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Chloroplasts are crucial players in the activation of defensive hormonal responses during plant-pathogen interactions. Here, we show that a plant virus-encoded protein re-localizes from the plasma membrane to chloroplasts upon activation of plant defense, interfering with the chloroplast-dependent anti-viral salicylic acid (SA) biosynthesis. Strikingly, we have found that plant pathogens from different kingdoms seem to have convergently evolved to target chloroplasts and impair SA-dependent defenses following an association with membranes, which relies on the co-existence of two subcellular targeting signals, an N-myristoylation site and a chloroplast transit peptide. This pattern is also present in plant proteins, at least one of which conversely activates SA defenses from the chloroplast. Taken together, our results suggest that a pathway linking plasma membrane to chloroplasts and activating defense exists in plants and that such pathway has been co-opted by plant pathogens during host-pathogen co-evolution to promote virulence through suppression of SA responses.
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Membrana Celular/inmunología , Cloroplastos/inmunología , Enfermedades de las Plantas/inmunología , Inmunidad de la Planta/inmunología , Transducción de Señal/inmunología , Proteínas de Arabidopsis/inmunología , Interacciones Huésped-Patógeno/inmunología , Ácido Salicílico/inmunología , Virulencia/inmunologíaRESUMEN
BACKGROUND: Abdominal aortic aneurysm (AAA) is a catastrophic disease with little effective therapy, likely due to the limited understanding of the mechanisms underlying AAA development and progression. ATF3 (activating transcription factor 3) has been increasingly recognized as a key regulator of cardiovascular diseases. However, the role of ATF3 in AAA development and progression remains elusive. METHODS: Genome-wide RNA sequencing analysis was performed on the aorta isolated from saline or Ang II (angiotensin II)-induced AAA mice, and ATF3 was identified as the potential key gene for AAA development. To examine the role of ATF3 in AAA development, vascular smooth muscle cell-specific ATF3 knockdown or overexpressed mice by recombinant adeno-associated virus serotype 9 vectors carrying ATF3, or shRNA-ATF3 with SM22α (smooth muscle protein 22-α) promoter were used in Ang II-induced AAA mice. In human and murine vascular smooth muscle cells, gain or loss of function experiments were performed to investigate the role of ATF3 in vascular smooth muscle cell proliferation and apoptosis. RESULTS: In both Ang II-induced AAA mice and patients with AAA, the expression of ATF3 was reduced in aneurysm tissues but increased in aortic lesion tissues. The deficiency of ATF3 in vascular smooth muscle cell promoted AAA formation in Ang II-induced AAA mice. PDGFRB (platelet-derived growth factor receptor ß) was identified as the target of ATF3, which mediated vascular smooth muscle cell proliferation in response to TNF-alpha (tumor necrosis factor-α) at the early stage of AAA. ATF3 suppressed the mitochondria-dependent apoptosis at the advanced stage by upregulating its direct target BCL2. Our chromatin immunoprecipitation results also demonstrated that the recruitment of NFκB1 and P300/BAF/H3K27ac complex to the ATF3 promoter induces ATF3 transcription via enhancer activation. NFKB1 inhibitor (andrographolide) inhibits the expression of ATF3 by blocking the recruiters NFKB1 and ATF3-enhancer to the ATF3-promoter region, ultimately leading to AAA development. CONCLUSIONS: Our results demonstrate a previously unrecognized role of ATF3 in AAA development and progression, and ATF3 may serve as a novel therapeutic and prognostic marker for AAA.
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Factor de Transcripción Activador 3 , Aneurisma de la Aorta Abdominal , Músculo Liso Vascular , Miocitos del Músculo Liso , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Animales , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/inducido químicamente , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Ratones , Masculino , Ratones Endogámicos C57BL , Apoptosis , Células Cultivadas , Angiotensina II , Proliferación Celular , Aorta Abdominal/patología , Aorta Abdominal/metabolismo , Modelos Animales de EnfermedadRESUMEN
Viruses manipulate the cells they infect in order to replicate and spread. Due to strict size restrictions, viral genomes have reduced genetic space; how the action of the limited number of viral proteins results in the cell reprogramming observed during the infection is a long-standing question. Here, we explore the hypothesis that combinatorial interactions may expand the functional landscape of the viral proteome. We show that the proteins encoded by a plant-infecting DNA virus, the geminivirus tomato yellow leaf curl virus (TYLCV), physically associate with one another in an intricate network, as detected by a number of protein-protein interaction techniques. Importantly, our results indicate that intra-viral protein-protein interactions can modify the subcellular localization of the proteins involved. Using one particular pairwise interaction, that between the virus-encoded C2 and CP proteins, as proof-of-concept, we demonstrate that the combination of viral proteins leads to novel transcriptional effects on the host cell. Taken together, our results underscore the importance of studying viral protein function in the context of the infection. We propose a model in which viral proteins might have evolved to extensively interact with other elements within the viral proteome, enlarging the potential functional landscape available to the pathogen.
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Begomovirus , Virus de Plantas , Solanum lycopersicum , Proteínas Virales/genética , Proteínas Virales/metabolismo , Proteoma/metabolismo , Enfermedades de las Plantas , Begomovirus/metabolismo , Virus de Plantas/metabolismoRESUMEN
During data transmission, the dynamic change of a scattering medium will make the measured transmission matrix (TM) invalid, so it is necessary to repeatedly measure the TM to achieve a long-time data transmission, which requires stopping the data transmission process frequently to measure the TM and leads to a reduction in the communication capacity. To solve this problem, we propose a TM tracking method during data transmission. In the case of more than three discrete levels of phase modulation, this method can realize the calibration of the TM with the intensity pictures captured by the camera and the recovered data, so it does not require stopping the data transmission process to measure the TM and thus avoids the loss of communication capacity. We have proved the feasibility of this method through simulations and experiments and realized the continuous transmission of random data and image data through a moving fiber with high accuracy.
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Childhood leukemia is a prevalent form of pediatric cancer, with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) being the primary manifestations. Timely treatment has significantly enhanced survival rates for children with acute leukemia. This study aimed to develop an early and comprehensive predictor for hematologic malignancies in children by analyzing nutritional biomarkers, key leukemia indicators, and granulocytes in their blood. Using a machine learning algorithm and ten indices, the blood samples of 826 children with ALL and 255 children with AML were compared to a control group of 200 healthy children. The study revealed notable differences, including higher indicators in boys compared to girls and significant variations in most biochemical indicators between leukemia patients and healthy children. Employing a random forest model resulted in an area under the curve (AUC) of 0.950 for predicting leukemia subtypes and an AUC of 0.909 for forecasting AML. This research introduces an efficient diagnostic tool for early screening of childhood blood cancers and underscores the potential of artificial intelligence in modern healthcare.
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Inteligencia Artificial , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Masculino , Femenino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/diagnóstico , Preescolar , Adolescente , Lactante , Aprendizaje Automático , Pronóstico , Biomarcadores de Tumor/sangre , Estudios de Casos y ControlesRESUMEN
BACKGROUND: Saccharomyces cerevisiae is an important microorganism in ethanol synthesis, and with sugarcane molasses as the feedstock, ethanol is being synthesized sustainably to meet growing demands. However, high-concentration ethanol fermentation based on high-concentration sugarcane molasses-which is needed for reduced energy consumption of ethanol distillation at industrial scale-is yet to be achieved. RESULTS: In the present study, to identify the main limiting factors of this process, adaptive laboratory evolution and high-throughput screening (Py-Fe3+) based on ARTP (atmospheric and room-temperature plasma) mutagenesis were applied. We identified high osmotic pressure, high temperature, high alcohol levels, and high concentrations of K+, Ca2+, K+ and Ca2+ (K+&Ca2+), and sugarcane molasses as the main limiting factors. The robust S. cerevisiae strains of NGT-F1, NGW-F1, NGC-F1, NGK+, NGCa2+ NGK+&Ca2+-F1, and NGTM-F1 exhibited high tolerance to the respective limiting factor and exhibited increased yield. Subsequently, ethanol synthesis, cell morphology, comparative genomics, and gene ontology (GO) enrichment analysis were performed in a molasses broth containing 250 g/L total fermentable sugars (TFS). Additionally, S. cerevisiae NGTM-F1 was used with 250 g/L (TFS) sugarcane molasses to synthesize ethanol in a 5-L fermenter, giving a yield of 111.65 g/L, the conversion of sugar to alcohol reached 95.53%. It is the highest level of physical mutagenesis yield at present. CONCLUSION: Our results showed that K+ and Ca2+ ions primarily limited the efficient production of ethanol. Then, subsequent comparative transcriptomic GO and pathway analyses showed that the co-presence of K+ and Ca2+ exerted the most prominent limitation on efficient ethanol production. The results of this study might prove useful by promoting the development and utilization of green fuel bio-manufactured from molasses.
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Calcio , Etanol , Fermentación , Melaza , Potasio , Saccharomyces cerevisiae , Saccharum , Etanol/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharum/metabolismo , Calcio/metabolismo , Potasio/metabolismoRESUMEN
Separation of C2H6/C2H4 mixtures is of significant importance in the chemical industry but remains a challenge due to the physicochemical similarities of C2H6 and C2H4. Herein, a metal-organic framework (MOF), [Zn4(µ4-O)(PCTF)3]n (Zn-PCTF) (PCTF2-= 5-trifluoromethyl-1H-pyrazole-4-carboxylic), is provided for the removal of C2H6 from C2H6/C2H4 mixtures. Zn-PCTF displays a three-dimensional framework featuring one-dimensional pore channels with periodic bottleneck segments. The well-balanced C2H6 adsorption capacity (79.0 cm3 g-1 at 298 K) and C2H6/C2H4 selectivity (1.8) for Zn-PCTF under ambient conditions boost Zn-PCTF with highly promising potentials for efficient purification of C2H4 from C2H6/C2H4 mixtures, which is verified by the dynamic column breakthrough experiments. The well-matched caged pores and suitable pore chemistry (particularly the presence of abundant Lewis base sites (N, O, and F) on the pore surfaces) for C2H6 account for the high-performance C2H6/C2H4 separation of Zn-PCTF unveiled by computational simulations.
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Adsorption separation of the Xe/Kr mixture remains a tough issue since Xe and Kr have an inert nature and similar sizes. Here we present a chlorinated metal-organic framework (MOF) [JXNU-19(Cl)] and its nonchlorinated analogue (JXNU-19) for Xe/Kr separation. The two isostructural MOFs constructed from the heptanuclear cobalt-hydroxyl clusters bridged by organic ligands are three-dimensional structures. Detailed contrast of the Xe/Kr adsorption separation properties of the MOF shows that significantly enhanced Xe uptakes and Xe/Kr adsorption selectivity (17.1) are observed for JXNU-19 as compared to JXNU-19(Cl). The main binding sites for Xe in the MOF revealed by computational simulations are far away from the chlorine sites, suggesting that the introduction of the chlorine groups results in the unfavorable Xe adsorption for JXNU-19(Cl). The optimal pores, high surface area, and multiple strong Xe-framework interactions facilitate the effective Xe/Kr separation for JXNU-19.
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Developing "turn on" fluorescent probes was desirable for the detection of the effective anticoagulant agent heparin in clinical applications. Through combining the aggregation induced emission (AIE) fluorogen tetraphenylethene (TPE) and heparin specific binding peptide AG73, the promising "turn on" fluorescent probe TPE-1 has been developed. Nevertheless, although TPE-1 could achieve the sensitive and selective detection of heparin, the low proteolytic stability and undesirable poor solubility may limit its widespread applications. In this study, seven TPE-1 derived fluorescent probes were rationally designed, efficiently synthesized and evaluated. The stability and water solubility were systematically estimated. Especially, to achieve real-time monitoring of proteolytic stability, the novel Abz/Dnp-based "turn on" probes that employ the internally quenched fluorescent (IQF) mechanism were designed and synthesized. Moreover, the detection ability of synthetic fluorescent probes for heparin were systematically evaluated. Importantly, the performance of d-type peptide fluorescent probe XH-6 indicated that d-type amino acid substitutions could significantly improve the proteolytic stability without compromising its ability of heparin sensing, and attaching solubilizing tag 2-(2-aminoethoxy) ethoxy) acid (AEEA) could greatly enhance the solubility. Collectively, this study not only established practical strategies to improve both the water solubility and proteolytic stability of "turn on" fluorescent probes for heparin sensing, but also provided valuable references for the subsequent development of enzymatic hydrolysis-resistant d-type peptides based fluorescent probes.
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Colorantes Fluorescentes , Heparina , Péptidos , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Heparina/análisis , Heparina/química , Péptidos/química , Péptidos/síntesis química , Estructura Molecular , Humanos , Espectrometría de FluorescenciaRESUMEN
BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) can undergo inadequate osteogenesis or excessive adipogenesis as they age due to changes in the bone microenvironment, ultimately resulting in decreased bone density and elevated risk of fractures in senile osteoporosis. This study aims to investigate the effects of osteocyte senescence on the bone microenvironment and its influence on BMSCs during aging. RESULTS: Primary osteocytes were isolated from 2-month-old and 16-month-old mice to obtain young osteocyte-derived extracellular vesicles (YO-EVs) and senescent osteocyte-derived EVs (SO-EVs), respectively. YO-EVs were found to significantly increase alkaline phosphatase activity, mineralization deposition, and the expression of osteogenesis-related genes in BMSCs, while SO-EVs promoted BMSC adipogenesis. Neither YO-EVs nor SO-EVs exerted an effect on the osteoclastogenesis of primary macrophages/monocytes. Our constructed transgenic mice, designed to trace osteocyte-derived EV distribution, revealed abundant osteocyte-derived EVs embedded in the bone matrix. Moreover, mature osteoclasts were found to release osteocyte-derived EVs from bone slices, playing a pivotal role in regulating the functions of the surrounding culture medium. Following intravenous injection into young and elderly mouse models, YO-EVs demonstrated a significant enhancement of bone mass and biomechanical strength compared to SO-EVs. Immunostaining of bone sections revealed that YO-EV treatment augmented the number of osteoblasts on the bone surface, while SO-EV treatment promoted adipocyte formation in the bone marrow. Proteomics analysis of YO-EVs and SO-EVs showed that tropomyosin-1 (TPM1) was enriched in YO-EVs, which increased the matrix stiffness of BMSCs, consequently promoting osteogenesis. Specifically, the siRNA-mediated depletion of Tpm1 eliminated pro-osteogenic activity of YO-EVs both in vitro and in vivo. CONCLUSIONS: Our findings suggested that YO-EVs played a crucial role in maintaining the balance between bone resorption and formation, and their pro-osteogenic activity declining with aging. Therefore, YO-EVs and the delivered TPM1 hold potential as therapeutic targets for senile osteoporosis.
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Vesículas Extracelulares , Células Madre Mesenquimatosas , Osteocitos , Osteogénesis , Tropomiosina , Animales , Masculino , Ratones , Adipogénesis , Diferenciación Celular , Células Cultivadas , Vesículas Extracelulares/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Ratones Endogámicos C57BL , Ratones Transgénicos , Osteoclastos/metabolismo , Osteocitos/metabolismo , Osteoporosis/metabolismo , Tropomiosina/metabolismo , Tropomiosina/genéticaRESUMEN
Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.
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Autofagia , Frío , Exosomas , Ratones Endogámicos C57BL , MicroARNs , Osteogénesis , Animales , Autofagia/efectos de los fármacos , Ratones , Exosomas/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Osteogénesis/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Osteoporosis/patología , Diferenciación Celular/efectos de los fármacos , Huesos/metabolismo , Femenino , Densidad Ósea , Sirolimus/farmacologíaRESUMEN
BACKGROUND: The use of emulsion gels to protect and deliver probiotics has become an important topic in the food industry. This study used transglutaminase (TGase) to regulate ovalbumin (OVA) to prepare a novel emulsion gel. The effects of OVA concentration and the addition of TGase on the microstructure, rheological properties, water-holding capacity, and stability of the emulsion gels were investigated. RESULTS: With the addition of TGase and the increasing OVA, the particle size of the emulsion gels decreased significantly (P < 0.05). The gels with TGase exhibited greater water holding, hardness, and chewiness to some extent by forming a more uniform and stable system. After simulated digestion, the survival rate of Bifidobacterium lactis embedded in OVA emulsion gels improved significantly in comparison with the oil-water mixture as a result of the protective effect of the emulsion gel encapsulation. CONCLUSION: By increasing the OVA content and adding TGase, the rheological characteristics, stability, and encapsulation capability of the OVA emulsion gel could be enhanced, providing a theoretical basis for the use of emulsion gels to construct probiotic delivery systems. © 2023 Society of Chemical Industry.
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Transglutaminasas , Agua , Ovalbúmina , Emulsiones/química , Transglutaminasas/química , Geles/química , Reología , Agua/química , BacteriasRESUMEN
BACKGROUND: Castration-resistant prostate cancer often metastasizes to the bone, and such bone metastases eventually become resistant to available therapies, leading to the death of patients. Enriched in the bone, TGF-ß plays a pivotal role in bone metastasis development. However, directly targeting TGF-ß or its receptors has been challenging for the treatment of bone metastasis. We previously found that TGF-ß induces and then depends on the acetylation of transcription factor KLF5 at K369 to regulate multiple biological processes, including the induction of EMT, cellular invasiveness, and bone metastasis. Acetylated KLF5 (Ac-KLF5) and its downstream effectors are thus potential therapeutic targets for treating TGF-ß-induced bone metastasis in prostate cancer. METHODS: A spheroid invasion assay was applied to prostate cancer cells expressing KLF5K369Q, which mimics Ac-KLF5, to screen 1987 FDA-approved drugs for invasion suppression. Luciferase- and KLF5K369Q-expressing cells were injected into nude mice via the tail artery to model bone metastasis. Bioluminescence imaging, micro-CT), and histological analyses were applied to monitor and evaluate bone metastases. RNA-sequencing, bioinformatic, and biochemical analyses were used to understand nitazoxanide (NTZ)-regulated genes, signaling pathways, and the underlying mechanisms. The binding of NTZ to KLF5 proteins was evaluated using fluorescence titration, high-performance liquid chromatography (HPLC), and circular dichroism (CD) analysis. RESULTS: NTZ, an anthelmintic agent, was identified as a potent invasion inhibitor in the screening and validation assays. In KLF5K369Q-induced bone metastasis, NTZ exerted a potent inhibitory effect in preventive and therapeutic modes. NTZ also inhibited osteoclast differentiation, a cellular process responsible for bone metastasis induced by KLF5K369Q. NTZ attenuated the function of KLF5K369Q in 127 genes' upregulation and 114 genes' downregulation. Some genes' expression changes were significantly associated with worse overall survival in patients with prostate cancer. One such change was the upregulation of MYBL2, which functionally promotes bone metastasis in prostate cancer. Additional analyses demonstrated that NTZ bound to the KLF5 protein, KLF5K369Q bound to the promoter of MYBL2 to activate its transcription, and NTZ attenuated the binding of KLF5K369Q to the MYBL2 promoter. CONCLUSIONS: NTZ is a potential therapeutic agent for bone metastasis induced by the TGF-ß/Ac-KLF5 signaling axis in prostate cancer and likely other cancers.
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Neoplasias de la Próstata , Humanos , Masculino , Ratones , Animales , Ratones Desnudos , Neoplasias de la Próstata/genética , Factores de Transcripción , Factor de Crecimiento Transformador beta , Línea Celular Tumoral , Factores de Transcripción de Tipo Kruppel/genéticaRESUMEN
Structured light was usually studied by two-dimensional (2D) transverse eigenmodes. Recently, the three-dimensional (3D) geometric modes as coherent superposed states of eigenmodes opened new topological indices to shape light, that optical vortices can be coupled on multiaxial geometric rays, but only limited to azimuthal vortex charge. Here, we propose a new structured light family, multiaxial super-geometric modes, enabling full radial and azimuthal indices coupled to multiaxial rays, and they can be directly generated from a laser cavity. Exploiting combined intra- and extra-cavity astigmatic mode conversions, we experimentally verify the versatile tunability of complex orbital angular momentum and SU(2) geometry beyond the limit of prior multiaxial geometric modes, opening new dimensions to revolutionize applications such as optical trapping, manufacturing, and communications.
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Data transmission based on the transmission matrix method has realized the multiplexing of a large number of orbital angular momentum (OAM) modes under scattering, which encodes the data by modulating the amplitude of the OAM modes. However, this amplitude modulation (amplitude encoding) method has obvious cross talk when the number of output modes is small, resulting in a non-negligible bit error rate. Here, a multi-channel data transmission method based on OAM phase modulation (phase encoding) under scattering is proposed. This method can resist the multiple-scattering effect of multimode fibers and realize accurate data transmission with very few rows of camera pixels for output mode measurement, which is suitable for high-speed data transmission under scattering. Experimentally, we have achieved a bit error rate of less than 0.005% in the data transmission of a color image through a 60 m multimode fiber with only 2 rows of camera pixels for output mode measurement. Experiments also showed that the proposed method has a higher stability than amplitude encoding when the proportion of "1" or "0" in the code changes.
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PURPOSE: To explore the potential pathogenesis and clinical features of second primary glioblastoma (spGBM) following first primary renal cell carcinoma (fpRCC). METHODS: Patients with spGBM after fpRCC were enrolled from our institution and the SEER dataset. Sanger sequencing, whole genome sequencing, and immunehistochemistry were used to detect molecular biomarkers. RESULTS: Four and 122 cases from our institution and the SEER dataset, respectively, were collected with an overall median age of 69 years at spGBM diagnosis following fpRCC. The median interval time between fpRCC and spGBM was 50.7 months and 4 years, for the four and 122 cases respectively. The median overall survival time was 11.2 and 6.0 months for the two datasets. In addition, spGBM patients of younger age (< 75 years) or shorter interval time (< 1 year) had favorable prognosis (p = 0.081 and 0.05, respectively). Moreover, the spGBM cases were molecularly classified as TERT only paired with TP53 mutation, PIK3CA mutation, EGFR alteration, low tumor mutation burden, and stable microsatellite status. CONCLUSIONS: This is the first study to investigate the pathogenesis and clinical features of spGBM following spRCC. We found that spGBMs are old-age related, highly malignant, and have short survival time. Moreover, they might be misdiagnosed and treated as brain metastases from RCC. Thus, the incidence of spGBMs after fpRCC is underestimated. Further studies are needed to investigate the underlying molecular mechanisms and clinical biomarkers for the development of spGBM following fpRCC.
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Carcinoma de Células Renales , Glioblastoma , Neoplasias Renales , Humanos , Anciano , Carcinoma de Células Renales/patología , Glioblastoma/patología , Mutación , Genómica , Biomarcadores de Tumor/genética , Pronóstico , Neoplasias Renales/patologíaRESUMEN
Ovalbumin (OVA), the most abundant protein in egg whites, has been widely used in various industries. Currently, the structure of OVA has been clearly established, and the extraction of high-purified OVA has become feasible. However, the allergenicity of OVA is still a serious problem because it can cause severe allergic reactions and may even be life-threatening. The structure and allergenicity of the OVA can be altered by many processing methods. In this article, a detailed description on the structure and a comprehensive overview on the extraction protocols and the allergenicity of OVA was documented. Additionally, the information on assembly and potential applications of OVA was summarized and discussed in detail. Physical treatment, chemical modification, and microbial processing can be applied to alter the IgE-binding capacity of OVA by changing its structure and linear/sequential epitopes. Furthermore, research indicated that OVA could assemble with itself or other biomolecules into various forms (particles, fibers, gels, and nanosheets), which expanded its application in the food field. OVA also shows excellent application prospects, including food preservation, functional food ingredients and nutrient delivery. Therefore, OVA demonstrates significant investigation value as a food grade ingredient.
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Herein, a metal-organic framework (MOF), {[(Me2NH2)4][Cd(H2O)6][Cd18(TrZ)12(TPD)15(DMF)6]}n (denoted as JXNU-18, TrZ = triazolate), constructed from the unique cucurbituril-shaped Cd18(TrZ)12 secondary building units bridged by 2,5-thiophenedicarboxylic (TPD2-) ligands, is presented. The formation of the cucurbituril-shaped Cd18(TrZ)12 unit is unprecedented, demonstrating the geometric compatibility of the organic linkers and the coordination configurations of the cadmium atoms. Each Cd18(TrZ)12 unit is connected to eight neighboring Cd18(TrZ)12 units through 30 TPD2- linkers, affording the three-dimensional structure of JXNU-18. More interesting is that JXNU-18 displays an efficient C2H2/CO2 separation ability, as revealed by the gas adsorption experiments and dynamic gas breakthrough experiments, which afford insights into the potential applications of JXNU-18 in gas separation. The tubular pores composed of two Cd18(TrZ)12 units bridged by six 2,5-thiophenedicarboxylic linkers provide the suitable pore space for C2H2 trapping, as unveiled by computational simulations.
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Nitrogen mustards (NMs) are an important class of chemotherapeutic drugs and have been widely employed for the treatment of various cancers. However, due to the high reactivity of nitrogen mustard, most NMs react with proteins and phospholipids within the cell membrane. Therefore, only a very small fraction of NMs can reach the reach nucleus, alkylating and cross-linking DNA. To efficiently penetrate the cell membrane barrier, the hybridization of NMs with a membranolytic agent may be an effective strategy. Herein, the chlorambucil (CLB, a kind of NM) hybrids were first designed by conjugation with membranolytic peptide LTX-315. However, although LTX-315 could help large amounts of CLB penetrate the cytomembrane and enter the cytoplasm, CLB still did not readily reach the nucleus. Our previous work demonstrated that the hybrid peptide NTP-385 obtained by covalent conjugation of rhodamine B with LTX-315 could accumulate in the nucleus. Hence, the NTP-385-CLB conjugate, named FXY-3, was then designed and systematically evaluated both in vitro and in vivo. FXY-3 displayed prominent localization in the cancer cell nucleus and induced severe DNA double-strand breaks (DSBs) to trigger cell apoptosis. Especially, compared with CLB and LTX-315, FXY-3 exhibited significantly increased in vitro cytotoxicity against a panel of cancer cell lines. Moreover, FXY-3 showed superior in vivo anticancer efficiency in the mouse cancer model. Collectively, this study established an effective strategy to increase the anticancer activity and the nuclear accumulation of NMs, which will provide a valuable reference for future nucleus-targeting modification of nitrogen mustards.
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Neoplasias , Compuestos de Mostaza Nitrogenada , Animales , Ratones , Clorambucilo/farmacología , ADN/metabolismo , Nitrógeno , Compuestos de Mostaza Nitrogenada/farmacología , Péptidos/farmacologíaRESUMEN
Cytotoxic peptides derived from spider venoms have been considered as promising candidates for anticancer treatment. The novel cell penetrating peptide LVTX-8, which is a 25-residue amphipathic α-helical peptide isolated from spider Lycosa vittata, exhibited potent cytotoxicity and is a potential precursor for further anticancer drug development. Nevertheless, LVTX-8 may be easily degraded by multiple proteases, inducing the proteolytic stability problem and short half-life. In this study, ten LVTX-8-based analogs were rationally designed and the efficient manual synthetic method was established by the DIC/Oxyma based condensation system. The cytotoxicity of synthetic peptides was systematically evaluated against seven cancer cell lines. Seven of the derived peptides exhibited high cytotoxicity towards tested cancer in vitro, which was better than or comparable to that of natural LVTX-8. In particular, both N-acetyl and C-hydrazide modified LVTX-8 (825) and the conjugate methotrexate (MTX)-GFLG-LVTX-8 (827) possessed more durable anticancer efficiency, higher proteolytic stability, as well as lower hemolysis. Finally, we confirmed that LVTX-8 could disrupt the integrity of cell membrane, target the mitochondria and reduce the mitochondrial membrane potential to induce the cell death. Taken together, the structural modifications were conducted on LVTX-8 for the first time and the stability significantly improved derivatives 825 and 827 may provide useful references for the modifications of cytotoxic peptides.