RESUMEN
Genetic screening identifies the atypical tetraspanin TM4SF1 as a strong mediator of metastatic reactivation of breast cancer. Intriguingly, TM4SF1 couples the collagen receptor tyrosine kinase DDR1 to the cortical adaptor syntenin 2 and, hence, to PKCα. The latter kinase phosphorylates and activates JAK2, leading to the activation of STAT3. This non-canonical mechanism of signaling induces the expression of SOX2 and NANOG; sustains the manifestation of cancer stem cell traits; and drives metastatic reactivation in the lung, bone, and brain. Bioinformatic analyses and pathological studies corroborate the clinical relevance of these findings. We conclude that non-canonical DDR1 signaling enables breast cancer cells to exploit the ubiquitous interstitial matrix component collagen I to undergo metastatic reactivation in multiple target organs.
Asunto(s)
Neoplasias de la Mama/patología , Receptor con Dominio Discoidina 1/metabolismo , Metástasis de la Neoplasia , Transducción de Señal , Animales , Antígenos de Superficie/metabolismo , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Receptor con Dominio Discoidina 1/química , Humanos , Neoplasias Pulmonares/secundario , Ratones , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/patologíaRESUMEN
In recent years, certain luminous extragalactic optical transients have been observed to last only a few days1. Their short observed duration implies a different powering mechanism from the most common luminous extragalactic transients (supernovae), whose timescale is weeks2. Some short-duration transients, most notably AT2018cow (ref. 3), show blue optical colours and bright radio and X-ray emission4. Several AT2018cow-like transients have shown hints of a long-lived embedded energy source5, such as X-ray variability6,7, prolonged ultraviolet emission8, a tentative X-ray quasiperiodic oscillation9,10 and large energies coupled to fast (but subrelativistic) radio-emitting ejecta11,12. Here we report observations of minutes-duration optical flares in the aftermath of an AT2018cow-like transient, AT2022tsd (the 'Tasmanian Devil'). The flares occur over a period of months, are highly energetic and are probably nonthermal, implying that they arise from a near-relativistic outflow or jet. Our observations confirm that, in some AT2018cow-like transients, the embedded energy source is a compact object, either a magnetar or an accreting black hole.
RESUMEN
Brain metastasis, most commonly originating from lung cancer, increases cancer morbidity and mortality. Although metastatic colonization is the rate-limiting and most complex step of the metastatic cascade, the underlying mechanisms are poorly understood. Here, in vivo genome-wide CRISPR-Cas9 screening revealed that loss of interferon-induced transmembrane protein 1 (IFITM1) promotes brain colonization of human lung cancer cells. Incipient brain metastatic cancer cells with high expression of IFITM1 secrete microglia-activating complement component 3 and enhance the cytolytic activity of CD8+ T cells by increasing the expression and membrane localization of major histocompatibility complex class I. After activation, microglia (of the innate immune system) and cytotoxic CD8+ T lymphocytes (of the adaptive immune system) were found to jointly eliminate cancer cells by releasing interferon-gamma and inducing phagocytosis and T-cell-mediated killing. In human cancer clinical trials, immune checkpoint blockade therapy response was significantly correlated with IFITM1 expression, and IFITM1 enhanced the brain metastasis suppression efficacy of PD-1 blockade in mice. Our results exemplify a novel mechanism through which metastatic cancer cells overcome the innate and adaptive immune responses to colonize the brain, and suggest that a combination therapy increasing IFITM1 expression in metastatic cells with PD-1 blockade may be a promising strategy to reduce metastasis.
Asunto(s)
Neoplasias Encefálicas , Neoplasias Pulmonares , Humanos , Animales , Ratones , Linfocitos T CD8-positivos , Receptor de Muerte Celular Programada 1 , Neoplasias Pulmonares/patología , Encéfalo/patologíaRESUMEN
Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Structural modeling and biochemical assays were used to understand the effect of these variants on SEPHS1 function. We found that a variant at residue Trp352 results in local structural changes of the C-terminal region of SEPHS1 that decrease the overall thermal stability of the enzyme. In contrast, variants of a solvent-exposed residue Arg371 do not impact enzyme stability and folding but could modulate direct protein-protein interactions of SEPSH1 with cellular factors in promoting cell proliferation and development. In neuronal SH-SY5Y cells, we assessed the impact of SEPHS1 variants on cell proliferation and ROS production and investigated the mRNA expression levels of genes encoding stress-related selenoproteins. Our findings provided evidence that the identified SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis. Our study supports the hypothesis that SEPHS1 plays a critical role during human development and provides a basis for further investigation into the molecular mechanisms employed by SEPHS1. Furthermore, our data suggest that variants in SEPHS1 are associated with a neurodevelopmental disorder.
Asunto(s)
Discapacidad Intelectual , Anomalías Musculoesqueléticas , Trastornos del Neurodesarrollo , Animales , Niño , Humanos , Discapacidades del Desarrollo/genética , Exones , Discapacidad Intelectual/genética , Mamíferos/genética , Hipotonía Muscular/genética , Anomalías Musculoesqueléticas/genética , Neuroblastoma/genética , Trastornos del Neurodesarrollo/genética , Especies Reactivas de OxígenoRESUMEN
The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-ß ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung, but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific antimetastatic signals in order to undergo reactivation.
Asunto(s)
Neoplasias de la Mama/patología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Pulmonares/secundario , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Discovering and engineering herbicide-resistant genes is a crucial challenge in crop breeding. This study focuses on the 4-hydroxyphenylpyruvate dioxygenase Inhibitor Sensitive 1-Like (HSL) protein, prevalent in higher plants and exhibiting weak catalytic activity against many ß-triketone herbicides (ß-THs). The crystal structures of maize HSL1A complexed with ß-THs were elucidated, identifying four essential herbicide-binding residues and explaining the weak activity of HSL1A against the herbicides. Utilizing an artificial evolution approach, we developed a series of rice HSL1 mutants targeting the four residues. Then, these mutants were systematically evaluated, identifying the M10 variant as the most effective in modifying ß-THs. The initial active conformation of substrate binding in HSL1 was also revealed from these mutants. Furthermore, overexpression of M10 in rice significantly enhanced resistance to ß-THs, resulting in a notable 32-fold increase in resistance to methyl-benquitrione. In conclusion, the artificially evolved M10 gene shows great potential for the development of herbicide-resistant crops.
Asunto(s)
Resistencia a los Herbicidas , Herbicidas , Oryza , Proteínas de Plantas , Oryza/genética , Oryza/metabolismo , Resistencia a los Herbicidas/genética , Herbicidas/farmacología , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Fitomejoramiento/métodos , Plantas Modificadas Genéticamente/genética , MutaciónRESUMEN
SignificanceThere is a common consensus that lode gold deposits mostly precipitated from metamorphic fluids via fluid boiling and/or fluid-rock interaction, but whether magmatic hydrothermal fluids and the mixing of such fluids with an external component have played a vital role in the formation of lode gold deposits remains elusive. We use garnet secondary ion mass spectrometry oxygen isotope analysis to demonstrate that the world-class Dongping lode gold deposit has been formed by multiple pulses of magmatic hydrothermal fluids and their mixing with large volumes of meteoric water. This study opens an opportunity to tightly constrain the origin of lode gold deposits worldwide and other hydrothermal systems that may have generated giant ore deposits in the Earth's crust.
RESUMEN
In photoelectrochemical (PEC) cells, selective oxidation of organic substrates coupled with hydrogen evolution represents a promising approach for value-added chemical production and solar energy conversion. In this study, we report on PEC epoxidation of alkenes at a ruthenium dye-sensitized photoanode in a CH3CN/H2O mixed solvent with LiBr as a mediator and water as the oxygen source. The dye-sensitized photoanode was found to exhibit significant advantages in the simultaneous improvement of charge separation and suppression of charge recombination. First, LiBr as a redox mediator plays a critical role in charge separation, leading to an excellent excited electron injection efficiency of 95% and a high dye regeneration efficiency of 87%. Second, the predominant charge recombination pathway on the dye-sensitized photoanode is efficiently blocked by the reaction between alkene and the in situ generated bromine oxidant. As a result, the current system achieved a remarkable photocurrent density of over 4 mA cm-2 with a record-high incident photo-to-current efficiency (IPCE) of 51% and extraordinary selectivity of up to 99% for the epoxidation of a wide range of alkenes. Meanwhile, nearly 100% Faradaic efficiency for hydrogen evolution was obtained. The performance shown here exceeds that obtained by metal oxide-based semiconductor photoanodes under comparable conditions, demonstrating the great potential of dye-sensitized photoelectrodes for organic synthesis owing to their diversity and tunability.
RESUMEN
The activation of innate immunity following transplantation has been identified as a crucial factor in allograft inflammation and rejection. However, the role of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signaling-mediated innate immunity in the pathogenesis of allograft rejection remains unclear. Utilizing a well-established murine model of corneal transplantation, we demonstrated increased expression of cGAS and STING in rejected-corneal allografts compared with syngeneic (Syn) and normal (Nor) corneas, along with significant activation of the cGAS/STING pathway, as evidenced by the enhanced phosphorylation of TANK-binding kinase 1and interferon regulatory factor 3. Pharmacological and genetic inhibition of cGAS/STING signaling markedly delayed corneal transplantation rejection, resulting in prolonged survival time and reduced inflammatory infiltration. Furthermore, we observed an increase in the formation of neutrophil extracellular traps (NETs) in rejected allografts, and the inhibition of NET formation through targeting peptidylarginine deiminase 4 and DNase I treatment significantly alleviated immune rejection and reduced cGAS/STING signaling activity. Conversely, subconjunctival injection of NETs accelerated corneal transplantation rejection and enhanced the activation of the cGAS/STING pathway. Collectively, these findings demonstrate that NETs contribute to the exacerbation of allograft rejection via cGAS/STING signaling, highlighting the targeting of the NETs/cGAS/STING signaling pathway as a potential strategy for prolonging allograft survival.
Asunto(s)
Trasplante de Córnea , Trampas Extracelulares , Rechazo de Injerto , Nucleotidiltransferasas , Transducción de Señal , Animales , Masculino , Ratones , Aloinjertos , Trampas Extracelulares/metabolismo , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Rechazo de Injerto/metabolismo , Supervivencia de Injerto/inmunología , Inmunidad Innata , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Neutrófilos/metabolismo , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/genéticaRESUMEN
Quantitative analysis of cell-free RNA (cfRNA) in plasma sample can be used for screening, diagnosing, and prognosticating of multiple diseases. Here, we report a quantitative CRISPR/Cas digital imaging platform (qCasdip) for the detection of various cfRNAs, including circular RNAs and miRNAs, in clinical samples at the attomolar (aM) level without the need for preamplification. Digital counting strategy provides qCasdip quantitative ability with a linear detection range of 102-106 aM. Meanwhile, qCasdip demonstrated cfRNA profiling in clinical plasma samples, improving the diagnosis of breast cancer. These data highlight the potential of qCasdip to quantitatively assess the molecular patterns of specific cfRNA panels in plasma, thereby providing a novel liquid biopsy solution to enhance disease diagnosis.
RESUMEN
OBJECTIVE: Immune-mediated necrotizing myopathy (IMNM) is pathologically characterized by diffuse myofiber necrosis and regeneration, myophagocytosis, and a sparse inflammatory infiltrate. The monocyte chemoattractant protein-1 (MCP-1) is a key chemokine that regulates monocyte/macrophage infiltration into injured tissues. The interleukin-6 (IL-6) signalling in the induction of MCP-1 expression has not been investigated in IMNM. METHODS: MCP-1 expression in muscle specimens was assessed using immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR). Levels of multiple serological cytokines were evaluated using the Meso Scale Discovery electrochemiluminescence system. Flow cytometry, RT-qPCR, enzyme-linked immunosorbent assay, western blot, dual-luciferase reporter assays, and chromatin immunoprecipitation-qPCR were performed to explore the effects of IL-6 signalling on MCP-1 production in human myoblasts. RESULTS: MCP-1 was scattered and was positively expressed within myofibers and a few inflammatory cells in the muscles of patients with IMNM. Sarcoplasmic MCP-1 expression significantly correlated with myonecrosis, myoregeneration, and inflammatory infiltration. Serum MCP-1, IL-6, and the soluble form of the IL-6 receptor (sIL-6R) were elevated in patients with IMNM compared with controls. Serological MCP-1 levels were significantly associated with serum IL-6 expression and clinical disease severity in IMNM patients. The IL-6/sIL-6R complex induced MCP-1 expression via the signal transducer and activator of transcription 3 (STAT3) pathway in human myoblasts. Mechanistically, phospho-STAT3 was enriched in the MCP-1 promoter region and promoted the transcription. CONCLUSION: IL-6 trans-signalling may contribute to the immunopathogenesis of IMNM by augmenting inflammation through regulation of MCP-1 expression in IMNM.
RESUMEN
We achieved an ultrahigh Q surface lattice resonance (SLR) using a conventional U-shaped split ring resonator (U-SRR) array. Numerical results confirmed by semi-analytical analysis show that with the transmission resonance amplitude up to 0.8, the Q-factor of the SLR can still surpass 104. The physical mechanisms of the ultrahigh Q-factor were also investigated. Besides the radiation suppression provided by conventional SLR, the unique geometry of the U-SRR can further offer dual radiation suppression mechanisms: reduction of the dipole moment and excitation of the in-plane quadrupole. We expect that the proposed ultrahigh Q SLR platform will be explored for more flexible and advanced nanoscale devices.
RESUMEN
INTRODUCTION: Aberrant miR-320a has been reported to be involved in the tumorigenesis of several cancers. In our previous study, we identified the low expression of circulating miR-320a in patients with somatotroph pituitary neuroendocrine tumor (PitNET); however, the role of miR-320a in somatotroph PitNET proliferation is still unclear. METHODS: Cell viability and colony formation assays were used to detect the effect of miR-320a and BCAT1 on GH3 cells. TargetScan was used to identify the target genes of miR-320a. Dual-luciferase reporter gene assay was used to explore the relation between miR-320a and BCAT1. Transcriptome and proteome analyses were performed between somatotroph PitNETs and healthy controls. The expression level of miR-320a in somatotroph PitNETs were detected by RT-qPCR and Western blot. RESULTS: miR-320a mimics inhibit cell proliferation, while miR-320a inhibitors promote cell proliferation in GH3 cells. An overlap analysis using a Venn diagram revealed that BCAT1 is the only target gene of miR-320a overexpressed in somatotroph PitNETs compared to healthy controls, as revealed by both microarray and proteomics results. A dual-luciferase reporter gene assay showed that miR-320a may bind to the BCAT1-3'UTR. The transfection of miR-320a mimics downregulated the expression and miR-320a inhibitors and upregulated the expression of BCAT1 in GH3 cells. The interference of BCAT1 expression in GH3 cells downregulated cell proliferation and growth. Pan-cancer analyses demonstrated that high BCAT1 expression often indicates a poor prognosis. CONCLUSION: Our findings illustrate that miR-320a may function as a tumor suppressor and BCAT1 may promote tumor progression. miR-320a may inhibit the growth of somatotroph PitNETs by targeting BCAT1.
Asunto(s)
Adenoma , Adenoma Hipofisario Secretor de Hormona del Crecimiento , MicroARNs , Tumores Neuroendocrinos , Somatotrofos , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Somatotrofos/metabolismo , Tumores Neuroendocrinos/genética , Línea Celular Tumoral , Proliferación Celular/genética , Adenoma/genética , Luciferasas/genética , Luciferasas/metabolismo , Regulación Neoplásica de la Expresión Génica , Transaminasas/genética , Transaminasas/metabolismoRESUMEN
PURPOSE: To compare the outcomes of big-bubble deep anterior lamellar keratoplasty (BB-DALK) and penetrating keratoplasty (PKP) in the management of medically unresponsive Acanthamoeba keratitis (AK). METHODS: This retrospective study included 27 eyes of BB-DALK and 24 eyes of PKP from a tertiary ophthalmology care centre. Glucocorticoid eye drops were subsequently added to the treatment plan 2 months postoperatively based on the evaluation using confocal laser scanning microscopy. The clinical presentations, best-corrected visual acuity (BCVA), postoperative refractive outcomes, graft survival, and Acanthamoeba recurrence were analyzed. RESULTS: The AK patients included in the study were in stage 2 or stage 3, and the percentage of patients in stage 3 was higher in the PKP group (P = 0.003). Clinical presentations were mainly corneal ulcers and ring infiltrates, and endothelial plaques, hypopyon, uveitis and glaucoma were more common in the PKP group (P = 0.007). The BCVA and the graft survival rate showed no statistically significant differences between the two groups at 1 year after surgery. However, 3 years postoperatively, the BCVA of 0.71 ± 0.64 logMAR, the graft survival rate of 89.5%, and the endothelial cell density of 1899 ± 125 cells per square millimeter in the BB-DALK group were significantly better than those of the PKP group (P = 0.010, 0.046, and 0.032, respectively). 3 eyes (11.1%) in the BB-DALK group and 2 eyes (8.3%) in the PKP group experienced Acanthamoeba recurrence, but the rates showed no statistically significant difference between the two groups (P = 1.000). In the PKP group, immune rejection and elevated intraocular pressure were observed in 5 and 6 eyes, respectively. CONCLUSION: Corneal transplantation is recommended for AK patients unresponsive to antiamoebic agents. The visual acuity and graft survival can be maintained after BB-DALK surgery. Acanthamoeba recurrence is not related to the surgical approach performed, whereas complete dissection of the infected corneal stroma and delayed prescribing of glucocorticoid eye drops were important to prevent recurrence.
Asunto(s)
Queratitis por Acanthamoeba , Trasplante de Córnea , Glaucoma , Humanos , Queratitis por Acanthamoeba/tratamiento farmacológico , Queratitis por Acanthamoeba/cirugía , Queratoplastia Penetrante , Glucocorticoides , Estudios Retrospectivos , Soluciones OftálmicasRESUMEN
Emerging data suggest a close correlation between ambient fine particle (AFP) exposure and eye disorders and pinpoint potential threats of AFPs to eye health in humans. However, the possible passage (including direct intrusion) and the interactions of AFPs with the eye microenvironment in addition to morphological and physiological injuries remain elusive. To this end, the likely transport of AFPs into the eyes via blood-ocular barrier (BOB) in humans and animals was investigated herein. Exogenous particles were recognized inside human eyes with detailed structural and chemical fingerprints. Importantly, comparable AFPs were found in sera with constant structural and chemical fingerprints, hinting at the translocation pathway from blood circulation into the eye. Furthermore, we found that the particle concentrations in human eyes from patients with diabetic retinopathy were much higher than those from patients with no fundus pathological changes (i.e., myopia), indicating that the damaged BOB increased the possibility of particle entrance. Our diseased animal model further corroborated these findings. Collectively, our results offer a new piece of evidence on the intrusion of exogenous particles into human eyes and provide an explanation for AFP-induced eye disorders, with substantially increased risk in susceptible individuals with BOB injuries.
Asunto(s)
Material Particulado , Humanos , Animales , Ojo/patología , MasculinoRESUMEN
Androgen receptor (AR) plays a crucial role in various physiological processes. Dysregulation of AR signaling has been implicated in several diseases, such as prostate cancer and androgenetic alopecia. Therefore, the development of drugs that specifically target AR has gained significant attention in the field of drug discovery. This review provides an overview of the synthetic routes of clinically approved small molecule drugs targeting AR and discusses the clinical applications of these drugs in the treatment of AR-related diseases. The review also highlights the challenges and future perspectives in this field, including the need for improved drug design and the exploration of novel therapeutic targets. Through an integrated analysis of the therapeutic applications, synthetic methodologies, and mechanisms of action associated with these approved drugs, this review facilitates a holistic understanding of the versatile roles and therapeutic potential of AR-targeted interventions. Overall, this comprehensive review serves as a valuable resource for medicinal chemists interested in the development of small-molecule drugs targeting AR.
Asunto(s)
Neoplasias de la Próstata , Receptores Androgénicos , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Descubrimiento de Drogas , Diseño de Fármacos , Transducción de SeñalRESUMEN
BACKGROUND: This study aims to evaluate the clinical outcomes and efficacy of a modified tectonic corneoscleral graft (TCG) in patients suffering from devastating corneoscleral infections. METHODS: Thirty-eight eyes from 38 patients who underwent the modified TCG were included in this study. The outcomes measured were recurrence rates, best-corrected visual acuity (BCVA), ocular surface stability, postoperative complications, and graft survival. RESULTS: Among the 38 patients, 23 had fungal infections, 9 had bacterial infections and 6 had Pythium insidiosum infections. At the final follow-up, with an average duration of 25.1 ± 8.6 months, the rate of monocular blindness decreased from 100 to 58%. Significant improvements in LogMAR BCVA were observed from preoperative to postoperative measurements (P < 0.001). Thirty-two eyes (84.2%) maintained a stable ocular surface. The survival rate of ocular surface stability was 84.2%±5.9% at one year and 57.7%±9.7% at three years post-surgery. Twenty eyes (52.6%) retained a clear graft, with a survival rate for graft clarity was 81.6%±6.3% at one year and 36.0%±10.8% at three years post-surgery. The incidence of immune rejection was 36.8%. Corneal epithelial defects were observed in ten patients, and choroidal detachment occurred in four patients. No cases of elevated intraocular pressure were detected. CONCLUSIONS: The modified TCG is effective in eradicating infections, preserving the eyeball, and maintaining useful vision in cases of devastating corneoscleral infections. Regular use of tacrolimus, timely administration of glucocorticoids, and good patient compliance can help mitigate postoperative challenges.
Asunto(s)
Supervivencia de Injerto , Agudeza Visual , Humanos , Masculino , Femenino , Persona de Mediana Edad , Agudeza Visual/fisiología , Adulto , Anciano , Estudios Retrospectivos , Esclerótica/cirugía , Esclerótica/trasplante , Trasplante de Córnea/métodos , Adulto Joven , Enfermedades de la Córnea/cirugía , Adolescente , Enfermedades de la Esclerótica/cirugía , Estudios de Seguimiento , Infecciones Fúngicas del Ojo/cirugía , Infecciones del OjoRESUMEN
To better assess the practical value and avoid potential risks of the traditionally medicinal and edible basidiomycete Schizophyllum commune, which may arise from undescribed metabolites, a combination of elicitors was introduced for the first time to discover products from cryptic and low-expressed gene clusters under laboratory cultivation. Treating S. commune NJFU21 with the combination of five elicitors led to the upregulated production of a class of unusual linear diterpene-derived variants, including eleven new ones (1-11), along with three known ones (12-14). The structures and stereochemistry were determined by 1D and 2D NMR, HRESIMS, ECD, OR and VCD calculations. Notably, the elongation terminus of all the diterpenes was decorated by an unusual butenedioic acid moiety. Compound 1 was a rare monocyclic diterpene, while 2-6 possessed a tetrahydrofuran moiety. The truncated metabolites 4, 5 and 13 belong to the trinorditerpenes. All the diterpenes displayed approximately 70% scavenging of hydroxyl radicals at 50 µM and null cytotoxic activity at 10 µM. In addition, compound 1 exhibited potent antifungal activity against the plant pathogenic fungi Colletotrichum camelliae, with MIC values of 8 µg/mL. Our findings indicated that this class of diterpenes could provide valuable protectants for cosmetic ingredients and the lead compounds for agricultural fungicide development.
Asunto(s)
Diterpenos , Schizophyllum , Diterpenos/farmacología , Diterpenos/química , Diterpenos/metabolismo , Schizophyllum/metabolismo , Schizophyllum/genética , Estructura Molecular , Regulación hacia Arriba/efectos de los fármacos , HumanosRESUMEN
We proposed and verified a scheme of chaos synchronization for integrated five-section semiconductor lasers with matching parameters. The simulation results demonstrated that the integrated five-section semiconductor laser could generate a chaotic signal within a large parameter range of the driving currents of five sections. Subsequently, chaos synchronization between two integrated five-section semiconductor lasers with matched parameters was realized by using a common noise signal as a driver. Moreover, it was found that the synchronization was sensitive to the current mismatch in all five sections, indicating that the driving currents of the five sections could be used as keys of chaotic optical communication. Therefore, this synchronization scheme provides a candidate to increase the dimension of key space and enhances the security of the system.
RESUMEN
Site-specific imaging of target genes using CRISPR probes is essential for understanding the molecular mechanisms of gene function and engineering tools to modulate its downstream pathways. Herein, we develop CRISPR/Cas9-mediated signal amplification by exchange reaction (CasSABER) for programmable in situ imaging of low and nonrepetitive regions of the target gene in the cell nucleus. The presynthesized primer-exchange reaction (PER) probe is able to hybridize multiple fluorophore-bearing imager strands to specifically light up dCas9/sgRNA target-bound gene loci, enabling in situ imaging of fixed cellular gene loci with high specificity and signal-to-noise ratio. In combination with a multiround branching strategy, we successfully detected nonrepetitive gene regions using a single sgRNA. As an intensity-codable and orthogonal probe system, CasSABER enables the adjustable amplification of local signals in fixed cells, resulting in the simultaneous visualization of multicopy and single-copy gene loci with similar fluorescence intensity. Owing to avoiding the complexity of controlling in situ mutistep enzymatic reactions, CasSABER shows good reliability, sensitivity, and ease of implementation, providing a rapid and cost-effective molecular toolkit for studying multigene interaction in fundamental research and gene diagnosis.