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The major pathogen Staphylococcus aureus has to cope with host-derived oxidative stress to cause infections in humans. Here, we report that S. aureus tolerates high concentrations of hypothiocyanous acid (HOSCN), a key antimicrobial oxidant produced in the respiratory tract. We discovered that the flavoprotein disulfide reductase (FDR) MerA protects S. aureus from this oxidant by functioning as a HOSCN reductase, with its deletion sensitizing bacteria to HOSCN. Crystal structures of homodimeric MerA (2.4 Å) with a Cys43 -Cys48 intramolecular disulfide, and reduced MerACys43 S (1.6 Å) showed the FAD cofactor close to the active site, supporting that MerA functions as a group I FDR. MerA is controlled by the redox-sensitive repressor HypR, which we show to be oxidized to intermolecular disulfides under HOSCN stress, resulting in its inactivation and derepression of merA transcription to promote HOSCN tolerance. Our study highlights the HOSCN tolerance of S. aureus and characterizes the structure and function of MerA as a major HOSCN defense mechanism. Crippling the capacity to respond to HOSCN may be a novel strategy for treating S. aureus infections.
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Oxidorreductasas , Staphylococcus aureus , Humanos , Disulfuros , Oxidantes , Oxidorreductasas/metabolismo , Staphylococcus aureus/enzimología , Staphylococcus aureus/metabolismoRESUMEN
MOTIVATION: Predicting cell locations is important since with the understanding of cell locations, we may estimate the function of cells and their integration with the spatial environment. Thus, the DREAM challenge on single-cell transcriptomics required participants to predict the locations of single cells in the Drosophila embryo using single-cell transcriptomic data. RESULTS: We have developed over 50 pipelines by combining different ways of preprocessing the RNA-seq data, selecting the genes, predicting the cell locations and validating predicted cell locations, resulting in the winning methods which were ranked second in sub-challenge 1, first in sub-challenge 2 and third in sub-challenge 3. In this paper, we present an R package, SCTCwhatateam, which includes all the methods we developed and the Shiny web application to facilitate the research on single-cell spatial reconstruction. All the data and the example use cases are available in the Supplementary data.
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Análisis de la Célula Individual/métodos , Transcriptoma , Algoritmos , Animales , Biología Computacional/métodos , Drosophila/embriología , Análisis de Secuencia de ARN/métodosRESUMEN
MOTIVATION: Identifying meaningful cancer driver genes in a cohort of tumors is a challenging task in cancer genomics. Although existing studies have identified known cancer drivers, most of them focus on detecting coding drivers with mutations. It is acknowledged that non-coding drivers can regulate driver mutations to promote cancer growth. In this work, we propose a novel node importance-based network analysis (NIBNA) framework to detect coding and non-coding cancer drivers. We hypothesize that cancer drivers are crucial to the formation of community structures in cancer network, and removing them from the network greatly perturbs the network structure thereby critically affecting the functioning of the network. NIBNA detects cancer drivers using a three-step process: first, a condition-specific network is built by incorporating gene expression data and gene networks; second, the community structures in the network are estimated; and third, a centrality-based metric is applied to compute node importance. RESULTS: We apply NIBNA to the BRCA dataset, and it outperforms existing state-of-art methods in detecting coding cancer drivers. NIBNA also predicts 265 miRNA drivers, and majority of these drivers have been validated in literature. Further we apply NIBNA to detect cancer subtype-specific drivers, and several predicted drivers have been validated to be associated with cancer subtypes. Lastly, we evaluate NIBNA's performance in detecting epithelial-mesenchymal transition drivers, and we confirmed 8 coding and 13 miRNA drivers in the list of known genes. AVAILABILITY AND IMPLEMENTATION: The source code can be accessed at https://github.com/mandarsc/NIBNA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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MOTIVATION: Unravelling cancer driver genes is important in cancer research. Although computational methods have been developed to identify cancer drivers, most of them detect cancer drivers at population level. However, two patients who have the same cancer type and receive the same treatment may have different outcomes because each patient has a different genome and their disease might be driven by different driver genes. Therefore new methods are being developed for discovering cancer drivers at individual level, but existing personalized methods only focus on coding drivers while microRNAs (miRNAs) have been shown to drive cancer progression as well. Thus, novel methods are required to discover both coding and miRNA cancer drivers at individual level. RESULTS: We propose the novel method, pDriver, to discover personalized cancer drivers. pDriver includes two stages: (i) constructing gene networks for each cancer patient and (ii) discovering cancer drivers for each patient based on the constructed gene networks. To demonstrate the effectiveness of pDriver, we have applied it to five TCGA cancer datasets and compared it with the state-of-the-art methods. The result indicates that pDriver is more effective than other methods. Furthermore, pDriver can also detect miRNA cancer drivers and most of them have been confirmed to be associated with cancer by literature. We further analyze the predicted personalized drivers for breast cancer patients and the result shows that they are significantly enriched in many GO processes and KEGG pathways involved in breast cancer. AVAILABILITY AND IMPLEMENTATION: pDriver is available at https://github.com/pvvhoang/pDriver. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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The shape of energy dispersions near the band-edges plays a decisive role in the transport properties, especially the carrier mobility, of semiconductors. In this work, we design and investigate the γ phase of tin monoxide and monochalcogenides γ-SnX (X = O, S, Se, and Te) through first-principles simulations. γ-SnX is found to be dynamically stable with phonon dispersions containing only positive phonon frequencies. Due to the hexagonal atomic lattice, the mechanical properties of γ-SnX single-layers are directionally isotropic and their elastic constants meet Born's criterion for mechanical stability. Our calculation results indicate that all four single-layers of γ-SnX are semiconductors with the Mexican-hat dispersions. The biaxial strain not only greatly changes the electronic structures of the γ-SnX single-layers, but also can cause a phase transition from semiconductor to metal. Meanwhile, the effects of an electric field on the electron states of γ-SnX single-layers are insignificant. γ-SnX structures have high electron mobility and their electron mobility is highly directional isotropic along the two transport directions x and y. The findings not only initially introduce the γ phase of group IV-VI compounds, but also serve as a premise for further studies on this material family with potential applications in the future, both theoretically and experimentally.
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MOTIVATION: Identifying cancer driver genes is a key task in cancer informatics. Most existing methods are focused on individual cancer drivers which regulate biological processes leading to cancer. However, the effect of a single gene may not be sufficient to drive cancer progression. Here, we hypothesize that there are driver gene groups that work in concert to regulate cancer, and we develop a novel computational method to detect those driver gene groups. RESULTS: We develop a novel method named DriverGroup to detect driver gene groups by using gene expression and gene interaction data. The proposed method has three stages: (i) constructing the gene network, (ii) discovering critical nodes of the constructed network and (iii) identifying driver gene groups based on the discovered critical nodes. Before evaluating the performance of DriverGroup in detecting cancer driver groups, we firstly assess its performance in detecting the influence of gene groups, a key step of DriverGroup. The application of DriverGroup to DREAM4 data demonstrates that it is more effective than other methods in detecting the regulation of gene groups. We then apply DriverGroup to the BRCA dataset to identify driver groups for breast cancer. The identified driver groups are promising as several group members are confirmed to be related to cancer in literature. We further use the predicted driver groups in survival analysis and the results show that the survival curves of patient subpopulations classified using the predicted driver groups are significantly differentiated, indicating the usefulness of DriverGroup. AVAILABILITY AND IMPLEMENTATION: DriverGroup is available at https://github.com/pvvhoang/DriverGroup. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Neoplasias de la Mama , Oncogenes , Neoplasias de la Mama/genética , Redes Reguladoras de Genes , Humanos , MutaciónRESUMEN
A key task in cancer genomics research is to identify cancer driver genes. As these genes initialise and progress cancer, understanding them is critical in designing effective cancer interventions. Although there are several methods developed to discover cancer drivers, most of them only identify coding drivers. However, non-coding RNAs can regulate driver mutations to develop cancer. Hence, novel methods are required to reveal both coding and non-coding cancer drivers. In this paper, we develop a novel framework named Controllability based Biological Network Analysis (CBNA) to uncover coding and non-coding cancer drivers (i.e. miRNA cancer drivers). CBNA integrates different genomic data types, including gene expression, gene network, mutation data, and contains a two-stage process: (1) Building a network for a condition (e.g. cancer condition) and (2) Identifying drivers. The application of CBNA to the BRCA dataset demonstrates that it is more effective than the existing methods in detecting coding cancer drivers. In addition, CBNA also predicts 17 miRNA drivers for breast cancer. Some of these predicted miRNA drivers have been validated by literature and the rest can be good candidates for wet-lab validation. We further use CBNA to detect subtype-specific cancer drivers and several predicted drivers have been confirmed to be related to breast cancer subtypes. Another application of CBNA is to discover epithelial-mesenchymal transition (EMT) drivers. Of the predicted EMT drivers, 7 coding and 6 miRNA drivers are in the known EMT gene lists.
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MicroARNs/genética , Neoplasias/genética , Oncogenes , ARN no Traducido/genética , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Biología Computacional , Bases de Datos Genéticas , Transición Epitelial-Mesenquimal/genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Modelos Genéticos , Mutación , ARN Mensajero/genética , ARN Neoplásico/genética , Factores de Transcripción/genéticaRESUMEN
In this paper, detailed investigations of the electronic and optical properties of a Janus SnSSe monolayer under a biaxial strain and electric field using ab initio methods are presented. Our calculations indicate that the Janus SnSSe monolayer is a semiconductor with an indirect band gap larger/lower than that of the SnSe2/SnS2 monolayer. To obtain accurate estimates of the band gap, both Perdew-Burke-Ernzerhof (PBE) and Heyd-Scuseria-Ernzerhof (HSE06) hybrid functionals have been used and the effect of spin-orbit coupling has also been included. While the influence of the electric field on the electronic and optical properties of the Janus SnSSe monolayer is quite weak, biaxial strain plays a key role in controlling these properties. The Janus SnSSe monolayer has a wide absorption spectrum, from visible light to the ultraviolet region. At equilibrium, the maximum absorption coefficient of the monolayer is up to 11.152 × 104 cm-1 in the ultraviolet region and it can be increased by strain engineering. With high absorption intensity in the visible light area and being able to tune the absorbance by strain, the Janus SnSSe monolayer becomes a promising material for applications in optoelectronic devices.
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Antibody-mediated rejection has emerged as the leading cause of late graft loss in kidney transplant recipients, and inhibition of donor-specific antibody production should lead to improved transplant outcomes. The fusion protein cytotoxic T lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) blocks T cell activation and consequently inhibits T-dependent B cell antibody production, and the current paradigm is that CTLA4-Ig is effective with naïve T cells and less so with activated or memory T cells. In this study, we used a mouse model of allosensitization to investigate the efficacy of continuous CTLA4-Ig treatment, initiated 7 or 14 days after sensitization, for inhibiting ongoing allospecific B cell responses. Delayed treatment with CTLA4-Ig collapsed the allospecific germinal center B cell response and inhibited alloantibody production. Using adoptively transferred T cell receptor transgenic T cells and a novel approach to track endogenous graft-specific T cells, we demonstrate that delayed CTLA4-Ig minimally inhibited graft-specific CD4(+) and T follicular helper responses. Remarkably, delaying CTLA4-Ig until day 6 after transplantation in a fully mismatched heart transplant model inhibited alloantibody production and prevented acute rejection, whereas transferred hyperimmune sera reversed the effects of delayed CTLA4-Ig. Collectively, our studies revealed the unexpected efficacy of CTLA4-Ig for inhibiting ongoing B cell responses even when the graft-specific T cell response was robustly established.
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Linfocitos B/inmunología , Antígeno CTLA-4/inmunología , Rechazo de Injerto/prevención & control , Trasplante de Corazón/efectos adversos , Inmunoconjugados/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Femenino , Rechazo de Injerto/etiología , Supervivencia de Injerto/inmunología , Isoanticuerpos/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Trasplante HomólogoRESUMEN
T cell receptor transgenic (TCR-Tg) T cells are often used as tracer populations of antigen-specific responses to extrapolate findings to endogenous T cells. The extent to which TCR-Tg T cells behave purely as tracer cells or modify the endogenous immune response is not clear. To test the impact of TCR-Tg T cell transfer on endogenous alloimmunity, recipient mice were seeded with CD4+ or CD8+ TCR-Tg or polyclonal T cells at the time of cardiac allograft transplantation. Only CD4+ TCR-Tg T cells accelerated rejection and, unexpectedly, led to a dose-dependent decrease in both transferred and endogenous T cells infiltrating the graft. In contrast, recipients of CD4+ TCR-Tg T cells exhibited enhanced endogenous donor-specific CD8+ T cell activation in the spleen and accelerated alloantibody production. Introduction of CD4+ TCR-Tg T cells also perturbed the intragraft accumulation of innate cell populations. Transferred CD4+ TCR-Tg T cells alter many aspects of endogenous alloimmunity, suggesting that caution should be used when interpreting experiments using these adoptively transferred cells because the overall nature of allograft rejection may be altered. These results also may have implications for adoptive CD4+ T cell immunotherapy in tumor and infectious clinical settings because cell infusion may have additional effects on natural immune responses.
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Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Rechazo de Injerto/inmunología , Trasplante de Corazón , Isoanticuerpos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/inmunología , Traslado Adoptivo , Aloinjertos , Animales , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/metabolismoRESUMEN
The problem actuality is caused by significant enhancement of the incidence rate for inflammatory diseases of the head and neck tissues, first of all of the oral cavity floor abscesses and phlegmons, which causes severe forms of mediastinitis while inadequate treatment. The authors have had established, that Toll-like receptors (TLR) initiate a cascade of anti-inflammatory reactions of the inborn immunity, followed by synthesis of a certain cytokines, and their genetic polymorphism changes the immune reactivity of the organism. Trustworthy correlation of the gene TLR4 (rs4986790) polymorphism 896A/G was proved with high risk of the odontogenic phlegmon of the oral cavity floor occurrence, what would permit to prognosticate the disease course in early terms, to optimize the schemes of its prophylaxis and treatment.
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Celulitis (Flemón)/genética , Suelo de la Boca/metabolismo , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/genética , Adulto , Alelos , Celulitis (Flemón)/inmunología , Celulitis (Flemón)/patología , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Boca/inmunología , Boca/metabolismo , Boca/patología , Suelo de la Boca/inmunología , Suelo de la Boca/patología , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/inmunologíaRESUMEN
The mesolimbic dopamine (DA) system (MDS) is the canonical "reward" pathway that has been studied extensively in the context of the rewarding properties of sex, food, and drugs of abuse. In contrast, very little is known about the role of the MDS in the processing of the rewarding and aversive properties of social stimuli. Social interactions can be characterized by their salience (i.e., importance) and their rewarding or aversive properties (i.e., valence). Here, we test the novel hypothesis that projections from the medial ventral tegmental area (VTA) to the nucleus accumbens (NAc) core codes for the salience of social stimuli through the phasic release of DA in response to both rewarding and aversive social stimuli. In contrast, we hypothesize that projections from the lateral VTA to the NAc shell codes for the rewarding properties of social stimuli by increasing the tonic release of DA and the aversive properties of social stimuli by reducing the tonic release of DA. Using DA amperometry, which monitors DA signaling with a high degree of temporal and anatomical resolution, we measured DA signaling in the NAc core or shell while rewarding and aversive social interactions were taking place. These findings, as well as additional anatomical and functional studies, provide strong support for the proposed neural circuitry underlying the response of the MDS to social stimuli. Together, these data provide a novel conceptualization of how the functional and anatomical heterogeneity within the MDS detect and distinguish between social salience, social reward, and social aversion. Significance Statement: Social interactions of both positive and negative valence are highly salient stimuli that profoundly impact social behavior and social relationships. Although DA projections from the VTA to the NAc are involved in reward and aversion little is known about their role in the saliency and valence of social stimuli. Here, we report that DA projections from the mVTA to the NAc core signal the salience of social stimuli, whereas projections from the lVTA to the NAc shell signal valence of social stimuli. This work extends our current understanding of the role of DA in the MDS by characterizing its subcircuit connectivity and associated function in the processing of rewarding and aversive social stimuli.
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Objective: The impact of establishing a pulmonary embolism response team (PERT) in patients with pulmonary embolism (PE) has been proven in many developed countries. However, the efficacy of a PERT largely depends on expertise and infrastructure. This study explored the benefit of establishing a PERT in developing countries with limited healthcare resources by comparing the outcomes of patients with acute PE before and after PERT establishment at University Medical Center Ho Chi Minh City in Vietnam. Methods: We conducted a single-center observational study from January 1, 2019, to August 1, 2021. All patients with PE confirmed on computed tomography were included. Patients admitted before PERT establishment were treated by cardiologists alone, while those hospitalized after PERT establishment were managed by the PERT. Results: A total of 130 patients were included (pre-PERT estab-lishment: 51 patients; post-PERT establishment: 79 patients). The demographic characteristics, severity of PE, and clinical and laboratory findings were similar between the two groups. The post-PERT establishment group had a lower incidence rate of major and clinically relevant nonmajor bleeding (11.3% vs. 31.4%, p = 0.005) and required more interventional therapies (16.5% vs. 3.9%, p = 0.046) than did the pre-PERT establishment group. The in-hospital mortality rate decreased in the post-PERT establishment group compared with that in the pre-PERT establishment group (8.9% vs. 21.6%, p = 0.041). Conclusions: Involvement of the PERT in PE management was associated with improved outcomes of patients with PE, including reduced bleeding and mortality rates in a resource-constrained hospital.
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Países en Desarrollo , Embolia Pulmonar , Humanos , Mortalidad Hospitalaria , Hospitalización , Hospitales , Embolia Pulmonar/terapiaRESUMEN
OBJECTIVE: This report aimed to characterize clinical and imaging characteristics and outcomes of the patients with lower cervical spine injury combined with spinal cord paralysis who underwent posterior cervical spine surgery. PATIENTS AND METHODS: Between January 2019 and December 2020, a retrospective evaluation of prospectively collected data at one institution was conducted. We included all patients who were diagnosed with subaxial cervical spine injuries (C3-7), had spinal cord paralysis, and underwent posterior cervical spine surgery. Clinical profile, preoperative characteristics, intraoperative data, and postoperative outcomes were retrieved from prospective patients' medical records and computerized database. RESULTS: Among 70 selected patients, most were male (66, 94.29%) and the average age was 48.41 ± 14.33 years. Most of them worked in agriculture (90.4%). Clinical symptoms included neck pain (58, 82.86%), cervical radiculopathy (50, 71.43%), loss of sensation (44, 62.86%), and decreased sensation (21, 30.00%). The most frequent cervical spinal injuries involved C5 (28.57%), followed by C7 (14.29%). Circular muscle dysfunction was present in 65 (92.86%) patients. Early complications included respiratory failure (12.85%), pneumonia (11.42%), bedsores (8.57%), and urinary tract infection (7.14%). Common late complications included movement disorder (48.21%), muscle weakness and stiffness (37.50%), sensory disturbances (32.14%), urinary tract infection (17.86%), bedsores (16.07%), and pneumonia (5.36%). Patients after surgery and at follow-up had a significant improvement compared to preoperative assessment according to the AIS classification, and recovery of smooth muscle. Three patients died within 1 month following surgery, 3 within 1-3 month(s), 2 within 3-6 months, and 1 case beyond 6 months. CONCLUSIONS: In hospital-based clinical condition with limited practice approach, our study indicated specific clinical and imaging characteristics of Vietnamese patients with lower cervical spine injury combined with spinal cord paralysis. With high postoperative mortality rate, commonly late complications after posterior cervical spine surgical approach were pain and difficulty in neck movement, muscle weakness and stiffness, and nerve root pain.
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Úlcera por Presión , Enfermedades de la Columna Vertebral , Traumatismos Vertebrales , Adulto , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Debilidad Muscular , Dolor , Parálisis , Complicaciones Posoperatorias , Estudios Prospectivos , Estudios Retrospectivos , Médula Espinal , Resultado del TratamientoRESUMEN
Abstract: we present our experiences of a patient with right femoral artery and right coronary artery pseudoaneurysms after percutaneous coro-nary intervention (PCI). These complications are rare in transfemoral coronary intervention. The patient underwent PCI to treat a chronic total occlusion (CTO) lesion at the right coronary artery (RCA) and developed sepsis due to Staphylococcus aureus infection following the use of femoral artery closure devices (FACD). To solve these complications, the patient underwent two vascular surgeries and a coronary artery bypass grafting (CABG) to the RCA. To manage these conditions, we need to recognize them early and treat them properly by surgery. Interventional cardiologists should keep in mind that there are potential vascular complications associated with a PCI using FACD.
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Aneurisma Falso , Oclusión Coronaria , Intervención Coronaria Percutánea , Aneurisma Falso/diagnóstico por imagen , Aneurisma Falso/etiología , Aneurisma Falso/terapia , Oclusión Coronaria/cirugía , Vasos Coronarios/cirugía , Arteria Femoral/cirugía , Humanos , Intervención Coronaria Percutánea/efectos adversos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
The traditional way for discovering genes which drive cancer (namely cancer drivers) neglects the dynamic information of cancer development, even though it is well known that cancer progresses dynamically. To enhance cancer driver discovery, we expand cancer driver concept to dynamic cancer driver as a gene driving one or more bio-pathological transitions during cancer progression. Our method refers to the fact that cancer should not be considered as a single process but a compendium of altered biological processes causing the disease to develop over time. Reciprocally, different drivers of cancer can potentially be discovered by analysing different bio-pathological pathways. We propose a novel approach for causal inference of genes driving one or more core processes during cancer development (i.e. dynamic cancer driver). We use the concept of pseudotime for inferring the latent progression of samples along a biological transition during cancer and identifying a critical event when such a process is significantly deviated from normal to carcinogenic. We infer driver genes by assessing the causal effect they have on the process after such a critical event. We have applied our method to single-cell and bulk sequencing datasets of breast cancer. The evaluation results show that our method outperforms well-recognized cancer driver inference methods. These results suggest that including information of the underlying dynamics of cancer improves the inference process (in comparison with using static data), and allows us to discover different sets of driver genes from different processes in cancer. R scripts and datasets can be found at https://github.com/AndresMCB/DynamicCancerDriver.
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Algoritmos , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genéticaRESUMEN
OBJECTIVE: The direct effects of adipokines on skeletal muscle metabolism have been well established. As the combinatorial effects of adipokine mixtures are likely to be of more physiological relevance, we used a coculture system of primary rat adipocytes and L6 skeletal muscle cells to examine the effects of adiponectin derived from primary rat adipocytes on rat skeletal muscle cells. RESULTS: We showed that coculture with adipocytes stimulated glucose uptake in L6 cells within 30 min and this correlated with an increase of glucose transporter isoform 4 (GLUT4) localization to the plasma membrane. These effects were dependent on the reorganization of the actin cytoskeleton, demonstrated by rhodamine-labeled phalloidin immunofluorescence, as cytochalasin D attenuated the glucose uptake induced by adipocyte-conditioned media. Temporal analysis revealed that enhanced glucose uptake was maintained after 24 h of coculture, and this was attributed to an increase in both GLUT1 expression and the cell surface content of GLUT4. We established a role for adiponectin in mediating these effects as antibody-mediated neutralization attenuated the metabolic effects of adipocyte-conditioned media. Furthermore, compound C blocked these effects, suggesting an important role for AMPK. Importantly, when we compared the effects of full-length recombinant adiponectin with adipocyte-conditioned media, we confirmed that recombinant adiponectin was unable to stimulate glucose uptake in L6 cells despite having an important role in adipocyte-conditioned media. CONCLUSIONS: Our results demonstrate the importance of examining the effects of adipokines in the context of physiologically relevant mixtures to accurately determine their metabolic effects on skeletal muscle.
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Adipocitos/metabolismo , Adipoquinas/fisiología , Glucosa/metabolismo , Leptina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Adipoquinas/farmacología , Adiponectina/farmacología , Animales , Transporte Biológico/fisiología , Membrana Celular/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Medios de Cultivo Condicionados/farmacología , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Masculino , Fibras Musculares Esqueléticas/efectos de los fármacos , Ratas , Ratas Wistar , Proteínas Recombinantes/farmacologíaRESUMEN
The membrane bound large-conductance, calcium-activated potassium channel (BKCa) is an important regulator of neuronal activity. Here we describe the identification and structure-activity relationship of a novel class of potent tetrahydroquinoline BKCa agonists. An example from this class of BKCa agonists was shown to depress the spontaneous neuronal discharges in an electrophysiological model of migraine.
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Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/agonistas , Neuronas/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Fenómenos Electrofisiológicos/efectos de los fármacos , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/patología , Modelos Biológicos , Ratas , Relación Estructura-Actividad , Núcleos del Trigémino/citologíaRESUMEN
Background: In designing responses to the COVID-19 pandemic, it is critical to understand what has already worked well. We aimed to identify countries with emerging success stories from whom policymakers might draw important lessons. Methods: We developed a process to first include countries with large enough populations that results were unlikely to be due to chance, that had sufficient cases for response mechanisms to be tested, and that shared the necessary publicly available data. Within these countries, we looked at indicators suggesting success in terms of detecting disease, containing the outbreak, and treating those who were unwell. To support comparability, we measured indicators per capita (per million) and across time. We then used the indicators to identify three countries with emerging success stories to include some diversity in global region, population demographics and form of government. Results: We identified 66 countries that met our inclusion criteria on 18 th May 2020. Several of these countries had indicators of success against the set indicators at different times in the outbreak. Vietnam had high levels of testing and successful containment with no deaths reported. South Korea had high levels of testing early in the outbreak, supporting containment. Germany had high levels of sustained testing and slower increases in cases and deaths than seen in other comparable settings. Conclusions: At the time of our assessment, Vietnam and South Korea were able to contain the outbreak of COVID-19 and avoid the exponential growth in cases seen elsewhere. Germany had more cases and deaths, but was nevertheless able to contain and mitigate the outbreak. Despite the many limitations to the data currently available, looking at comparative data can help identify countries from whom we can draw lessons, so that countries can inform and adapt their strategies for success in response to COVID-19.
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Determining groundwater recharge is in particular in areas with Monsoon rainfall a challenge. Several methods were used to estimate groundwater recharge for the first time ever for the urban area of Hanoi city, Vietnam. Water table fluctuation method (WTF), hydrograph analyses including recession curve displacement, graphical separation, the Automated Web GIS-Base Hydrology Analysis Tool (WHAT), and empirical formulas were utilized. The mean recharge is approximately 340â¯mm/year accounting for 20% of precipitation in the period 1996 to 2009 with a certain decrease during this period. Baseflow separation methods show the highest values, whereas the displacement recession curve obtains the lowest recharge. The WTF methods approximate values are close to the mean value of all other proxies. The differences between all proxies are around 10%, and Spearman correlation is statistically significant. This indicates that these methods can be used to estimate recharge for this area. With long-term data, however, the results of WTF appear more consistent and more reasonable than the other approaches.