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Carboxylesterase 1 (CES1), a member of the serine hydrolase superfamily, is involved in a wide range of xenobiotic and endogenous substances metabolic reactions in mammals. The inhibition of CES1 could not only alter the metabolism and disposition of related drugs, but also be benefit for treatment of metabolic disorders, such as obesity and fatty liver disease. In the present study, we aim to develop potential inhibitors of CES1 and reveal the preferred inhibitor structure from a series of synthetic pyrazolones (compounds 1-27). By in vitro high-throughput screening method, we found compounds 25 and 27 had non-competitive inhibition on CES1-mediated N-alkylated d-luciferin methyl ester (NLMe) hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. Additionally, Compounds 25, 26 and 27 can inhibit CES1-mediated fluorescent probe hydrolysis in live HepG2 cells with effect. Besides, compounds 25, 26 and 27 could effectively inhibit the accumulation of lipid droplets in mouse adipocytes cells. These data not only provided study basis for the design of newly CES1 inhibitors. The present study not only provided the basis for the development of lead compounds for novel CES1 inhibitors with better performance, but also offered a new direction for the explore of candidate compounds for the treatment of hyperlipidemia and related diseases.
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Adipocitos , Hidrolasas de Éster Carboxílico , Inhibidores Enzimáticos , Pirazolonas , Humanos , Hidrolasas de Éster Carboxílico/metabolismo , Hidrolasas de Éster Carboxílico/antagonistas & inhibidores , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/citología , Animales , Ratones , Pirazolonas/farmacología , Pirazolonas/química , Pirazolonas/síntesis química , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Estructura Molecular , Células Hep G2 , Diferenciación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células 3T3-L1RESUMEN
To optimize the extraction process of crude polysaccharides from Atractylodes and elaborate the mechanism of Atractylodes polysaccharides in treating diarrhea owing to spleen deficiency, so as to lay a foundation for further development and utilization of Atractylodes lancea, we used an orthogonal test to optimize the extraction process and established a model of spleen deficiency. It was further combined with histopathology and intestinal flora to elaborate the mechanism of Atractylodes polysaccharides in the treatment of spleen-deficiency diarrhea. The optimized extraction conditions were as follows: the ratio of material to liquid was 1:25; the rotational speed was 150 rpm; the extraction temperature was 60°C; the extraction time was 2 h; and the extraction rate was about 23%. The therapeutic effect of Atractylodes polysaccharides on a spleen-deficiency diarrhea model in mice showed that the water content of stools and diarrhea grade in the treatment group were alleviated, and the levels of gastrin, motilin and d-xylose were improved. The analysis results based on gut microbiota showed that the model group had a higher diversity of gut microbiota than the normal group and treatment group, and the treatment group could correct the diversity of gut microbiota in model mice. Analysis based on the level of phylum and genus showed that the treatment group could inhibit the abundance of Helicobacter pylori genus and increase beneficial bacteria genera. The conclusion was that the optimized extraction process of Atractylodes polysaccharides was reasonable and feasible, and had a good therapeutic effect on spleen deficiency diarrhea.
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Atractylodes , Microbioma Gastrointestinal , Ratones , Animales , Bazo , Atractylodes/química , Rizoma/química , Polisacáridos , Diarrea/tratamiento farmacológicoRESUMEN
OBJECTIVE: To discuss the value of computed tomography (CT) iterative reconstruction technique combined with target scanning in the diagnosis of solid pseudopapillary tumor of the pancreas (SPTP). METHODS: The clinical information and CT examination data of 27 patients with SPTP were retrospectively analyzed, and the general condition and CT performance of the patients were observed. The CT image reconstruction algorithm of all patients used iterative reconstruction technique combined with the application of target scanning technique. RESULTS: A total of 27 patients were included in this study, including 6 males and 21 females, aged 14-72 years with a mean age of 39.6 ± 13.6 years. SPTP was more common in young and middle-aged females, with a low level of tumor markers, dominated by cystic-solid tumors. The combination of CT iterative reconstruction technology and targeted scanning revealed the following: the capsule of SPTP was clear and complete, where calcifications were visible, solid components were progressively enhanced, and rare pancreatic and bile duct dilation was seen. Tumors were cystic-solid in 18 of 27 patients with SPTP, of which the solid components showed isodensity or slightly low-density, with calcifications. The solid components and cyst walls were mildly enhanced during the arterial phase, and were progressively enhanced during the parenchymal phase, portal vein phase, and delayed phase, with their enhancement degree lower than that of normal pancreatic parenchyma, and pancreatic and bile duct dilation was rare. There were no statistical differences in tumor location, morphology, growth pattern, integrity of capsule, cystic or solid, calcifications, and enhancement features between the male group and the female group (P > 0.05). CONCLUSION: The iterative reconstruction combined with target scanning clearly displayed the CT features of tumors, helping the diagnosis and clinical treatment of the disease.
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Calcinosis , Neoplasias Pancreáticas , Persona de Mediana Edad , Humanos , Masculino , Femenino , Adulto , Estudios Retrospectivos , Páncreas/patología , Neoplasias Pancreáticas/patología , Tomografía Computarizada por Rayos X/métodosRESUMEN
Atomically dispersed cerium species, anchored to high-area alumina by unsaturated penta-coordinated aluminum, strongly interact with atomically dispersed Cu species to provide active centers for water-gas shift reaction (WGSR). The alumina-anchored Ce3+ species stabilize atomically dispersed Cu+ to form Cu+-Ce3+ active complexes and they work synergistically to enhance low-temperature WGSR activity. This work offers alternative approaches to developing low-cost catalysts for the WGSR process.
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Objectives: The objective of this network meta-analysis is to systematically compare the efficacy of diverse progestin-based combination regimens in treating patients diagnosed with endometrial cancer or atypical endometrial hyperplasia. The primary goal is to discern the optimal combination treatment regimen through a comprehensive examination of their respective effectiveness. Methods: We systematically searched four prominent databases: PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials, for randomized controlled trials addressing the efficacy of progestins or progestin combinations in the treatment of patients with endometrial cancer or atypical endometrial hyperplasia. The search spanned from the inception of these databases to December 2023. Key outcome indicators encompassed survival indices, criteria for assessing efficacy, as well as pregnancy and relapse rate. This study was registered in PROSPERO (CRD42024496311). Results: From the 1,558 articles initially retrieved, we included 27 studies involving a total of 5,323 subjects in our analysis. The results of the network meta-analysis revealed that the mTOR inhibitor+megestrol acetate (MA)+tamoxifen regimen secured the top rank in maintaining stable disease (SD) (SUCRA=73.4%) and extending progression-free survival (PFS) (SUCRA=72.4%). Additionally, the progestin combined with tamoxifen regimen claimed the leading position in enhancing the partial response (PR) (SUCRA=75.2%) and prolonging overall survival (OS) (SUCRA=80%). The LNG-IUS-based dual progestin regimen emerged as the frontrunner in improving the complete response (CR) (SUCRA=98.7%), objective response rate (ORR) (SUCRA=99.1%), pregnancy rate (SUCRA=83.7%), and mitigating progression (SUCRA=8.0%) and relapse rate (SUCRA=47.4%). In terms of safety, The LNG-IUS-based dual progestin regimen had the lowest likelihood of adverse events (SUCRA=4.2%), while the mTOR inhibitor regimen (SUCRA=89.2%) and mTOR inbitor+MA+tamoxifen regimen (SUCRA=88.4%) had the highest likelihood of adverse events. Conclusions: Patients diagnosed with endometrial cancer or atypical endometrial hyperplasia exhibited the most favorable prognosis when undergoing progestin combination therapy that included tamoxifen, mTOR inhibitor, or LNG-IUS. Notably, among these options, the LNG-IUS-based dual progestin regimen emerged as particularly promising for potential application. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42024496311.
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Photothermal therapy (PTT) is a promising clinical antitumor strategy. However, local hyperthermia inevitably induces heat damage to adjacent normal tissues, while alternative mild-temperature therapy (MPTT, T < 45 °C) is also inefficient due to the overexpressed hyperthermia-induced heat shock proteins (HSPs) by cancer cells. Therefore, developing PTT strategies with minimizing damage to healthy tissues with improved cellular temperature sensitivity is extremely valuable for clinical application. Herein, we proposed the strategy of disrupting the intracellular redox environment via destroying the ROS-defending systems to promote MPTT. The gold(III) porphyrin-Fe3+-tannic acid nanocomplexes (AuTPP@TA-Fe NPs) were achieved via interfacial cohesion and supramolecular assembly of bioadhesive species, which could trigger the Fenton reaction to produce ·OH radicals and downregulation of reductive TrxR enzyme and mitochondrial chaperone protein Hsp60. The aggravation of oxides and the inactivation of Hsp60 provide favorable pathways for impeding the heat shock-induced self-repair mechanism of cancer cells, which strengthens AuTPP@TA-Fe NPs mediated MPTT.
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Oro , Oxidación-Reducción , Terapia Fototérmica , Humanos , Oro/química , Porfirinas/química , Porfirinas/efectos de la radiación , Porfirinas/farmacología , Animales , Chaperonina 60/química , Chaperonina 60/metabolismo , Ratones , Línea Celular Tumoral , Metaloporfirinas/química , Metaloporfirinas/farmacología , Neoplasias/terapia , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéuticoRESUMEN
The detection of volatile organic compounds (VOCs) in breath has become a potential method for early cancer screening. Although this approach has attracted increasing attention from the both scientific and medical communities, it has not received appreciable traction in the clinical setting. There are two main obstacles. One involves the identification of specific biomarkers or combinations thereof especially in early cancer. The other is the lack the specialized equipment for breath analysis having the appropriate sensitivity and specificity. Using metabolomics, this chapter examines the research strategies involving gas biomarkers in cancer patient breath, cancer cell gas metabolites and synthetic biomarkers. We briefly explore gas biomarkers of seven cancers and introduce principles of detection and clinical application. Large analytical instruments and small sensor technology are highlighted. Challenges to VOC analysis are presented including clinical use, extraction and detection, miniaturization efforts and examination of metabolic VOC pathways. Finally, VOCs in cancer and in exhaled breath detection technology are summarized and future prospects explored.
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Pruebas Respiratorias , Neoplasias , Compuestos Orgánicos Volátiles , Humanos , Compuestos Orgánicos Volátiles/análisis , Pruebas Respiratorias/métodos , Neoplasias/diagnóstico , Neoplasias/metabolismo , Biomarcadores de Tumor/análisis , Espiración , Metabolómica/métodosRESUMEN
BACKGROUND: Postoperative pancreatic fistula (POPF) contributes significantly to morbidity and mortality after pancreaticoduodenectomy (PD). However, the underlying mechanisms remain unclear. This study explored this pathology in the pancreatic stumps and elucidated the mechanisms of POPF following PD. CASE SUMMARY: Pathological analysis and 16S rRNA gene sequencing were performed on specimens obtained from two patients who underwent complete pancreatectomy for grade C POPF after PD. Gradient inflammation is present in the pancreatic stump. The apoptosis was lower than that in the normal pancreas. Moreover, neutrophil-dominated inflammatory cells are concentrated in the ductal system. Notably, neutrophils migrated through the ductal wall in acinar duct metaplasia-formed ducts. Additionally, evidence indicates that gut microbes migrate from the digestive tract. Gradient inflammation occurs in pancreatic stumps after PD. CONCLUSION: The mechanisms underlying POPF include high biochemical activity in the pancreas, mechanical injury, and digestive reflux. To prevent POPF and address pancreatic inflammation and reflux, breaking the link with anastomotic dehiscence is practical.
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Supercontinuum (SC) light source has advanced ultrafast laser spectroscopy in condensed matter science, biology, physics, and chemistry. Compared to the frequently used photonic crystal fibers and bulk materials, femtosecond laser filamentation in gases is damage-immune for supercontinuum generation. A bottleneck problem is the strong jitters from filament induced self-heating at kHz repetition rate level. We demonstrated stable kHz supercontinuum generation directly in air with multiple mJ level pulse energy. This was achieved by applying an external DC electric field to the air plasma filament. Beam pointing jitters of the 1 kHz air filament induced SC light were reduced by more than 2 fold. The stabilized high repetition rate laser filament offers the opportunity for stable intense SC generation and its applications in air.
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α-Synuclein (α-syn) can form oligomers, protofibrils, and fibrils, which are associated with the pathogenesis of Parkinson's disease and other synucleinopathies. Both the lipid peroxidation product 4-oxo-2-nonenal (ONE) and agitation can induce aggregation of α-syn and phosphorylated α-syn. Thus, clarification of the characteristics of different α-syn species could help to select suitable aggregates for diagnosis and elucidate the pathogenesis of diseases. Here, we characterized ONE-induced wild-type (WT) α-syn aggregates (OW), ONE-induced phosphorylated α-syn (p-α-syn) aggregates (OP), agitation-induced α-syn preformed fibrils (PFF), and agitation-induced p-α-syn preformed fibrils (pPFF). Thioflavin T (ThT) dying demonstrated that OW and OP had fewer fibrils than the PFF and pPFF. Transmission electron microscopy revealed that the lengths of PFF and pPFF were similar, but the diameters differed. OW and OP had more compact structures than PFF and pPFF. Aggregation of p-α-syn was significantly faster than WT α-syn. Furthermore, OW and OP were more sodium dodecyl sulfate-stable and proteinase K-resistant, suggesting greater stability and compactness, while aggregates of PFF and pPFF were more sensitive to proteinase K treatment. Both ONE- and agitation-induced aggregates were cytotoxic when added exogenously to SH-SY5Y cells with increasing incubation times, but the agitation-induced aggregates caused cell toxicity in a shorter time and more p-α-syn inclusions. Similarly, p-proteins were more cytotoxic than non-p-proteins. Finally, all four aggregates were used as standard antigens to establish sandwich enzyme-linked immunosorbent assay (ELISA). The results showed that the recognition efficiency of OW and OP was more sensitive than that of PFF and pPFF. The OW- and OP-specific ELISA for detection of p-α-syn and α-syn in plasma samples of Thy1-α-syn transgenic mice showed that the content of aggregates could reflect the extent of disease. ONE and agitation induced the formation of α-syn aggregates with distinct biophysical properties and biomedical applications.
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Aldehídos , Agregado de Proteínas , alfa-Sinucleína , alfa-Sinucleína/metabolismo , alfa-Sinucleína/química , Aldehídos/metabolismo , Fosforilación , Humanos , Animales , Ratones , Línea Celular Tumoral , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Fenómenos BiofísicosRESUMEN
Nowadays, the widespread use of organophosphorus pesticides (OPs) in agricultural production leads to varying degrees of residues in crops, which pose a potential threat to human health. Conventional methods used in national standard for the detection of OPs in fruits and vegetables require expensive instruments or cumbersome sample pretreatment steps for the analysis. To address these challenges, in this work, we took advantage of the peroxidase-like activity of PtCu3 alloy nanocrystals (NCs) for a colorimetric and smartphone assisted sensitive detection of OPs. With the assist of a smartphone, the concentration of OPs on the peel of fruits could be obtained by comparing the B/RG value (the brightness value of blue divided by those of red and green) of a test strip with a calibration curve. This work not only provides a facile and cost-effective method to detect pesticides but also makes a positive contribution to food safety warning.
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Técnicas Biosensibles , Plaguicidas , Humanos , Plaguicidas/análisis , Compuestos Organofosforados/análisis , Colorimetría , Frutas/química , Teléfono Inteligente , Acetilcolinesterasa/química , Técnicas Biosensibles/métodosRESUMEN
The construction of ultrathin porous membranes with stable structures is critical for achieving efficient gas separation. Inspired by the binary-cooperative structural features of bones and teeth-composed of rigid hydroxyapatite and flexible collagen, which confer excellent mechanical strength-a binary-cooperative porous membrane constructed with gel-state zeolitic imidazolate frameworks (g-ZIFs), synthesized using a metal-gel-induced strategy, is proposed. The enlarged cavity size and flexible frameworks of the g-ZIF nanoparticles significantly improve gas adsorption and diffusion, respectively. After thermal treatment, the coordination structures forming rigid segments in the g-ZIF membranes appear at the stacked g-ZIF boundaries, exhibiting a higher Young's modulus than the g-ZIF nanoparticles, denoted as the flexible segments. The g-ZIF membranes demonstrate excellent tensile and compression resistances, attributed to the effective translation of binary-cooperative effects of rigidity and flexibility into the membranes. The resulting dual-aperture structure, composed of g-ZIF nanoparticles surrounded by nanoscale apertures at the boundaries, yields a membrane with a stable CO2 permeance of 4834 GPU and CO2/CH4 selectivity of 90 within 3.0 MPa.
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Targeted reprogramming of cancer-associated fibroblasts (CAFs) is one of the most essential cancer therapies. However, how to reprogram active CAFs toward deactivated state still remains immense challenge. To tackle this challenge, herein, one perylene N, N'-bis(2-((dimethylammonium)ethylene)-2-(methoxylethyl))-1, 6, 7, 12-tetrachloroperylene-3, 4, 9, 10-tetracarboxylic diimide (PDIC-OC) is prepared, which can trigger endogenous reactive oxygen species (ROS) burst to result in cytoskeletal dysfunction and cell apoptosis so that suppress transforming growth factor ß (TGF-ß) production. As a result, PDIC-OC can reprogram the activated CAFs and relieve immunosuppressive tumor microenvironment by efficient polarization of M2-typed macrophages into M1-typed ones, downregulation of alpha-smooth muscle actin (α-SMA), alleviation of hypoxic state to promote infiltration of cytotoxic T lymphocytes, and ultimately realizes outstanding antitumor performance on B16F10 tumor-xenografted and lung-metastatic mouse model even at low concentration of 1 mg kg-1 body weight. This work thus presents a novel strategy that cytoskeleton dysfunction and cell apoptosis cooperatively suppress the secretion of TGF-ß to reprogram CAFs and meanwhile clarifies intrinsic mechanism for perylene-triggered chemo-immunotherapy against hypoxic tumors.
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Fibroblastos Asociados al Cáncer , Citoesqueleto , Inmunoterapia , Perileno , Animales , Perileno/análogos & derivados , Perileno/farmacología , Perileno/química , Ratones , Citoesqueleto/metabolismo , Citoesqueleto/efectos de los fármacos , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/patología , Inmunoterapia/métodos , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Apoptosis/efectos de los fármacos , Humanos , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos C57BLRESUMEN
Metal-catalyzed semi-hydrogenation of alkynes is an important step in organic synthesis to produce diverse chemical compounds. However, conventional noble metal catalysts often suffer from poor selectivity owing to over-hydrogenation. Here, we demonstrate a high-loading bimetallic AgCu-C3N4 single-atom catalyst (SAC) for alkyne semi-hydrogenation. The AgCu-C3N4 SACs exhibit higher activity and selectivity (99%) than their low-loading variants due to the synergistic interaction of heteronuclear Ag-Cu sites at small inter-site distances. Using a combination of techniques such as phenylacetylene-DRIFTS, H2-temperature programmed desorption and DFT calculations, we showed that the cooperative bimetallic interaction during alkyne semi-hydrogenation was achieved by isolated Ag centers as hydrogen activation sites and isolated Cu centers as alkyne activation sites. Our work highlights the importance of achieving high catalyst loading to reduce the inter-site distance in bimetallic SACs for cooperative interactions, which can potentially open new catalytic pathways for synthesizing fine chemicals and pharmaceuticals.
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Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the cell invasion and migration assay data shown in Fig. 6 and the cell proliferation assay experiments shown in Fig. 2 were strikingly similar to data appearing in different form in other articles by different authors; furthermore, in Fig. 2, for the '10 mM metformin' experiment, certain of the glioma cells appeared to be strikingly similar to other cells contained within the same data panels. Owing to the fact that the contentious data in the above article had already been published elsewhere or were under consideration for publication prior to its submission to Molecular Medicine Reports, and owing to concerns with the authenticity of certain of the data, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 20: 887894, 2019; DOI: 10.3892/mmr.2019.10369].
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Fruit cracking affects both the yield and economic efficiency of citrus; however, the underlying mechanism remains unclear. Therefore, this study focused on resistant and susceptible cultivars to identify the mechanisms underlying fruit cracking. The results showed that in 'Mingrijian', pectin morphological transformation and hemicellulose and lignin degradation in the pericarp were important contributing factors. During the critical fruit-cracking period (115-150 days after flowering), the water-soluble pectin, protopectin, and lignin contents in the pericarp of 'Daya' presented inverse changes relative to those in 'Mingrijian', thus enhancing the mechanical properties and resistance of pericarp. From 115 to 150 days after flowering, the soluble sugar content in the pulp of 'Mingrijian' increased rapidly by 97.35%, aiding in pulp water absorption and expansion. Moreover, the soluble protein content in the pericarp of 'Mingrijian' exhibited a declining trend and was lower than that of 'Daya', thus affecting the overall metabolism. The superoxide dismutase (SOD) activity in the pericarp of 'Mingrijian' gradually decreased from 115 to 180 days after flowering, while the peroxidase (POD) activity remained at a low level, resulting in weaker antioxidant capacity and lower environmental resistance. This study provides valuable insights into the mechanisms of citrus fruit cracking, laying the foundation for preventive and control strategies.
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The growth of all-inorganic perovskite single-crystal microstructures on substrates is a promising approach for constructing photonic and electronic microdevices. However, current preparation methods typically involve direct control of ions or atoms, which often depends on specific lattice-matched substrates for epitaxial growth and other stringent conditions that limit the mild preparation and flexibility of device integration. Herein, we present the on-substrate fabrication of CsPbBr3 single-crystal microstructures obtained via a nanoparticle self-assembly assisted low-temperature sintering (NSALS) method. Sintering guided by self-assembled atomically oriented superlattice embryos facilitated the formation of single-crystal microstructures under mild conditions without substrate dependence. The as-prepared on-substrate microstructures exhibited a consistent out-of-plane orientation with a carrier lifetime of up to 82.7 ns. Photodetectors fabricated by using these microstructures exhibited an excellent photoresponse of 9.15 A/W, and the dynamic optical response had a relative standard deviation as low as 0.1831%. The discrete photosensor microarray chip with 174000 pixels in a 100 mm2 area showed a response difference of less than 6%. This method of nanoscale particle-controlled single crystal growth on a substrate offers a perspective for mild-condition preparation and in situ repair of crystals of various types. This advancement can propel the flexible integration and widespread application of perovskite devices.
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The 'Okitsu No. 58' citrus variety is highly prone to fruit cracking, which jeopardizes yield and results in economic losses. In this study, we investigated the impacts of spraying 5 distinct concentrations (0.1, 0.2, 0.3, 0.4, and 0.5 g/L) of chelated calcium (Ca) or silicon (Si) fertilizers at the young fruit stage (60-90 days after flowering, DAF) on fruit cracking and quality in the citrus variety 'Okitsu No. 58'. The results showed either Ca or Si fertilizer treatments reduced fruit cracking. We found that all Ca and partial Si treatments (0.4 and 0.5 g/L) significantly promoted the accumulation of Ca content in the peel. Notably, Ca or Si treatments significantly reduced polygalacturonase (PG) activity and inhibited the production of water-soluble pectin (WSP) in the peel. Additionally, Ca or Si treatments elevated the superoxide dismutase (SOD) activity and decreased the malondialdehyde (MDA) content of the peels. Changes in these parameters likely contributed to strengthening the durability of peel cell wall constituents, thus enhancing the fruit's resistance to fruit cracking. Overall, except for the C3 (0.3 g/L of Ca), Ca or Si fertilizers contributed to fruit conventional quality, mainly in terms of higher soluble sugars (SS) and SS/TA (titratable acid). Therefore, our findings will provide a reference for the prevention and control of citrus fruit cracking and the development of new fertilizers.
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We recently detected a HKU4-related coronavirus in subgenus Merbecovirus (named pangolin-CoV-HKU4-P251T) from a Malayan pangolin1. Here we report isolation and characterization of pangolin-CoV-HKU4-P251T, the genome sequence of which is closest to that of a coronavirus from the greater bamboo bat (Tylonycteris robustula) in Yunnan Province, China, with a 94.3% nucleotide identity. Pangolin-CoV-HKU4-P251T is able to infect human cell lines, and replicates more efficiently in cells that express human-dipeptidyl-peptidase-4 (hDPP4)-expressing and pangolin-DPP4-expressing cells than in bat-DPP4-expressing cells. After intranasal inoculation with pangolin-CoV-HKU4-P251, hDPP4-transgenic female mice are likely infected, showing persistent viral RNA copy numbers in the lungs. Progressive interstitial pneumonia developed in the infected mice, characterized by the accumulation of macrophages, and increase of antiviral cytokines, proinflammatory cytokines, and chemokines in lung tissues. These findings suggest that the pangolin-borne HKU4-related coronavirus has a potential for emerging as a human pathogen by using hDPP4.
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Infecciones por Coronavirus , Coronavirus , Pangolines , Animales , Femenino , Humanos , Ratones , China , Quirópteros , Citocinas , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/metabolismo , Ratones Transgénicos , Pangolines/virologíaRESUMEN
Various SARS-CoV-2-related coronaviruses have been increasingly identified in pangolins, showing a potential threat to humans. Here we report the infectivity and pathogenicity of the SARS-CoV-2-related virus, PCoV-GX/P2V, which was isolated from a Malayan pangolin (Manis javanica). PCoV-GX/P2V could grow in human hepatoma, colorectal adenocarcinoma cells, and human primary nasal epithelial cells. It replicated more efficiently in cells expressing human angiotensin-converting enzyme 2 (hACE2) as SARS-CoV-2 did. After intranasal inoculation to the hACE2-transgenic mice, PCoV-GX/P2V not only replicated in nasal turbinate and lungs, but also caused interstitial pneumonia, characterized by infiltration of mixed inflammatory cells and multifocal alveolar hemorrhage. Existing population immunity established by SARS-CoV-2 infection and vaccination may not protect people from PCoV-GX/P2V infection. These findings further verify the hACE2 utility of PCoV-GX/P2V by in vivo experiments using authentic viruses and highlight the importance for intensive surveillance to prevent possible cross-species transmission.