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1.
Nature ; 616(7957): 482-487, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37076728

RESUMEN

Partitioning of americium from lanthanides (Ln) present in used nuclear fuel plays a key role in the sustainable development of nuclear energy1-3. This task is extremely challenging because thermodynamically stable Am(III) and Ln(III) ions have nearly identical ionic radii and coordination chemistry. Oxidization of Am(III) to Am(VI) produces AmO22+ ions distinct with Ln(III) ions, which has the potential to facilitate separations in principle. However, the rapid reduction of Am(VI) back to Am(III) by radiolysis products and organic reagents required for the traditional separation protocols including solvent and solid extractions hampers practical redox-based separations. Herein, we report a nanoscale polyoxometalate (POM) cluster with a vacancy site compatible with the selective coordination of hexavalent actinides (238U, 237Np, 242Pu and 243Am) over trivalent lanthanides in nitric acid media. To our knowledge, this cluster is the most stable Am(VI) species in aqueous media observed so far. Ultrafiltration-based separation of nanoscale Am(VI)-POM clusters from hydrated lanthanide ions by commercially available, fine-pored membranes enables the development of a once-through americium/lanthanide separation strategy that is highly efficient and rapid, does not involve any organic components and requires minimal energy input.

2.
Circ Res ; 133(11): 944-958, 2023 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-37869877

RESUMEN

BACKGROUND: ß1AR (beta-1 adrenergic receptor) and ß2AR (beta-2 adrenergic receptor)-mediated cyclic adenosine monophosphate signaling has distinct effects on cardiac function and heart failure progression. However, the mechanism regulating spatial localization and functional compartmentation of cardiac ß-ARs remains elusive. Emerging evidence suggests that microtubule-dependent trafficking of mRNP (messenger ribonucleoprotein) and localized protein translation modulates protein compartmentation in cardiomyocytes. We hypothesized that ß-AR compartmentation in cardiomyocytes is accomplished by selective trafficking of its mRNAs and localized translation. METHODS: The localization pattern of ß-AR mRNA was investigated using single molecule fluorescence in situ hybridization and subcellular nanobiopsy in rat cardiomyocytes. The role of microtubule on ß-AR mRNA localization was studied using vinblastine, and its effect on receptor localization and function was evaluated with immunofluorescent and high-throughput Förster resonance energy transfer microscopy. An mRNA protein co-detection assay identified plausible ß-AR translation sites in cardiomyocytes. The mechanism by which ß-AR mRNA is redistributed post-heart failure was elucidated by single molecule fluorescence in situ hybridization, nanobiopsy, and high-throughput Förster resonance energy transfer microscopy on 16 weeks post-myocardial infarction and detubulated cardiomyocytes. RESULTS: ß1AR and ß2AR mRNAs show differential localization in cardiomyocytes, with ß1AR found in the perinuclear region and ß2AR showing diffuse distribution throughout the cell. Disruption of microtubules induces a shift of ß2AR transcripts toward the perinuclear region. The close proximity between ß2AR transcripts and translated proteins suggests that the translation process occurs in specialized, precisely defined cellular compartments. Redistribution of ß2AR transcripts is microtubule-dependent, as microtubule depolymerization markedly reduces the number of functional receptors on the membrane. In failing hearts, both ß1AR and ß2AR mRNAs are redistributed toward the cell periphery, similar to what is seen in cardiomyocytes undergoing drug-induced detubulation. This suggests that t-tubule remodeling contributes to ß-AR mRNA redistribution and impaired ß2AR function in failing hearts. CONCLUSIONS: Asymmetrical microtubule-dependent trafficking dictates differential ß1AR and ß2AR localization in healthy cardiomyocyte microtubules, underlying the distinctive compartmentation of the 2 ß-ARs on the plasma membrane. The localization pattern is altered post-myocardial infarction, resulting from transverse tubule remodeling, leading to distorted ß2AR-mediated cyclic adenosine monophosphate signaling.


Asunto(s)
Insuficiencia Cardíaca , Infarto del Miocardio , Ratas , Animales , Hibridación Fluorescente in Situ , Insuficiencia Cardíaca/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , AMP Cíclico/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Microtúbulos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Adenosina Monofosfato/metabolismo , Adenosina Monofosfato/farmacología
3.
Genomics ; 116(2): 110810, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38402913

RESUMEN

This study generated whole genome DNA methylation maps to characterize DNA methylomes of grape (cv. 'Cabernet Franc') skins and examine their functional significance during grape skin coloration. We sampled grape skin tissues at three key stages (the early stage of grape berry swelling, the late stage of grape berry swelling and the veraison) during which the color of grape berries changed from green to red. DNA methylation levels of grape skins at the three stages were higher in transposable element regions than in the genic regions, and the CG and CHG DNA methylation levels of the genic region were higher than the CHH DNA methylation levels. We identified differentially methylated regions (DMRs) in S2_vs_S1 and S3_vs_S1. The results indicated that DMRs predominantly occurred within the CHH context during grape skin coloration. Many gene ontology (GO)-enriched DMR-related genes were involved in "nucleotide binding," "catalytic activity" and "ribonucleotide binding" terms; however, many KEGG-enriched DMR-related genes were involved in the "flavonoid biosynthesis" pathway. Our results could provide an important foundation for future research on the development mechanism of grape berries.


Asunto(s)
Vitis , Vitis/genética , Metilación de ADN , Frutas , Genes de Plantas , Análisis de Secuencia de ARN
4.
J Mol Cell Cardiol ; 194: 3-15, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38844061

RESUMEN

Diabetic cardiomyopathy (DCM) is a heart failure syndrome, and is one of the major causes of morbidity and mortality in diabetes. DCM is mainly characterized by ventricular dilation, myocardial hypertrophy, myocardial fibrosis and cardiac dysfunction. Clinical studies have found that insulin resistance is an independent risk factor for DCM. However, its specific mechanism of DCM remains unclear. 8-hydroxyguanine DNA glycosylase 1(OGG1)is involved in DNA base repair and the regulation of inflammatory genes. In this study, we show that OGG1 was associated with the occurrence of DCM. for the first time. The expression of OGG1 was increased in the heart tissue of DCM mice, and OGG1 deficiency aggravated the cardiac dysfunction of DCM mice. Metabolomics show that OGG1 deficiency resulted in obstruction of glycolytic pathway. At the molecular level, OGG1 regulated glucose uptake and insulin resistance by interacting with PPAR-γ in vitro. In order to explore the protective effect of exogenous OGG1 on DCM, OGG1 adeno-associated virus was injected into DCM mice through tail vein in the middle stage of the disease. We found that the overexpression of OGG1 could improve cardiac dysfunction of DCM mice, indicating that OGG1 had a certain therapeutic effect on DCM. These results demonstrate that OGG1 is a new molecular target for the treatment of DCM and has certain clinical significance.


Asunto(s)
ADN Glicosilasas , Cardiomiopatías Diabéticas , Resistencia a la Insulina , Animales , ADN Glicosilasas/metabolismo , ADN Glicosilasas/genética , ADN Glicosilasas/deficiencia , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/patología , Ratones , Masculino , PPAR gamma/metabolismo , Glucosa/metabolismo , Miocardio/metabolismo , Miocardio/patología , Modelos Animales de Enfermedad , Glucólisis , Humanos , Ratones Endogámicos C57BL
5.
Mol Biol Evol ; 40(2)2023 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-36661848

RESUMEN

The evolution of phenotypic plasticity plays an essential role in adaptive responses to climate change; however, its regulatory mechanisms in marine organisms which exhibit high phenotypic plasticity still remain poorly understood. The temperature-responsive trait oleic acid content and its major gene stearoyl-CoA desaturase (Scd) expression have diverged in two allopatric congeneric oyster species, cold-adapted Crassostrea gigas and warm-adapted Crassostrea angulata. In this study, genetic and molecular methods were used to characterize fatty acid desaturation and membrane fluidity regulated by oyster Scd. Sixteen causative single-nucleotide polymorphisms (SNPs) were identified in the promoter/cis-region of the Scd between wild C. gigas and C. angulata. Further functional experiments showed that an SNP (g.-333C [C. gigas allele] >T [C. angulata allele]) may influence Scd transcription by creating/disrupting the binding motif of the positive trans-factor Y-box factor in C. gigas/C. angulata, which mediates the higher/lower constitutive expression of Scd in C. gigas/C. angulata. Additionally, the positive trans-factor sterol-regulatory element-binding proteins (Srebp) were identified to specifically bind to the promoter of Scd in both species, and were downregulated during cold stress in C. gigas compared to upregulated in C. angulata. This partly explains the relatively lower environmental sensitivity (plasticity) of Scd in C. gigas. This study serves as an experimental case to reveal that both cis- and trans-variations shape the diverged pattern of phenotypic plasticity, which provides new insights into the formation of adaptive traits and the prediction of the adaptive potential of marine organisms to future climate change.


Asunto(s)
Crassostrea , Estearoil-CoA Desaturasa , Animales , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Temperatura , Adaptación Fisiológica/genética , Polimorfismo de Nucleótido Simple , Crassostrea/genética , Crassostrea/metabolismo
6.
Anal Chem ; 96(26): 10827-10834, 2024 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-38885015

RESUMEN

Kidney diseases have become an important global health concern due to their high incidence, inefficient diagnosis, and poor prognosis. Devising direct methods, especially imaging means, to assess renal function is the key for better understanding the mechanisms of various kidney diseases and subsequent development of effective treatment. Herein, we developed a fluorinated ferrous chelate-based sensitive probe, 1,7-DO2A-Fe(II)-F18 (Probe 1), for 19F magnetic resonance imaging (MRI). This highly fluorinated probe (containing 18 chemically equivalent 19F atoms with a fluorine content at 35 wt %) achieves a 15-time enhancement in signal intensity compared with the fluorine-containing ligand alone due to the appropriately regulated 19F relaxation times by the ferrous ion, which significantly increases imaging sensitivity and reduces acquisition time. Owing to its high aqueous solubility, biostability, and biocompatibility, this probe could be rapidly cleared by kidneys, which provides a means for monitoring renal dysfunction via 19F MRI. With this probe, we accomplish in vivo imaging of the impaired renal dysfunction caused by various kidney diseases including acute kidney injury, unilateral ureteral obstruction, and renal fibrosis at different stages. Our study illustrates the promising potential of Probe 1 for in vivo real-time visualization of kidney dysfunction, which is beneficial for the study, diagnosis, and even stratification of different kidney diseases. Furthermore, the design strategy of our probe is inspiring for the development of more high-performance 19F MRI probes for monitoring various biological processes.


Asunto(s)
Halogenación , Animales , Ratones , Sondas Moleculares/química , Riñón/diagnóstico por imagen , Riñón/patología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Compuestos Ferrosos/química , Imagen por Resonancia Magnética , Enfermedades Renales/diagnóstico por imagen , Imagen por Resonancia Magnética con Fluor-19/métodos , Flúor/química
7.
J Neuroinflammation ; 21(1): 86, 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38584255

RESUMEN

Ischemic stroke is the leading cause of adult disability. Ischemia leads to progressive neuronal death and synapse loss. The engulfment of stressed synapses by microglia further contributes to the disruption of the surviving neuronal network and related brain function. Unfortunately, there is currently no effective target for suppressing the microglia-mediated synapse engulfment. Stimulator of interferon genes (STING) is an important participant in innate immune response. In the brain, microglia are the primary cell type that mediate immune response after brain insult. The intimate relationship between STING and microglia-mediated neuroinflammation has been gradually established. However, whether STING affects other functions of microglia remains elusive. In this study, we found that STING regulated microglial phagocytosis of synapses after photothrombotic stroke. The treatment of STING inhibitor H151 significantly improved the behavioral performance of injured mice in grid-walking test, cylinder test, and adhesive removal test after stroke. Moreover, the puncta number of engulfed SYP or PSD95 in microglia was reduced after consecutive H151 administration. Further analysis showed that the mRNA levels of several complement components and phagocytotic receptors were decreased after STING inhibition. Transcriptional factor STAT1 is known for regulating most of the decreased molecules. After STING inhibition, the nucleus translocation of phosphorylated STAT1 was also suppressed in microglia. Our data uncovered the novel regulatory effects of STING in microglial phagocytosis after stroke, and further emphasized STING as a potential drug-able target for post-stroke functional recovery.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular , Animales , Humanos , Ratones , Isquemia Encefálica/metabolismo , Microglía/metabolismo , Fagocitosis , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/metabolismo , Sinapsis/metabolismo
8.
Bioinformatics ; 39(1)2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-36637188

RESUMEN

MOTIVATION: Accurately predicting cancer survival is crucial for helping clinicians to plan appropriate treatments, which largely improves the life quality of cancer patients and spares the related medical costs. Recent advances in survival prediction methods suggest that integrating complementary information from different modalities, e.g. histopathological images and genomic data, plays a key role in enhancing predictive performance. Despite promising results obtained by existing multimodal methods, the disparate and heterogeneous characteristics of multimodal data cause the so-called modality gap problem, which brings in dramatically diverse modality representations in feature space. Consequently, detrimental modality gaps make it difficult for comprehensive integration of multimodal information via representation learning and therefore pose a great challenge to further improvements of cancer survival prediction. RESULTS: To solve the above problems, we propose a novel method called cross-aligned multimodal representation learning (CAMR), which generates both modality-invariant and -specific representations for more accurate cancer survival prediction. Specifically, a cross-modality representation alignment learning network is introduced to reduce modality gaps by effectively learning modality-invariant representations in a common subspace, which is achieved by aligning the distributions of different modality representations through adversarial training. Besides, we adopt a cross-modality fusion module to fuse modality-invariant representations into a unified cross-modality representation for each patient. Meanwhile, CAMR learns modality-specific representations which complement modality-invariant representations and therefore provides a holistic view of the multimodal data for cancer survival prediction. Comprehensive experiment results demonstrate that CAMR can successfully narrow modality gaps and consistently yields better performance than other survival prediction methods using multimodal data. AVAILABILITY AND IMPLEMENTATION: CAMR is freely available at https://github.com/wxq-ustc/CAMR. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Neoplasias , Humanos , Genoma
9.
Ann Surg Oncol ; 31(2): 1264-1267, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37907702

RESUMEN

BACKGROUND: Surgical resection remains the sole approach to achieving long-term survival in cholangiocarcinoma cases. The universally recognised standard procedures for such cases include pancreaticoduodenectomy (PD) or hemihepatectomy accompanied by bile duct reconstruction. Nevertheless, some patients may still attain curative intent through bile duct segmental resection (BDR). However, these procedures are still in the experimental stage and should only be recommended for carefully chosen patients. METHODS: A 57-year-old male patient was admitted to our department after two weeks of escalating jaundice and abdominal discomfort. Upon admission, his total bilirubin was recorded at 102 µmol/L, and his direct bilirubin was 87 µmol/L. His carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP) levels were normal. Enhanced computed tomography (CT) and magnetic resonance imaging (MRI) scans revealed a thickened and enhanced biliary tree extending from the cystic duct junction to the common hepatic duct no vascular invasion indicated by three-dimensional reconstruction. RESULTS: The patient underwent laparoscopic resection of the extrahepatic bile duct, accompanied by radical lymphadenectomy with skeletonisation and biliary reconstruction, was successfully conducted within 320 min, with a minimal blood loss of only 50 ml. The histological grading of the procedure was T2bN0M0 (stage II). The patient was discharged on the sixth postoperative day without complications. Following this, he underwent a regimen of single-agent capecitabine chemotherapy. After an 18-month follow-up period, no recurrence was observed. CONCLUSIONS: Our experience suggests that in selected patients diagnosed with middle bile duct cholangiocarcinoma, laparoscopic resection could potentially reach the standard of lymphadenectomy through skeletonisation.


Asunto(s)
Neoplasias de los Conductos Biliares , Conductos Biliares Extrahepáticos , Colangiocarcinoma , Laparoscopía , Masculino , Humanos , Persona de Mediana Edad , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Laparoscopía/métodos , Conductos Biliares Extrahepáticos/cirugía , Conductos Biliares Extrahepáticos/patología , Conductos Biliares Intrahepáticos/patología , Bilirrubina
10.
Exp Eye Res ; 242: 109857, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38479724

RESUMEN

Penetrating keratoplasty remains the most common treatment to restore vision for corneal diseases. Immune rejection after corneal transplantation is one of the major causes of graft failure. In recent years, Rho-associated protein kinase (ROCK) inhibitors have been found to be associated with the activation of the STATs pathway and are widely studied in autoimmune diseases. Therefore, it may be possible that the ROCK inhibitors also participate in the local and systemic immune regulation in corneal transplantation through activation of the STATs pathway and affect the CD4+ T cell differentiation. This study aimed to explore the role of ROCK-STATs pathway in the occurrence of immune rejection in corneal transplantation by applying Y27632, a ROCK inhibitor, to the recipient mice and peripheral CD4+ T cells. We found that Y27632 significantly up-regulated the phosphorylation level of STAT5 in both spleen and lymph nodes, down-regulated the phosphorylation level of STAT3 in the CD4+ T cells in the spleen. It also increased the proportion of CD4+CD25+Foxp3+Helios+ Tregs while decreased CD4+IL17A+ -Th17 cells. Moreover, Y27632 also reduced the proportion of dendritic cells in both spleen and lymph nodes, as well as the expression level of CD86 on their surfaces in the spleen, while the proportion of macrophages was not affected. The expression levels of ROCK1, ROCK2, CD11c and IL-17A mRNA were also found to be low in the graft tissue while the expression of Helios was upregulated. Rho-kinase inhibitor can modulate the balance of Tregs/Th17 by regulating the phosphorylation levels of both STAT3 and STAT5, thereby inhibiting the occurrence of immune rejection in allogeneic corneal transplantation.


Asunto(s)
Amidas , Linfocitos T CD4-Positivos , Rechazo de Injerto , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Piridinas , Factor de Transcripción STAT3 , Factor de Transcripción STAT5 , Quinasas Asociadas a rho , Animales , Ratones , Rechazo de Injerto/metabolismo , Rechazo de Injerto/prevención & control , Quinasas Asociadas a rho/antagonistas & inhibidores , Linfocitos T CD4-Positivos/inmunología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/metabolismo , Amidas/farmacología , Amidas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Modelos Animales de Enfermedad , Fosforilación , Citometría de Flujo , Queratoplastia Penetrante , Western Blotting , Trasplante de Córnea , Masculino
11.
Exp Eye Res ; 245: 109953, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38838974

RESUMEN

The objective of this study was to investigate the biological feasibility and surgical applicability of decellularized porcine small intestinal submucosa (DSIS) in conjunctiva reconstruction. A total of 52 Balb/c mice were included in the study. We obtained the DSIS by decellularization, evaluated the physical and biological properties of DSIS in vitro, and further evaluated the effect of surgical transplantation of DSIS scaffold in vivo. The histopathology and ultrastructural analysis results showed that the scaffold retained the integrity of the fibrous morphology while removing cells. Biomechanical analysis showed that the elongation at break of the DSIS (239.00 ± 12.51%) were better than that of natural mouse conjunctiva (170.70 ± 9.41%, P < 0.05). Moreover, in vivo experiments confirmed the excellent biocompatibility of the decellularized scaffolds. In the DSIS group, partial epithelialization occurred at day-3 after operation, and the conjunctival injury healed at day-7, which was significantly faster than that in human amniotic membrane (AM) and sham surgery (SHAM) group (P < 0.05). The number and distribution of goblet cells of transplanted DSIS were significantly better than those of the AM and SHAM groups. Consequently, the DSIS scaffold shows excellent biological characteristics and surgical applicability in the mouse conjunctival defect model, and DSIS is expected to be an alternative scaffold for conjunctival reconstruction.


Asunto(s)
Conjuntiva , Mucosa Intestinal , Intestino Delgado , Ratones Endogámicos BALB C , Ingeniería de Tejidos , Andamios del Tejido , Animales , Ratones , Conjuntiva/citología , Porcinos , Mucosa Intestinal/trasplante , Mucosa Intestinal/citología , Intestino Delgado/trasplante , Ingeniería de Tejidos/métodos , Procedimientos de Cirugía Plástica/métodos , Células Caliciformes/citología , Modelos Animales de Enfermedad , Masculino
12.
Mol Pharm ; 21(7): 3613-3622, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38853512

RESUMEN

The mesenchymal-epithelial transition factor (c-Met) is a receptor tyrosine kinase linked to the proliferation, survival, invasion, and metastasis of several types of cancers, including colorectal cancer (CRC), particularly when aberrantly activated. Our study strategically designs peptides derived from interactions between c-Met and the antibody Onartuzumab. By utilizing a cyclic strategy, we achieved significantly enhanced peptide stability and affinity. Our in vitro assessments confirmed that the cyclic peptide HYNIC-cycOn exhibited a higher affinity (KD = 83.5 nM) and greater specificity compared with its linear counterpart. Through in vivo experiments, [99mTc]Tc-HYNIC-cycOn displayed exceptional tumor-targeting capabilities and minimal absorption in nontumor cells, as confirmed by single-photon emission computed tomography. Notably, the ratios of tumor to muscle and tumor to intestine, 1 h postinjection, were 4.78 ± 0.86 and 3.24 ± 0.47, respectively. Comparable ratios were observed in orthotopic CRC models, recording 4.94 ± 0.32 and 3.88 ± 0.41, respectively. In summary, [99mTc]Tc-HYNIC-cycOn shows substantial promise as a candidate for clinical applications. We show that [99mTc]Tc-HYNIC-cycOn can effectively target and visualize c-Met-expressing tumors in vivo, providing a promising approach for enhancing diagnostic accuracy when detecting c-Met in CRC.


Asunto(s)
Neoplasias Colorrectales , Péptidos Cíclicos , Proteínas Proto-Oncogénicas c-met , Neoplasias Colorrectales/diagnóstico por imagen , Proteínas Proto-Oncogénicas c-met/metabolismo , Péptidos Cíclicos/química , Humanos , Animales , Ratones , Línea Celular Tumoral , Ratones Desnudos , Tomografía Computarizada de Emisión de Fotón Único/métodos , Ratones Endogámicos BALB C , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Langmuir ; 40(33): 17786-17795, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39120944

RESUMEN

Exploring nucleation pathways has been a research hot spot in the fields of crystal engineering. In this work, vanillin as a model compound was utilized to explore the factors influencing different nucleation pathways with or without liquid-liquid phase separation (LLPS). A thermodynamic phase diagram of vanillin in the mixed solvent system of water and acetone from 10 to 55 °C was determined. It was found that the occurrence of LLPS might be related to different nucleation pathways. Under the guidance of a thermodynamic phase diagram, Raman spectroscopy and molecular simulation were applied to investigate the influencing factors of different nucleation paths. It was found that the degree of solvation is a key factor determining the nucleation path, and strong solvation could lead to LLPS. Additionally, the molecular self-assembly evolution during the crystallization process was further investigated by using small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS). The findings indicate that larger clusters with a diffuse transition layer may lead to LLPS during the nucleation process.

14.
Microb Cell Fact ; 23(1): 48, 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38347541

RESUMEN

BACKGROUND: The three-finger proteins are a collection of disulfide bond rich proteins of great biomedical interests. Scalable recombinant expression and purification of bioactive three-finger proteins is quite difficult. RESULTS: We introduce a working pipeline for expression, purification and validation of disulfide-bond rich three-finger proteins using E. coli as the expression host. With this pipeline, we have successfully obtained highly purified and bioactive recombinant α-Βungarotoxin, k-Bungarotoxin, Hannalgesin, Mambalgin-1, α-Cobratoxin, MTα, Slurp1, Pate B etc. Milligrams to hundreds of milligrams of recombinant three finger proteins were obtained within weeks in the lab. The recombinant proteins showed specificity in binding assay and six of them were crystallized and structurally validated using X-ray diffraction protein crystallography. CONCLUSIONS: Our pipeline allows refolding and purifying recombinant three finger proteins under optimized conditions and can be scaled up for massive production of three finger proteins. As many three finger proteins have attractive therapeutic or research interests and due to the extremely high quality of the recombinant three finger proteins we obtained, our method provides a competitive alternative to either their native counterparts or chemically synthetic ones and should facilitate related research and applications.


Asunto(s)
Escherichia coli , Cuerpos de Inclusión , Escherichia coli/metabolismo , Proteínas Recombinantes , Cuerpos de Inclusión/metabolismo , Disulfuros/metabolismo
15.
Pharm Res ; 41(8): 1737-1754, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39078577

RESUMEN

PURPOSE: The primary problem with climbazole (CLB), a broad-spectrum imidazole antifungal drug, is its low water solubility. In order to increase its water solubility and antifungal activity, three new multi-component crystals were synthesized in this work, and the intermolecular interactions were systematically studied. This work helps to optimize the CLB product formulation and extend its application prospects. METHODS: In this work, three novel multi-component crystals, CLB-malonic acid (CLB-MA) salt, CLB-succinic acid (CLB-SA) cocrystal and CLB-adipic acid (CLB-AA) cocrystal, were successfully synthesized. And the crystal structure, thermodynamic properties, solubility, dissolution, hygroscopicity, and antifungal activity of the three multi-component crystals were fully characterized by single-crystal X-ray diffraction (SCXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic water vapor adsorption (DVS) and powder dissolution tests, etc. The molecular interactions and molecular stacking in multi-component crystals were studied by Hirshfeld surface (HS), molecular surface electrostatic potential (MEP), interaction region indication (IRI) and atom and molecule (AIM) techniques. RESULTS: The results show that the three multi-component crystals have good moisture resistance stability, and their water solubility is 6-22 times that of pure CLB. Meanwhile, the measurement of the minimum inhibitory concentration (MIC) proves that the cocrystal/salt has a stronger antifungal activity than climbazole. Quantum chemistry calculations of crystal structure visualized and quantified the interactions that exist in multi-component crystals, and explored the microscopic mechanisms underlying the different performance of multi-component crystals.


Asunto(s)
Antifúngicos , Cristalización , Solubilidad , Agua , Antifúngicos/farmacología , Antifúngicos/química , Agua/química , Imidazoles/química , Imidazoles/farmacología , Cristalografía por Rayos X , Pruebas de Sensibilidad Microbiana , Difracción de Rayos X , Termodinámica , Humectabilidad
16.
Environ Sci Technol ; 58(33): 14929-14939, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39126388

RESUMEN

Membrane distillation (MD) has great potential in the management of hypersaline water for zero liquid discharge (ZLD) due to its high salinity tolerance. However, the membrane wetting issue significantly restricts its practical application. In this study, a composite membrane tailored for extreme concentrations and even crystallization of hypersaline water is synthesized by coating a commercial hydrophobic porous membrane with a composite film containing a dense polyamide layer, a cation exchange layer (CEL), and an anion exchange layer (AEL). When used in direct contact MD for treating a 100 g L-1 NaCl hypersaline solution, the membrane achieves supersaturation of feed solution and a salt crystal yield of 38.0%, with the permeate concentration at <5 mg L-1. The composite membrane also demonstrates ultrahigh antiwetting stability in 360 h of long-term operation. Moreover, ion diffusion analysis reveals that the ultrahigh wetting resistance of the composite membrane is attributed to the bipolar AEL and CEL that eliminate ion crossover. The literature review elucidates that the composite membrane is superior to state-of-the-art membranes. This study demonstrates the great potential of the composite membrane for direct crystallization of hypersaline water, offering a promising approach to filling the gap between reverse osmosis and conventional thermal desalination processes for ZLD application.


Asunto(s)
Cristalización , Destilación , Membranas Artificiales , Salinidad , Agua/química , Purificación del Agua/métodos
17.
Audiol Neurootol ; 29(2): 146-166, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-37963433

RESUMEN

INTRODUCTION: The aim of the study was to investigate differences in the intra- and inter-network functional connectivity (FC) of the brain using resting-state functional magnetic resonance imaging (rs-fMRI) in patients with tinnitus, with (T + H) or without hearing loss (T). METHODS: We performed rs-fMRI on 82 participants (21 T, 32 T + H, and 29 healthy controls). An independent component analysis (ICA) was performed to obtain the resting-state networks (RSNs) and calculate the differences in FC. Moreover, we investigated the relationships between networks using functional network connectivity analysis. RESULTS: We identified nine major RSNs, including the auditory network; default mode network; executive control network (ECN), including the right frontoparietal network and left frontoparietal network (LFPN); somatomotor network (SMN); dorsal attention network; ventral attention network; salience network (SN); and visual network (VN). These RSNs were extracted in all groups using ICA. Compared with that in the control group, we observed reduced FC between the LFPN and VN in the T group and between the LFPN and SN in the T + H group. The inter-network connectivity analysis revealed decreased network interactions in the SMN (IC 22)-ECN (IC 2), SMN (IC 22)-VN (IC 8), and VN (IC 14)-SN (IC 3) connections in the T + H group, compared with the healthy control group. Furthermore, we observed significantly decreased network interactions in the SMN (IC 22)-VN (IC 8) in the T group. CONCLUSIONS: Our results indicated abnormalities within the brain networks of the T and T + H groups, including the SMN, ECN, and VN, compared with the control group. Furthermore, both T and T + H groups demonstrated reduced FC between the LFPN, VN, and SMN. There were no significant differences between the T and the T + H groups. Furthermore, we observed reduced FC between the right olfactory cortex and the orbital part of the right middle frontal gyrus, right precentral gyrus, left dorsolateral superior frontal gyrus, and right triangular part of the inferior frontal gyrus within the T and T + H groups. Thus, disruptions in brain regions responsible for attention, stimulus monitoring, and auditory orientation contribute to tinnitus generation.


Asunto(s)
Sordera , Pérdida Auditiva , Acúfeno , Humanos , Mapeo Encefálico/métodos , Acúfeno/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Pérdida Auditiva/diagnóstico por imagen
18.
Environ Res ; 248: 118213, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38280526

RESUMEN

Global ocean salinity is changing under rapid climate change and intensified anthropogenic activity. Increased differences in salinity threaten marine biodiversity, organismal survival, and evolution, particularly sessile invertebrates dwelling in highly fluctuating intertidal and estuarine environments. Comparing the responses of closely related species to salinity changes can provide insights into the adaptive mechanisms underlying inter- and intraspecific divergence in salinity tolerance, but are poorly understood in marine bivalves. We collected wild individuals of four Crassostrea species, in addition to two populations of the same species from their native habitats and determined the dynamics of hydrolyzed amino acids (HAAs) and transcriptional responses to hypersaline stress. In response to hypersaline stress, species/populations inhabiting natural high-salinity sea environments showed higher survival and less decline in HAAs than that of congeners inhabiting low-salinity estuaries. Thus, native environmental salinity shapes oyster tolerance. Notably, a strong negative correlation between the decline in HAAs and survival indicated that the HAAs pool could predict tolerance to hypersaline challenge. Four HAAs, including glutamine (Glu), aspartic acid (Asp), alanine (Ala) and glycine (Gly), were identified as key amino acids that contributed substantially to the emergency response to hypersaline stress. High-salinity-adapted oyster species only induced substantial decreases in Glu and Asp, whereas low-salinity-adapted congeners further incresaed Ala and Gly metabolism under hypersaline stress. The dynamics of the content and gene expression responsible for key amino acids pathways revealed the importance of maintaining the balance between energy production and ammonia detoxification in divergent hypersaline responses among oyster species/populations. High constructive or plastic expression of evolutionarily expanded gene copies in high-salinity-adapted species may contribute to their greater hypersaline tolerance. Our findings reveal the adaptive mechanism of key amino acids in salinity adaptation in marine bivalves and provide new avenues for the prediction of adaptive potential and aquaculture with high-salinity tolerant germplasms.


Asunto(s)
Crassostrea , Humanos , Animales , Crassostrea/genética , Amoníaco , Aminoácidos , Ambiente , Ecosistema , Salinidad
19.
Environ Res ; 258: 119397, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-38876419

RESUMEN

Global warming and unpredictable nature possess a negative impact on fisheries and the daily activities of other habitats. GIS and remote sensing approach is an effective tool to determine the morphological characteristics of the lake. The present study addresses the interactive effect of climate and landuse changes hit on fish catch in lake fisheries. We used a combination of the landscape disturbance index, vulnerability index, and loss index to construct a complete ecological risk assessment framework based on the landscape structure of regional ecosystems. The results indicate an increase from around 45%-76% in the percentage of land susceptible to moderate to ecological severe risk in the landscape from 2004 to 2023. Since 1950, temperature changes have increased by 0.4%, precipitation has decreased by 6%, and water levels have decreased by 4.2%, based on the results. The results indicate that landuse, water temperature, precipitation, and water depth significantly impact the aquaculture system. The findings strongly suggest integrating possible consequences of environmental change on fish yield for governance modeling techniques to minimize their effects.


Asunto(s)
Cambio Climático , Explotaciones Pesqueras , Peces , Lagos , Animales , Medición de Riesgo , Temperatura
20.
Bull Math Biol ; 86(4): 41, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38491224

RESUMEN

This paper examines the short-term or transient dynamics of SIR infectious disease models in patch environments. We employ reactivity of an equilibrium and amplification rates, concepts from ecology, to analyze how dispersals/travels between patches, spatial heterogeneity, and other disease-related parameters impact short-term dynamics. Our findings reveal that in certain scenarios, due to the impact of spatial heterogeneity and the dispersals, the short-term disease dynamics over a patch environment may disagree with the long-term disease dynamics that is typically reflected by the basic reproduction number. Such an inconsistence can mislead the public, public healthy agencies and governments when making public health policy and decisions, and hence, these findings are of practical importance.


Asunto(s)
Enfermedades Transmisibles , Modelos Epidemiológicos , Humanos , Modelos Biológicos , Conceptos Matemáticos , Enfermedades Transmisibles/epidemiología , Ecología , Número Básico de Reproducción , Dinámica Poblacional
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