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Unlike inorganic nanoparticles, organic nanoparticles (oNPs) offer the advantage of "interior tailorability," thereby enabling the controlled variation of physicochemical characteristics and functionalities, for example, by incorporation of diverse functional small molecules. In this study, a unique inimer-based microemulsion approach is presented to realize oNPs with enhanced control of chemical and mechanical properties by deliberate variation of the degree of hyperbranching or cross-linking. The use of anionic cosurfactants led to oNPs with superior uniformity. Benefitting from the high initiator concentration from inimer and preserved chain-end functionality during atom transfer radical polymerization (ATRP), the capability of oNPs as a multifunctional macroinitiator for the subsequent surface-initiated ATRP was demonstrated. This facilitated the synthesis of densely tethered poly(methyl methacrylate) brush oNPs. Detailed analysis revealed that exceptionally high grafting densities (~1 nm-2) were attributable to multilayer surface grafting from oNPs due to the hyperbranched macromolecular architecture. The ability to control functional attributes along with elastic properties renders this "bottom-up" synthetic strategy of macroinitiator-type oNPs a unique platform for realizing functional materials with a broad spectrum of applications.
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OBJECTIVE: SET domain-containing protein 1A (SETD1A) histone lysine N-methyltransferase may serve as a biomarker for the auxiliary diagnosis and treatment assessment of schizophrenia (SCZ). The aim of this study was to compare serum levels of SETD1A protein between patients with SCZ and health controls. METHODS: Patients with SCZ and health controls were recruited from the Sixth Hospital of Changchun and the 'Survey on Chronic Diseases and Risk Factors among Adults in Jilin Province', respectively. The quantifications of lysine N-methyltransferase in peripheral serum were conducted by the ELISA method, and data was analyzed using the R software. RESULTS: Forty patients with SCZ (mean age: 33.97 ± 5.99 years) and forty healthy controls (mean age: 39.07 ± 4.62 years) were included. There was significantly lower concentration of SETD1A protein in the SCZ group compared with the control group (P < 0.001). This significant difference still exists after stratification by sex (P < 0.05). CONCLUSION: Our study demonstrates that decreased levels of serum SETD1A protein may be utilized as a possible peripheral biomarker for schizophrenia.
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Biomarcadores , N-Metiltransferasa de Histona-Lisina , Esquizofrenia , Humanos , Esquizofrenia/sangre , Esquizofrenia/diagnóstico , Masculino , Femenino , N-Metiltransferasa de Histona-Lisina/sangre , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Persona de Mediana EdadRESUMEN
Poly(vinylidene fluoride) (PVDF) shows excellent chemical and thermal resistance and displays high dielectric strength and unique piezoelectricity, which are enabling for applications in membranes, electric insulators, sensors, or power generators. However, its low polarity and lack of functional groups limit wider applications. While inert, PVDF has been modified by grafting polymer chains by atom transfer radical polymerization (ATRP), albeit via an unclear mechanism, given the strong C-F bonds. Herein, we applied eosin Y and green-light-mediated ATRP to modify PVDF-based materials. The method gave nearly quantitative (meth)acrylate monomer conversions within 2 h without deoxygenation and without the formation of unattached homopolymers, as confirmed by control experiments and DOSY NMR measurements. The gamma distribution model that accounts for broadly dispersed polymers in DOSY experiments was essential and serves as a powerful tool for the analysis of PVDF. The NMR analysis of poly(methyl acrylate) graft chain-ends on PVDF-CTFE (statistical copolymer with chlorotrifluoroethylene) was carried out successfully for the first time and showed up to 23 grafts per PVDF-CTFE chain. The grafting density was tunable depending on the solvent composition and light intensity during the grafting. The initiation proceeded either from the C-Cl sites of PVDF-CTFE or via unsaturations in the PVDF backbones. The dehydrofluorinated PVDF was 20 times more active than saturated PVDF during the grafting. The method was successfully applied to modify PVDF, PVDF-HFP, and Viton A401C. The obtained PVDF-CTFE-g-PnBMA materials were investigated in more detail. They featured slightly lower crystallinity than PVDF-CTFE (12-18 vs 24.3%) and had greatly improved mechanical performance: Young's moduli of up to 488 MPa, ductility of 316%, and toughness of 46 × 106 J/m3.
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Anodized titania nanotubes have been considered as an effective coating for bone implants due to their ability to induce osteogenesis, whereas the osteogenic mechanism is not fully understood. Our previous study has revealed the potential role of autophagy in osteogenic regulation of nanotubular surface, whereas how the autophagy is activated remains unknown. In this study, we focused on the cell membrane curvature-sensing protein Bif-1 and its effect on the regulation of autophagy. Both autophagosomes formation and autophagic flux were enhanced on the nanotubular surface, as indicated by LC3-II accumulation and p62 degradation. In the meanwhile, the Bif-1 was significantly upregulated, which contributed to autophagy activation and osteogenic differentiation through Beclin-1/PIK3C3 signaling pathway. In conclusion, these findings have bridged the gap between extracellular physical nanotopography and intracellular autophagy activation, which may provide a deeper insight into the signaling transition from mechanical to biological across the cell membrane.
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Autofagia , Beclina-1 , Diferenciación Celular , Membrana Celular , Osteogénesis , Transducción de Señal , Propiedades de Superficie , Animales , Membrana Celular/metabolismo , Ratones , Beclina-1/metabolismo , Titanio/química , Nanotubos/química , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Humanos , Osteoblastos/citología , Osteoblastos/metabolismo , Línea CelularRESUMEN
The intricate electrophysiological functions and anatomical structures of spinal cord tissue render the establishment of in vitro models for spinal cord-related diseases highly challenging. Currently, both in vivo and in vitro models for spinal cord-related diseases are still underdeveloped, complicating the exploration and development of effective therapeutic drugs or strategies. Organoids cultured from human induced pluripotent stem cells (hiPSCs) hold promise as suitable in vitro models for spinal cord-related diseases. However, the cultivation of spinal cord organoids predominantly relies on Matrigel, a matrix derived from murine sarcoma tissue. Tissue-specific extracellular matrices are key drivers of complex organ development, thus underscoring the urgent need to research safer and more physiologically relevant organoid culture materials. Herein, we have prepared a rat decellularized brain extracellular matrix hydrogel (DBECMH), which supports the formation of hiPSC-derived spinal cord organoids. Compared with Matrigel, organoids cultured in DBECMH exhibited higher expression levels of markers from multiple compartments of the natural spinal cord, facilitating the development and maturation of spinal cord organoid tissues. Our study suggests that DBECMH holds potential to replace Matrigel as the standard culture medium for human spinal cord organoids, thereby advancing the development of spinal cord organoid culture protocols and their application in in vitro modeling of spinal cord-related diseases.
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Encéfalo , Hidrogeles , Células Madre Pluripotentes Inducidas , Organoides , Médula Espinal , Organoides/efectos de los fármacos , Organoides/citología , Organoides/metabolismo , Humanos , Animales , Médula Espinal/citología , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Encéfalo/metabolismo , Ratas , Matriz Extracelular Descelularizada/química , Matriz Extracelular Descelularizada/farmacología , Matriz Extracelular/metabolismo , Matriz Extracelular/química , Laminina/farmacología , Laminina/química , Proteoglicanos/química , Ratas Sprague-Dawley , Combinación de Medicamentos , ColágenoRESUMEN
Spinal cord organoids are of significant value in the research of spinal cord-related diseases by simulating disease states, thereby facilitating the development of novel therapies. However, the complexity of spinal cord structure and physiological functions, along with the lack of human-derived inducing components, presents challenges in the in vitro construction of human spinal cord organoids. Here, we introduce a novel human decellularized placenta-derived extracellular matrix hydrogel (DPECMH) and, combined with a new induction protocol, successfully construct human spinal cord organoids. The human placenta-sourced decellularized extracellular matrix (dECM), verified through hematoxylin and eosin staining, DNA quantification, and immunofluorescence staining, retained essential ECM components such as elastin, fibronectin, type I collagen, laminin, and so forth. The temperature-sensitive hydrogel made from human placenta dECM demonstrated good biocompatibility and promoted the differentiation of human induced pluripotent stem cell (hiPSCs)-derived spinal cord organoids into neurons. It displayed enhanced expression of laminar markers in comparison to Matrigel and showed higher expression of laminar markers compared to Matrigel, accelerating the maturation process of spinal cord organoids and demonstrating its potential as an organoid culture substrate. DPECMH has the potential to replace Matrigel as the standard additive for human spinal cord organoids, thus advancing the development of spinal cord organoid culture protocols and their application in the in vitro modeling of spinal cord-related diseases.
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Diferenciación Celular , Matriz Extracelular Descelularizada , Hidrogeles , Células Madre Pluripotentes Inducidas , Organoides , Placenta , Médula Espinal , Humanos , Organoides/citología , Organoides/metabolismo , Organoides/efectos de los fármacos , Femenino , Placenta/citología , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Embarazo , Hidrogeles/química , Hidrogeles/farmacología , Médula Espinal/citología , Médula Espinal/metabolismo , Diferenciación Celular/efectos de los fármacos , Matriz Extracelular Descelularizada/farmacología , Matriz Extracelular Descelularizada/química , Matriz Extracelular/metabolismo , Matriz Extracelular/química , Laminina/farmacología , Laminina/químicaRESUMEN
Using cascaded Mach-Zehnder interferometers (CMZIs) provides an attractive option for realizing coarse wavelength-division (de)multiplexing (CWDM) filters with low losses, low crosstalk, flat tops, and high scalability. However, they usually have large footprints and insufficient fabrication tolerances, due to the inferior performance of conventional directional couplers (DCs) used for MZIs. Here, a four-channel CMZI wavelength-division (de)multiplexer based on novel Bezier-shape DCs with compact footprints, broad bandwidths and decent fabrication tolerances. For the fabricated (de)multiplexer with 20-nm channel spacing, the excess loss is less than 0.5â dB and the crosstalk is lower than -19.5â dB in the 1-dB bandwidth of 12.8â nm. For the case with a core-width deviation of ±20â nm, the device still performs very well with low losses and low crosstalk. Compared to the state-of-the-art MZI-based CWDM filters, the present device has slightly high performances and a footprint of 0.012 mm2 shrunk greatly by â¼3-folds. This work can be extended for more channels and other material platforms.
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Linear polyisoprene (PI) and SiO2-g-PI particle brushes were synthesized by both conventional and activators regenerated by electron transfer (ARGET) atom transfer radical polymerization (ATRP). The morphology and solution state study on the particle brushes by transmission electron microscopy (TEM) and dynamic light scattering (DLS) confirmed the successful grafting of PI ligands on the silica surface. The presence of nanoparticle clusters suggests low grafting density (associated with the limited initiation efficiency of ARGET for PI). Nevertheless, particle brushes with very high molecular weights, Mn > 300,000, were prepared, which significantly improved the dispersion of silica nanoparticles and also contributed to excellent mechanical performance. The reinforcing effects of SiO2 nanofillers and very high molecular weight PI ligands were investigated by dynamic mechanical analysis (DMA) as well as computational simulation for the cured linear PI homopolymer/SiO2-g-PI particle brush bulk films.
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Researchers have always been interested in polysaccharide degradation because of the increased biological activity and usability following degradation. In this work, low molecular weight galactomannan (LMW-GM) was produced through the degradation of galactomannan by H2O2 and oxalic acid (OA). The optimal reaction conditions were found by conducting the response surface optimization experiment based on single-factor experiment and kinetics analysis. Under these conditions, the LMW-GM yield was 69.48 ± 1.02 %. Ultimately, an analysis of the degradation process revealed that OA attacked GM indiscriminately, and H2O2 has a stronger effect on the removal of branched chains while degrading GM. Hence, the degradation steps were rearranged as H2O2 was added 20 min before OA at a constant total time. The LMW-GM yield was successfully increased to 76.49 ± 1.27 %. The goal of this work is hopefully to give a theoretical foundation for the low-cost preparation and industrial production of the degradation of galactomannan.
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Fabaceae , Galactosa/análogos & derivados , Peróxido de Hidrógeno , Ácido Oxálico , Peso Molecular , MananosRESUMEN
As newly discovered substrate anchored extracellular vesicles, migrasomes (Migs) may bring a new opportunity for manipulating target cells bioactivities. In this study, the M2 macrophages derived Migs are obtained by titania nanotubes surface (NTs). Due to the benefits of nanostructuring, the NTs surface is not only able to induce RAW264.7 for M2 polarization but also to generate more Migs formation, which can be internalized by following seeded mesenchymal stem cells (MSCs). Then, the NTs surface induced Migs are collected by density-gradient centrifugation for MSCs treatment. As indicated by immunofluorescence staining, alkaline phosphatase activity, and alizarin red staining, the osteogenic differentiation capacity of MSCs is significantly enhanced by Migs treatment, in line with the dosage. By RNA-sequence analysis, the enhancement of osteogenic differentiation is correlated with PI3K-AKT pathway activation that may originate from the M2 polarization state of donor cells. Finally, the Migs are coated onto Ti surface for therapeutic application. Both the in vitro and in vivo analysis reveal that the Migs coated Ti implant shows significant enhancement of osteogenesis. In conclusion, this study suggests that the nanosurface may be a favorable platform for Migs production, which may bring a new concept for tissue regeneration.
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Diferenciación Celular , Macrófagos , Células Madre Mesenquimatosas , Nanotubos , Osteogénesis , Titanio , Titanio/química , Titanio/farmacología , Osteogénesis/efectos de los fármacos , Animales , Nanotubos/química , Ratones , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Células RAW 264.7 , Macrófagos/metabolismo , Macrófagos/citología , Macrófagos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/química , Propiedades de Superficie , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Current evidence shows an inter-country inconsistency in the effect of lesion size on the technical difficulty of gastric endoscopic submucosal dissection (ESD). We aimed to evaluate the specific correlation and quantify the ensuing risks. This retrospective study consisted of 405 ESD cases with gastric single lesion from April 2015 to April 2023. The correlation and risk prediction of lesion size with technical difficulty was explored to provide further clinical evidence. An additive generalized model and recursive algorithm were used to describe the non-linear association, and a linear two-piece regression was constructed to analyze the inflection point. Subgroup analysis and interaction were used to explore intergroup characteristics. Overall, difficult cases had larger lesion sizes, and the more significant the increase, the higher the risk of technical difficulty. In the full model, after adjusting for all covariates, each 1 mm, 3 mm, 5 mm, 7 mm, and one standard increase in lesion size increased the risk of technical difficulty by 8%, 26%, 42%, 72%, and 125%, respectively. There is a nonlinear positive correlation between lesion size and risk of technical difficulty, and the premeditated inflection point was 40 (mm) via two-piecewise linear regression and recursive algorithm. Subgroup analysis showed a stronger correlation between lesion size and difficult ESD in the upper site and submucosal fibrosis groups. Available evidence suggests that lesion size as a risk signal nonlinearly increases the technical difficulty of gastric ESD procedure, especially in cases of upper site and submucosal fibrosis, which deserves further investigation.
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Resección Endoscópica de la Mucosa , Fibrosis de la Submucosa Bucal , Neoplasias Gástricas , Humanos , Resección Endoscópica de la Mucosa/efectos adversos , Resección Endoscópica de la Mucosa/métodos , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Estudios Retrospectivos , Fibrosis de la Submucosa Bucal/patología , Mucosa Gástrica/cirugía , Mucosa Gástrica/patología , Fibrosis , Resultado del TratamientoRESUMEN
BACKGROUND: Intermittent hypoxia intervention (IHI) has been shown to reduces blood glucose and improves insulin resistance in type 2 diabetes (T2D) and has been suggested as a complementary or alternative intervention to exercise for individuals with limited mobility. Previous research on IHI has assessed cellular glucose uptake rather than utilization. The purpose of this study was to determine the effect of a 4-week IHI, with or without an aerobic exercise, on skeletal muscle glucose utilization as indicated by the changes in pyruvate, lactate, NAD+, and NADH, using a mouse model of diet-induced T2D. In addition, the effects of one exposure to hypoxia (acute) and of a 4-week IHI (chronic) were compared to explore their relationship. METHODS: C57BL/6J mice were randomly assigned to normal control and high-fat-diet groups, and the mice that developed diet-induced diabetes were assigned to diabetes control, and intervention groups with 1 hour (acute) or 4 weeks (1 hour/day, 6 days/week) exposure to a hypoxic envrionment (0.15 FiO2), exercise (treadmill run) in normoxia, and exercise in hypoxia, respectively, with N = 7 in each group. The effects of the interventions on concentrations of fasting blood glucose, muscle glucose, GLUT4, lactate, pyruvate, nicotinamide adenine dinucleotide (NAD+), and NADH were measured, and statistically compared between the groups. RESULTS: Compared with diabetes control group, the mice treated in the hypoxic environment for 4 weeks showed a significantly higher pyruvate levels and lower lactate/pyruvate ratios in the quadriceps muscle, and the mice exposed to hypoxia without or with aerobic exercise for either for 4 weeks or just 1 hour showed higher NAD+ levels and lower NADH/NAD+ ratios. CONCLUSIONS: Exposure to moderate hypoxia for either one bout or 4 weeks significantly increased the body's mitochondrial NAD cyclethe in diabetic mice even in the absence of aerobic exercise. The hypoxia and exercise interventions exhibited synergistic effects on glycolysis. These findings provide mechanistic insights into the effects of IHI in respect of the management of hyperglycemia.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Humanos , Animales , Ratones , Glucosa , Glucemia , NAD , Ratones Endogámicos C57BL , Músculo Esquelético , Resistencia a la Insulina/fisiología , Modelos Animales de Enfermedad , Hipoxia , Lactatos , PiruvatosRESUMEN
Chemodynamic therapy (CDT), as an emerging therapeutic strategy, kills cancer cells by converting intracellular hydrogen peroxide (H2O2) into cytotoxic oxidizing hydroxyl radicals (â OH). However, the therapeutic efficiency of CDT is compromised due to the insufficient endogenous H2O2 and metal catalysts in tumor cells. The use of multivalent polyphenols with multiple hydroxyl functions provides a facile yet robust means for efficient CDT augmentation. For this purpose, we reported herein the construction of polyphenol-metal nanoparticles (NPs) via a phenol-metal coordination strategy. The uniqueness of this study is the preparation of only one polymer construct with multivalency that can afford various supramolecular interactions for simultaneous "one-pot" loading of different therapeutic species, i.e., doxorubicin (DOX), glucose oxidases (GOD), and Fe3+ and further co-self-assembly into a stabilized nanomedicine for cascade amplified chemo-chemodynamic therapy. Specifically, the tumor intracellular acidic pH-triggered DOX release could serve for chemotherapy as well as enhance the intracellular H2O2 level. Together with the extra H2O2 and gluconic acid produced by the GOD-triggered glucose consumption, DOX@POAD-Fe@GOD NPs promoted Fe3+participation in the Fe-mediated Fenton reaction for cascade amplified chemo-chemodynamic therapy. Notably, this formulation displayed a greater anti-tumor effect with a tumor inhibition ratio 1.6-fold higher than that of free DOX in a BALB/c mice model bearing 4T1 tumors. Overall, the multivalent polyphenol-metal nanoplatform developed herein integrates chemotherapy, starvation therapy, and CDT for synergistic enhanced anticancer efficiency, which shows great potential for clinical translations. STATEMENT OF SIGNIFICANCE: Chemodynamic therapy (CDT) generally suffers from compromised therapeutic efficiency due to insufficient endogenous H2O2 and metal catalysts in tumor cells. To develop a facile yet robust strategy for efficient CDT augmentation, we reported herein construction of a multivalent polyphenol-metal nanoplatform, DOX@POAD-Fe@GOD nanoparticles (NPs) via a phenol-metal coordination strategy. This nanoplatform integrates multiple supramolecular dynamic interactions not only for simultaneously safe encapsulation of doxorubicin (DOX), Fe3+, and glucose oxidases (GOD), but also for cascade amplified chemo-chemodynamic therapy. Specifically, the intracellular acidic pH-triggered dissociation of DOX@POAD-Fe@GOD NPs promoted the release of Fe3+, DOX, and GOD for significantly increased ROS levels that can accelerate Fenton reactions for cascaded chemotherapy, starvation therapy, and CDT with amplified antitumor efficiency in vivo.
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Nanopartículas , Neoplasias , Animales , Ratones , Polifenoles/farmacología , Peróxido de Hidrógeno , Fenoles , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Glucosa Oxidasa , Metales , Ratones Endogámicos BALB C , Glucosa , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico , Microambiente TumoralRESUMEN
"Self-healing" has emerged as a concept to increase the functional stability and durability of polymer materials in applications and thus to benefit the sustainability of polymer-based technologies. Recently, van der Waals (vdW)-driven "self-healing" of sequence-controlled acrylate-based copolymers due to "key-and-lock"- or "ring-and-lock"-type interactions has generated considerable interest as a viable route toward engineering polymers with "self-healing" ability. This contribution systematically evaluates the time, temperature, and composition dependence of the mechanical recovery of acrylate-based copolymer and homopolymer systems subject to cut-and-adhere testing. "Self-healing" in n-butyl acrylate/methyl methacrylate (BA/MMA)- or n-butyl acrylate/styrene (BA/Sty)-based copolymers with varying composition and sequence is found to correlate with the bulk viscoelastic properties of materials and to follow a similar trend as other tested acrylate-based homo- and copolymers. This suggests that "self-healing" in this class of materials is more related to the chain dynamics of bulk materials rather than composition- or sequence-dependent specific interactions.
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Silicon T centers present the promising possibility of generating optically active spin qubits in an all-silicon device. However, these color centers exhibit long excited state lifetimes and a low Debye-Waller factor, making them dim emitters with low efficiency into the zero-phonon line. Nanophotonic cavities can solve this problem by enhancing radiative emission into the zero-phonon line through the Purcell effect. In this work, we demonstrate cavity-enhanced emission from a single T center in a nanophotonic cavity. We achieve a 2 order of magnitude increase in the brightness of the zero-phonon line relative to waveguide-coupled emitters, a 23% collection efficiency from emitter to fiber, and an overall emission efficiency into the zero-phonon line of 63.4%. We also observe a lifetime enhancement of 5, corresponding to a Purcell factor exceeding 18 when correcting for the emission to the phonon sideband. These results pave the way toward efficient spin-photon interfaces in silicon photonics.
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BACKGROUND: Mutations in the DNA polymerase delta 1 (POLD1) exonuclease domain cause DNA proofreading defects, hypermutation, hereditary colorectal and endometrial cancer, and are predictive of immunotherapy response. Exonuclease activity is carried out by two magnesium cations, bound to four highly conserved, negatively charged amino acids (AA) consisting of aspartic acid at amino acid position 316 (p.D316), glutamic acid at position 318 (p.E318), p.D402, and p.D515 (termed DEDD motif). Germline polymorphisms resulting in charge-discordant AA substitutions in the DEDD motif are classified as variants of uncertain significance (VUSs) by laboratories and thus would be considered clinically inactionable. We hypothesize this mutation class is clinically pathogenic. METHODS: A review of clinical presentation was performed in our index patient with a POLD1(p.D402N) heterozygous proband with endometrial cancer. Implications of this mutation class were evaluated by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review, in silico analysis with orthogonal biochemical confirmation, and whole-exome and RNA sequencing analysis of the patient's tumor and engineered cell lines. RESULTS: Our systematic review favored a Mendelian disease mutation class associated with endometrial and colorectal cancers. In silico analysis predicted defective protein function, confirmed by biochemical assay demonstrating loss of nuclease activity. A POLD1-specific mutational signature was found in both the patient's tumor and POLD1(p.D402N) overexpressing cell. Furthermore, paired whole-exome/transcriptome analysis of endometrial tumor demonstrated hypermutation and T cell-inflamed gene expression profile (GEP), which are joint predictive biomarkers for pembrolizumab. Our patient showed a deep, durable response to immune checkpoint inhibitor (ICI). CONCLUSION: Charge-discordant AA substitution in the DEDD motif of POLD1 is detrimental to DNA proofreading and should be reclassified as likely pathogenic and possibly predictive of ICI sensitivity.
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Cyclodextrin (CD)-based supramolecular hydrogels are polymer network systems with the ability to rapidly form reversible three-dimensional porous structures through multiple cross-linking methods, offering potential applications in drug delivery. Although CD-based supramolecular hydrogels have been increasingly used in a wide range of applications in recent years, a comprehensive description of their structure, mechanical property modulation, drug loading, delivery, and applications in biomedical fields from a cross-linking perspective is lacking. To provide a comprehensive overview of CD-based supramolecular hydrogels, this review systematically describes their design, regulation of mechanical properties, modes of drug loading and release, and their roles in various biomedical fields, particularly oncology, wound dressing, bone repair, and myocardial tissue engineering. Additionally, this review provides a rational discussion on the current challenges and prospects of CD-based supramolecular hydrogels, which can provide ideas for the rapid development of CD-based hydrogels and foster their translation from the laboratory to clinical medicine.
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Ciclodextrinas , Ciclodextrinas/química , Hidrogeles/química , Sistemas de Liberación de Medicamentos , Polímeros/química , Ingeniería de Tejidos/métodosRESUMEN
Gradient poly(methyl methacrylate/n-butyl acrylate) copolymers, P(MMA/BA), with various compositional ratios, were grafted from surface-modified silica nanoparticles (SiO2-g-PMMA-grad-PBA) via complete conversion surface-initiated activator regenerated by electron transfer (SI-ARGET) atom transfer radical polymerization (ATRP). Miniemulsion as the reaction medium effectively confined the interparticle brush coupling within micellar compartments, preventing macroscopic gelation and enabling complete conversion. Isolation of dispersed and gelled fractions revealed dispersed particle brushes to feature a higher Young's modulus, toughness, and ultimate strain compared with those of the "gel" counterparts. Upon purification, brush nanoparticles from the dispersed phase formed uniform microstructures. Uniaxial tension testing revealed a "mechanical synergy" for copolymers with MMA/BA = 3:2 molar ratio to concurrently exhibit higher toughness and stiffness. When compared with linear analogues of similar composition, the brush nanoparticles with gradient copolymers had better mechanical properties, attributed to the synergistic effects of the combination of composition and propagation orientation, highlighting the significance of architectural design for tethered brush layers of such hybrid materials.
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The occurrence and development of tumors require the metabolic reprogramming of cancer cells, namely the alteration of flux in an autonomous manner via various metabolic pathways to meet increased bioenergetic and biosynthetic demands. Tumor cells consume large quantities of nutrients and produce related metabolites via their metabolism; this leads to the remodeling of the tumor microenvironment (TME) to better support tumor growth. During TME remodeling, the immune cell metabolism and antitumor immune activity are affected. This further leads to the escape of tumor cells from immune surveillance and therefore to abnormal proliferation. This review summarizes the regulatory functions associated with the abnormal biosynthesis and activity of metabolic signaling molecules during the process of tumor metabolic reprogramming. In addition, we provide a comprehensive description of the competition between immune cells and tumor cells for nutrients in the TME, as well as the metabolites required for tumor metabolism, the metabolic signaling pathways involved, and the functionality of the immune cells. Finally, we summarize current research targeted at the development of tumor immunotherapy. We aim to provide new concepts for future investigations of the mechanisms underlying the metabolic reprogramming of tumors and explore the association of these mechanisms with tumor immunity.
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Reprogramación Metabólica , Neoplasias , Humanos , Transducción de Señal , Vigilancia Inmunológica , Inmunoterapia , Microambiente TumoralRESUMEN
The heterogeneous integration of silicon with III-V materials provides a way to overcome silicon's limited optical properties toward a broad range of photonic applications. Hybrid modes are a promising way to integrate such heterogeneous Si/III-V devices, but it remains unclear how to utilize these modes to achieve photonic crystal cavities. Herein, using 3D finite-difference time-domain simulations, we propose a hybrid Si-GaAs photonic crystal cavity design that operates at telecom wavelengths and can be fabricated without requiring careful alignment. The hybrid cavity consists of a patterned silicon waveguide that is coupled to a wider GaAs slab featuring InAs quantum dots. We show that by changing the width of the silicon cavity waveguide, we can engineer the hybrid modes and control the degree of coupling to the active material in the GaAs slab. This provides the ability to tune the cavity quality factor while balancing the device's optical gain and nonlinearity. With this design, we demonstrate cavity mode confinement in the GaAs slab without directly patterning it, enabling strong interaction with the embedded quantum dots for applications such as low-power-threshold lasing and optical bistability (156 nW and 18.1 µW, respectively). This heterogeneous integration of an active III-V material with silicon via a hybrid cavity design suggests a promising approach for achieving on-chip light generation and low-power nonlinear platforms.