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1.
Mol Ther ; 32(1): 74-83, 2024 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-37990495

RESUMEN

Recombinant adeno-associated virus (rAAV) vectors could be manufactured by plasmid transfection into human embryonic kidney 293 (HEK293) cells or baculovirus infection of Spodoptera frugiperda (Sf9) insect cells. However, systematic comparisons between these systems using large-scale, high-quality AAV vectors are lacking. rAAV from Sf9 cells (Sf9-rAAV) at 2-50 L and HEK293 cells (HEK-rAAV) at 2-200 L scales were characterized. HEK-rAAV had ∼40-fold lower yields but ∼10-fold more host cell DNA measured by droplet digital PCR and next-generation sequencing, respectively. The electron microscope observed a lower full/empty capsid ratio in HEK-rAAV (70.8%) than Sf9-rAAV (93.2%), while dynamic light scattering and high-performance liquid chromatography analysis showed that HEK-rAAV had more aggregation. Liquid chromatography tandem mass spectrometry identified different post-translational modification profiles between Sf9-rAAV and HEK-rAAV. Furthermore, Sf9-rAAV had a higher tissue culture infectious dose/viral genome than HEK-rAAV, indicating better infectivity. Additionally, Sf9-rAAV achieved higher in vitro transgene expression, as measured by ELISA. Finally, after intravitreal dosing into a mouse laser choroidal neovascularization model, Sf9-rAAV and HEK-rAAV achieved similar efficacy. Overall, this study detected notable differences in the physiochemical characteristics of HEK-rAAV and Sf9-rAAV. However, the in vitro and in vivo biological functions of the rAAV from these systems were highly comparable. Sf9-rAAV may be preferred over HEK293-rAAV for advantages in yields, full/empty ratio, scalability, and cost.


Asunto(s)
Vectores Genéticos , Riñón , Animales , Ratones , Humanos , Células HEK293 , Vectores Genéticos/genética , Transfección , Células Sf9 , Dependovirus/genética
2.
Nucleic Acids Res ; 51(15): 7972-7987, 2023 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-37395399

RESUMEN

DNA-dependent protein kinase (DNA-PK) plays a critical role in non-homologous end joining (NHEJ), the predominant pathway that repairs DNA double-strand breaks (DSB) in response to ionizing radiation (IR) to govern genome integrity. The interaction of the catalytic subunit of DNA-PK (DNA-PKcs) with the Ku70/Ku80 heterodimer on DSBs leads to DNA-PK activation; however, it is not known if upstream signaling events govern this activation. Here, we reveal a regulatory step governing DNA-PK activation by SIRT2 deacetylation, which facilitates DNA-PKcs localization to DSBs and interaction with Ku, thereby promoting DSB repair by NHEJ. SIRT2 deacetylase activity governs cellular resistance to DSB-inducing agents and promotes NHEJ. SIRT2 furthermore interacts with and deacetylates DNA-PKcs in response to IR. SIRT2 deacetylase activity facilitates DNA-PKcs interaction with Ku and localization to DSBs and promotes DNA-PK activation and phosphorylation of downstream NHEJ substrates. Moreover, targeting SIRT2 with AGK2, a SIRT2-specific inhibitor, augments the efficacy of IR in cancer cells and tumors. Our findings define a regulatory step for DNA-PK activation by SIRT2-mediated deacetylation, elucidating a critical upstream signaling event initiating the repair of DSBs by NHEJ. Furthermore, our data suggest that SIRT2 inhibition may be a promising rationale-driven therapeutic strategy for increasing the effectiveness of radiation therapy.


Asunto(s)
Roturas del ADN de Doble Cadena , Proteínas Quinasas , ADN/genética , ADN/metabolismo , Reparación del ADN por Unión de Extremidades , Reparación del ADN , Proteína Quinasa Activada por ADN/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Autoantígeno Ku/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Quinasas/genética , Sirtuina 2/genética , Sirtuina 2/metabolismo , Humanos
3.
Neuroimage ; 297: 120700, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38942103

RESUMEN

People perform better collectively than individually, a phenomenon known as the collective benefit. To pursue the benefit, they may learn from previous behaviors, come to know whose initial opinion should be valued, and develop the inclination to take it as the collective one. Such learning may affect interpersonal brain communication. To test these hypotheses, this study recruited participant dyads to conduct a perceptual task on which they made individual decisions first and then the collective one. The enhanced interpersonal brain synchronization (IBS) between participants was explored when individual decisions were in disagreement vs. agreement. Computational modeling revealed that participant dyads developed the dyad inclination of taking the higher-able participants', not the lower-able ones' decisions as their collective ones. Brain analyses unveiled the enhanced IBS at frontopolar areas, premotor areas, supramarginal gyri, and right temporal-parietal junctions. The premotor IBS correlated negatively with dyad inclination and collective benefit in the absence of correction. The Granger causality analyses further supported the negative relation of dyad inclination with inter-brain communication. This study highlights that dyads learn to weigh individuals' decisions, resulting in dyad inclinations, and explores associated inter-brain communication, offering insights into the dynamics of collective decision-making.

4.
Plant Cell Environ ; 47(6): 2044-2057, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38392920

RESUMEN

Blue light photoreceptor cryptochrome 1 (CRY1) in herbaceous plants plays crucial roles in various developmental processes, including cotyledon expansion, hypocotyl elongation and anthocyanin biosynthesis. However, the function of CRY1 in perennial trees is unclear. In this study, we identified two ortholog genes of CRY1 (PagCRY1a and PagCRY1b) from Populus, which displayed high sequence similarity to Arabidopsis CRY1. Overexpression of PagCRY1 substantially inhibited plant growth and promoted secondary xylem development in Populus, while CRISPR/Cas9-mediated knockout of PagCRY1 enhanced plant growth and delayed secondary xylem development. Moreover, overexpression of PagCRY1 dramatically increased anthocyanin accumulation. The further analysis supported that PagCRY1 functions specifically in response to blue light. Taken together, our results demonstrated that modulating the expression of blue light photoreceptor CRY1 ortholog gene in Populus could significantly influence plant biomass production and the process of wood formation, laying a foundation for further investigating the light-regulated tree growth.


Asunto(s)
Antocianinas , Proteínas de Arabidopsis , Criptocromos , Regulación de la Expresión Génica de las Plantas , Luz , Populus , Madera , Populus/genética , Populus/metabolismo , Populus/crecimiento & desarrollo , Criptocromos/metabolismo , Criptocromos/genética , Antocianinas/biosíntesis , Antocianinas/metabolismo , Madera/metabolismo , Madera/crecimiento & desarrollo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente , Xilema/metabolismo , Xilema/genética , Xilema/crecimiento & desarrollo , Fotorreceptores de Plantas/metabolismo , Fotorreceptores de Plantas/genética , Luz Azul
5.
Phys Rev Lett ; 132(6): 066701, 2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38394558

RESUMEN

Frustrated spin systems have traditionally proven challenging to understand, owing to a scarcity of controlled methods for their analyses. By contrast, under strong magnetic fields, certain aspects of spin systems admit simpler and universal description in terms of hardcore bosons. The bosonic formalism is anchored by the phenomenon of Bose-Einstein condensation (BEC), which has helped explain the behaviors of a wide range of magnetic compounds under applied magnetic fields. Here, we focus on the interplay between frustration and externally applied magnetic field to identify instances where the BEC paradigm is no longer applicable. As a representative example, we consider the antiferromagnetic J_{1}-J_{2}-J_{3} model on the square lattice in the presence of a uniform external magnetic field, and demonstrate that the frustration-driven suppression of the Néel order leads to a Lifshitz transition for the hardcore bosons. In the vicinity of the Lifshitz point, the physics becomes unmoored from the BEC paradigm, and the behavior of the system, both at and below the saturation field, is controlled by a Lifshitz multicritical point. We obtain the resultant universal scaling behaviors, and provide strong evidence for the existence of a frustration and magnetic-field driven correlated bosonic liquid state along the entire phase boundary separating the Néel phase from other magnetically ordered states.

6.
Artículo en Inglés | MEDLINE | ID: mdl-38913036

RESUMEN

A novel chemoheterotrophic iron-reducing micro-organism, designated as strain LSZ-M11000T, was isolated from sediment of the Marianas Trench. Phylogenetic analysis based on the 16S rRNA gene revealed that strain LSZ-M11000T belonged to genus Tepidibacillus, with 97 % identity to that of Tepidibacillus fermentans STGHT, a mesophilic bacterium isolated from the Severo-Stavropolskoye underground gas storage facility in Russia. The polar lipid profile of strain LSZ-M11000T consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, as well as other unidentified phospholipids and lipids. The major fatty acids were C16 : 0 (28.4 %), C18 : 0 (15.8 %), iso-C15 : 0 (12.9 %), and anteiso-C15 : 0 (12.0 %). Strain LSZ-M11000T had no menaquinone. Genome sequencing revealed that the genome size of strain LSZ-M11000T was 2.97 Mb and the DNA G+C content was 37.9 mol%. The average nucleotide identity values between strain LSZ-M11000T and its close phylogenetic relatives, Tepidibacillus fermentans STGHT and Tepidibacillus decaturensis Z9T, were 76.4 and 72.6 %, respectively. The corresponding DNA-DNA hybridization estimates were 20.9 and 23.4 %, respectively. Cells of strain LSZ-M11000T were rod-shaped (1.0-1.5×0.3-0.5 µm). Using pyruvate as an electron donor, it was capable of reducing KMnO4, MnO2, As(V), NaNO3, NaNO2, Na2SO4, Na2S2O3, and K2Cr2O7. Based on phenotypic, genotypic, and phylogenetic evidence, strain LSZ-M11000T is proposed to be a novel strain of the genus Tepidibacillus, for which the name Tepdibacillus marianensis is proposed. The type strain is LSZ-M11000T (=CCAM 1008T=JCM 39431T).


Asunto(s)
Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano , Ácidos Grasos , Sedimentos Geológicos , Hierro , Fosfolípidos , Filogenia , ARN Ribosómico 16S , Análisis de Secuencia de ADN , ARN Ribosómico 16S/genética , Sedimentos Geológicos/microbiología , ADN Bacteriano/genética , Federación de Rusia , Hierro/metabolismo , Procesos Heterotróficos , Hibridación de Ácido Nucleico , Bacillaceae/clasificación , Bacillaceae/genética , Bacillaceae/aislamiento & purificación , Secuenciación Completa del Genoma , Oxidación-Reducción
7.
Acta Pharmacol Sin ; 45(6): 1160-1174, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38438581

RESUMEN

Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4ß2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-ß-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.


Asunto(s)
Neuronas GABAérgicas , Hiperalgesia , Ratones Endogámicos C57BL , Receptores Nicotínicos , Animales , Receptores Nicotínicos/metabolismo , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/fisiología , Masculino , Hiperalgesia/metabolismo , Hiperalgesia/tratamiento farmacológico , Ratones , Porción Reticular de la Sustancia Negra/metabolismo , Porción Reticular de la Sustancia Negra/efectos de los fármacos , Nicotina/farmacología , Analgésicos/farmacología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Capsaicina/farmacología , Acetilcolina/metabolismo , Optogenética , Umbral del Dolor/efectos de los fármacos
8.
Arch Insect Biochem Physiol ; 115(1): e22067, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38014568

RESUMEN

Cricotopus is a large and diverse genus of non-biting midges composed of several subgenera. Complete mitogenome sequences are available for very few Cricotopus species. The subgenus Pseudocricotopus unites species with unusual morphological structures in adult male and pupal stages, however, molecular methods are needed to verify the placement of this subgenus within Cricotopus. We obtained mitogenomes of C. (Pseudocricotopus) cf. montanus and nine other Cricotopus species for phylogenetic analysis, coupled with two Rheocricotopus species and one Synorthocladius species as outgroups. The structure of the mitogenome was similar among these Cricotopus species, exhibiting A+T bias and retaining ancestral gene order. Mutation rate, estimated as Ka/Ks, varied among genes, and was highest for ATP8 and lowest for COI. The phylogenetic relationships among species of Cricotopus, Rheocricotopus and Synorthocladius was reconstructed using Bayesian inference and maximum likelihood estimation. The phylogenetic trees confirmed placement of subgenus Pseudocricotopus, represented by Cricotopus cf. montanus, within Cricotopus. Our study increases the library of chironomid mitogenomes and provides insight into the properties of their constituent genes.


Asunto(s)
Chironomidae , Genoma Mitocondrial , Animales , Chironomidae/genética , Chironomidae/anatomía & histología , Filogenia , Teorema de Bayes , Pupa
9.
Nanomedicine ; 55: 102723, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38007064

RESUMEN

OBJECTIVE: Osteoarthritis (OA) is characterized by progressive cartilage degeneration and absence of curative therapies. Therefore, more efficient therapies are compellingly needed. Both mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) and Icariin (ICA) are promising for repair of cartilage defect. This study proposes that ICA may be combined to potentiate the cartilage repair capacity of MSC-EVs. MATERIALS AND METHODS: MSC-EVs were isolated from sodium alginate (SA) and hyaluronic acid (HA) composite hydrogel (SA-HA) cell spheroid culture. EVs and ICA were combined in SA-HA hydrogel to test therapeutic efficacy on cartilage defect in vivo. RESULTS: EVs and ICA were synergistic for promoting both proliferation and migration of MSCs and inflammatory chondrocytes. The combination therapy led to strikingly enhanced repair on cartilage defect in rats, with mechanisms involved in the concomitant modulation of both cartilage degradation and synthesis makers. CONCLUSION: The MSC-EVs-ICA/SA-HA hydrogel potentially constitutes a novel therapy for cartilage defect in OA.


Asunto(s)
Vesículas Extracelulares , Células Madre Mesenquimatosas , Osteoartritis , Animales , Ratas , Hidrogeles/farmacología , Ácido Hialurónico/farmacología , Ácido Hialurónico/metabolismo , Cartílago , Condrocitos/metabolismo , Osteoartritis/tratamiento farmacológico , Regeneración , Vesículas Extracelulares/metabolismo
10.
Nano Lett ; 23(5): 2023-2030, 2023 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-36797055

RESUMEN

Topological phonons and magnons potentially enable low-loss, quantum coherent, and chiral transport of information and energy at the atomic scale. Van der Waals magnetic materials are promising to realize such states due to their recently discovered strong interactions among the electronic, spin, and lattice degrees of freedom. Here, we report the first observation of coherent hybridization of magnons and phonons in monolayer antiferromagnet FePSe3 by cavity-enhanced magneto-Raman spectroscopy. The robust magnon-phonon cooperativity in the 2D limit occurs even in zero magnetic field, which enables nontrivial band inversion between longitudinal and transverse optical phonons caused by the strong coupling with magnons. The spin and lattice symmetry theoretically guarantee magnetic-field-controlled topological phase transition, verified by nonzero Chern numbers calculated from the coupled spin-lattice model. The 2D topological magnon-phonon hybridization potentially offers a new route toward quantum phononics and magnonics with an ultrasmall footprint.

11.
Circulation ; 146(4): 303-315, 2022 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-35861850

RESUMEN

BACKGROUND: More than one-fifth of the world's population consumes Chinese cuisines regularly, but no evidence-based healthy diets fitting the Chinese food culture are available for implementation. METHODS: A multicenter, patient- and outcome assessor-blind, randomized feeding trial was conducted among 265 participants with 130 to 159 mm Hg baseline systolic blood pressure (SBP) for 4 major Chinese cuisines (Shangdong, Huaiyang, Cantonese, Szechuan). After a 7-day run-in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine-based Chinese heart-healthy diet for another 28 days. The primary outcome was SBP, and secondary outcomes included diastolic blood pressure and food preference score. Linear regression models were used to estimate the intervention effects and adjustments for the center. The incremental cost per 1 mm Hg reduction in SBP was also calculated. RESULTS: A total of 265 participants were randomized (135 on the Chinese heart-healthy diet and 130 on the control diet), with 52% women, mean age of 56.5±9.8 years, and mean SBP and diastolic blood pressure of 139.4±8.3 and 88.1±8.0 mm Hg, respectively, at baseline. The change in SBP and diastolic blood pressure from baseline to the end of the study in the control group was -5.0 (95% CI, -6.5 to -3.5) mm Hg and -2.8 (95% CI, -3.7 to -1.9) mm Hg, respectively. The net difference of change between the 2 groups in SBP and diastolic blood pressure were -10.0 (95% CI, -12.1 to -7.9) mm Hg and -3.8 (95% CI, -5.0 to -2.5) mm Hg, respectively. The effect size did not differ among cuisines (P for interaction=0.173). The mean food preference score was 9.5 (with 10 the best preferred) at baseline, and the net change during intervention was 0.1 (95% CI, -0.1 to 0.2; P=0.558). The incremental cost-effectiveness ratio per 1 mm Hg SBP reduction was CNY 0.4 (USD 0.06) per day. No difference in the number of adverse events was found between the 2 groups (P=0.259), and none of the adverse events was associated with the intervention. CONCLUSIONS: The Chinese heart-healthy diet is effective, palatable, and cost-effective in reducing blood pressure in Chinese adults with high blood pressure, with a clinically significant effect applicable across major Chinese cuisine cultures. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03882645.


Asunto(s)
Hipertensión , Hipotensión , Adulto , Anciano , Antihipertensivos/uso terapéutico , Presión Sanguínea , Dieta Saludable , Femenino , Humanos , Hipertensión/inducido químicamente , Hipertensión/epidemiología , Hipertensión/prevención & control , Masculino , Persona de Mediana Edad , Método Simple Ciego
12.
Apoptosis ; 28(7-8): 1060-1075, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37060507

RESUMEN

The aberrantly up-regulated CDK9 can be targeted for cancer therapy. The CDK inhibitor dinaciclib (Dina) has been found to drastically sensitizes cancer response to TRAIL-expressing extracellular vesicle (EV-T). However, the low selectivity of Dina has limited its application for cancer. We propose that CDK9-targeted siRNA (siCDK9) may be a good alternative to Dina. The siCDK9 molecules were encapsulated into EV-Ts to prepare a complexed nanodrug (siEV-T). It was shown to efficiently suppress CDK9 expression and overcome TRAIL resistance to induce strikingly augmented apoptosis in lung cancer both in vitro and in vivo, with a mechanism related to suppression of both anti-apoptotic factors and nuclear factor-kappa B pathway. Therefore, siEV-T potentially constitutes a novel, highly effective and safe therapy for cancers.


Asunto(s)
Neoplasias Pulmonares , FN-kappa B , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Apoptosis , Línea Celular Tumoral , ARN Interferente Pequeño/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Quinasa 9 Dependiente de la Ciclina/genética
13.
Cancer Immunol Immunother ; 72(1): 23-37, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35661905

RESUMEN

PURPOSE: Immune checkpoint inhibitors (ICIs) have shown durable responses in various malignancies. However, the response to ICI therapy is unpredictable, and investigation of predictive biomarkers needs to be improved. EXPERIMENTAL DESIGN: In total, 120 patients receiving ICI therapy and 40 patients receiving non-ICI therapy were enrolled. Peripheral blood immune cell markers (PBIMs), as liquid biopsy biomarkers, were analyzed by flow cytometry before ICI therapy, and before the first evaluation. In the ICI cohort, patients were randomly divided into training (n = 91) and validation (n = 29) cohorts. Machine learning algorithms were applied to construct the prognostic and predictive immune-related models. RESULTS: Using the training cohort, a peripheral blood immune cell-based signature (BICS) based on four hub PBIMs was developed. In both the training and the validation cohorts, and the whole cohort, the BICS achieved a high accuracy for predicting overall survival (OS) benefit. The high-BICS group had significantly shorter progression-free survival and OS than the low-BICS group. The BICS demonstrated the predictive ability of patients to achieve durable clinical outcomes. By integrating these PBIMs, we further constructed and validated the support vector machine-recursive and feature elimination classifier model, which robustly predicts patients who will achieve optimal clinical benefit. CONCLUSIONS: Dynamic PBIM-based monitoring as a noninvasive, cost-effective, highly specific and sensitive biomarker has broad potential for prognostic and predictive utility in patients receiving ICI therapy.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Algoritmos , Citometría de Flujo , Biopsia Líquida
14.
Blood ; 137(23): 3259-3271, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-33512434

RESUMEN

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is an aggressive subtype of T-cell ALL. Although genetic mutations hyperactivating cytokine receptor/Ras signaling are prevalent in ETP-ALL, it remains unknown how activated Ras signaling contributes to ETP-ALL. Here, we find that in addition to the frequent oncogenic RAS mutations, wild-type (WT) KRAS transcript level was significantly downregulated in human ETP-ALL cells. Similarly, loss of WT Kras in NrasQ61R/+ mice promoted hyperactivation of extracellular signal-regulated kinase (ERK) signaling, thymocyte hyperproliferation, and expansion of the ETP compartment. Kras-/-; NrasQ61R/+ mice developed early onset of T-cell malignancy that recapitulates many biological and molecular features of human ETP-ALL. Mechanistically, RNA-sequencing analysis and quantitative proteomics study identified that Rasgrp1, a Ras guanine nucleotide exchange factor, was greatly downregulated in mouse and human ETP-ALL. Unexpectedly, hyperactivated Nras/ERK signaling suppressed Rasgrp1 expression and reduced Rasgrp1 level led to increased ERK signaling, thereby establishing a positive feedback loop to augment Nras/ERK signaling and promote cell proliferation. Corroborating our cell line data, Rasgrp1 haploinsufficiency induced Rasgrp1 downregulation and increased phosphorylated ERK level and ETP expansion in NrasQ61R/+ mice. Our study identifies Rasgrp1 as a negative regulator of Ras/ERK signaling in oncogenic Nras-driven ETP-like leukemia.


Asunto(s)
Regulación hacia Abajo , Regulación Leucémica de la Expresión Génica , Factores de Intercambio de Guanina Nucleótido , Proteínas de Unión al GTP Monoméricas , Mutación Missense , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Proteínas Proto-Oncogénicas p21(ras)/deficiencia , Sustitución de Aminoácidos , Animales , Proliferación Celular/genética , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Noqueados , Proteínas de Unión al GTP Monoméricas/genética , Proteínas de Unión al GTP Monoméricas/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Proto-Oncogénicas p21(ras)/metabolismo
15.
Blood ; 137(1): 61-74, 2021 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-32640012

RESUMEN

NRAS Q61 mutations are prevalent in advanced/relapsed multiple myeloma (MM) and correlate with poor patient outcomes. Thus, we generated a novel MM model by conditionally activating expression of endogenous NrasQ61R and an MYC transgene in germinal center (GC) B cells (VQ mice). VQ mice developed a highly malignant MM characterized by a high proliferation index, hyperactivation of extracellular signal-regulated kinase and AKT signaling, impaired hematopoiesis, widespread extramedullary disease, bone lesions, kidney abnormalities, preserved programmed cell death protein 1 and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain immune-checkpoint pathways, and expression of human high-risk MM gene signatures. VQ MM mice recapitulate most of the biological and clinical features of human advanced/high-risk MM. These MM phenotypes are serially transplantable in syngeneic recipients. Two MM cell lines were also derived to facilitate future genetic manipulations. Combination therapies based on MEK inhibition significantly prolonged the survival of VQ mice with advanced-stage MM. Our study provides a strong rationale to develop MEK inhibition-based therapies for treating advanced/relapsed MM.


Asunto(s)
Linfocitos B/patología , Modelos Animales de Enfermedad , Proteínas de Unión al GTP Monoméricas/genética , Mieloma Múltiple/genética , Proteínas Proto-Oncogénicas c-myc/genética , Animales , Centro Germinal/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mieloma Múltiple/patología , Transgenes
16.
Eur J Nucl Med Mol Imaging ; 50(3): 937-950, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36346437

RESUMEN

PURPOSE: This prospective study was aimed to investigate the potential utility of [18F]fibroblast activation protein inhibitor (FAPI) PET/CT for evaluating focal liver lesions (FLLs) with [18F]FDG non-avidity. METHODS: From January 2021 to March 2022, this prospective study included 80 FLLs that were not avid on [18F]FDG PET/CT from 37 patients, then underwent [18F]FAPI PET/CT. All patients with FLL(s) with biopsy-proof or follow-up confirmation were categorized into four subgroups (20 hepatocellular carcinomas [HCCs]/5 non-HCC malignancies/4 inflammatory FLLs/8 benign noninflammatory FLLs). The diagnostic value of [18F]FAPI for detecting liver malignancy was determined by visual evaluation. Differences in the maximum standardized uptake value (SUVmax) and lesion-to-background ratio (LBR) obtained from [18F]FAPI PET/CT among the four subgroups were analyzed by semiquantitative analysis. RESULTS: Among the thirty-seven enrolled participants (34 males; median age 57 years, range 48-67 years), on visual evaluation, the sensitivity, specificity, and accuracy of [18F]FAPI PET for detecting liver malignancy in the patient-based analysis were 96.0% (24/25), 58.3% (7/12), and 83.8% (31/37), respectively. On semiquantitative analysis, the SUVmax and LBR of [18F]FAPI PET in liver malignancy (33 HCC lesions; 19 non-HCC malignant lesions) were significantly higher than those in 11 benign noninflammatory FLLs [HCC: SUVmax: 6.4 vs. 4.5, P = 0.017; LBR: 5.1 vs. 1.5, P = 0.003; non-HCC: SUVmax: 5.5 vs. 4.5, P = 0.008; LBR: 4.4 vs. 1.5, P = 0.042]. Notably, there was no significant difference in the SUVmax of [18F]FAPI PET between 33 HCC lesions and 17 inflammatory FLLs (6.4 vs. 8.2, P = 0.37), but the LBR of [18F]FAPI PET in HCC were significantly lower than that in inflammatory FLLs (5.1 vs. 9.1, P = 0.003). CONCLUSIONS: [18F]FAPI PET/CT shows high sensitivity in detecting HCC and non-HCC malignancy with [18F]FDG non-avidity. [18F]FAPI might be a promising radiopharmaceutical for the differential diagnosis of benign noninflammatory FLLs and liver malignancy with [18F]FDG non-avidity.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Masculino , Humanos , Persona de Mediana Edad , Anciano , Tomografía Computarizada por Tomografía de Emisión de Positrones , Fluorodesoxiglucosa F18 , Estudios Prospectivos , Carcinoma Hepatocelular/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Radioisótopos de Galio
17.
Reprod Biol Endocrinol ; 21(1): 80, 2023 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-37658414

RESUMEN

BACKGROUND: Thin endometrium is considered suboptimal for embryo implantation, leading to compromised pregnancy rates without effective therapies. While some studies have reported promoted endometrial growth after a period of hyperbaric oxygen therapy (HBOT) in patients with intrauterine adhesion, there have been no reports in patients with resistant thin endometrium. The purpose of this study was to investigate the impact of HBOT on endometrium growth and pregnancy outcomes in patients with resistant thin endometrium during frozen embryo transfer (FET) treatments. METHODS: This prospective pre-post cohort study was conducted at a university-affiliated assisted reproductive medical center between October 2021 and December 2022. Patients who had experienced at least one canceled transfer cycle due to a thin endometrium(< 7 mm) on the endometrium transformation day, despite the use of standard therapies as well as adjuvant therapies, were enrolled in the study. Patients were assigned voluntarily to either the HBOT group or the concurrent control group. The HBOT group received daily HBOT for at least 10 days during the proliferative phase, in addition to the routine endometrium preparation methods and the concurrent control group underwent cycles without HBOT. Propensity score matching (PSM) was used to ensure comparability between the groups. Both self-control and case-control comparisons were conducted. The primary outcome measured was endometrial thickness (ET) on the day of endometrium transformation. Secondary outcomes included intrauterine pregnancy rate (IPR), embryo implantation rate (IR), miscarriage rate, and others. RESULTS: Patients in the HBOT group demonstrated a significantly thicker endometrial thickness on the day of endometrium transformation after undergoing therapy (5.76 ± 1.66 vs. 6.57 ± 1.23, P = 0.002). This improvement was accompanied by a decreased rate of cycle cancellations. Baseline parameters and endometrial thickness were comparable between the HBOT group and the concurrent control group during the cycle. The IPR was similar in patients who received cleavage-stage embryos (0.0% vs. 6.7%, P = 1.00), but significantly higher in patients in the HBOT group who received blastocysts (53.8% vs. 18.2%, P = 0.017). CONCLUSIONS: A period of HBOT prior to endometrium transformation contributes to increased endometrial thickness and facilitates blastocyst implantation in patients with resistant thin endometrium during FET treatments. TRIAL REGISTRATION: The trial was registered on the Chinese Clinical Trial Registry (registration no. ChiCTR2300072831, retrospectively registered).


Asunto(s)
Oxigenoterapia Hiperbárica , Femenino , Embarazo , Humanos , Estudios de Cohortes , Estudios Prospectivos , Endometrio , Transferencia de Embrión
18.
Langmuir ; 39(7): 2589-2597, 2023 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-36774656

RESUMEN

Biomimetic structures based on the magnetic response have attracted ever-increasing attention in droplet manipulation. Till now, most methods for droplet manipulation by a magnetic response are only applicable to a single droplet. It is still a challenge to achieve on-demand and precise control of multiple droplets (≥2). In this paper, a strategy for on-demand manipulation of multiple droplets based on magnetism-responsive slanted micropillar arrays (MSMAs) is proposed. The Glaco-modified superhydrophobic surface is the basis of multiple-droplet manipulation. The droplet's motion mode (pinned, unidirectional, and bidirectional) can be readily fine-tuned by changing the volume of droplets and the speed of the magnetic field. The rapid movement of droplets (10-80 mm/s) in the horizontal direction is realized by the unidirectional waves of the micropillar array driven by a specific magnetic field. The bending angle of micropillars can be rapidly and reversibly adjusted from 0 to 90° under the action of a magnetic field. Meanwhile, the liquid-involved light, electric switch, and biomedical detection can be designed by manipulating the droplets on demand. The superiority of MSMAs in multiple-droplet programmable manipulation opens up an avenue for applications in microfluidic and biomedical engineering.

19.
Inorg Chem ; 62(18): 7069-7078, 2023 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-37126858

RESUMEN

Due to the trade-off barrier between high storage capacity and high selectivity, the controllable and systematic design of metal-organic frameworks (MOFs) aiming at performance optimization is still challenging. Herein, considering the effectiveness of alkoxy group functionalization and a pore-space partition strategy, a series of rigid Mg-pacs-MOFs (SNNU-10-n, n = 1-6) with flexible side chains are built for the first time, realizing systematic pore environmental modification. The steric hindrance effects, electron-donating ability, and the flexibility of alkoxy groups are considered as key factors, which lead to a regular change of gas adsorption capacity and selectivity. Notably, methoxy-modified SNNU-10-1 with moderately high storage capacities of C2H2 (139.4 cm3 g-1), C2H4 (100.4 cm3 g-1), CO2 (105.0 cm3 g-1), and high selectivity values for equimolar C2H2/CH4 (431.8), C2H4/CH4 (164.2), and CO2/CH4 (16.1) mixture separation at 273 K and 100 kPa achieves an ideal gas uptake-selectivity balance. Breakthrough experiments verified that it could effectively separate the above-mentioned mixtures under ambient conditions, and GCMC simulation provides a deep understanding of methoxy group functionalization. Undoubtedly, this work not only realizes controllable regulation of gas adsorption behavior but also proves the validity of improving selectivity by alkoxy groups in those platforms with high gas-uptake potential to overcome the trade-off barrier.

20.
Org Biomol Chem ; 21(40): 8084-8088, 2023 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-37768024

RESUMEN

To evaluate the contribution of host-guest chemistry in fluorescence enhancement under aqueous conditions, two benzo[a]phenoxazine derivatives with the adamantyl group were prepared. After they formed stable complexes with methyl-ß-cyclodextrin, their emissions at 625-825 nm were greatly increased and fluorescence quantum yields reached 11.5-12.6% in aqueous solution. Furthermore, they were successfully applied in fluorescence labeling of organelles in HeLa cells.

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