , Proteínas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Niño , Estudios de Cohortes , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Factores de Riesgo , Transactivadores/genética , Regulación hacia Arriba/genética , Secuenciación del Exoma , Adulto Joven
19.
Clin Genet ; 99(6): 802-811, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33646620

RESUMEN

Previous genotyping-based assays have identified non-coding variants of several interleukins (ILs) being associated with genetic susceptibility to leprosy. However, understanding of the involvement of coding variants within all IL family genes in leprosy was still limited. To obtain the full mutation spectrum of all ILs in leprosy, we performed a targeted deep sequencing of coding regions of 58 ILs genes in 798 leprosy patients (age 56.2 ± 14.4; female 31.5%) and 990 healthy controls (age 38.1 ± 14.0; female 44.3%) from Yunnan, Southwest China. mRNA expression alterations of ILs in leprosy skin lesions or in response to M. leprae treatment were estimated by using publicly available expression datasets. Two coding variants in IL27 (rs17855750, p.S59A, p = 4.02 × 10-8 , odds ratio [OR] = 1.748) and IL1RN (rs45507693, p.A106T, p = 1.45 × 10-5 , OR = 3.629) were significantly associated with leprosy risk. mRNA levels of IL27 and IL1RN were upregulated in whole blood cells after M. leprae stimulation. These data showed that IL27 and IL1RN are leprosy risk genes. Further functional study is required for characterizing the exact role of ILs in leprosy.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Interleucinas/genética , Lepra/genética , Polimorfismo de Nucleótido Simple/genética , Pueblo Asiatico/genética , Estudios de Casos y Controles , China , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/genética
20.
J Med Genet ; 57(9): 605-609, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-31862729

RESUMEN

BACKGROUND: Ovarian clear cell carcinoma (OCCC) arises from endometriosis and represents a difficult-to-treat gynaecological malignancy, in part, because its spatial intratumour heterogeneity and temporal evolutionary trajectories have not been explicitly defined. METHODS: We performed whole-genome sequencing on six pathologically confirmed patients with OCCC. An R package named KataegisPortal was developed to identify and annotate loci of localised hypermutations. Immunohistochemical staining was conducted on a tissue microarray containing 143 OCCC specimens. RESULTS: Multiregion analysis demonstrated considerable degrees of subclonal diversification, ascribable to dynamic mutagenic processes, as well as macroevolutionary events including the acquisition of aneuploidy and chromoplexy. KataegisPortal unveiled APOBEC-mediated kataegis in the early phases of OCCC pathogenesis. We further showed evidence that APOBEC3A and APOBEC3B were frequently expressed in OCCC and possibly regulated by the MAPK pathway. Notably, APOBEC3B-expressing OCCC displayed favourable prognosis and appreciable immunogenicity manifested by marked cytotoxic T-cell infiltration. CONCLUSIONS: These results point to an appealing model of punctuated tumour evolution underlying OCCC neoplastic transformation and progression, which may pose formidable challenges of early detection and intervention, and indicate the intratumour heterogeneity of cancer-driving alterations, yielding important implications for molecular diagnosis and targeted treatment of this lethal disease.


Asunto(s)
Adenocarcinoma de Células Claras/genética , Citidina Desaminasa/genética , Antígenos de Histocompatibilidad Menor/genética , Neoplasias Ováricas/genética , Proteínas/genética , Adenocarcinoma de Células Claras/patología , Adulto , Anciano , Biomarcadores de Tumor/genética , Transformación Celular Neoplásica/genética , Endometriosis , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/patología
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