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N-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve in vivo efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior in vivo efficacy compared to triantennary GalNAc-conjugated siRNAs.
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Enfermedades Cardiovasculares , Hepatocitos , Humanos , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/química , Análisis Costo-Beneficio , ARN Bicatenario , Acetilgalactosamina/química , Proteína 3 Similar a la AngiopoyetinaRESUMEN
This study aimed to explore the pharmacodynamics and mechanisms of different processing methods of Ligustrum lucidum Ait. (LLA) in addressing kidney-yin deficiency (KYD). Forty-eight Sprague-Dawley rats were divided into eight groups based on their weight. The KYD model was established by intragastric administration of levothyroxine sodium. Each group was administered the corresponding treatment for 15 consecutive days. The general condition of the rats during the treatment period was observed. In addition, the levels of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and the ratio of cAMP to cGMP in the serum of rats from different groups were measured. Serum samples were analyzed using the ultra-performance liquid chromatography (UPLC)-Orbitrap Fusion MS technique for metabolomics analysis. Compared with the model group, the general condition of the rats in the wine-steamed L. lucidum group (WL) and salt-steamed L. lucidum group (SSL) groups showed significant improvement. The serum levels of cAMP, cGMP, and the cAMP-to-cGMP ratio tended to return to normal. Metabolic analysis identified 38 relevant biomarkers and revealed 3 major metabolic pathways: phenylalanine, tyrosine, and tryptophan biosynthesis; phenylalanine metabolism; and sphingolipid metabolism. The different processing methods of LLA demonstrated therapeutic effects on KYD in rats, likely related to the restoration of disturbed metabolism by adjusting the levels of endogenous metabolites in the kidney. The SSL demonstrated significantly superior effects compared with the other four types of LLA processed products.
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The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2⯵g/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.
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Toxinas Marinas , Microcistinas , Sirtuinas , Espermatogonias , Animales , Masculino , Ratones , Apoptosis , Proliferación Celular , Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN , Toxinas Marinas/metabolismo , Toxinas Marinas/toxicidad , Ratones Endogámicos ICR , Microcistinas/metabolismo , Microcistinas/toxicidad , Semen , Sirtuinas/efectos de los fármacos , Sirtuinas/metabolismo , Espermatogonias/efectos de los fármacos , Espermatogonias/metabolismoRESUMEN
The regulatory mechanisms that link WRKY gene expression to fruit ripening are largely unknown. Using transgenic approaches, we showed that a WRKY gene from wild strawberry (Fragaria vesca), FvWRKY48, may be involved in fruit softening and ripening. We showed that FvWRKY48 is localized to the nucleus and that degradation of the pectin cell wall polymer homogalacturonan, which is present in the middle lamella and tricellular junction zones of the fruit, was greater in FvWRKY48-OE (overexpressing) fruits than in empty vector (EV)-transformed fruits and less substantial in FvWRKY48-RNAi (RNA interference) fruits. Transcriptomic analysis indicated that the expression of pectate lyase A (FvPLA) was significantly downregulated in the FvWRKY48-RNAi receptacle. We determined that FvWRKY48 bound to the FvPLA promoter via a W-box element through yeast one-hybrid, electrophoretic mobility shift, and chromatin immunoprecipitation quantitative polymerase chain reaction experiments, and ß-glucosidase activity assays suggested that this binding promotes pectate lyase activity. In addition, softening and pectin degradation were more intense in FvPLA-OE fruit than in EV fruit, and the middle lamella and tricellular junction zones were denser in FvPLA-RNAi fruit than in EV fruit. We speculated that FvWRKY48 maybe increase the expression of FvPLA, resulting in pectin degradation and fruit softening.
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Fragaria , Pared Celular/genética , Pared Celular/metabolismo , Fragaria/genética , Fragaria/metabolismo , Frutas/genética , Frutas/metabolismo , Regulación de la Expresión Génica de las Plantas , Pectinas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/metabolismo , Polisacárido LiasasRESUMEN
Despite recent advances in cancer therapy, anthracycline-based combination therapy remains the standardized first-line strategy and has been found to have effective antitumor actions. Anthracyclines are extremely cardiotoxic, which limits the use of these powerful chemotherapeutic agents. Although numerous studies have been conducted on the cardiotoxicity of anthracyclines, the precise mechanisms by which doxorubicin causes cardiomyocyte death and myocardial dysfunction remain incompletely understood. This review highlights recent updates in mechanisms and therapies involved in doxorubicin-induced cardiomyocyte death, including autophagy, ferroptosis, necroptosis, pyroptosis, and apoptosis, as well as mechanisms of cardiovascular dysfunction resulting in myocardial atrophy, defects in calcium handling, thrombosis, and cell senescence. We sought to uncover potential therapeutic approaches to manage anthracycline cardiotoxicity via manipulation of crucial targets involved in doxorubicin-induced cardiomyocyte death and dysfunction.
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Berry curvature is a fundamental element to characterize topological quantum physics, while a full measurement of Berry curvature in momentum space was not reported for topological states. Here we achieve two-dimensional Berry curvature reconstruction in a photonic quantum anomalous Hall system via Hall transport measurement of a momentum-resolved wave packet. Integrating measured Berry curvature over the two-dimensional Brillouin zone, we obtain Chern numbers corresponding to -1 and 0. Further, we identify bulk-boundary correspondence by measuring topology-linked chiral edge states at the boundary. The full topological characterization of photonic Chern bands from Berry curvature, Chern number, and edge transport measurements enables our photonic system to serve as a versatile platform for further in-depth study of novel topological physics.
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INTRODUCTION: Since the implementation of national stay-at-home orders during the COVID-19 pandemic, there has been rising concerns regarding prolonged social isolation that many individuals face. Given the link between increased stress and alcohol and drug use, our study investigated admission trends and patterns of alcohol and drug use in trauma patients. METHODS: This was a single center, retrospective cohort study comparing trauma patients admitted before the pandemic and during the first wave. We compared patient demographics, injury characteristics, and outcomes of substance screen negative, positive, and unscreened patients admitted. Patients screened positive if they had a positive urine drug screen (UDS) and/or a blood alcohol concentration (BAC) ≥10 mg/dL. RESULTS: There were 3906 trauma admissions in the year prior to and 3469 patients in the first year of the pandemic. No significant demographic differences were presented across time periods. Rates of UDS and BAC screening remained consistent. Equivalent rates of alcohol and drug positivity occurred (34% versus 33%, 17% versus 18%, P = 0.49). The total prevalence of alcohol use disorders (4% versus 5%, P < 0.001) and psychiatric disorders (6% versus 7%, P = 0.02) increased during the pandemic. CONCLUSIONS: The prevalence of diagnosed alcohol use and psychiatric disorders in trauma patients increased during the COVID-19 pandemic while rates of acute alcohol and drug screen positivity remained the same. These observations suggest a possible link between pandemic stressors and exacerbation of alcohol use and psychiatric conditions in trauma patients. During a changing pandemic landscape, it remains pertinent to increased screening for these conditions regardless of substance screen positivity upon admission.
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Alcoholismo , COVID-19 , Heridas y Lesiones , Humanos , Pandemias , Nivel de Alcohol en Sangre , Estudios Retrospectivos , Centros Traumatológicos , COVID-19/epidemiología , Etanol , Heridas y Lesiones/epidemiologíaRESUMEN
Sleep deprivation (SD) causes deficits in off-line memory consolidation, but the underlying network oscillation mechanisms remain unclear. Hippocampal sharp wave ripple (SWR) oscillations play a critical role in off-line memory consolidation. Therefore, we trained mice to learn a hippocampus-dependent trace eyeblink conditioning (tEBC) task and explored the influence of 1.5-h postlearning SD on hippocampal SWRs and related spike dynamics during recovery sleep. We found an increase in hippocampal SWRs during postlearning sleep, which predicted the consolidation of tEBC in conditioned mice. In contrast, sleep-deprived mice showed a loss of tEBC learning-induced increase in hippocampal SWRs during recovery sleep. Moreover, the sleep-deprived mice exhibited weaker reactivation of tEBC learning-associated pyramidal cells in hippocampal SWRs during recovery sleep. In line with these findings, tEBC consolidation was impaired in sleep-deprived mice. Furthermore, sleep-deprived mice showed augmented fast excitation from pyramidal cells to interneurons and enhanced participation of interneurons in hippocampal SWRs during recovery sleep. Among various interneurons, parvalbumin-expressing interneurons specifically exhibited overexcitation during hippocampal SWRs. Our findings suggest that altered hippocampal SWRs and associated spike dynamics during recovery sleep may be candidate network oscillation mechanisms underlying SD-induced memory deficits.
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Hipocampo , Privación de Sueño , Animales , Hipocampo/fisiología , Ratones , Parvalbúminas/metabolismo , Células Piramidales/fisiología , SueñoRESUMEN
Our previous study showed 1-Nitropyrene (1-NP) exposure disrupted testicular testosterone synthesis in mouse, but the exact mechanism needs further investigation. The present research found 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum (ER) stress inhibitor, recovered 1-NP-induced ER stress and testosterone synthases reduction in TM3 cells. GSK2606414, a protein kinase-like ER kinase (PERK) kinase inhibitor, attenuated 1-NP-induced PERK-eukaryotic translation initiation factor 2α (eIF2α) signaling activation and downregulation of steroidogenic proteins in TM3 cells. Both 4-PBA and GSK2606414 attenuated 1-NP-induced steroidogenesis disruption in TM3 cells. Further studies used N-Acetyl-L-cysteine (NAC) as a classical antioxidant to explore whether oxidative stress-activated ER stress mediated 1-NP-induced testosterone synthases reduction and steroidogenesis disruption in TM3 cells and mouse testes. The results showed NAC pretreatment mitigated oxidative stress, and subsequently attenuated ER stress, particularly PERK-eIF2α signaling activation, and downregulation of testosterone synthases in 1-NP-treated TM3 cells. More importantly, NAC extenuated 1-NP-induced testosterone synthesis in vitro and in vivo. The current work indicated that oxidative stress-caused ER stress, particularly PERK-eIF2α pathway activation, mediates 1-NP-downregulated steroidogenic proteins and steroidogenesis disruption in TM3 cells and mouse testes. Significantly, the current study provides a theoretical basis and demonstrates the experimental evidence for the potential application of antioxidant, such as NAC, in public health prevention, particularly in 1-NP-induced endocrine disorder.
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Antioxidantes , Testículo , Masculino , Ratones , Animales , Testículo/metabolismo , Antioxidantes/metabolismo , Factor 2 Eucariótico de Iniciación/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Testosterona/metabolismo , Estrés Oxidativo , Acetilcisteína/farmacología , Acetilcisteína/metabolismoRESUMEN
In this paper, a quadratic convolution neural network (QCNN) using both audio and vibration signals is utilized for bearing fault diagnosis. Specifically, to make use of multi-modal information for bearing fault diagnosis, the audio and vibration signals are first fused together using a 1 × 1 convolution. Then, a quadratic convolution neural network is applied for the fusion feature extraction. Finally, a decision module is designed for fault classification. The proposed method utilizes the complementary information of audio and vibration signals, and is insensitive to noise. The experimental results show that the accuracy of the proposed method can achieve high accuracies for both single and multiple bearing fault diagnosis in the noisy situations. Moreover, the combination of two-modal data helps improve the performance under all conditions.
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This study aimed to monitor the incidence of migraine non-remission after percutaneous patent foramen ovale (PFO) closure and to discuss relevant risk factors. Recently, evidence of a relationship between the presence of PFO and migraines has been found, and PFO closure has been pointed out as a possible treatment for migraineurs.A retrospective analysis was conducted, which involved 139 patients diagnosed with PFO and associated migraine who underwent percutaneous PFO closure in The First Affiliated Hospital of Zhengzhou University from October 2019 to April 2021. All the considered patients were evaluated using the Headache Impact Test (HIT-6™) and classified with a score higher than 55 points before closure. The HIT-6™ score was re-evaluated 1-6 months after the intervention. HIT-6™ ≤ 55 was defined as headache remission (n = 93) and > 55 as headache non-remission (n = 46). A logistic regression model was developed to identify the risk factors of headache non-remission after PFO closure.The incidence of headache non-remission after PFO closure was 33.09%. Statistically significant differences were observed between the two groups as regards age and serum phosphorus level (P < 0.05). History of smoking, atrial fibrillation, absolute lymphocyte count, platelet-to-lymphocyte ratio, and interventricular septal thickness were identified as independent risk factors for headache non-remission following PFO closure, which were statistically significant (P < 0.05).
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Foramen Oval Permeable , Foramen Oval , Trastornos Migrañosos , Dispositivo Oclusor Septal , Humanos , Foramen Oval Permeable/complicaciones , Foramen Oval Permeable/cirugía , Estudios Retrospectivos , Resultado del Tratamiento , Trastornos Migrañosos/etiología , Trastornos Migrañosos/complicaciones , Cefalea/complicaciones , Factores de Riesgo , Cateterismo Cardíaco/efectos adversos , Dispositivo Oclusor Septal/efectos adversosRESUMEN
More than 95% of phytophagous true bug (Hemiptera: Heteroptera) species belong to four superfamilies: Miroidea (Cimicomorpha), Pentatomoidea, Coreoidea, and Lygaeoidea (all Pentatomomorpha). These iconic groups of highly diverse, overwhelmingly phytophagous insects include several economically prominent agricultural and silvicultural pest species, though their evolutionary history has not yet been well resolved. In particular, superfamily- and family-level phylogenetic relationships of these four lineages have remained controversial, and the divergence times of some crucial nodes for phytophagous true bugs have hitherto been little known, which hampers a better understanding of the evolutionary processes and patterns of phytophagous insects. In the present study, we used 150 species and concatenated nuclear and mitochondrial protein-coding genes and rRNA genes to infer the phylogenetic relationships within the Terheteroptera (Cimicomorpha + Pentatomomorpha) and estimated their divergence times. Our results support the monophyly of Cimicomorpha, Pentatomomorpha, Miroidea, Pentatomoidea, Pyrrhocoroidea, Coreoidea, and Lygaeoidea. The phylogenetic relationships across phytophagous lineages are largely congruent at deep nodes across the analyses based on different datasets and tree-reconstructing methods with just a few exceptions. Estimated divergence times and ancestral state reconstructions for feeding habit indicate that phytophagous true bugs explosively radiated in the Early Cretaceous-shortly after the angiosperm radiation-with the subsequent diversification of the most speciose clades (Mirinae, Pentatomidae, Coreinae, and Rhyparochromidae) in the Late Cretaceous.
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Heterópteros , Magnoliopsida , Animales , Evolución Biológica , Heterópteros/genética , FilogeniaRESUMEN
INTRODUCTION: Female researchers are underrepresented in academic surgery. While they are increasingly producing original research, they lag male researchers in productivity. This disparity is not well understood within the nascent field of global surgery. The following study examines gender parity in global surgery research presented at the Academic Surgical Congress and within subsequent publications. METHODS: Abstracts presented at the Academic Surgical Congress (ASC) between 2015 and 2019 in "Global Surgery" sessions were reviewed to obtain title, the first author (FA) and senior author (SA). The authors were classified by gender. The Scopus database was queried by two reviewers for abstracts with corresponding publications, citations, and journal impact factors. Statistical analysis was conducted using chi-square analysis and t-tests where appropriate. RESULTS: Of a total of 6635 abstracts, 218 global surgery abstracts over a 5-year period were identified. Of these abstracts, 96 (44%) had female FAs, while 56 (26%) had female SAs. When comparing gender, female (44%) FAs and male (56%) FAs were equally represented. While SAs were significantly less likely to be female (26% versus 74%, P < 0.0001), female senior authorship increased significantly within the study period. Output with respect to publications, citations, and journal impact factors were equal by gender. CONCLUSIONS: This study presents 5 y of gender trends in global surgery scholarly work presented at the ASC. Despite an overall predominance of male senior authors, the paradigm is shifting with a recent trend to gender parity. Male and female authors have equal output and are equally impactful. Findings of gender equity in academic global surgery are encouraging, and further study of other disciplines are warranted.
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Congresos como Asunto/estadística & datos numéricos , Identidad de Género , Cirugía General/estadística & datos numéricos , Salud Global/estadística & datos numéricos , Femenino , Humanos , MasculinoRESUMEN
Doxorubicin (DOX) is a commonly used anticancer drug, but it is inefficient as a therapeutic due to a lack of targeting. Peptide-tuned self-assembly of DOX offers a strategy to improve targeting for greater efficacy. In this work, we designed and prepared an amphiphilic tumor cell-targeting peptide, P14 (AAAAFFFHHHGRGD), able to encapsulate DOX by self-assembly to form tumor cell-targeting and pH-sensitive nano-micelles. The results showed a critical P14-micelle concentration of 1.758 mg l-1and an average particle size of micelles of 121.64 nm, with entrapment and drug-loading efficiencies of 28.02% ± 1.35% and 12.06% ± 0.59%, respectively. The prepared micelles can release 73.52 ± 1.27% DOX within 24 h in pH 4.5 medium, and the drug cumulative release profile of micelles can be described by the first-order model. Compared with free DOX, the micelles exhibited an increased ability to inhibit tumor cell growth and cause tumor apoptosisin vitro, with IC50values of DOX and P14-DOX micelles against human breast cancer cells (MCF-7) of 0.91 ± 0.07 and 0.75 ± 0.06µg ml-1, respectively, and cellular apoptotic rates of DOX and P14-DOX micelles of 70.3% and 42.4%, respectively. Cellular uptake experiments revealed high concentrations of micelles around and inside MCF-7 cells, demonstrating that micelles can target tumor cells. These results indicate the excellent potential for the application of this amphiphilic peptide as a carrier for small-molecule drugs and suggest a strategy for the design of effective anti-tumor drugs.
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Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Portadores de Fármacos , Nanoestructuras/química , Péptidos/metabolismo , Antibióticos Antineoplásicos/química , Apoptosis/efectos de los fármacos , Doxorrubicina/química , Composición de Medicamentos/métodos , Liberación de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Cinética , Células MCF-7 , Micelas , Terapia Molecular Dirigida , Nanoestructuras/ultraestructura , Péptidos/síntesis químicaRESUMEN
Calcium deficiency usually causes accelerated quality deterioration in postharvest fruit, whereas the underlining mechanism is still unclear. Here, we report that calcium deficiency induced the development of bitter pit on the surface of apple peels compared with the healthy appearance in control apples during postharvest storage. Physiological analysis indicates that calcium-deficient peels contained higher levels of superoxide anion (O2â¢-), malondialdehyde (MDA), total phenol, flavonoid contents and polyphenol oxidase (PPO) activity, and reduced calcium, H2S production, anthocyanin, soluble protein content, and peroxidase (POD) activity compared with those in calcium-sufficient peels. The principal component analysis (PCA) results show that calcium content, ROS, and H2S production were the main factors between calcium-deficient and calcium-sufficient apple peels. Transcriptome data indicated that four calmodulin-like proteins (CMLs), seven AP2/ERFs, and three bHLHs transcripts were significantly differentially expressed in calcium-deficient apple peels. RT-qPCR and correlation analyses further revealed that CML5 expression was significantly positively correlated with the expression of ERF2/17, bHLH2, and H2S production related genes. In addition, transcriptional co-activation of CML5 by ERF2 and bHLH2 was demonstrated by apple transient expression assays and dual-luciferase reporter system experiments. Therefore, these findings provide a basis for studying the molecular mechanism of postharvest quality decline in calcium-deficient apples and the potential interaction between Ca2+ and endogenous H2S.
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Sulfuro de Hidrógeno/metabolismo , Malus/metabolismo , Proteínas de Plantas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transcriptoma , Antocianinas/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Catecol Oxidasa/metabolismo , Flavonoides/metabolismo , Almacenamiento de Alimentos , Frutas/genética , Frutas/metabolismo , Malus/genética , Factores de Terminación de Péptidos/genética , Factores de Terminación de Péptidos/metabolismo , Fenoles/metabolismo , Fenotipo , Proteínas de Plantas/genética , Análisis de Componente PrincipalRESUMEN
BACKGROUND: Ginkgo biloba, a typical dioecious plant, is a traditional medicinal plant widely planted. However, it has a long juvenile period, which severely affected the breeding and cultivation of superior ginkgo varieties. RESULTS: In order to clarify the complex mechanism of sexual differentiation in G. biloba strobili. Here, a total of 3293 miRNAs were identified in buds and strobili of G. biloba, including 1085 known miRNAs and 2208 novel miRNAs using the three sequencing approaches of transcriptome, small RNA, and degradome. Comparative transcriptome analysis screened 4346 and 7087 differentially expressed genes (DEGs) in male buds (MB) _vs_ female buds (FB) and microstrobilus (MS) _vs_ ovulate strobilus (OS), respectively. A total of 6032 target genes were predicted for differentially expressed miRNA. The combined analysis of both small RNA and transcriptome datasets identified 51 miRNA-mRNA interaction pairs that may be involved in the process of G. biloba strobili sexual differentiation, of which 15 pairs were verified in the analysis of degradome sequencing. CONCLUSIONS: The comprehensive analysis of the small RNA, RNA and degradome sequencing data in this study provided candidate genes and clarified the regulatory mechanism of sexual differentiation of G. biloba strobili from multiple perspectives.
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Flores/crecimiento & desarrollo , Flores/genética , Flores/ultraestructura , Ginkgo biloba/genética , MicroARNs/genética , ARN de Planta/genética , Diferenciación Sexual/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Ginkgo biloba/crecimiento & desarrollo , Secuenciación de Nucleótidos de Alto Rendimiento , Plantas Medicinales/genética , Plantas Medicinales/crecimiento & desarrollo , Análisis de Secuencia de ARN , TranscriptomaRESUMEN
Aldosterone produced in adrenal glands by angiotensin II (Ang II) is known to elicit myocardial fibrosis and hypertrophy. This study was designed to test the hypothesis that Ang II causes cardiac morphological changes through the steroidogenic acute regulatory protein (StAR)/aldosterone synthase (AS)-dependent aldosterone synthesis primarily initiated in the heart. Sprague-Dawley rats were randomized to following groups: Ang II infusion for a 4-week period, treatment with telmisartan, spironolactone or adrenalectomy during Ang II infusion. Sham-operated rats served as control. Relative to Sham rats, Ang II infusion significantly increased the protein levels of AT1 receptor, StAR, AS and their tissue expression in the adrenal glands and heart. In coincidence with reduced aldosterone level in the heart, telmisartan, an AT1 receptor blocker, significantly down-regulated the protein level and expression of StAR and AS. Ang II induced changes in the expression of AT1/StAR/AS were not altered by an aldosterone receptor antagonist spironolactone. Furthermore, Ang II augmented migration of macrophages, protein level of TGFß1, phosphorylation of Smad2/3 and proliferation of myofibroblasts, accompanied by enhanced perivascular/interstitial collagen deposition and cardiomyocyte hypertrophy, which all were significantly abrogated by telmisartan or spironolactone. However, adrenalectomy did not fully suppress Ang II-induced cell migration/proliferation and fibrosis/hypertrophy, indicating a role of aldosterone synthesized within the heart in pathogenesis of Ang II induced injury. These results indicate that myocardial fibrosis and hypertrophy stimulated by Ang II is associated with tissue-specific activation of aldosterone synthesis, primarily mediated by AT1/StAR/AS signaling pathways.
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Angiotensina II/metabolismo , Cardiomegalia/etiología , Cardiomegalia/metabolismo , Cardiomiopatías/etiología , Cardiomiopatías/metabolismo , Citocromo P-450 CYP11B2/metabolismo , Fosfoproteínas/genética , Glándulas Suprarrenales/metabolismo , Animales , Biomarcadores , Biopsia , Cardiomegalia/patología , Cardiomiopatías/patología , Colágeno/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Fibrosis , Inmunohistoquímica , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Modelos Biológicos , Miocardio/metabolismo , Miocardio/patología , Miofibroblastos/metabolismo , Ratas , Receptor de Angiotensina Tipo 1/metabolismo , Transducción de Señal , Proteína Smad2/metabolismo , Proteína smad3/metabolismoRESUMEN
Because of the high protein content and rich meat quality of crayfish Procambarus clarkii, it has become widely popular in China in recent years and has a high economic value. When P. clarkii is stimulated by heavy metals, it reacts to oxidation. P. clarkii has evolved antioxidant defense systems, including antioxidant enzymes such as catalase (CAT). The hexavalent form of Cr (VI) is a pathogenic factor that is of particular concern in aqueous systems because of its great toxicity to living organisms. In this study, we characterized the transcriptome of P. clarkii using a RNA sequencing method and performed a comparison between K2Cr2O7-treated samples and controls. In total, 34,237 unigenes were annotated. We identified 5098 significantly differentially expressed genes (DEGs), including 2536 and 2562 were significantly up-regulated and down-regulated, respectively. In addition, quantitative real time-PCR (qRT-PCR) confirmed the up-regulation of a random selection of DEGs. Our results contribute to a more comprehensive understanding of the antioxidant defense system used by P. clarkii in response to heavy metal stress.
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Astacoidea/efectos de los fármacos , Cromatos/toxicidad , Compuestos de Potasio/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Antioxidantes/metabolismo , Astacoidea/genética , Astacoidea/metabolismo , Perfilación de la Expresión Génica , TranscriptomaRESUMEN
Procambarus clarkii is one of the most economically important species in Chinese aquaculture, and is widely cultured. Infection of P. clarkii populations with bacterial pathogens causes high mortality and great economic loss, therefore disease control is of significant economic importance. P. clarkii is a model system for studying immune responses in invertebrates, and its immune system consists solely of the innate response. In the present study, we examined gene expression related to immune function in P. clarkii in response to pathogen challenge. The transcriptome of hepatopancreas tissue from P. clarkii challenged with peptidoclycan (PGN) was analyzed and compared to control specimens. After assembly and annotation, 48,661 unigenes were identified with an average length of 671.54 bp. A total of 2533 differentially expressed genes (DEGs) were obtained, including 765 significantly up-regulated unigenes and 1757 significantly down-regulated unigenes. Gene ontology (GO) analysis demonstrated 19 biological process subcategories, 16 cellular component subcategories, and 17 molecular function subcategories that were enriched among these DEGs. Enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed enrichment among immune responses pathways. Taken together, this study not only enriches the existing P. clarkii transcriptome database, but also elucidates immune responses of crayfish that are activated in response to PGN challenge.
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Astacoidea/genética , Perfilación de la Expresión Génica , Hepatopáncreas/efectos de los fármacos , Peptidoglicano/farmacología , Animales , Astacoidea/inmunología , Ontología de Genes , Hepatopáncreas/inmunologíaRESUMEN
BACKGROUND: Rat bite fever (RBF), a severe infectious disease, can result from transmission of the pathogen Streptobacillus moniliformis (S. moniliformis) by rat bite. RBF diagnosis can be overlooked. CASE PRESENTATION: We present a case of RBF in a Chinese patient who was infected with S. moniliformis in mainland China. Meta-next generation sequencing (mNGS) was used to identify potential pathogens and detected S. moniliformis genome sequences in the pustular sample in less than 72 h. Then the diagnosis was validated by polymerase chain reaction analysis. Despite having severe RBF with complications, this 54-year-old male patient was successfully cured with penicillin as a result of timely pathogen-based diagnosis. CONCLUSIONS: Physicians should inquire about recent rat exposure and consider the possibility of RBF when a patient develops unexplained fever and rashes. mNGS is a new diagnostic technology and may identify RBF pathogens even when blood culture results are negative.