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The dual activation of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a promising therapeutic strategy for managing type 2 diabetes and obesity. Tirzepatide, a dual agonist peptide, has exhibited superior clinical efficacy in glycemic and weight control compared to selective GLP-1R agonists. Nevertheless, the structural basis of Tirzepatide's extended half-life, attributed to an acylation side chain on the parent peptide, raises questions regarding its partial agonistic activity. Employing molecular dynamics simulations, we explored the dynamic processes of peptide-receptor interactions. We uncovered a crucial salt bridge between parent peptide and GLP-1R/GIPR at K20, a feature not discernible in cryo-electron microscopy structures. Building upon these insights, we developed an optimization strategy based on the parent peptide which involved repositioning the acylation side chain. The results of both in vitro and in vivo experiments demonstrated that the optimized peptide has twofold to threefold increase in agonistic activity compared to Tirzepatide while maintaining its extended half-life in plasma. This led to the design of BGM0504, which proved to be more effective than its predecessor, Tirzepatide, in both laboratory and animal studies.
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Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Simulação de Dinâmica Molecular , Obesidade , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Animais , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/metabolismo , Masculino , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Peptídeos/química , Peptídeos/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 2 , Polipeptídeo Inibidor GástricoRESUMO
The landscape of sex differences in Colorectal Cancer (CRC) has not been well characterized with respect to the mechanisms of action for oncogenes such as KRAS. However, our recent study showed that tumors from male patients with KRAS mutations have decreased iron-dependent cell death called ferroptosis. Building on these findings, we further examined ferroptosis in CRC, considering both sex of the patient and KRAS mutations, using public databases and our in-house CRC tumor cohort. Through subsampling inference and variable importance analysis (VIMP), we identified significant differences in gene expression between KRAS mutant and wild type tumors from male patients. These genes suppress (e.g., SLC7A11 ) or drive (e.g., SLC1A5 ) ferroptosis, and these findings were further validated with Gaussian mixed models. Furthermore, we explored the prognostic value of ferroptosis regulating genes and discovered sex- and KRAS-specific differences at both the transcriptional and metabolic levels by random survival forest with backward elimination algorithm (RSF-BE). Of note, genes and metabolites involved in arginine synthesis and glutathione metabolism were uniquely associated with prognosis in tumors from males with KRAS mutations. Additionally, drug repurposing is becoming popular due to the high costs, attrition rates, and slow pace of new drug development, offering a way to treat common and rare diseases more efficiently. Furthermore, increasing evidence has shown that ferroptosis inhibition or induction can improve drug sensitivity or overcome chemotherapy drug resistance. Therefore, we investigated the correlation between gene expression, metabolite levels, and drug sensitivity across all CRC primary tumor cell lines using data from the Genomics of Drug Sensitivity in Cancer (GDSC) resource. We observed that ferroptosis suppressor genes such as DHODH , GCH1 , and AIFM2 in KRAS mutant CRC cell lines were resistant to cisplatin and paclitaxel, underscoring why these drugs are not effective for these patients. The comprehensive map generated here provides valuable biological insights for future investigations, and the findings are supported by rigorous analysis of large-scale publicly available data and our in-house cohort. The study also emphasizes the potential application of VIMP, Gaussian mixed models, and RSF-BE models in the multi-omics research community. In conclusion, this comprehensive approach opens doors for leveraging precision molecular feature analysis and drug repurposing possibilities in KRAS mutant CRC.
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BACKGROUND: Leukemia represents the most prevalent childhood malignancy. Understanding the symptom clusters (SCs) associated with leukemia may help develop an effective care plan for affected children. OBJECTIVES: The aims of this study were to summarize the methods of identifying SCs; ascertain the types, attributes, and changing patterns of SCs during different chemotherapy phases; and provide a point of reference for the subsequent improvement of symptom management in pediatric leukemia. METHODS: The methodological framework employed was the Joanna Briggs Institute Scoping Review Guide. A comprehensive search was conducted across various databases, including PubMed, EMBASE, CINAHL, Web of Science, MEDLINE, Scopus, and China National Knowledge Infrastructure from inception until July 15, 2023. RESULTS: A total of 14 articles were included in this review, 6 in English and 8 in Chinese. The Memorial Symptom Assessment Scale 10-18 is the most commonly used instrument, whereas factor analysis is the most common statistical method for SC identification. The SCs were classified into 12 categories. The most severe SCs varied across different phases. Specifically, the emotional cluster dominated the prechemotherapy phase, the gastrointestinal cluster surfaced during postinduction therapy, and the consolidation and maintenance therapy phases revealed the self-image disorder cluster. CONCLUSION: Various consistent and dynamic SCs manifest among pediatric patients with leukemia undergoing chemotherapy. IMPLICATIONS FOR PRACTICE: Future research endeavors should formulate clear criteria to determine the stability and consistency of SCs, validate SC composition and characteristics, and devise precise symptom management protocols based on SC characteristics in the distinct chemotherapy phases.
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Survival differences exist in colorectal cancer (CRC) patients by sex and disease stage. However, the potential molecular mechanism(s) are not well understood. Here we show that asparagine synthetase (ASNS) and G protein-coupled estrogen receptor-1 (GPER1) are critical sensors of nutrient depletion and linked to poorer outcomes for females with CRC. Using a 3D spheroid model of isogenic SW48 KRAS wild-type (WT) and G12A mutant (MT) cells grown under a restricted nutrient supply, we found that glutamine depletion inhibited cell growth in both cell lines, whereas ASNS and GPER1 expression were upregulated in KRAS MT versus WT. Estradiol decreased growth in KRAS WT but had no effect on MT cells. Selective GPER1 and ASNS inhibitors suppressed cell proliferation with increased caspase-3 activity of MT cells under glutamine depletion condition particularly in the presence of estradiol. In a clinical colon cancer cohort from The Cancer Genome Atlas, both high GPER1 and ASNS expression were associated with poorer overall survival for females only in advanced stage tumors. These results suggest KRAS MT cells have mechanisms in place that respond to decreased nutrient supply, typically observed in advanced tumors, by increasing the expression of ASNS and GPER1 to drive cell growth. Furthermore, KRAS MT cells are resistant to the protective effects of estradiol under nutrient deplete conditions. The findings indicate that GPER1 and ASNS expression, along with the interaction between nutrient supply and KRAS mutations shed additional light on the mechanisms underlying sex differences in metabolism and growth in CRC, and have clinical implications in the precision management of KRAS mutant CRC.
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Introduction: Vascular calcification is a major cause of cardiovascular accidents in patients with type 2 diabetes mellitus. This study aimed to investigate the impact of carbohydrates on gut microbiota and aortic calcification in diabetic ApoE-/- mice. Methods: The diabetic ApoE-/- mice were randomly divided into 4 groups: ketogenic diet group, low carbohydrate diet group, medium carbohydrate diet group, and high carbohydrate diet group. The mice were fed continuously for 6 months, with blood glucose, blood ketone and body weight monitored monthly. Lipid metabolism indicators and inflammatory factors were detected using ELISA. The intestinal barrier, atherosclerotic lesion areas, and vascular calcifications were analyzed based on their morphology. Gut microbiota was analyzed using 16S rRNA genes. Results: We found that ketogenic diet played some roles improving glucose, lipid metabolism, and inflammation. Ketogenic diet could improve the intestinal barrier to some extent and increase intestinal bacteria. Compared to the other three groups, the relative abundance of genus Allobaculum, species Blautia producta and Clostridium Ramosum in the ketogenic diet group was significantly increased (P <0.05), which has protective effects in diabetic ApoE-/- mice. Conclusion: Ketogenic diet could delay the onset of aortic atherosclerosis, aortic calcification and improve intestinal barrier function in diabetic ApoE-/- mice.
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INTRODUCTION: With China's urbanization and demographic shifts significantly affecting elder care, this study examines the alignment of community-based elder care services in Hangzhou's Hemu Community. It addresses the gap in understanding how these services meet the needs of an aging population in a rapidly changing social context. METHODS: A comprehensive mixed-methods approach was utilized, involving interviews with community residents, observations of elder care service operations and thorough document analysis. The objective was to evaluate the adequacy, utilization and satisfaction levels concerning these elder care services. RESULTS: The research identified that, although the services generally meet the community's needs, there are notable challenges in content specificity, quality assurance and promotional efforts. These challenges lead to resistance among older adults. Additionally, issues with service visibility and the lack of robust feedback mechanisms were noted. CONCLUSION: This study highlights the critical need for a cooperative strategy involving government, community organizations, social entities and businesses in enhancing elder care services. It suggests that improvements in service visibility, content quality and targeted promotion are crucial to address the evolving needs of the aging population and to reduce reluctance in service utilization.
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Serviços de Saúde Comunitária , Serviços de Saúde para Idosos , Humanos , China , Idoso , Masculino , Feminino , Serviços de Saúde para Idosos/organização & administração , Serviços de Saúde para Idosos/normas , Serviços de Saúde Comunitária/organização & administração , Serviços de Saúde Comunitária/estatística & dados numéricos , Necessidades e Demandas de Serviços de Saúde , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Entrevistas como AssuntoRESUMO
The Biginelli reaction, a three-component cyclocondensation reaction, is an important member of the multicomponent reaction (MCR) family. In this study, we conducted end-group modifications on a variety of biodegradable polyesters, including poly(1,4-butylene adipate) (PBA), poly(ε-caprolactone) (PCL), polylactic acid (PLA), and poly(p-dioxanone) (PPDO), based on the precursor polyethylene glycol (PEG). By combining two polymers through the Biginelli multi-component reaction, four new biodegradable polyester copolymers, namely DHPM-PBA, DHPM-PCL, DHPM-PLA, and DHPM-PPDO, were formed. These Biginelli reactions demonstrated exceptional completeness, validating the efficiency of the synthesis strategy. Although the introduction of various polyesters lead to different properties, such as crystallinity and cytotoxicity, the newly synthesized 3,4-dihydro-2(H)-pyrimidinone compounds (DHPMs) exhibit enhanced hydrophilicity and can self-assemble in water and N,N-dimethylformamide (DMF) solution to form micelles with a controllable size. Furthermore, DHPM-PPDO promotes cellular growth and has potential applications in wound healing and tissue engineering. In conclusion, this method demonstrates great universality and methodological significance and offers insights into the medical applications of polyethylene glycol.
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Infrared optoelectronic sensors have attracted considerable research interest over the past few decades due to their wide-ranging applications in military, healthcare, environmental monitoring, industrial inspection, and human-computer interaction systems. A comprehensive understanding of infrared optoelectronic sensors is of great importance for achieving their future optimization. This paper comprehensively reviews the recent advancements in infrared optoelectronic sensors. Firstly, their working mechanisms are elucidated. Then, the key metrics for evaluating an infrared optoelectronic sensor are introduced. Subsequently, an overview of promising materials and nanostructures for high-performance infrared optoelectronic sensors, along with the performances of state-of-the-art devices, is presented. Finally, the challenges facing infrared optoelectronic sensors are posed, and some perspectives for the optimization of infrared optoelectronic sensors are discussed, thereby paving the way for the development of future infrared optoelectronic sensors.
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Efficient interactions between an adhesive and a substrate surface at the molecular level are the basis for the formation of robust adhesion, which substantially relies on interfacial wetting. However, strong adhesives usually improve cohesion but compromise interfacial properties. Herein, we have reported a kind of robust supramolecular adhesive based on the outstanding mobility and interfacial wettability of adhesive precursors. In situ fast photopolymerization endows supramolecular adhesives with more outstanding adhesion for both smooth and rough surfaces in air and underwater in contrast to their counterparts from thermal polymerization. In addition to their low viscosity and high monomer concentration, supramolecular adhesive precursors without any organic solvents possess well-defined hydrogen bonding interactions. These superior properties consistently contribute to the wetting of the substrate and the formation of adhesive polymers with high molecular weights. This work highlights that enhancing interfacial wetting between an adhesive and a substrate is a promising route to achieving robust adhesion.
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The efficiency and longevity of metal-halide perovskite solar cells are typically dictated by nonradiative defect-mediated charge recombination. In this work, we demonstrate a vapor-based amino-silane passivation that reduces photovoltage deficits to around 100 millivolts (>90% of the thermodynamic limit) in perovskite solar cells of bandgaps between 1.6 and 1.8 electron volts, which is crucial for tandem applications. A primary-, secondary-, or tertiary-amino-silane alone negatively or barely affected perovskite crystallinity and charge transport, but amino-silanes that incorporate primary and secondary amines yield up to a 60-fold increase in photoluminescence quantum yield and preserve long-range conduction. Amino-silane-treated devices retained 95% power conversion efficiency for more than 1500 hours under full-spectrum sunlight at 85°C and open-circuit conditions in ambient air with a relative humidity of 50 to 60%.
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Multifunctional sensors have played a crucial role in constructing high-integration electronic networks. Most of the current multifunctional sensors rely on multiple materials to simultaneously detect different physical stimuli. Here, we demonstrate the large piezo-pyroelectric effect in ferroelectric Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) single crystals for simultaneous pressure and temperature sensing. The outstanding piezoelectric and pyroelectric properties of PMN-PT result in rapid response speed and high sensitivity, with values of 46 ms and 28.4 nA kPa-1 for pressure sensing, and 1.98 s and 94.66 nC °C-1 for temperature detection, respectively. By leveraging the distinct differences in the response speed of piezoelectric and pyroelectric responses, the piezo-pyroelectric effect of PMN-PT can effectively detect pressure and temperature from mixed-force thermal stimuli, which enables a robotic hand for stimuli classification. With appealing multifunctionality, fast speed, high sensitivity, and compact structure, the proposed self-powered bimodal sensor therefore holds significant potential for high-performance artificial perception.
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Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and metastasize. We show that creatine levels in metastatic breast cancer cell lines and secondary metastatic tumors are driven by the ubiquitous mitochondrial creatine kinase (CKMT1). We discover that, while CKMT1 is highly expressed in primary tumors and promotes cell viability, it is downregulated in metastasis. We further show that CKMT1 downregulation, as seen in breast cancer metastasis, drives up mitochondrial reactive oxygen species (ROS) levels. CKMT1 downregulation contributes to the migratory and invasive potential of cells by ROS-induced upregulation of adhesion and degradative factors, which can be reversed by antioxidant treatment. Our study thus reconciles conflicting evidence about the roles of metabolites in the creatine metabolic pathway in breast cancer progression and reveals that tight, context-dependent regulation of CKMT1 expression facilitates cell viability, cell migration, and cell invasion, which are hallmarks of metastatic spread.
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Neoplasias da Mama , Creatina Quinase Mitocondrial , Espécies Reativas de Oxigênio , Animais , Feminino , Humanos , Camundongos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Creatina Quinase , Creatina Quinase Mitocondrial/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Mitocôndrias/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Cognitive impairment is increasingly recognized as an important comorbidity and complication of type 2 diabetes (T2D), affecting patients' quality of life and diabetes management. Dynamic brain activity indicators can reflect changes in key neural activity patterns of cognition and behavior. PURPOSE: To investigate dynamic functional connectivity (DFC) changes and spontaneous brain activity based on resting-state functional magnetic resonance imaging (rs-fMRI) in patients with T2D, exploring their correlations with clinical features. STUDY TYPE: Retrospective. SUBJECTS: Forty-five healthy controls (HCs) (22 males and 23 females) and 102 patients with T2D (57 males and 45 females). FIELD STRENGTH/SEQUENCE: 3.0 T/T1-weighted imaging and rs-fMRI with gradient-echo planar imaging sequence. ASSESSMENT: Functional networks were created using independent component analysis. DFC states were determined using sliding window approach and k-means clustering. Spontaneous brain activity was assessed using dynamic regional homogeneity (dReHo) variability. STATISTICAL TESTS: One-way analysis of variance and post hoc analysis were used to compare the essential information including demographics, clinical data, and features of DFC and dReHo among groups. Diagnostic performance was assessed using receiver operating characteristic (ROC) curve. P-values <0.05 were taken to indicate statistical significance. RESULTS: T2D group had significantly decreased mean dwell time and fractional windows in state 4 compared to HC. T2D with mild cognitive impairment showed significantly increased dReHo variability in left superior occipital gyrus compared to T2D with normal cognition. Mean dwell time and number of fractional windows of state 4 both showed significant positive correlations with the Montreal cognitive assessment scores (r = 0.309; r = 0.308, respectively) and the coefficient of variation of dReHo was significantly positively correlated with high-density lipoprotein cholesterol (r = 0.266). The integrated index had an area under the curve of 0.693 (95% confidence interval = 0.592-0.794). DATA CONCLUSION: Differences in DFC and dynamic characteristic of spontaneous brain activity associated with T2D-related functional impairment may serve as indicators for predicting symptom progression and assessing cognitive dysfunction. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.
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BACKGROUND: Mounting evidence indicates that although some plant-based diets are healthful, others are not. Changes in the gut microbiome and microbiome-dependent metabolites, such as trimethylamine N-oxide (TMAO), may explain differential health effects of plant-based diets. However, human data are sparse on whether qualitatively distinct types of plant-based diets differentially affect gut microbiome diversity, composition, particularly at the species level, and/or metabolites. OBJECTIVES: We aimed to examine cross-sectional associations of different plant-based indices with adult gut microbiome diversity, composition, and the metabolite TMAO. METHODS: We studied 705 adults in the Baltimore Longitudinal Study of Aging with data for diet, fecal microbiome (shotgun metagenomic sequencing), and key covariates. We derived healthful plant-based diet index (hPDI) and unhealthful plant-based diet index (uPDI) using data from food frequency questionnaires. We examined plant-based diet indices with microbiome α-diversity (richness and evenness measures), ß-diversity (Bray-Curtis and UniFrac measures), composition (species level), and plasma TMAO. We used regression models to determine associations before and after adjustment for age, sex, education, physical activity, smoking status, body mass index, and total energy intake. RESULTS: The analytic sample (mean age, 71.0 years, SD = 12.8 years) comprised 55.6% female and 67.5% non-Hispanic White participants. hPDI was positively and uPDI negatively associated with microbiome α-diversity, driven by microbial evenness (Pielou P < 0.05). hPDI was also positively associated with relative abundance of 3 polysaccharide-degrading bacterial species (Faecalibacterium prausnitzii, Eubacterium eligens, and Bacteroides thetaiotaomicron) and inversely associated with 6 species (Blautia hydrogenotrophica, Doreasp CAG 317, Eisenbergiella massiliensis, Sellimonas intestinalis, Blautia wexlerae, and Alistipes shahii). Furthermore, hPDI was inversely associated with TMAO. Associations did not differ by age, sex, or race. CONCLUSIONS: Greater adherence to a healthful plant-based diet is associated with microbiome features that have been linked to positive health; adherence to an unhealthful plant-based diet has opposing or null associations with these features.
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Microbioma Gastrointestinal , Metilaminas , Adulto , Idoso , Humanos , Envelhecimento , Baltimore , Estudos Transversais , Dieta , Dieta Baseada em Plantas , Dieta Vegetariana , Estudos Longitudinais , Masculino , Feminino , Pessoa de Meia-IdadeRESUMO
Over the past decade, CdS QDs have become versatile semiconductors. Surface modification of CdS QDs has become an interesting case study, as it can eliminate surface defects and improve their photochemical properties. In this study, we report a new strategy of using carbon quantum dots containing a large number of thiol groups (CQDs-SH) as a passivating agent for the stabilization of CdS quantum dots (QDs). Various characterization techniques have clearly revealed that the CdS QDs have been successfully passivated by CQDs-SH. The photocatalytic performance of CQDs-SH/CdS QDs was investigated for the degradation of the insecticide imidacloprid from an aqueous solution. Parameters affecting the photodegradation process, including the light source, photocatalyst amount, initial concentration of the pollutant, radiation time, pH, oxidizing agent, and temperature, were investigated. Furthermore, the HPLC technique was applied to quantitatively analyze imidacloprid and its degradation products. The results of the HPLC analysis revealed that under simulated visible light at pH 9, imidacloprid scarcely existed after 90 min of irradiation (90.13% degradation). The LC-MS method was also used to detect the degradation products and investigate the mechanism of photodegradation of the pesticide. The results showed that the CQDs-SH/CdS QDs composite was a promising photocatalyst for the degradation of imidacloprid in wastewater.
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Distinct from the traditional diagnostic/prognostic biomarker (adopted as the indicator of disease state/process), the therapeutic biomarker (ThMAR) has emerged to be very crucial in the clinical development and clinical practice of all therapies. There are five types of ThMAR that have been found to play indispensable roles in various stages of drug discovery, such as: Pharmacodynamic Biomarker essential for guaranteeing the pharmacological effects of a therapy, Safety Biomarker critical for assessing the extent or likelihood of therapy-induced toxicity, Monitoring Biomarker indispensable for guiding clinical management by serially measuring patients' status, Predictive Biomarker crucial for maximizing the clinical outcome of a therapy for specific individuals, and Surrogate Endpoint fundamental for accelerating the approval of a therapy. However, these data of ThMARs has not been comprehensively described by any of the existing databases. Herein, a database, named 'TheMarker', was therefore constructed to (a) systematically offer all five types of ThMAR used at different stages of drug development, (b) comprehensively describe ThMAR information for the largest number of drugs among available databases, (c) extensively cover the widest disease classes by not just focusing on anticancer therapies. These data in TheMarker are expected to have great implication and significant impact on drug discovery and clinical practice, and it is freely accessible without any login requirement at: https://idrblab.org/themarker.
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Biomarcadores , Bases de Dados Factuais , Humanos , Descoberta de Drogas , Terapêutica , Prognóstico , DoençaRESUMO
Target discovery is one of the essential steps in modern drug development, and the identification of promising targets is fundamental for developing first-in-class drug. A variety of methods have emerged for target assessment based on druggability analysis, which refers to the likelihood of a target being effectively modulated by drug-like agents. In the therapeutic target database (TTD), nine categories of established druggability characteristics were thus collected for 426 successful, 1014 clinical trial, 212 preclinical/patented, and 1479 literature-reported targets via systematic review. These characteristic categories were classified into three distinct perspectives: molecular interaction/regulation, human system profile and cell-based expression variation. With the rapid progression of technology and concerted effort in drug discovery, TTD and other databases were highly expected to facilitate the explorations of druggability characteristics for the discovery and validation of innovative drug target. TTD is now freely accessible at: https://idrblab.org/ttd/.
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Bases de Dados de Produtos Farmacêuticos , Humanos , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Terapia de Alvo MolecularRESUMO
Here, the authors report that co-crystallization of fluorophores with matrix-assisted laser desorption/ionization (MALDI) imaging matrices significantly enhances fluorophore brightness up to 79-fold, enabling the amplification of innate tissue autofluorescence. This discovery facilitates FluoMALDI, the imaging of the same biological sample by both fluorescence microscopy and MALDI imaging. The approach combines the high spatial resolution and specific labeling capabilities of fluorescence microscopy with the inherently multiplexed, versatile imaging capabilities of MALDI imaging. This new paradigm simplifies registration by avoiding physical changes between fluorescence and MALDI imaging, allowing to image the exact same cells in tissues with both modalities. Matrix-fluorophore co-crystallization also facilitates applications with insufficient fluorescence brightness. The authors demonstrate feasibility of FluoMALDI imaging with endogenous and exogenous fluorophores and autofluorescence-based FluoMALDI of brain and kidney tissue sections. FluoMALDI will advance structural-functional microscopic imaging in cell biology, biomedicine, and pathology.
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Encéfalo , Rim , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Cristalização , Microscopia de Fluorescência , Rim/diagnóstico por imagemRESUMO
BACKGROUND: Natural killer (NK) cells hold great promise in treating diverse hematopoietic and solid tumors. Despite their availability from peripheral blood and cord blood, stem cell-derived NK cells offer an 'off-the-shelf' solution. Hematopoietic stem and progenitor cells (HSPCs) derived from cord blood pose no risk to the newborn or mother and are virtually ideal sources for NK cell differentiation. METHODS: We developed a modified protocol to differentiate HSPCs to NK cells under serum-free conditions using defined factors. The HSPC-derived NK (HSC-NK) cells could be expanded in a K562 feeder cell-dependent manner. Furthermore, using lentivirus transduction, chimeric antigen receptor (CAR)-modified HSPCs could be differentiated into NK cells, leading to the establishment of CAR-NK cells. RESULTS: The efficiency of NK cell differentiation from HSPCs was increased through the simple modulation of osmotic pressure by the addition of sodium chloride or glucose. Furthermore, the hyperosmosis-primed HSC-NK cells exhibited enhanced proliferation capacity and maintained normal functional characteristics, including transcriptome and antitumor efficacy. The optimized protocol yielded approximately 1.8 million NK cells from a single CD34-positive cell within a 28-day cycle, which signifies more than a ten-fold increase in efficiency relative to the conventional methods. This optimized protocol was also suitable for generating CAR-NK cells with high yields compared to standard conditions. CONCLUSIONS: The results of this study establish high osmotic pressure as a simple yet powerful adjustment that significantly enhances the efficiency and functionality of HSC-NK cells, including CAR-NK cells. This optimized protocol could lead to cost-effective, high-yield NK cell therapies, potentially revolutionizing cancer immunotherapy strategies.
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Sangue Fetal , Neoplasias , Recém-Nascido , Humanos , Células Matadoras Naturais , Células-Tronco Hematopoéticas/metabolismo , Diferenciação Celular , Neoplasias/metabolismoRESUMO
Dispersion of colloidal particles in water or oil is extensively desired for industrial and environmental applications. However, it often strongly depends on indispensable assistance of chemical surfactants or introduction of nanoprotrusions onto the particle surface. Here we demonstrate the omnidispersity of hydrophilic-hydrophobic heterostructure particles (HL-HBPs), synthesized by a surface heterogeneous nanostructuring strategy. Photo-induced force microscopy (PiFM) and adhesion force images both indicate the heterogeneous distribution of hydrophilic domains and hydrophobic domains on the particle surface. These alternating domains allow HL-HBPs to be dispersed in various solvents with different polarity and boiling point. The HL-HBPs can efficiently adsorb organic dyes from water and release them into organic solvents within several seconds. The surface heterogeneous nanostructuring strategy provides an unconventional approach to achieve omnidispersion of colloidal particles beyond surface modification, and the omnidispersible HL-HBPs demonstrate superior capability for dye recycle merely by solvent exchange. These omnidispersible HL-HBPs show great potentials in industrial process and environmental protection.