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Changes in the amount of daylight (photoperiod) alter physiology and behaviour1,2. Adaptive responses to seasonal photoperiods are vital to all organisms-dysregulation associates with disease, including affective disorders3 and metabolic syndromes4. The circadian rhythm circuitry is implicated in such responses5,6, yet little is known about the precise cellular substrates that underlie phase synchronization to photoperiod change. Here we identify a brain circuit and system of axon branch-specific and reversible neurotransmitter deployment that are critical for behavioural and sleep adaptation to photoperiod. A type of neuron called mrEn1-Pet17 in the mouse brainstem median raphe nucleus segregates serotonin from VGLUT3 (also known as SLC17A8, a proxy for glutamate) to different axonal branches that innervate specific brain regions involved in circadian rhythm and sleep-wake timing8,9. This branch-specific neurotransmitter deployment did not distinguish between daylight and dark phase; however, it reorganized with change in photoperiod. Axonal boutons, but not cell soma, changed neurochemical phenotype upon a shift away from equinox light/dark conditions, and these changes were reversed upon return to equinox conditions. When we genetically disabled Vglut3 in mrEn1-Pet1 neurons, sleep-wake periods, voluntary activity and clock gene expression did not synchronize to the new photoperiod or were delayed. Combining intersectional rabies virus tracing and projection-specific neuronal silencing, we delineated a preoptic area-to-mrEn1Pet1 connection that was responsible for decoding the photoperiodic inputs, driving the neurotransmitter reorganization and promoting behavioural synchronization. Our results reveal a brain circuit and periodic, branch-specific neurotransmitter deployment that regulates organismal adaptation to photoperiod change.
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Adaptación Fisiológica , Axones , Ritmo Circadiano , Neurotransmisores , Fotoperiodo , Animales , Femenino , Ratones , Adaptación Fisiológica/fisiología , Sistemas de Transporte de Aminoácidos Acídicos/deficiencia , Sistemas de Transporte de Aminoácidos Acídicos/genética , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Axones/metabolismo , Axones/fisiología , Ritmo Circadiano/fisiología , Proteínas CLOCK/genética , Oscuridad , Núcleo Dorsal del Rafe/citología , Núcleo Dorsal del Rafe/metabolismo , Vías Nerviosas/fisiología , Neurotransmisores/metabolismo , Área Preóptica/citología , Área Preóptica/metabolismo , Terminales Presinápticos/metabolismo , Terminales Presinápticos/fisiología , Virus de la Rabia , Serotonina/metabolismo , Sueño/fisiología , Vigilia/fisiologíaRESUMEN
Crouzon syndrome is a congenital craniofacial disorder caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2). It is characterized by the premature fusion of cranial sutures, leading to a brachycephalic head shape, and midfacial hypoplasia. The aim of this study was to investigate the effect of the FGFR2 mutation on the microarchitecture of cranial bones at different stages of postnatal skull development, using the FGFR2C342Y mouse model. Apart from craniosynostosis, this model shows cranial bone abnormalities. High-resolution synchrotron microtomography images of the frontal and parietal bone were acquired for both FGFR2C342Y/+ (Crouzon, heterozygous mutant) and FGFR2+/+ (control, wild-type) mice at five ages (postnatal days 1, 3, 7, 14 and 21, n = 6 each). Morphometric measurements were determined for cortical bone porosity: osteocyte lacunae and canals. General linear model to assess the effect of age, anatomical location and genotype was carried out for each morphometric measurement. Histological analysis was performed to validate the findings. In both groups (Crouzon and wild-type), statistical difference in bone volume fraction, average canal volume, lacunar number density, lacunar volume density and canal volume density was found at most age points, with the frontal bone generally showing higher porosity and fewer lacunae. Frontal bone showed differences between the Crouzon and wild-type groups in terms of lacunar morphometry (average lacunar volume, lacunar number density and lacunar volume density) with larger, less dense lacunae around the postnatal age of P7-P14. Histological analysis of bone showed marked differences in frontal bone only. These findings provide a better understanding of the pathogenesis of Crouzon syndrome and will contribute to computational models that predict postoperative changes with the aim to improve surgical outcome.
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The physics of nonlinear optical materials is incredibly versatile, with the design of novel materials and structures offering numerous degrees of freedom. Nevertheless, weak inherent nonlinearity of conventional optical materials continues to hinder the progress of a number of important applications. In this study, we delve into the realm of broadband enhancement of nonlinearity within one-dimensional (1d) plasmonic metamaterials, exploring its intricate connection with nonlocality. Specifically, we introduce a phenomenological framework for quantifying the effective third-order nonlinear susceptibility of 1d multiphase plasmonic nanostructures, utilizing heavily doped semiconductors, and subsequently applying this approach using realistic material parameters. Both direct and inverse problems of nonlinearity enhancement have been addressed. Our findings demonstrate a remarkable capability to significantly augment the third-order nonlinear susceptibility across a defined frequency range, while concurrently gauging the impact of nonlocality on this enhancement.
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Precision measurements by the Alpha Magnetic Spectrometer (AMS) on the International Space Station of the deuteron (D) flux are presented. The measurements are based on 21×10^{6} D nuclei in the rigidity range from 1.9 to 21 GV collected from May 2011 to April 2021. We observe that over the entire rigidity range the D flux exhibits nearly identical time variations with the p, ^{3}He, and ^{4}He fluxes. Above 4.5 GV, the D/^{4}He flux ratio is time independent and its rigidity dependence is well described by a single power law âR^{Δ} with Δ_{D/^{4}He}=-0.108±0.005. This is in contrast with the ^{3}He/^{4}He flux ratio for which we find Δ_{^{3}He/^{4}He}=-0.289±0.003. Above â¼13 GV we find a nearly identical rigidity dependence of the D and p fluxes with a D/p flux ratio of 0.027±0.001. These unexpected observations indicate that cosmic deuterons have a sizable primarylike component. With a method independent of cosmic ray propagation, we obtain the primary component of the D flux equal to 9.4±0.5% of the ^{4}He flux and the secondary component of the D flux equal to 58±5% of the ^{3}He flux.
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This Letter presents results of a search for the mixing of a sub-eV sterile neutrino with three active neutrinos based on the full data sample of the Daya Bay Reactor Neutrino Experiment, collected during 3158 days of detector operation, which contains 5.55×10^{6} reactor ν[over ¯]_{e} candidates identified as inverse beta-decay interactions followed by neutron capture on gadolinium. The analysis benefits from a doubling of the statistics of our previous result and from improvements of several important systematic uncertainties. No significant oscillation due to mixing of a sub-eV sterile neutrino with active neutrinos was found. Exclusion limits are set by both Feldman-Cousins and CLs methods. Light sterile neutrino mixing with sin^{2}2θ_{14}â³0.01 can be excluded at 95% confidence level in the region of 0.01 eV^{2}â²|Δm_{41}^{2}|â²0.1 eV^{2}. This result represents the world-leading constraints in the region of 2×10^{-4} eV^{2}â²|Δm_{41}^{2}|â²0.2 eV^{2}.
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The search for high-performance catalysts to improve the catalytic activity for an oxygen reduction reaction (ORR) is crucial for developing a proton exchange membrane fuel cell. Using the first-principles method, we have performed computational screening on a series of transition metal (TM) atoms embedded in monolayer Nb2S2C to enhance the ORR activity. Through the scaling relationship and volcano plot, our results reveal that the introduction of a single Ni or Rh atom through substitutional doping into monolayer Nb2S2C yields promising ORR catalysts with low overpotentials of 0.52 and 0.42 V, respectively. These doped atoms remain intact on the monolayer Nb2S2C even at elevated temperatures. Importantly, the catalytic activity of the Nb2S2C doped with a TM atom can be effectively correlated with an intrinsic descriptor, which can be computed based on the number of d orbital electrons and the electronegativity of TM and O atoms.
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AIM: To investigate the value of the combined model based on spectral quantitative parameters, radiomics features, imaging and clinical features to distinguish the benign and malignant pure ground-glass nodules (pGGNs). MATERIALS AND METHODS: A retrospective analysis of 113 patients with single pGGNs who underwent non-contrast enhancement examination of the chest on dual-layer spectral detector CT (SDCT) with two weeks before surgery was performed in our hospital. These patients were randomized into training and testing cohorts. Regions of interest based on the conventional 120 kVp poly energetic image of SDCT were outlined. Then the optimal features were extracted and selected to construct radiomic model. A combined model combining vacuole sign, electron density (ED) value and the rad score of radiomics model was built by logistic regression analysis. A nomogram was built in a training cohort and the performance of the models was evaluated in the training and testing cohorts by receiver operating characteristic curves, calibration curves and decision curve analysis. RESULTS: ED value [Odds Ratio (OR):1.100; 95% confidence interval (CI):1.027-1.166)] and vacuole sign (OR:3.343; 95% CI:0.881-12.680) were independent risk factors for the malignant pGGNs in the training cohort. A combined model was constructed using radiomics features, ED value and vacuole sign. And the AUC was 0.910 (95% CI, 0.825-0.997) and 0.850 (95% CI, 0.714-0.981) in the training and testing cohorts, respectively. CONCLUSION: The combined model based on SDCT has high specificity and sensitivity for distinguishing the benign and malignant pGGNs, suggesting the model can further improve diagnostic performance, and using a nomogram is helpful for individualized predictions.
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BACKGROUND: The prevalence of diabetic dyslipidemia has gradually increased worldwide and individuals with hypertriglyceridemia often have a high polygenic burden of triglyceride (TG)-increasing variants. However, the contribution of genetic variants to dyslipidemia in patients with type 2 diabetes (T2D) remains limited. Therefore, in this study, we aimed to investigate the genetic characteristics of longitudinal changes in TG levels among patients with T2D and summarize the genetic effects of polygenic risk score (PRS) on TG trajectory and risk of diabetic complications. METHODS: We conducted a case-control study. A total of 11,312 patients with T2D with longitudinal TG and genetic data were identified from a large hospital database in Taiwan. We then performed a genome-wide association study and calculated the relative PRS. RESULTS: In total, 21 single-nucleotide polymorphisms (SNPs) related to TG trajectory were identified and yielded an area under the receiver operating characteristic curve (ROC) of 0.712 for high TG trajectory risk among Taiwanese patients with T2D. A cumulative genetic effect was observed for high TG trajectory, even when considering the adherence of a lipid-lowering agent in stratified analysis. An increased PRS increases high TG trajectory risk in a logistic regression model (odds ratio = 1.55; 95% confidence interval [CI] = 1.31-1.83 in the validation cohort). The TG-specific PRS was associated with the risk of diabetic microvascular complications, including diabetic retinopathy and nephropathy (with hazard ratios of 1.11 [95% CI = 1.01-1.21, P = 0.027] and 1.05 [95% CI = 1.01-1.1, P = 0.018], respectively). CONCLUSIONS: This study may contribute to the identification of patients with T2D who are at risk of abnormal TG levels and diabetic microvascular complications using polygenic information.
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BACKGROUND: Irregular menstruation is a major health problem among women, although its association with nightshift work remains controversial. AIMS: To study the association between nightshift work and irregular menstrual cycle among female workers and investigate any differences according to sleep quality, working hours or obesity. METHODS: This study included female workers who underwent health examinations from 2012 to 2019. Nightshift work, working hours, sleep quality and menstrual cycles were assessed using self-administered questionnaires. Irregular menstrual cycle was defined as self-reported irregular or ≥36 days. Adjusted odds ratios and 95% confidence intervals (CIs) were calculated by multivariable logistic regression; adjusted hazard ratios (95% CIs) for incident irregular menstrual cycle were calculated by Cox proportional hazard models with time-dependent analysis. RESULTS: The study participants were 87 147 in the cross-sectional study and 41 516 in the longitudinal study. After adjusting for all covariates in the cross-sectional analyses, the odds ratio for prevalent irregular menstrual cycle among female nightshift workers versus the reference was 1.26 (95% CI 1.2-1.33). In the cohort study, the adjusted hazard ratio for incident irregular menstrual cycle among nightshift workers was 1.95 (95% CI 1.61-2.35) in the period after 6 years. No significant differences were observed among subgroups stratified by sleep quality, working hours or obesity. CONCLUSIONS: Nightshift work is associated with an increased risk of both prevalent and incident irregular menstrual cycle in female workers without significant interactions by sleep quality, working hours or obesity.
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Ciclo Menstrual , Trastornos de la Menstruación , Femenino , Humanos , Estudios de Seguimiento , Estudios de Cohortes , Estudios Transversales , Estudios Longitudinales , Trastornos de la Menstruación/etiología , Trastornos de la Menstruación/complicaciones , Obesidad/epidemiología , Obesidad/complicacionesRESUMEN
Objective: To investigate the effects of sirolimus combined with anti-CD20 monoclonal antibody desensitization on the prognosis of patients with haploidentical stem cell transplantation (haplo-SCT). Methods: Fifteen consecutive patients who received haplo-SCT and pre-transplant donor specific anti-human leukocyte antigen (HLA) antibody (DSA) positive [mean fluorescence intensity (MFI)≥2 000] in the Institute of Hematological Diseases from November 2021 to March 2023 were retrospectively recruited into the desensitized group. There were 4 males and 11 females, with a median age [M(Q1, Q3)] of 48 (37, 59) years. All patients were desensitized with sirolimus combined with anti-CD20 monoclonal antibody. The non-desensitized group included 29 patients with haplo-SCT who had not received desensitization treatment from August 2012 to June 2016. There were 12 males and 17 females with a median age of 42 (26, 50) years. Up to October 1, 2023, the median follow-up time was 13 (9, 18) months in the study group and 23 (14, 29) months in the control group. The changes of MFI before and after desensitization treatment and the prognosis of patients in the desensitized group were compared, including the incidence of primary implantation failure (pGF), neutrophil implantation time, platelet implantation time, grade â ¡-â £ acute graft-versus-host disease (GVHD) and chronic GVHD incidence, non-recurrence related mortality, event-free survival rate, disease-free survival rate and overall survival rate. The survival curve was drawn by Kaplan-Meier method, and the survival rate between groups was compared with Log-rank test. Results: After desensitization treatment, the level of DSA MFI in the desensitized group decreased from 8 879 (7 544, 11 495) to 3 781 (1 638, 4 165) after desensitization treatment (P<0.01). All of the patients achieved hematopoietic recovery, and the median time for neutrophil and platelet engraftment were 14 (11, 15) and 20 (18, 25) days, respectively. The incidence of pGF in the desensitized group was 0, which was lower than that in the non-desensitized group (34.5%, 10/29) (P=0.011). The expected 1-year disease-free survival rate and overall survival rate in the desensitized group were 100% (15/15) and 100% (15/15) respectively, while those in the non-desensitized group were 75.9% (22/29) and 75.9% (22/29) respectively, the difference was not statistically significant (both P>0.05). The one-year event-free survival rate in the desensitized group was expected to be 100% (15/15), which was higher than that in the non-desensitized group (51.3%, 15/29) (P=0.002). Conclusion: Sirolimus combined with anti-CD20 monoclonal antibody desensitization therapy can reduce the DSA level of haplo-SCT recipients, promote hematopoietic engraftment after transplantation, and avoid the occurrence of pGF after transplantation.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Masculino , Femenino , Humanos , Sirolimus/uso terapéutico , Estudios Retrospectivos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Pronóstico , Enfermedad Injerto contra Huésped/etiología , Anticuerpos Monoclonales , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodosRESUMEN
Objective: To examine the early to mid-term clinical outcomes of aortic valve repair in patients with bicuspid aortic insufficiency. Methods: This is a retrospective cohort study. The clinical data of 124 patients with BAV insufficiency who underwent aortic valve repair from January 2017 to June 2023 in the Department of Cardiovascular Surgery at Fuwai Hospital were analyzed retrospectively. There were 117 males and 7 females with an age of (38.1±12.7) years (range: 14 to 65 years). Depending on whether the aortic sinus was replaced or not, surgical approaches were divided into valve sparing root replacement (reimplantation, remodeling, modified remodeling) and isolated aortic valve repair (annuloplasty, isolated aortic valve leaflet repair). Perioperative and follow-up data were collected. Kaplan-Meier method was used to plot the curves of survival rate, free recurrence rate of massive aortic valve insufficiency and free re-operation rate, and Log-rank test was used for comparison between groups. Results: Among the surgeries, there were 47 cases of reimplantation, 8 cases of remodeling, 8 cases of modified remodeling, 48 cases of aortic annuloplasty (external annuloplasty in 22 cases, CV-0 annuloplasty in 26 cases), and 13 cases of isolated leaflet repair. Leaflet plication was the most used leaflet repair technique, used in 103 patients. The cardiopulmonary bypass time was (133.7±56.9) minutes (range: 48 to 461 minutes), and aortic cross-clamp time was (103.8±47.8) minutes (range: 25 to 306 minutes), with no surgical mortality. All patients underwent outpatient or telephone follow-up. The cumulative follow-up time was 340.3 person-years and the mean follow-up time was (M (IQR)) 34.0 (25.5) months (range: 3 to 76 months). The 5-year survival rate was 98.4%, the 5-year freedom from significant insufficiency rate was 93.4% and the 5-year freedom from aortic valve reoperation rate was 95.6%. The subgroup analysis revealed a significantly better freedom from the significant insufficiency rate in the aortic valve annular reduction group compared to the non-reduction group (P<0.01). Conclusions: Aortic valve repair in patients with bicuspid aortic insufficiency could obtain steady early to mid-term outcomes. Aortic annuloplasty can reduce the risk of recurrent aortic valve insufficiency in patients undergoing aortic repair.
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Insuficiencia de la Válvula Aórtica , Válvula Aórtica , Enfermedad de la Válvula Aórtica Bicúspide , Humanos , Masculino , Femenino , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Enfermedad de la Válvula Aórtica Bicúspide/cirugía , Insuficiencia de la Válvula Aórtica/cirugía , Válvula Aórtica/cirugía , Válvula Aórtica/anomalías , Adolescente , Adulto Joven , Resultado del Tratamiento , Anciano , Enfermedades de las Válvulas Cardíacas/cirugía , Anuloplastia de la Válvula Cardíaca/métodos , Tasa de SupervivenciaRESUMEN
This study was designed to examine the anti-oxidative stress effect of dimethyl fumarate (DMF) on pentylenetetrazole (PTZ)-induced epileptic mice, and to evaluate the correlation of its mechanism with the nuclear factor E2-related factor 2 (Nrf2)-mediated signaling pathway. The experimental mice were separated into three groups: control, model, and DMF groups. Mice in the model group were administered PTZ to establish an epilepsy model, mice in the DMF group were administered DMF concurrently when modeling, and mice in the control group were administered a 0.9% NaCl solution. The latency, severity, and frequency of epileptic seizures in mice after each treatment were recorded, and the modelling success rate was computed at the conclusion of the experiment. The mice were euthanized, their levels of malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD), 8-hydroxy-deoxyguanosine (8-OHdG), and Nrf2 were measured, and the electron microscope was used to examine the mitochondrial damage of brain tissue. The latency of epileptic seizures was longer in the DMF group compared to the model group (P<0.05). The levels of MDA and ROS in the DMF group were lower than those in the model group (P<0.0001), and the activity of SOD in the DMF group was higher than that in the model group (P<0.0001); however, the levels of MDA and ROS were elevated and the activity of SOD was lower in both groups relative to the control group. The levels of 8-OHdG were lower in the DMF group than the model group (P<0.0001), however, the levels were higher in both groups compared to the control group. Mitochondrial abnormalities were more prevalent in the model group than in the DMF group, and more prevalent in both groups compared to the control group. The DMF group contained more Nrf2 content than the model group (P<0.0001), and both groups contained more Nrf2 than the control group. We concluded that the mechanism by which DMF reduced the level of oxidative stress in epileptic mice might involve the Nrf2-mediated signaling pathway.
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Dimetilfumarato , Epilepsia , Animales , Ratones , Antioxidantes/farmacología , Antioxidantes/metabolismo , Dimetilfumarato/farmacología , Dimetilfumarato/uso terapéutico , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Pentilenotetrazol/farmacología , Especies Reactivas de Oxígeno/metabolismo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Superóxido Dismutasa/metabolismoRESUMEN
The autogenous bone ring technique is among the approaches for vertical alveolar ridge augmentation, and this technique can enable simultaneous implantation. However, the outcomes can be compromised due to donor site morbidity, shifting of the bone ring graft positioning, and inaccurate implant placement. In recent decades, dynamic navigation systems have been introduced into the field of implantology, allowing the accuracy of outcomes to be improved. This Technical Note describes the use of dynamic navigation to guide bone ring surgery, which is expected to enable more precise and predictable bone augmentation and implantation procedures, reduce the risk of injuries to the adjacent anatomical structures, and achieve better treatment outcomes.
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Aumento de la Cresta Alveolar , Implantación Dental Endoósea , Arcada Parcialmente Edéntula , Cirugía Asistida por Computador , Humanos , Aumento de la Cresta Alveolar/métodos , Implantación Dental Endoósea/métodos , Cirugía Asistida por Computador/métodos , Arcada Parcialmente Edéntula/cirugía , Trasplante Óseo/métodos , Resultado del Tratamiento , Femenino , Persona de Mediana EdadRESUMEN
BACKGROUND/AIM: Chronic lymphocytic leukemia is a slowly-progressing disease in which symptoms often do not manifest until years after disease onset. In advanced stages, infection and bleeding are common. Past studies have shown that the interaction between CDK4/6 inhibitors and chemotherapy drugs can enhance the anti-tumor efficacy of drugs and limit toxicity. Therefore, in this study, the treatment effects of combining the CDK4/6 inhibitor LEE011 with chemotherapy drugs bendamustine or hydroxyurea were investigated in vitro. MATERIALS AND METHODS: The mouse lymphocytic leukemia cell line L1210 was treated with LEE011 combined with hydroxyurea or bendamustine. Western blot and flow cytometry were performed to elucidate the mechanisms behind tumor suppression. RESULTS: LEE011 combined with hydroxyurea or bendamustine significantly inhibited proliferation of L1210 cell lines in a concentration- and time-dependent manner as well as increased the arrest of cells in G1 and S phases. The combination of LEE011 with hydroxyurea also reduced the phosphorylation of Rb while increased the expression of total Rb protein. Furthermore, reduced expression of GPX4, which is a key protein in ferroptosis, indicates that the tumor suppression effects of this drug combination could involve ferroptosis. CONCLUSION: CDK4/6 inhibitor LEE011 treatment alone may not be a suitable treatment option for lymphocytic leukemia; however, our findings in vitro support the combination of LEE011 with chemotherapy drugs to enhance anti-tumor activity in lymphocytic leukemia.
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Aminopiridinas , Hidroxiurea , Neoplasias , Purinas , Animales , Ratones , Proliferación Celular , Hidroxiurea/farmacología , Clorhidrato de Bendamustina , Proteínas Inhibidoras de las Quinasas Dependientes de la Ciclina , Quinasa 4 Dependiente de la Ciclina , Línea Celular TumoralRESUMEN
ADP-ribosylation plays a significant role in various biological processes including genomic stability maintenance, transcriptional regulation, energy metabolism, and cell death. Using macrodomain pull-down assay with microglia lysates and MALDI-TOF-MS analysis, we identified vimentin as a major protein highly ADP-ribosylated by the poly(ADP-ribose) polymerases-1 (PARP-1) in response to LPS. ABT-888, a potent inhibitor of PARP-1/2 blocks the disassembly and ADP-ribosylation of vimentin. PARP-1 is a highly abundant nuclear protein. Its nuclear functions in repairing DNA damages induced by various stress signals, such as inflammatory stresses, have been well studied. In contrast, limited studies have been done on the cytoplasmic role(s) of PARP-1. Our study focuses on the cytoplasmic role of PARP-1 during microglia activation. Using immunofluorescence microscopy and Western blotting, we showed that a significant amount of PARP-1 is present in the cytosol of microglia cells stimulated and activated by LPS. Live cell imaging showed the translocation of nuclear PARP-1-EGFP to the cytoplasm in vesicular structures upon LPS stimulation. ABT-888 and U0126 can block this translocation. Immunofluorescence staining with various organelle marker antibodies revealed that PARP-1 vesicles show colocalization with Lamin A/C, suggesting they might be derived from the nuclear envelope through nuclear envelope budding. In conclusion, we demonstrated that PARP-1 is translocated from the nucleus to cytoplasm via vesicles upon LPS stimulation and that cytoplasmic PARP-1 causes ADP-ribosylation and disassembly of vimentin filaments during microglia activation induced by LPS.
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BACKGROUND AND PURPOSE: Myelin maturation occurs in late fetal life to early adulthood, with the most rapid changes observed in the first few years of infancy. To quantify the degree of myelination, a specific MR imaging sequence is required to measure the changes in tissue proton relaxivity (R1). R1 positively correlates with the degree of myelination maturation at a given age. Similar to head circumference charts, these data can be used to develop normal growth charts for specific white matter tracts to detect pathologies involving abnormal myelination. MATERIALS AND METHODS: This is a cross-sectional study using normal clinical pediatric brain MR images with the MP2RAGE sequence to generate T1 maps. The T1 maps were segmented to 75 brain regions from a brain atlas (white matter and gyri). Statistical modeling for all subjects across regions and the age range was computed, and estimates of population-level percentile ranking were computed to describe the effective myelination rate as a function of age. Test-retest analysis was performed to assess reproducibility. Logistic trendline and regression were performed for selected white matter regions and plotted for growth charts. RESULTS: After exclusion for abnormal MR imaging or diseases affecting myelination from the electronic medical record, 103 subject MR images were included, ranging from birth to 17 years of age. Test-retest analysis resulted in a high correlation for white matter (r = 0.88) and gyri (r = 0.95). All white matter regions from the atlas had significant P values for logistic regression with R 2 values ranging from 0.41 to 0.99. CONCLUSIONS: These data can serve as a myelination growth chart to permit patient comparisons with normal levels with respect to age and brain regions, thus improving detection of developmental disorders affecting myelin.
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The development of van der Waals heterostructures has introduced unconventional phenomena that emerge at atomically precise interfaces. For example, interlayer excitons in two-dimensional transition metal dichalcogenides show intriguing optical properties at low temperatures. Here we report on room-temperature observation of interface excitons in mixed-dimensional heterostructures consisting of two-dimensional tungsten diselenide and one-dimensional carbon nanotubes. Bright emission peaks originating from the interface are identified, spanning a broad energy range within the telecommunication wavelengths. The effect of band alignment is investigated by systematically varying the nanotube bandgap, and we assign the new peaks to interface excitons as they only appear in type-II heterostructures. Room-temperature localization of low-energy interface excitons is indicated by extended lifetimes as well as small excitation saturation powers, and photon correlation measurements confirm antibunching. With mixed-dimensional van der Waals heterostructures where band alignment can be engineered, new opportunities for quantum photonics are envisioned.
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Objective: To investigate the impact of donor human leukocyte antigen (HLA) -Bw4 expression on natural killer (NK) cell reconstitution and transplant outcomes in recipients undergoing haploidentical hematopoietic stem cell transplantation (HSCT) from maternal or related donors without ex vivo T-cell depletion. Methods: This study prospectively enrolled 32 patients who received T-replete haploidentical HSCT from maternal or collateral donors (cohort 1) to evaluate the facilitating effect of donor HLA-Bw4 expression on NK cell reconstitution. Furthermore, a retrospective analysis was conducted on 278 patients who underwent T-replete haploidentical HSCT from maternal or collateral donors (cohort 2) to analyze the impact of donor HLA-Bw4 expression on HSCT outcomes. Thus, a comparison was made between the effects of donor HLA-Bw4 expression on HSCT outcomes in patients receiving or not receiving post-transplant cyclophosphamide (PT-Cy) conditioning. Results: Donors expressing HLA-Bw4 alleles facilitated NK cell reconstitution and functional recovery, which remained unaffected by PT-Cy. Donors with HLA-Bw4 expression were associated with reduced transplant-related mortality (TRM), particularly mortality related to infections. The use of PT-Cy did not impact the ability of donor HLA-Bw4 to decrease TRM. Conclusion: In haploidentical HSCT from maternal or related donors without ex vivo T-cell depletion, the presence of donor HLA-Bw4 expression promotes rapid NK cell reconstitution and functional recovery and is significantly associated with lower TRM, especially infection-related mortality. These findings underscore the clinical significance of donor HLA-Bw4 expression in patients who underwent HSCT. Hence, the consideration of donor HLA-Bw4 in recipient selection and HSCT strategies holds important clinical implications.
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Antígenos HLA-B , Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales , Trasplante Haploidéntico , Humanos , Células Asesinas Naturales/inmunología , Adulto , Femenino , Masculino , Trasplante de Células Madre Hematopoyéticas/métodos , Adulto Joven , Adolescente , Persona de Mediana Edad , Antígenos HLA-B/genética , Estudios Retrospectivos , Estudios Prospectivos , Donantes de Tejidos , Niño , Alelos , Preescolar , Acondicionamiento Pretrasplante/métodosRESUMEN
Background: Glioblastoma (GBM) is an aggressive brain tumor giving a poor prognosis with the current treatment options. The advent of chimeric antigen receptor (CAR) T-cell therapy revolutionized the field of immunotherapy and has provided a new set of therapeutic options for refractory blood cancers. In an effort to apply this therapeutic approach to solid tumors, various immune cell types and CAR constructs are being studied. Notably, macrophages have recently emerged as potential candidates for targeting solid tumors, attributed to their inherent tumor-infiltrating capacity and abundant presence in the tumor microenvironment. Materials and methods: In this study, we developed a chemically defined differentiation protocol to generate macrophages from human pluripotent stem cells (hPSCs). A GBM-specific CAR was genetically incorporated into hPSCs to generate CAR hPSC-derived macrophages. Results: The CAR hPSC-derived macrophages exhibited potent anticancer activity against GBM cells in vitro. Conclusion: Our findings demonstrate the feasibility of generating functional CAR-macrophages from hPSCs for adoptive immunotherapy, thereby opening new avenues for the treatment of solid tumors, particularly GBM.