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A thermal lens insensitive regenerative amplifier (RA) with a dual Yb:CaYAlO4 (Yb:CYA) crystal configuration for extending gain spectra is demonstrated for the first time, to the best of our knowledge. By orthogonalizing the orientation of two a-cut Yb:CYA crystals in one RA, the Q switched spectrum with a full width at half maximum of 15.4â nm is generated, which is 1.5 and 1.6 times of the Q switched spectral bandwidth with π- and σ-polarization, respectively. With chirped pulses injection, this RA can deliver laser pulses with an average power exceeding 10 W at the repetition rate of 20-800 kHz and pulse energy of 1.5 mJ at 1 kHz. This is the highest average power from the Yb:CYA RA to the best of our knowledge. Finally, compressed pulses of 163 fs with 92% overall efficiency are realized. Thanks to the heat insensitive cavity design and excellent thermodynamic properties of the Yb:CYA crystal, the output laser beam is close to the diffraction limit with an M2 value of 1.07 × 1.07.
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BACKGROUND: Sleep loss and its associated conditions (e.g. cognitive deficits) represent a large societal burden, but the underlying mechanisms of these cognitive deficits remain unknown. This study assessed the effect of dexmedetomidine (DEX) on cognitive decline induced by sleep loss. METHODS: C57BL/6 mice were subjected to chronic sleep restriction (CSR) for 20 h (5 pm-1 pm the next day) daily for 7 days, and cognitive tests were subsequently carried out. The neuromolecular and cellular changes that occurred in the presence and absence of DEX (100 µg kg-1, i.v., at 1 pm and 3 pm every day) were also investigated. RESULTS: CSR mice displayed a decline in learning and memory by 12% (P<0.05) in the Y-maze and by 18% (P<0.01) in the novel object recognition test; these changes were associated with increases in microglial activation, CD68+ microglial phagosome counts, astrocyte-derived complement C3 secretion, and microglial C3a receptor expression (all P<0.05). Synapse elimination, as indicated by a 66% decrease in synaptophysin expression (P=0.0004) and a 45% decrease in postsynaptic density protein-95 expression (P=0.0003), was associated with the occurrence of cognitive deficits. DEX activated astrocytic α2A adrenoceptors and inhibited astrocytic complement C3 release to attenuate synapse elimination through microglial phagocytosis. DEX restored synaptic connections and reversed cognitive deficits induced by CSR. CONCLUSIONS: The results demonstrate that complement pathway activation associated with synapse elimination contributes to sleep loss-related cognitive deficits and that dexmedetomidine protects against sleep deprivation-induced complement activation. Dexmedetomidine holds potential for preventing cognitive deficits associated with sleep loss, which warrants further study.
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Dexmedetomidina , Privación de Sueño , Ratones , Animales , Privación de Sueño/complicaciones , Complemento C3/metabolismo , Complemento C3/farmacología , Dexmedetomidina/farmacología , Ratones Endogámicos C57BL , Activación de Complemento , Cognición , Hipocampo/metabolismo , Microglía/metabolismoRESUMEN
Stress is well known to contribute to the development of both neurological and psychiatric diseases. In the central nervous system, a role for STING (stimulator of interferon genes) in modulating immunological responses has been widely suggested, and this protein possesses both neurotoxic and neuroprotective properties. However, the potential role of the STING signalling pathway and the underlying regulatory mechanism in chronic stress have not been well established. In this study, C57BL/6 mice were subjected to intermittent restraint stress for 14 days (6 h/day), and sucrose preference, elevated plus maze, and tail suspension tests were performed by mice subjected to chronic restraint stress (RST). Here, we showed that RST mice displayed depression-like behaviours, accompanied by increased levels of proinflammatory cytokines in the brain. We also observed remarkably decreased levels of the pathway components STING, p-TBK1 (phospho-TANK-binding kinase-1), and p-IRF3 (phospho-interferon regulatory factor-3) in the hippocampus and the prefrontal cortex of RST mice. Significant reductions in STING fluorescence intensity were also observed in the hippocampus and the prefrontal cortex of RST mice. Next, fluorescently labelled latex beads, flow cytometry, and CD68-positive cell counts were utilized to evaluate the phagocytic abilities of microglia in vivo and in vitro. Importantly, our results first indicated that activation of the STING pathway by administration of the STING agonist 2'3-cGAMP enhanced microglial phagocytosis and suppressed the release of the proinflammatory cytokines TNF-α, IL-6, and IL-1ß in the brains of RST mice, which further led to antidepressant effects. Based on the results of our study, the amelioration of stress-driven depression-like behaviours by activation of the STING pathway is associated with the suppression of neuroinflammation and enhanced phagocytosis.
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Factor 3 Regulador del Interferón , Microglía , Animales , Citocinas/metabolismo , Depresión/tratamiento farmacológico , Depresión/etiología , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/farmacología , Proteínas de la Membrana , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Enfermedades Neuroinflamatorias , Fagocitosis , Proteínas Serina-Treonina QuinasasRESUMEN
We demonstrate the simultaneous temporal contrast enhancement and spectral broadening via nonlinear elliptical polarization rotation in a solid thin plate. The efficiency, temporal contrast enhancement, spectral broadening, pulse compression and power stability are experimentally investigated. With this simple and efficient scheme, the temporal cleaned pulses with energy of 325 µJ and total efficiency of 30% are obtained. The temporal contrast and spectral bandwidth of the filtered pulse are 1011 and 104â nm, respectively. The pulse compressed from 180 fs to 45.8 fs is realized by utilizing chirped mirrors, corresponding to a compression factor of 3.93. With stable output power, presented scheme could be implemented in the ultra-intense femtosecond laser facilities.
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We demonstrate the generation of high average power femtosecond laser radiation by combination of an Nd-doped picosecond amplifier and a multi-pass cell device. With this efficient and robust scheme, the pulse duration of a picosecond amplifier is compressed from 9.13 ps to 477 fs, corresponding to a compression factor of 19.1. The average power before and after pulse compression is 77 W and 56.5 W respectively, so the overall transmission reaches 73.4%. The presented scheme offers a viable route toward low-cost and simple configuration high power femtosecond lasers driven by Nd-doped picosecond amplifiers.
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This study aimed to analyze the association between driver mutations and predictive markers for some anti-tumor agents in non-small cell lung cancer (NSCLC). A cohort of 785 Chinese patients with NSCLC who underwent resection from March 2016 to November 2017 in the First Affiliated Hospital of Guangzhou Medical University was investigated. The specimens were subjected to hybridization capture and sequence of 8 important NSCLC-related driver genes. In addition, the slides were tested for PD-L1, excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthase (TS) and ß-tubulin III by immunohistochemical staining. A total of 498 (63.4%) patients had at least 1 driver gene alteration. Wild-type, EGFR rare mutation (mut), ALK fusion (fus), RAS mut, RET fus and MET mut had relatively higher proportions of lower ERCC1 expression. EGFR 19del, EGFR L858R, EGFR rare mut, ALK fus, HER2 mut, ROS1 fus and MET mut were more likely to have TS low expression. Wild-type, EGFR L858R, EGFR rare mut and BRAF mut were associated with lower ß-tubulin III expression. In addition, wild-type, RAS mut, ROS1 fus, BRAF and MET mut had higher proportion of PD-L1 high expression. As a pilot validation, 21 wild-type patients with advanced NSCLC showed better depth of response and response rate to taxanes compared with pemetrexed/gemcitabine (31.2%/60.0% vs 26.6%/45.5%). Our study may aid in selecting the optimal salvage regimen after targeted therapy failure, or the chemo-regimen where targeted therapy has not been a routine option. Further validation is warranted.
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Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Mutación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Pemetrexed/administración & dosificación , Pronóstico , Taxoides/uso terapéutico , GemcitabinaRESUMEN
Hydrophobicity and molecular weight (MW) are two fundamental properties of dissolved organic matter (DOM) in wastewater treatment systems. This study proposes fluorescence Stokes shift and specific fluorescence intensity (SFI) as novel indicators of hydrophobicity and MW. These indicators originate from the energy gap and photon efficiency of the fluorescence process and can be readily extracted from a fluorescence excitation-emission matrix (EEM). The statistical linkages between these indicators and hydrophobicity/MW were explored through investigation of DOM across 10 full-scale membrane bioreactors treating municipal wastewater. Stokes shift was found to exhibit a general rule among the hydrophobicity components in the order of hydrophilic substances (HIS) < hydrophobic acids (HOA) < hydrophobic bases (HOB). The Stokes shift of 1.2 µm-1 is a critical border, above which the relative fluorescence correlated significantly with the HOA-related content (Pearson's r = 0.8). With regard to MW distribution (<1, 1-10, 10-100, and >100 kDa), SFI was found to be the most sensitive to the change of MW of <1 kDa proportion, especially at the excitation/emission wavelengths of 200-320/310-550 nm (r > 0.9). Hydrophobicity-related π conjugation and MW-dependent light exposure might be responsible for the correlations. These fluorescence indicators may be useful for convenient monitoring of DOM in wastewater treatment systems.
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Contaminantes Químicos del Agua , Reactores Biológicos , Sustancias Húmicas , Interacciones Hidrofóbicas e Hidrofílicas , Peso Molecular , Espectrometría de Fluorescencia , Aguas ResidualesRESUMEN
BACKGROUND: Underdevelopment of nose and chin in East Asians is quite common. Rhinoplasty and mentoplasty are effective procedures to solve the above-depicted defects and can achieve remarkable cosmetic effects. An autologous costal cartilage graft has become an ideal material for rhinoplasty, especially for revision surgery. However, many problems in the clinical application of costal cartilage remain unresolved. This study is to investigate application strategies of autologous costal cartilage grafts in rhino- and mentoplasty. METHODS: The methods involved are as follows: application of an integrated cartilage scaffold; comprehensive application of diced cartilage; and chin augmentation of an autologous costal cartilage graft. RESULTS: In this study, satisfactory facial contour appearance was immediately achieved in 28 patients after surgery; 21 patients had satisfactory appearance of the nose and chin during the 6- to 18-month follow-up. Cartilage resorption was not observed. Two patients had nasal tip skin redness and were cured after treatment. CONCLUSION: This procedure can be used to effectively solve: curvature of the costal cartilage segment itself; warping of the carved costal cartilage; and effective use of the costal cartilage segment. The procedure has achieved satisfactory outcomes, and its application is worth extending to clinical practice.
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Cartílago Costal/trasplante , Mentoplastia , Rinoplastia , Adolescente , Adulto , Autoinjertos/cirugía , Mentón/cirugía , Femenino , Humanos , Nariz/cirugía , Adulto JovenRESUMEN
Lactate dehydrogenase (LDH) is an essential metabolic enzyme that catalyzes the interconversion of pyruvate and lactate using NADH/NAD(+) as a co-substrate. Many cancer cells exhibit a glycolytic phenotype known as the Warburg effect, in which elevated LDH levels enhance the conversion of glucose to lactate, making LDH an attractive therapeutic target for oncology. Two known inhibitors of the human muscle LDH isoform, LDHA, designated 1 and 2, were selected, and their IC50 values were determined to be 14.4 ± 3.77 and 2.20 ± 0.15â µM, respectively. The X-ray crystal structures of LDHA in complex with each inhibitor were determined; both inhibitors bind to a site overlapping with the NADH-binding site. Further, an apo LDHA crystal structure solved in a new space group is reported, as well as a complex with both NADH and the substrate analogue oxalate bound in seven of the eight molecules and an oxalate only bound in the eighth molecule in the asymmetric unit. In this latter structure, a kanamycin molecule is located in the inhibitor-binding site, thereby blocking NADH binding. These structures provide insights into LDHA enzyme mechanism and inhibition and a framework for structure-assisted drug design that may contribute to new cancer therapies.
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L-Lactato Deshidrogenasa/antagonistas & inhibidores , L-Lactato Deshidrogenasa/química , Neoplasias/enzimología , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Isoenzimas/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Lactato Deshidrogenasa 5 , Simulación del Acoplamiento Molecular , NAD/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Ácido Oxálico/metabolismo , Conformación ProteicaRESUMEN
Natural deep eutectic solvents (NaDESs) are environmentally friendly and efficient for the componential extraction of traditional Chinese medicine compared to conventional organic solvents. In this study, NaDES was screened and employed to extract Danshen-Gegen (DG), and the extraction process was optimised by response surface methodology (RSM) and artificial neural networks (ANN) model. Besides, the in vitro security of extracts of DG were evaluated in PC12 cells. As a result, Betaine-Urea (Bet-Ur) was screened as extraction solvent and ANN model was more accurate than RSM model in optimising the extraction parameter. The extraction process optimised by ANN was as follows: 70% NaDES concentration, 80 mg/mL solid to liquid ratio, 67 °C ultrasonic temperature, and 33 min of ultrasonic time. The comprehensive value of extraction yield was 0.7251 ± 0.84%. IC50 of Bet-Ur, NaDES DG extract and aqueous DG extract were 0.15%, 0.3% and 10% (v/v).
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In this research, eight natural deep eutectic solvents (NaDESs) consisting of food-grade ingredients were screened for the extraction of four bioactive compounds (acteoside, cinnamic acid, angoroside C and harpagoside) from radix scrophulariae (RS). Among these NaDESs, Proline-Glycerol NaDES with higher comprehensive score was selected. The Criteria Importance Through Intercriteria Correlation (CRITIC) was applied to calculate the information entropy and the weight of indexes, and figured out a comprehensive score. The weights of acteoside, cinnamic acid, angoroside C and harpagoside were 0.369, 0.172, 0.241 and 0.218, respectively. Response surface methodology (RSM) mathematical model was used to optimize the extraction parameters. The optimal extraction parameters were as follows: extraction time with 42.21 min, NaDES concentration with 52.89%, solid-to-liquid ratio with 1 : 37.05 g/mL and the predicted value of comprehensive score was 0.885. Under the optimal condition, the comprehensive score was 0.903 ± 0.005. Finally, the antioxidant activity experiment revealed that the 1,1-Diphenyl-2-picrylhydrazyl · radical scavenging activity and hydroxyl radical scavenging activity of the extract at 2.0 mg/mL and 1.5 mg/mL were approximately equal to those of ascorbic acid, respectively. The results showed that the extraction condition optimized by RSM combined with CRITIC was reasonable and dependable, and the extract of radix scrophulariae exhibited good antioxidant activity.
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Sleep deprivation (SD) has been associated with several adverse effects, including cognitive deficit. Emerging evidence suggests microglia-associated neuroinflammation is a potential trigger of cognitive deficit after SD. Stimulator of interferon genes (STING) constitutes an important factor in host immune response to pathogenic organisms and is found in multiple cells, including microglia. STING is involved in neuroinflammation during neuronal degeneration, although how STING signaling affects SD-induced neuroinflammation remains unexplored. In the present study, the chronic sleep restriction (CSR) model was applied to examine the effects of STING signaling on cognition. The results revealed that cGAMP, a high-affinity and selective STING agonist, significantly improved cognitive deficit, alleviated neural injury, and relieved neuroinflammation in CSR mice by activating the STING-TBK1-IRF3 pathway. Moreover, triggering receptor expressed on myeloid cells 2 (TREM2) was upregulated in CSR mice treated with cGAMP, and this effect was abolished by STING knockout. TREM2 upregulation induced by cGAMP regulated the microglia from pro-inflammatory state to anti-inflammatory state, thereby relieving neuroinflammation in CSR mice. These findings indicate cGAMP-induced STING signaling activation alleviates SD-associated neuroinflammation and cognitive deficit by upregulating TREM2, providing a novel approach for the treatment of SD-related nerve injury.
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Long periods of sleep deprivation (SD) have serious effects on health. While the α2 adrenoceptor agonist dexmedetomidine (DEX) can improve sleep quality for patients who have insomnia, the effect of DEX on cognition and mechanisms after SD remains elusive. C57BL/6 mice were subjected to 20 h SD daily for seven days. DEX (100 µg/kg) was administered intravenously twice daily (at 1:00 p.m. and 3:00 p.m.) during seven days of SD. We found that systemic administration of DEX attenuated cognitive deficits by performing the Y maze and novel object recognition tests and increased DCX+, SOX2+, Ki67+, and BrdU+NeuN+/NeuN+ cell numbers in the dentate gyrus (DG) region of SD mice by using immunofluorescence, western blotting, and BrdU staining. DEX did not reverse the decrease in DCX+, SOX2+, or Ki67+ cell numbers in SD mice after administration of the α2A-adrenoceptor antagonist BRL-44408. Furthermore, the vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) expression was upregulated in SD+DEX mice compared with SD mice. Luminex analysis showed that the neurogenic effects of DEX were possibly related to the inhibition of neuroinflammation, including IL-1α, IL-2, CCL5, and CXCL1. Our results suggested that DEX alleviated the impaired learning and memory of SD mice potentially by inducing hippocampal neurogenesis via the VEGF-VEGFR2 signaling pathway and by suppressing neuroinflammation, and α2A adrenoceptors are required for the neurogenic effects of DEX after SD. This novel mechanism may add to our knowledge of DEX in the clinical treatment of impaired memory caused by SD.
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Dexmedetomidina , Ratones , Animales , Dexmedetomidina/farmacología , Dexmedetomidina/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Enfermedades Neuroinflamatorias , Privación de Sueño/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Bromodesoxiuridina/farmacología , Antígeno Ki-67/metabolismo , Ratones Endogámicos C57BL , Hipocampo , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Transducción de Señal , NeurogénesisRESUMEN
Sleep deprivation causes significant memory impairment in healthy adults. Extensive research has focused on identifying the biological mechanisms underlying memory impairment. Microglia-mediated synaptic elimination plays an indispensable role in sleep deprivation. Here, the potential role of the CD33/TREM2 signaling pathway in modulating memory decline during chronic sleep restriction (CSR) was evaluated. In this study, adult male C57BL/6 mice were sleep-restricted using an automated sleep deprivation apparatus for 20 h per day for 7 days. The Y-maze test revealed that spontaneous alternation was significantly reduced in CSR mice compared with control mice. The percentage of exploratory preference for the novel object in CSR mice was significantly decreased compared with that in control mice. These memory deficits correlated with aberrant microglial activation and increased phagocytic ability. Moreover, in CSR mice, the CD33 protein level in hippocampal tissue was significantly downregulated, but the TREM2 protein level was increased. In BV2 microglial cells, downregulation of CD33 increased TREM2 expression and improved microglial phagocytosis. Then, the sialic ligand monosialo-ganglioside 1 (GM1, 20 mg/kg, i.p.) was administered to mice once a day during CSR. Our results further showed that GM1 activated CD33 and consequently disturbed TREM2-mediated microglial phagocytosis. Finally, GM1 reversed CSR-induced synaptic loss and memory impairment via the CD33/TREM2 signaling pathway in the CA1 region of the hippocampus. This study provides novel evidence that activating CD33 and/or inhibiting TREM2 activity represent potential therapies for sleep loss-induced memory deficits through the modulation of microglial phagocytosis.
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Microglía , Privación de Sueño , Ratones , Masculino , Animales , Microglía/metabolismo , Privación de Sueño/complicaciones , Privación de Sueño/metabolismo , Gangliósido G(M1)/metabolismo , Ratones Endogámicos C57BL , Fagocitosis , Transducción de Señal , Trastornos de la Memoria/etiología , Trastornos de la Memoria/metabolismoRESUMEN
Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstrated in vitro potency against DMT1, desirable cell permeability properties and a dose-dependent inhibition of iron uptake in an acute rat model of iron hyperabsorption. Tricyclic compounds increased the in vitro potency by up to 16-fold versus the original hit. Diaryl compounds 6b and 14a demonstrated significant iron absorption inhibition in vivo with both 25 and 50 mg/kg doses. The diaryl and tricyclic compounds described in this report represent promising structural templates for further optimization.
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Proteínas de Transporte de Catión/antagonistas & inhibidores , Tiourea/química , Animales , Células CACO-2 , Proteínas de Transporte de Catión/metabolismo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Hierro/metabolismo , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/patología , Ratas , Relación Estructura-Actividad , Tiourea/síntesis química , Tiourea/farmacologíaRESUMEN
OBJECTIVE: The predicted amino acid sequence of locus plu4437-plu4436 in the genome of Photorhabdus luminescens TT01 (referred to as pirA2B2) has a consistency of 50% and 45% with locus plu4093-plu4092 (referred to as pirA1B1) , respectively. PirA1B1 has been confirmed with oral insecticidal activity against Plutella xylostella and mosquito. The purpose of the present study was to examine whether pirA2B2 possesses insecticidal activity. METHODS: pirA2, pirB2 and pirA2B2 genes were PCR amplified and cloned. The recombinant expression vector pQE-pirA2, pQE-pirB2 and pQE-pirA2B2 were constructed and transferred into E. coli M15, individually. The soluble PirA2, PirB2 and PirA2B2 proteins were detected from the supernatant of the recombinant M15 induced with IPTG by both SDS-PAGE and Western-blot. The proteins expressed in the three recombinant E. coli M15 strains were purified by affinity chromatography combined with desalination technology and then quantified individually. The heamocoal and oral insecticidal activities of the expressed proteins were analyzed against the larvae of Galleria mellonella and Spodoptera litura. RESULTS: The results show: 1. PirA2B2 had heamocoal insecticidal activity against the fifth instar larvae of both G. mellonella and S. litura, with an LD50 of 4.0 and 2.8 microg/larvae, respectively, 2. neither PirA2 nor PirB2 alone had heamocoal insecticidal activity against the insects tested, while the mixture of PirA2 and PirB2 reconstituted full activity, and 3. PirA2B2 showed no oral insecticidal activity to the first instar larvae of either G. mellonella or S. litura. CONCLUSION: pirA2B2 in the genome of P. luminescens TT01 is a binary insecticidal toxin gene. SIGNIFICANCE: The successful expression and purifcation of PirA2B2 laid a foundation for further study on the function, insecticidal mechanism and expression regulation of the binary toxins.
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Regulación Bacteriana de la Expresión Génica , Genes Bacterianos , Insecticidas/metabolismo , Photorhabdus/genética , Animales , Clonación Molecular , Insecticidas/farmacología , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/farmacología , SpodopteraRESUMEN
Sulfonated polysulfone (SPSF) with different sulfonation degrees (10%, 30%, and 50%) was added to polyethersulfone (PES) to improve the separation and antifouling performance of polyethersulfone ultrafiltration membranes. The PES/SPSF blend ultrafiltration membrane was prepared by the non-solvent induced phase inversion method (NIPS), and the effect of sulfonation degree on the ultrafiltration performance was studied. The compatibility of SPSF and PES was calculated by the group contribution method, and confirmed by differential scanning calorimetry (DSC). The morphology and surface roughness of the membrane were characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM), the chemical composition of the membrane was analyzed by X-ray photoelectron spectroscopy (XPS) and infrared spectroscopy (FTIR), and the permeability and anti-fouling performance of the blend membrane were studied through filtration experiments. The research shows that the flux and anti-fouling performance of the blend membrane have been improved after adding SPSF. When the sulfonation degree of the SPSF is 30%, the pure water flux of the blend membrane can reach 530 L m-2 h-1, the rejection rate of humic acid (HA) is 93%, the flux recovery rate of HA increases from 69.23% to 79.17%, and the flux recovery rate of BSA increases from 72.56% to 83%.
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Type 2 diabetic patients have high risk of developing cognitive dysfunction, in which neural structural plasticity has played a pivotal role. Paired immunoglobulin-like receptor B (PirB), a receptor mainly expressed in neurons, acts as a critical inhibitor of neurite outgrowth and neural plasticity. However, the role of PirB in type 2 diabetes-associated cognitive dysfunction remains unknown. In this study, learning and memory impairment was observed in 24-week-old db/db mice by performing Morris water maze task, and the number of synapses along with the length of postsynaptic density by transmission electron microscopy were reduced in the hippocampus of db/db mice. Furthermore, PirB expression in the hippocampus of db/db mice was significantly upregulated using western blotting and immunofluorescence analysis. In cultured hippocampal neurons, high glucose treatment reduced the length of the longest neurite as well as axon initial segment (AIS), whereas silencing PirB expression rescued high glucose-induced neurite outgrowth inhibition, but not AIS. Additionally, cognitive deficits, dendrite morphology defects, and synapse-related proteins loss in db/db mice were alleviated when PirB knockdown was performed by adeno-associated virus injection. In conclusion, PirB is involved in diabetes-associated cognitive dysfunction through modulation of axon outgrowth and dendritic remodeling, providing a potential therapeutic target for diabetes-associated cognitive dysfunction.
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Disfunción Cognitiva , Diabetes Mellitus Tipo 2 , Animales , Disfunción Cognitiva/metabolismo , Glucosa , Humanos , Inmunoglobulinas , Ratones , Ratones Endogámicos , Proyección Neuronal , Plasticidad Neuronal/fisiología , Receptores Inmunológicos/metabolismoRESUMEN
Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of Na(V)1.7 blockers were developed. Following the elimination of undesirable structural features, preliminary optimization of the oxindole C-3 and N-1 substituents afforded the simplified analogue 9b, which demonstrated a 10-fold increase in target potency versus the original HTS hit. A scaffold rigidification strategy then led to the discovery of XEN907, a novel spirooxindole Na(V)1.7 blocker. This lead compound, which in turn showed a further 10-fold increase in potency, represents a promising structure for further optimization efforts.
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Analgésicos/síntesis química , Analgésicos/farmacología , Indoles/síntesis química , Indoles/farmacología , Dolor , Canales de Sodio/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Analgésicos/química , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Indoles/química , Concentración 50 Inhibidora , Estructura Molecular , Canal de Sodio Activado por Voltaje NAV1.7 , Oxindoles , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
The hydrophobicity of ultrafiltration membranes is the main cause of membrane fouling and reduced permeability, so it is necessary to improve the hydrophilicity and anti-fouling performance of ultrafiltration membrane materials. MoS2 nanoparticles that were modified with polydopamine (PDA) and polyethyleneimine (PEI), named MoS2-PDA-PEI, were added to fabricate a polyethersulfone ultrafiltration membrane (PES/MoS2-PDA-PEI) for the first time. The effects of modified MoS2 nanoparticles on membrane performance were clarified. The results indicated that the permeability, rejection, and anti-fouling capability of the hybrid PES/MoS2-PDA-PEI membrane have been improved compared with the pristine PES membrane. When the content of MoS2-PDA-PEI nanoparticles in the membrane is 0.5%, the pure water flux of the hybrid membrane reaches 364.03 L m-2 h-1, and the rejection rate of bovine serum albumin (BSA) and humic acid (HA) is 96.5% and 93.2% respectively. The flux recovery rate of HA reached 97.06%. As expected, the addition of MoS2-PDA-PEI nanoparticles promotes the formation of the porous structure and improves the hydrophilicity of the membrane, thereby improving its antifouling performance.