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Polymyositis/Dermatomyositis (PM/DM) is an idiopathic inflammatory myopathy (IIM) manifesting mainly as symmetrical proximal muscle weakness and/or typical cutaneous features due to autoimmune mechanisms. Clinically amyopathic dermatomyositis (CADM) is a subset of DM that exhibits only the typical cutaneous features without any clinical muscle symptoms. Several autoantibodies have been found specifically in patients with PM/DM, including CADM patients. Anti-KS antibody is one of a group of anti-aminoacyl transfer RNA (ARS) antibodies that are mainly associated with fever, Raynaud's phenomenon, polyarthritis, and interstitial lung disease (ILD), whereas anti-TIF1-γ antibody is frequently found in DM patients with malignancy. Here, we report a CADM patient having both anti-KS antibody and anti-TIF1-γ antibody. This patient developed an acute exacerbation of ILD and was successfully treated with high dose corticosteroid pulse therapy together with immunosuppressive agents. Although earlier experience had indicated that the seminal characteristic of anti-KS-positive ILD was slowly developing disease onset with little or no progression over the clinical course, the present patient suffered rapidly progressive disease.
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Mitogen-activated protein kinase kinases (MAP2Ks) 1, 4, and 7 are potential targets for treating various diseases. Here, we solved the crystal structures of MAP2K1 and MAP2K4 complexed with covalent inhibitor 5Z-7-oxozeaenol (5Z7O). The elucidated structures showed that 5Z7O was non-covalently bound to the ATP binding site of MAP2K4, while it covalently attached to cysteine at the DFG-1 position of the deep ATP site of MAP2K1. In contrast, we previously showed that 5Z7O covalently binds to MAP2K7 via another cysteine on the solvent-accessible edge of the ATP site. Structural analyses and molecular dynamics calculations indicated that the configuration and mobility of conserved gatekeeper methionine located at the central ATP site regulated the binding and access of 5Z7O to the ATP site of MAP2Ks. These structural features provide clues for developing highly potent and selective inhibitors against MAP2Ks. Abbreviations: ATP, adenosine triphosphate; FDA, Food and Drug Administration; MAP2Ks, mitogen-activated protein kinase kinases; MD, molecular dynamics; NSCLC, non-small cell lung cancer; 5Z7O, 5Z-7-oxozeaenol; PDB, protein data bank; RMSD, root-mean-square deviation.
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Groundwater contamination by nitrates presents significant risks to both human health and the environment. In groundwater characterized as oligotrophic-low in organic carbon, but abundant in carbonate and phosphate-chemolithoautotrophic bacteria, including nitrate-reducing Fe(II)-oxidizing bacteria (NRFeOB), play a vital role in denitrification. The chemoautotrophic nitrate reduction is sensitive to environmental factors, including widespread iron oxides like hematite in nature. However, the specific mechanisms of this influence remain unclear. We examined the mechanism of how hematite impacts autotrophic nitrate reduction in a model NRFeOB community known as culture KS. We found that hematite enhances the rate of autotrophic nitrate reduction by promoting Fe(II) oxidation. Mössbauer spectroscopy detected a significant amount of adsorbed Fe(II) when hematite was present, leading to a reduction in dissolved ferrous iron. In conjunction with XRD data, it can be inferred that the formation of vivianite decreased, thereby increasing the Fe(II) activity in the reaction system. Within the culture KS bacterial consortium, hematite fosters the proliferation of autotrophic microorganisms, specifically Gallionellaceae, and amplifies the presence of denitrifying microbes, notably Rhodanobacter. This dual enhancement improves Fe(II) utilization and nitrate reduction capabilities. Our findings highlight intricate interactions between hematite and a model NRFeOB community, offering insights into groundwater nitrate removal mechanisms and the ecological strategies of autotrophic bacteria in mineral-rich environments.
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Procesos Autotróficos , Compuestos Férricos , Agua Subterránea , Nitratos , Fosfatos , Compuestos Férricos/metabolismo , Agua Subterránea/química , Agua Subterránea/microbiología , Fosfatos/metabolismo , Carbonatos , Desnitrificación , Contaminantes Químicos del Agua/metabolismo , Oxidación-Reducción , Hierro/metabolismo , Bacterias/metabolismo , Compuestos Ferrosos/metabolismoRESUMEN
Dietary potassium deficiency causes stimulation of sodium reabsorption leading to increased risk in blood pressure elevation. The distal convoluted tubule is the main rheostat linking plasma K+ levels to the activity of the Na-Cl cotransporter (NCC). This occurs through basolateral membrane potential sensing by Kir4.1/5.1; decrease in intracellular Cl-; activation of WNK4, interaction and phosphorylation of Ste20/SPS1-related Proline/Alanine-rich Kinase (SPAK); binding of the calcium-binding protein 39 (cab39) adaptor protein to SPAK leading to its trafficking to the apical membrane; and SPAK binding, phosphorylating, and activating NCC. As Kidney-Specific With-No-Lysine (K) Kinase 1 (WNK1) isoform (KS-WNK1) is another participant in this pathway, we examined its function in NCC regulation. We eliminated KS-WNK1 specifically in the DCT and demonstrated increased expression of WNK4 and L-WNK1 and increased phosphorylation of NCC. As in other KS-WNK1 models, the mice are not hyperkalemic. While wild-type mice under low dietary K+ conditions demonstrated increased NCC phosphorylation, the phosphorylation levels of the transporter, already high in the KS-WNK1, did not change under the low K+ diet. Thus, in the absence of KS-WNK1 the transporter has lost its sensitivity to low plasma K+. We also show that under low K+ conditions, in the absence of KS-WNK1, there is no formation of WNK bodies. These bodies are observed in adjacent segments, not affected by the targeting of KS-WNK1. As our data are overall consistent with those of the global KS-WNK1 knockout, they indicate that the DCT is the predominant segment affecting the salt transport regulated by KS-WNK1.
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Hydatigera kamiyai (H. kamiyai) is a new species within Hydatigera that has recently been resurrected. Voles and cats are hosts of H. kamiyai and have a certain impact on its health and economy. Moreover, the Qinghai-Tibetan plateau (QTP) is a research hotspot representing Earth's biodiversity, as its unique geographical environment and climatic conditions support the growth of a variety of mammals and provide favorable conditions for various parasites to complete their life history. The aim of this study was to reveal the phylogenetic relationships and divergence times of H. kamiyai strains isolated from Neodon fuscus on the QTP using morphological and molecular methods. In this study, we morphologically observed H. kamiyai and sequenced the whole mitochondrial genome. Then, we constructed phylogenetic trees with the maximum likelihood (ML) and Bayesian inference (BI) methods. The GTR alternative model was selected for divergence time analysis. These data demonstrated that the results were consistent with the general morphological characteristics of Hydatigera. The whole genome of H. kamiyai was 13,822 bp in size, and the A + T content (73%) was greater than the G + C content (27%). The Ka/Ks values were all <1, indicating that all 13 protein-coding genes (13 PCGs) underwent purifying selection during the process of evolution. The phylogenetic tree generated based on the 13 PCGs, cytochrom oxidase subunit I (COI), 18S rRNA and 28S rRNA revealed close phylogenetic relationships between H. kamiyai and Hydatigera, with high node support for the relationship. The divergence time based on 13 PCGs indicated that H. kamiyai diverged approximately 11.3 million years ago (Mya) in the Miocene. Interestingly, it diverged later than the period of rapid uplift in the QTP. We also speculated that H. kamiyai differentiation was caused by host differentiation due to the favorable living conditions brought about by the uplift of the QTP. As there have been relatively few investigations on the mitochondrial genome of H. kamiyai, our study could provide factual support for further studies of H. kamiyai on the QTP. We also emphasized the importance of further studies of its hosts, Neodon fuscus and cats, which will be important for further understanding the life cycle of H. kamiyai.
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Individuals with Kabuki syndrome present with immunodeficiency; however, how pathogenic variants in the gene encoding the histone-modifying enzyme lysine methyltransferase 2D (KMT2D) lead to immune alterations remain poorly understood. Following up on our prior report of KMT2D-altered integrin expression in B-cells, we performed targeted analyses of KMT2D's influence on integrin expression in T-cells throughout development (thymocytes through peripheral T-cells) in murine cells with constitutive- and conditional-targeted Kmt2d deletion. Using high-throughput RNA-sequencing and flow cytometry, we reveal decreased expression (both at the transcriptional and translational levels) of a cluster of leukocyte-specific integrins, which perturb aspects of T-cell activation, maturation, adhesion/localization, and effector function. H3K4me3 ChIP-PCR suggests that these evolutionary similar integrins are under direct control of KMT2D. KMT2D loss also alters multiple downstream programming/signaling pathways, including integrin-based localization, which can influence T-cell populations. We further demonstrated that KMT2D deficiency is associated with the accumulation of murine CD8+ single-positive (SP) thymocytes and shifts in both human and murine peripheral T-cell populations, including the reduction of the CD4+ recent thymic emigrant (RTE) population. Together, these data show that the targeted loss of Kmt2d in the T-cell lineage recapitulates several distinct features of Kabuki syndrome-associated immune deficiency and implicates epigenetic mechanisms in the regulation of integrin signaling.
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Regulación de la Expresión Génica , N-Metiltransferasa de Histona-Lisina , Integrinas , Proteína de la Leucemia Mieloide-Linfoide , Linfocitos T , Animales , Humanos , Ratones , Anomalías Múltiples , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Cara/anomalías , Regulación de la Expresión Génica/genética , Enfermedades Hematológicas , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Integrinas/metabolismo , Integrinas/genética , Activación de Linfocitos/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Proteínas de Neoplasias/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismo , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/inmunología , Enfermedades Vestibulares/metabolismoRESUMEN
Klinefelter syndrome (KS) is the most prevalent chromosomal disorder occurring in males. It is defined by an additional X chromosome, 47,XXY, resulting from errors in chromosomal segregation during parental gametogenesis. A major phenotype is impaired reproductive function, in the form of low testosterone and infertility. This review comprehensively examines the genetic and physiological factors contributing to infertility in KS, in addition to emergent assisted reproductive technologies, and the unique ethical challenges KS patients face when seeking infertility treatment. The pathology underlying KS is increased susceptibility for meiotic errors during spermatogenesis, resulting in aneuploid or even polyploid gametes. Specific genetic elements potentiating this susceptibility include polymorphisms in checkpoint genes regulating chromosomal synapsis and segregation. Physiologically, the additional sex chromosome also alters testicular endocrinology and metabolism by dysregulating interstitial and Sertoli cell function, collectively impairing normal sperm development. Additionally, epigenetic modifications like aberrant DNA methylation are being increasingly implicated in these disruptions. We also discuss assisted reproductive approaches leveraged in infertility management for KS patients. Application of assisted reproductive approaches, along with deep comprehension of the meiotic and endocrine disturbances precipitated by supernumerary X chromosomes, shows promise in enabling biological parenthood for KS individuals. This will require continued multidisciplinary collaboration between experts with background of genetics, physiology, ethics and clinical reproductive medicine.
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AIMS: Human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCM) could be a helpful tool to study the physiology and diseases of the human atrium. To fulfil this expectation, the electrophysiology of hiPSC-aCM should closely resemble the situation in the human atrium. Data on the contribution of the slowly activating delayed rectifier currents (IKs) to repolarization are lacking for both human atrium and hiPSC-aCM. METHODS AND RESULTS: Human atrial tissues were obtained from patients with sinus rhythm (SR) or atrial fibrillation (AF). Currents were measured in human atrial cardiomyocytes (aCM) and compared with hiPSC-aCM and used to model IKs contribution to action potential (AP) shape. Action potential was recorded by sharp microelectrodes. HMR-1556 (1â µM) was used to identify IKs and to estimate IKs contribution to repolarization. Less than 50% of hiPSC-aCM and aCM possessed IKs. Frequency of occurrence, current densities, activation/deactivation kinetics, and voltage dependency of IKs did not differ significantly between hiPSC-aCM and aCM, neither in SR nor AF. ß-Adrenoceptor stimulation with isoprenaline did not increase IKs neither in aCM nor in hiPSC-aCM. In tissue from SR, block of IKs with HMR-1556 did not lengthen the action potential duration, even when repolarization reserve was reduced by block of the ultra-rapid repolarizing current with 4-aminopyridine or the rapidly activating delayed rectifier potassium outward current with E-4031. CONCLUSION: I Ks exists in hiPSC-aCM with biophysics not different from aCM. As in adult human atrium (SR and AF), IKs does not appear to relevantly contribute to repolarization in hiPSC-aCM.
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Potenciales de Acción , Fibrilación Atrial , Canales de Potasio de Tipo Rectificador Tardío , Atrios Cardíacos , Células Madre Pluripotentes Inducidas , Miocitos Cardíacos , Humanos , Miocitos Cardíacos/fisiología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Atrios Cardíacos/fisiopatología , Canales de Potasio de Tipo Rectificador Tardío/metabolismo , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/metabolismo , Femenino , Células Cultivadas , Masculino , Persona de Mediana Edad , Cinética , Anciano , Diferenciación Celular , Modelos Cardiovasculares , Bloqueadores de los Canales de Potasio/farmacologíaRESUMEN
Here, we characterized the p.Arg583His (R583H) Kv7.1 mutation, identified in two unrelated families suffered from LQT syndrome. This mutation is located in the HС-HD linker of the cytoplasmic portion of the Kv7.1 channel. This linker, together with HD helix are responsible for binding the A-kinase anchoring protein 9 (AKAP9), Yotiao. We studied the electrophysiological characteristics of the mutated channel expressed in CHO-K1 along with KCNE1 subunit and Yotiao protein, using the whole-cell patch-clamp technique. We found that R583H mutation, even at the heterozygous state, impedes IKs activation. Molecular modeling showed that HС and HD helixes of the C-terminal part of Kv7.1 channel are swapped along the C-terminus length of the channel and that R583 position is exposed to the outer surface of HC-HD tandem coiled-coil. Interestingly, the adenylate cyclase activator, forskolin had a smaller effect on the mutant channel comparing with the WT protein, suggesting that R583H mutation may disrupt the interaction of the channel with the adaptor protein Yotiao and, therefore, may impair phosphorylation of the KCNQ1 channel.
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Proteínas de Anclaje a la Quinasa A , Proteínas del Citoesqueleto , Canal de Potasio KCNQ1 , Síndrome de QT Prolongado , Animales , Femenino , Humanos , Masculino , Proteínas de Anclaje a la Quinasa A/metabolismo , Proteínas de Anclaje a la Quinasa A/genética , Proteínas de Anclaje a la Quinasa A/química , Células CHO , Cricetulus , Proteínas del Citoesqueleto/química , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Canal de Potasio KCNQ1/genética , Canal de Potasio KCNQ1/metabolismo , Canal de Potasio KCNQ1/química , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/metabolismo , Modelos Moleculares , Mutación , Canales de Potasio con Entrada de Voltaje/química , Canales de Potasio con Entrada de Voltaje/genética , Canales de Potasio con Entrada de Voltaje/metabolismo , Unión ProteicaRESUMEN
Species delimitation based on lineage definition has become increasingly popular. However, these methods have been limited, especially for species that lack genomic data and are morphologically similar. The trickiest part for the species identification is that the interspecific and intraspecific boundaries are vague. Taking Prorocentrum (Dinophyta) as an example, analysis of cell morphology, growth, and toxin synthesis in both species of P. lima and P. arenarium does not provide a reliable basis for species delineation. However, through phylogenetic and genetic distance analyses of their ITS and LSU sequences, establishment of evolutionary tree based on orthologous gene sequences, and combining the results of automatic barcode gap discovery and Poisson tree processes models, it was sustained that P. arenarium does not belong to the P. lima complex and should be considered as an independent species. Interspecies genetic evolution analysis revealed that P. lima and P. arenarium may contribute to evolutionary direction that favors combating reverse environmental factors. In P. lima, viral invasion may be one of the reasons for its large genome size. In the study, P. lima complex has been selected as an example to enhance the taxonomic identification of microalgae through molecular and genetic evolution, offering valuable insights into refining taxonomic identification and promoting microbial biodiversity research in other species.IMPORTANCEMicroalgae, especially the species known as Prorocentrum, have received significant attention due to their ability to trigger harmful algal blooms and produce toxins. However, the boundaries between species and within species are ambiguous. Clear and comprehensive species delineation indicates that Prorocentrum arenarium should be considered as an independent species, separate from the Prorocentrum lima complex. Improving the classification and identification of microalgae through molecular and genetic evolution will provide reference points for other cryptic species. Prorocentrum occupy multiple ecological niches in marine environments, and studying their evolutionary direction contributes to understanding their ecological adaptations and community succession.
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Dinoflagelados , Evolución Molecular , Microalgas , Filogenia , Microalgas/genética , Microalgas/clasificación , Dinoflagelados/genética , Dinoflagelados/clasificación , Código de Barras del ADN TaxonómicoRESUMEN
One kind of angioproliferative disorder is Kaposi's sarcoma (KS). Growth of spindle-shaped cells, edema, inflammation, and neoangiogenesis are its defining features. Because it lacks the typical indicators of malignancy, it is classified as an intermediate neoplasm. People who are immunocompromised, receiving organ transplants, or receiving antiretroviral therapy are linked to KS. Although lymph node involvement by KS is extremely uncommon, when it does occur, it usually manifests as either the epidemic form in (Human Immuno-deficiency) HIV-positive patients or the endemic form in Africans. There are four primary clinical manifestations of KS that have been documented: endemic, epidemic, iatrogenic, and classic. The diagnosis of KS is made by history, physical examination, and tissue biopsy. When treating localized disease, highly active antiretroviral therapy (HAART) may be sufficient to either improve or completely eradicate the illness. Nonetheless, chemotherapy and HAART would be necessary in the case of widespread illness. Here, we present the case of a 28-year-old female patient who is HIV positive and has a viral load that is not detected. She presented with generalized lymphadenopathy of 8 months duration. She had no cutaneous manifestations. The lymphadenopathy involved the tonsils, axilla, inguinal, and an unusual site, intraparotid on both sides. After a pathologic examination of the lymph nodes, she was found to have epidemic-type KS and was treated with HAART and chemotherapy. In our nation, we are not aware of any published case reports pertaining to a case like this. The purpose of this case report is to raise physicians' awareness of this uncommon ailment and to encourage them to suspect KS when HIV patients exhibit generalized lymphadenopathy. The early initiation of systemic treatment is lifesaving for these patients.
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Klinefelter syndrome (KS) is the most frequent genetic anomaly in infertile men. Given its unclear mechanism, we aim to investigate critical genes and pathways in the pathogenesis of KS based on three bulk and one single-cell transcriptome data sets from Gene Expression Omnibus. We merged two data sets (GSE42331 and GSE47584) with human KS whole blood samples. When comparing the control and KS samples, five hub genes, including defensin alpha 4 (DEFA4), bactericidal permeability increasing protein (BPI), myeloperoxidase (MPO), intelectin 1 (ITLN1), and Xg Glycoprotein (XG), were identified. Besides, infiltrated degree of certain immune cells such as CD56bright NK cell were positively associated with the expression of ITLN1 and XG. Kyoto Encyclopedia of Genes and Genomes analysis identified upregulated phosphatidylinositol 3-kinase (PI3K)/AKT pathway in KS. Gene set enrichment analysis followed by gene set variation analysis confirmed the upregulation of G2M checkpoint and heme metabolism in KS. Thereafter, the GSE200680 data set was used for external validation of the expression variation of hub genes from healthy to KS testicular samples, and each hub gene yielded excellent discriminatory capability for KS without exception. At the single-cell level, the GSE136353 data set was utilized to evaluate intercellular communication between different cell types in KS patient, and strong correlations were detected between macrophages/ dendritic cells/ NK cells and the other cell types. Collectively, we provided hub genes, pathways, immune cell infiltration degree, and cell-cell communication in KS, warranting novel insights into the pathogenesis of this disease.
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Peptides are mid-size molecules (700-2000 g/mol) and have attracted particular interest as therapeutic modalities as they are superior in controlling protein-protein interactions, a process that is a typical drug target category, compared with small molecules (<500 g/mol). In 2020, we identified KS-58 (1333 g/mol) as a K-Ras(G12D)-inhibitory bicyclic peptide and suggested its cell membrane permeability. However, the membrane permeability mechanism had not been elucidated. In this study, we aim to clarify the mechanism by molecular dynamics (MD) simulations. Initially, we simulated the molecular conformations of KS-58 in water (a polar solvent) and in chloroform (a non-polar solvent). The identified stable conformations were significantly different in each solvent. KS-58 behaves as a chameleon-like molecule as it alters its polar surface area (PSA) depending on the solvent environment. It was also discovered that orientation of Asp's side chain is a critical energy barrier for KS-58 altering its conformation from hydrophilic to lipophilic. Taking these properties into consideration, we simulated its lipid bilayer membrane permeability. KS-58 shifted toward the inside of the lipid bilayer membrane with altering its conformations to lipophilic. When the simulation condition was set in deionized form of that carboxy group of Asp, KS-58 traveled deeper inside the cell membrane. PSA and the depth of the membrane penetration correlated. In vitro data suggested that cell membrane permeability of KS-58 is improved in weakly acidic conditions leading to partial deionization of the carboxy group. Our data provide an example of the molecular properties of mid-size peptides with membrane accessibility and propose an effective metadynamics approach to elucidate such molecular mechanisms by MD simulations.
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Membrana Dobles de Lípidos , Simulación de Dinámica Molecular , Péptidos Cíclicos , Membrana Dobles de Lípidos/química , Péptidos/química , Solventes/química , PermeabilidadRESUMEN
A total of 10 specimens of Alcyonacea corals were collected at depths ranging from 905 m to 1â¯633 m by the manned submersible Shenhai Yongshi during two cruises in the South China Sea (SCS). Based on mitochondrial genomic characteristics, morphological examination, and sclerite scanning electron microscopy, the samples were categorized into four suborders (Calcaxonia, Holaxonia, Scleraxonia, and Stolonifera), and identified as 9 possible new cold-water coral species. Assessments of GC-skew dissimilarity, phylogenetic distance, and average nucleotide identity (ANI) revealed a slow evolutionary rate for the octocoral mitochondrial sequences. The nonsynonymous ( Ka) to synonymous ( Ks) substitution ratio ( Ka/ Ks) suggested that the 14 protein-coding genes (PCGs) were under purifying selection, likely due to specific deep-sea environmental pressures. Correlation analysis of the median Ka/ Ks values of five gene families and environmental factors indicated that the genes encoding cytochrome b (cyt b) and DNA mismatch repair protein ( mutS) may be influenced by environmental factors in the context of deep-sea species formation. This study highlights the slow evolutionary pace and adaptive mechanisms of deep-sea corals.
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Antozoos , Genoma Mitocondrial , Animales , Antozoos/genética , Filogenia , China , Citocromos b/genéticaRESUMEN
The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic that emerged in 2019 has been an unprecedented event in international science, as it has been possible to sequence millions of genomes, tracking their evolution very closely. This has enabled various types of secondary analyses of these genomes, including the measurement of their sequence selection pressure. In this work, we have been able to measure the selective pressure of all the described SARS-CoV-2 genes, even analyzed by sequence regions, and we show how this type of analysis allows us to separate the genes between those subject to positive selection (usually those that code for surface proteins or those exposed to the host immune system) and those subject to negative selection because they require greater conservation of their structure and function. We have also seen that when another gene with an overlapping reading frame appears within a gene sequence, the overlapping sequence between the two genes evolves under a stronger purifying selection than the average of the non-overlapping regions of the main gene. We propose this type of analysis as a useful tool for locating and analyzing all the genes of a viral genome when an adequate number of sequences are available.IMPORTANCEWe have analyzed the selection pressure of all severe acute respiratory syndrome coronavirus 2 genes by means of the nonsynonymous (Ka) to synonymous (Ks) substitution rate. We found that protein-coding genes are exposed to strong positive selection, especially in the regions of interaction with other molecules (host receptor and genome of the virus itself). However, overlapping coding regions are more protected and show negative selection. This suggests that this measure could be used to study viral gene function as well as overlapping genes.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Proteínas , Genoma Viral/genética , Genes Virales/genéticaRESUMEN
IMPORTANCE: Kaposi's sarcoma (KS) is the most common cancer in HIV-infected patients caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Hyperinflammation is the hallmark of KS. In this study, we have shown that KSHV mediates hyperinflammation by inducing IL-1α and suppressing IL-1Ra. Mechanistically, KSHV miRNAs and vFLIP induce hyperinflammation by activating the NF-κB pathway. A common anti-inflammatory agent dexamethasone blocks KSHV-induced hyperinflammation and tumorigenesis by activating glucocorticoid receptor signaling to suppress IL-1α and induce IL-1Ra. This work has identified IL-1-mediated inflammation as a potential therapeutic target and dexamethasone as a potential therapeutic agent for KSHV-induced malignancies.
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Transformación Celular Neoplásica , Dexametasona , Herpesvirus Humano 8 , Receptores de Glucocorticoides , Sarcoma de Kaposi , Humanos , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Dexametasona/farmacología , Dexametasona/uso terapéutico , Glucocorticoides/farmacología , Glucocorticoides/uso terapéutico , Herpesvirus Humano 8/fisiología , Inflamación/virología , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Receptores de Glucocorticoides/metabolismo , Sarcoma de Kaposi/tratamiento farmacológicoRESUMEN
As an economically important tree, Gleditsia sinensis Lam. is widely planted. A lack of background genetic information on G. sinensis hinders molecular breeding. Based on PacBio single-molecule real-time (SMRT) sequencing and analysis of G. sinensis, a total of 95,183 non-redundant transcript sequences were obtained, of which 93,668 contained complete open reading frames (ORFs), 2,858 were long non-coding RNAs (LncRNAs) and 18,855 alternative splicing (AS) events were identified. Genes orthologous to different Gleditsia species pairs were identified, stress-related genes had been positively selected during the evolution. AGA, AGG, and CCA were identified as the universal optimal codon in the genus of Gleditsia. EIF5A was selected as a suitable fluorescent quantitative reference gene. 315 Cytochrome P450 monooxygenases (CYP450s) and 147 uridine diphosphate (UDP)-glycosyltransferases (UGTs) were recognized through the PacBio SMRT transcriptome. Randomized selection of GsIAA14 for cloning verified the reliability of the PacBio SMRT transcriptome assembly sequence. In conclusion, the research data lay the foundation for further analysis of the evolutionary mechanism and molecular breeding of Gleditsia.
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Gleditsia , Transcriptoma , Gleditsia/genética , Reproducibilidad de los Resultados , Empalme AlternativoRESUMEN
Inositol hexakisphosphate (IP6), a naturally occurring metabolite of inositol with specific functions in different organelles or tissues, participates in numerous physiological processes and plays a key role in mammalian metabolic regulation. However, current IP6 detection methods, i.e., high-performance liquid chromatography and gel electrophoresis, require sample destruction and lack spatiotemporal resolution. Here, we construct and characterize a genetically encoded fluorescence biosensor named HIPSer that enables ratiometric quantitative IP6 detection in HEK293T cells and subcellular compartments. We demonstrate that HIPSer has a high sensitivity and relative selectivity for IP6 in vitro. We also provide proof-of-concept evidence that HIPSer can monitor IP6 levels in real time in HEK293T cells and can be targeted for IP6 detection in the nucleus of HEK293T cells. Moreover, HIPSer could also detect changes in IP6 content induced by chemical inhibition of IP6-metabolizing enzymes in HEK293T cells. Thus, HIPSer achieves spatiotemporally precise detection of fluctuations in endogenous IP6 in live cells and provides a versatile tool for mechanistic investigations of inositol phosphate functions in metabolism and signaling.
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Fosfatos de Inositol , Ácido Fítico , Humanos , Fluorescencia , Células HEK293 , Fosfatos de Inositol/química , Fosfatos de Inositol/metabolismo , Ácido Fítico/química , Ácido Fítico/metabolismoRESUMEN
Composites are materials that are widely used in industry, including yachting, railway and aviation. The properties of these materials can be modified by changing the type of reinforcement, the type of matrix, as well as the use of additives in the form of fillers and nanofillers that improve their mechanical or specific parameters. Due to the fact that these materials are often used for important structures, computational models using FEM tools may not be sufficient to determine the actual strength parameters, and what is more, to check them during operation. When designing structures made of composite materials, it is necessary to use high safety factors due to their behavior under several different types of loads, which is still difficult to determine precisely. This situation makes these structures much heavier and characterized by much higher strength properties than those that would actually be needed. In this article, the Kolmogorov-Sinai (K-S) metric entropy was used to determine the transition from the elastic to the viscoelastic state in GFRP (glass fiber reinforced polymer) composite materials without and with the addition of nanoaluminum, during a static tensile test. Additionally, the acoustic emission method was used during the research. This signal was further processed, and graphs were made of the number of events and the amplitude as a function of time. The obtained values were plotted on tensile graphs. The influence of the nano-filler on these parameters was also analyzed. The presented results show that it is possible to determine additional parameters affecting the strength of the structure for any composite materials.