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1.
Genes Dev ; 33(13-14): 763-781, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31123064

RESUMEN

Coordinated induction, but also repression, of genes are key to normal differentiation. Although the role of lineage-specific transcription regulators has been studied extensively, their functional integration with chromatin remodelers, one of the key enzymatic machineries that control chromatin accessibility, remains ill-defined. Here we investigate the role of Mi-2ß, a SNF-2-like nucleosome remodeler and key component of the nucleosome remodeling and histone deacetylase (NuRD) complex in early B cells. Inactivation of Mi-2ß arrested differentiation at the large pre-B-cell stage and caused derepression of cell adhesion and cell migration signaling factors by increasing chromatin access at poised enhancers and chromosome architectural elements. Mi-2ß also supported IL-7R signaling, survival, and proliferation by repressing negative effectors of this pathway. Importantly, overexpression of Bcl2, a mitochondrial prosurvival gene and target of IL-7R signaling, partly rescued the differentiation block caused by Mi-2ß loss. Mi-2ß stably associated with chromatin sites that harbor binding motifs for IKAROS and EBF1 and physically associated with these transcription factors both on and off chromatin. Notably, Mi-2ß shared loss-of-function cellular and molecular phenotypes with IKAROS and EBF1, albeit in a distinct fashion. Thus, the nucleosome remodeler Mi-2ß promotes pre-B-cell differentiation by providing repression capabilities to distinct lineage-specific transcription factor-based regulatory networks.


Asunto(s)
Linfocitos B/citología , Diferenciación Celular/genética , Cromatina/metabolismo , ADN Helicasas/genética , ADN Helicasas/metabolismo , Regulación del Desarrollo de la Expresión Génica , Animales , Linaje de la Célula , Proliferación Celular/genética , Supervivencia Celular/genética , Células Cultivadas , Ratones , Factores de Transcripción
2.
Semin Immunol ; 59: 101602, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-35277300

RESUMEN

Formyl peptide receptor type 2 (FPR2) regulates the initiation and resolution phases of the inflammatory response. In the setting of heart injury and disease, dysregulated inflammation can potentiate maladaptive healing and pathological remodeling of the heart leading to cardiac dysfunction and failure. The potential to regulate and resolve adverse inflammation is postulated to improve outcome in the setting of heart disease. This review covers emerging concepts on the role of FPR2 in heart disease and strategies to activate pro-resolution processes to limit disease progression. We summarize key preclinical studies that support use of FPR2 agonists in heart disease. Finally, we briefly discuss the status of FPR2 agonists under evaluation in the clinic.


Asunto(s)
Cardiopatías , Receptores de Formil Péptido , Humanos , Inflamación/patología , Receptores de Formil Péptido/agonistas , Receptores de Formil Péptido/fisiología , Cicatrización de Heridas
3.
FASEB J ; 38(1): e23361, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-38085152

RESUMEN

Oocyte meiotic prophase I (MI) is an important event in female reproduction. Breast cancer amplified sequence 2 (BCAS2) is a component of the spliceosome. Previous reports have shown that BCAS2 is critical in male germ cell meiosis, oocyte development, and early embryo genome integrity. However, the role of BCAS2 in oocyte meiosis has not been reported. We used Stra8-GFPCre mice to knock out Bcas2 in oocytes during the pachytene phase. The results of fertility tests showed that Bcas2 conditional knockout (cKO) in oocytes results in infertility in female mice. Morphological analysis showed that the number of primordial follicles in the ovaries of 2-month-old (M) mice was significantly reduced and that follicle development was blocked. Further analysis showed that the number of primordial follicles decreased and that follicle development was slowed in 7-day postpartum (dpp) ovaries. Moreover, primordial follicles undergo apoptosis, and DNA damage cannot be repaired in primary follicle oocytes. Meiosis was abnormal; some oocytes could not reach the diplotene stage, and more oocytes could not develop to the dictyotene stage. Alternative splicing (AS) analysis revealed abnormal AS of deleted in azoospermia like (Dazl) and diaphanous related formin 2 (Diaph2) oogenesis-related genes in cKO mouse ovaries, and the process of AS was involved by CDC5L and PRP19.


Asunto(s)
Meiosis , Profase Meiótica I , Masculino , Femenino , Ratones , Animales , Meiosis/genética , Empalme Alternativo , ARN Mensajero/metabolismo , Oocitos/metabolismo , Proteínas de Neoplasias/metabolismo
4.
Cereb Cortex ; 34(4)2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38610084

RESUMEN

The application of wearable magnetoencephalography using optically-pumped magnetometers has drawn extensive attention in the field of neuroscience. Electroencephalogram system can cover the whole head and reflect the overall activity of a large number of neurons. The efficacy of optically-pumped magnetometer in detecting event-related components can be validated through electroencephalogram results. Multivariate pattern analysis is capable of tracking the evolution of neurocognitive processes over time. In this paper, we adopted a classical Chinese semantic congruity paradigm and separately collected electroencephalogram and optically-pumped magnetometer signals. Then, we verified the consistency of optically-pumped magnetometer and electroencephalogram in detecting N400 using mutual information index. Multivariate pattern analysis revealed the difference in decoding performance of these two modalities, which can be further validated by dynamic/stable coding analysis on the temporal generalization matrix. The results from searchlight analysis provided a neural basis for this dissimilarity at the magnetoencephalography source level and the electroencephalogram sensor level. This study opens a new avenue for investigating the brain's coding patterns using wearable magnetoencephalography and reveals the differences in sensitivity between the two modalities in reflecting neuron representation patterns.


Asunto(s)
Electroencefalografía , Magnetoencefalografía , Femenino , Masculino , Humanos , Semántica , Potenciales Evocados , Análisis Multivariante , China
5.
J Mol Cell Cardiol ; 187: 26-37, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38150867

RESUMEN

Stimulating cardiomyocyte proliferation in the adult heart has emerged as a promising strategy for cardiac regeneration following myocardial infarction (MI). The NRG1-ERBB4 signaling pathway has been implicated in the regulation of cardiomyocyte proliferation. However, the therapeutic potential of recombinant human NRG1 (rhNRG1) has been limited due to the low expression of ERBB4 in adult cardiomyocytes. Here, we investigated whether a fusion protein of rhNRG1 and an ERBB3 inhibitor (rhNRG1-HER3i) could enhance the affinity of NRG1 for ERBB4 and promote adult cardiomyocyte proliferation. In vitro and in vivo experiments were conducted using postnatal day 1 (P1), P7, and adult cardiomyocytes. Western blot analysis was performed to assess the expression and activity of ERBB4. Cardiomyocyte proliferation was evaluated using Ki67 and pH 3 immunostaining, while fibrosis was assessed using Masson staining. Our results indicate that rhNRG1-HER3i, but not rhNRG1, promoted P7 and adult cardiomyocyte proliferation. Furthermore, rhNRG1-HER3i improved cardiac function and reduced cardiac fibrosis in post-MI hearts. Administration of rhNRG1-HER3i inhibited ERBB3 phosphorylation while increasing ERBB4 phosphorylation in adult mouse hearts. Additionally, rhNRG1-HER3i enhanced angiogenesis following MI compared to rhNRG1. In conclusion, our findings suggest that rhNRG1-HER3i is a viable therapeutic approach for promoting adult cardiomyocyte proliferation and treating MI by enhancing NRG1-ERBB4 signaling pathway.


Asunto(s)
Cardiomiopatías , Infarto del Miocardio , Ratones , Animales , Humanos , Transducción de Señal , Miocitos Cardíacos/metabolismo , Neurregulina-1/uso terapéutico , Cardiomiopatías/metabolismo , Receptor ErbB-4/metabolismo
6.
BMC Bioinformatics ; 25(1): 95, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38438950

RESUMEN

BACKGROUND: Dynamical compensation (DC) provides robustness to parameter fluctuations. As an example, DC enables control of the functional mass of endocrine or neuronal tissue essential for controlling blood glucose by insulin through a nonlinear feedback loop. Researchers have shown that DC is related to the structural unidentifiability and the P -invariance property. The P -invariance property is a sufficient and necessary condition for the DC property. DC has been seen in systems with at least three dimensions. In this article, we discuss DC and P -invariance from an adaptive control perspective. An adaptive controller automatically adjusts its parameters to optimise performance, maintain stability, and deal with uncertainties in a system. RESULTS: We initiate our analysis by introducing a simplified two-dimensional dynamical model with DC, fostering experimentation and understanding of the system's behavior. We explore the system's behavior with time-varying input and disturbance signals, with a focus on illustrating the system's P -invariance properties in phase portraits and step-like response graphs. CONCLUSIONS: We show that DC can be seen as a case of ideal adaptive control since the system is invariant to the compensated parameter.


Asunto(s)
Insulina , Proyectos de Investigación , Investigación Empírica , Incertidumbre
7.
J Cell Mol Med ; 28(19): e70084, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39400399

RESUMEN

Cold-inducible RNA-binding protein (CIRP) is a stress-response protein that has been shown to protect cardiomyocytes under a variety of stress conditions from apoptosis. Our recent study showed that the expression of CIRP protein in the heart was downregulated in patients with heart failure and an animal model of ischaemia heart failure, but its role in heart failure is still unknown. The present study aimed at evaluating the potential role of CIRP on the heart in an animal model of myocardial infarction (MI). MI model of rats was induced by the ligation of the left coronary artery. CIRP overexpression was mediated by direct intracardiac injection of adeno-associated virus serotype 9 (AAV9) vectors carrying a CIRP coding sequence with a cardiac-specific promoter before the induction of the MI model. The effects of CIRP elevation on MI-induced heart were analysed through echocardiographic, pathological and molecular analysis. Our results showed that the intracardiac injection of AAV9 successfully mediated CIRP upregulation in cardiomyocytes. Upregulation of cardiac CIRP prevented MI-induced cardiac dysfunction and adverse remodelling, coupled with the reduced inflammatory response in the heart. Collectively, these results demonstrated the beneficial role of intracellular CIRP on the heart and suggest that CIRP may be a therapeutic target in ischaemic heart disease.


Asunto(s)
Dependovirus , Modelos Animales de Enfermedad , Infarto del Miocardio , Miocitos Cardíacos , Proteínas de Unión al ARN , Ratas Sprague-Dawley , Remodelación Ventricular , Animales , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/terapia , Infarto del Miocardio/patología , Dependovirus/genética , Masculino , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Remodelación Ventricular/genética , Vectores Genéticos/genética , Vectores Genéticos/administración & dosificación , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Proteínas y Péptidos de Choque por Frío
8.
J Cell Mol Med ; 28(17): e18553, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39239860

RESUMEN

Microbes are involved in a wide range of biological processes and are closely associated with disease. Inferring potential disease-associated microbes as the biomarkers or drug targets may help prevent, diagnose and treat complex human diseases. However, biological experiments are time-consuming and expensive. In this study, we introduced a new method called iPALM-GLMF, which modelled microbe-disease association prediction as a problem of non-negative matrix factorization with graph dual regularization terms and L 2 , 1 $$ {L}_{2,1} $$ norm regularization terms. The graph dual regularization terms were used to capture potential features in the microbe and disease space, and the L 2 , 1 $$ {L}_{2,1} $$ norm regularization terms were used to ensure the sparsity of the feature matrices obtained from the non-negative matrix factorization and to improve the interpretability. To solve the model, iPALM-GLMF used a non-negative double singular value decomposition to initialize the matrix factorization and adopted an inertial Proximal Alternating Linear Minimization iterative process to obtain the final matrix factorization results. As a result, iPALM-GLMF performed better than other existing methods in leave-one-out cross-validation and fivefold cross-validation. In addition, case studies of different diseases demonstrated that iPALM-GLMF could effectively predict potential microbial-disease associations. iPALM-GLMF is publicly available at https://github.com/LiangzheZhang/iPALM-GLMF.


Asunto(s)
Algoritmos , Humanos , Biología Computacional/métodos , Microbiota
9.
J Physiol ; 602(20): 5375-5389, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39316014

RESUMEN

It remains unclear whether feedback from group III/IV muscle afferents is of continuous significance for regulating the pulmonary response during prolonged (>5 min), steady-state exercise. To elucidate the influence of these sensory neurons on hyperpnoea, gas exchange efficiency, arterial oxygenation and acid-base balance during prolonged locomotor exercise, 13 healthy participants (4 females; 21 (3) years, V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ : 46 (8) ml/kg/min) performed consecutive constant-load cycling bouts at ∼50% (20 min), ∼75% (20 min) and ∼100% (5 min) of V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ with intact (CTRL) and pharmacologically attenuated (lumbar intrathecal fentanyl; FENT) group III/IV muscle afferent feedback from the legs. Pulmonary responses were continuously recorded and arterial blood (radial catheter) periodically collected throughout the exercise. Pulmonary gas exchange efficiency was evaluated using the alveolar-arterial P O 2 ${{P}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ difference ( A - a D O 2 ${\mathrm{A - a}}{{D}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ). There were no differences in any of the variables of interest between conditions before the start of the exercise. Pulmonary ventilation was up to 20% lower across all intensities during FENT compared to CTRL exercise (P < 0.001) and this hypoventilation was accompanied by an up to 10% lower arterial P O 2 ${{P}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ and a 2-4 mmHg higher P C O 2 ${{P}_{{\mathrm{C}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ (both P < 0.001). The exercise-induced widening of A - a D O 2 ${\mathrm{A - a}}{{D}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ was up to 25% larger during FENT compared to CTRL (P < 0.001). Importantly, the differences developed within the first minute of each stage and persisted, or further increased, throughout the remainder of each bout. These findings reflect a critical and time-independent significance of feedback from group III/IV leg muscle afferents for continuously regulating the ventilatory response, gas exchange efficiency, arterial oxygenation and acid-base balance during human locomotion. KEY POINTS: Feedback from group III/IV leg muscle afferents reflexly contributes to hyperpnoea during short duration (i.e. <5 min) locomotor exercise. Whether continuous feedback from these sensory neurons is obligatory to ensure adequate pulmonary responses during steady-state exercise of longer duration remains unknown. Lumbar intrathecal fentanyl was used to attenuate the central projection of group III/IV leg muscle afferents during prolonged locomotor exercise (i.e. 45 min) at intensities ranging from 50% to 100% of V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ . Without affecting the metabolic rate, afferent blockade compromised pulmonary ventilation and gas exchange efficiency, consistently impairing arterial oxygenation and facilitating respiratory acidosis throughout exercise. These findings reflect the time-independent significance of feedback from group III/IV muscle afferents for regulating exercise hyperpnoea and gas exchange efficiency, and thus for optimizing arterial oxygenation and acid-base balance, during prolonged human locomotion.


Asunto(s)
Ejercicio Físico , Músculo Esquelético , Intercambio Gaseoso Pulmonar , Humanos , Femenino , Intercambio Gaseoso Pulmonar/fisiología , Masculino , Ejercicio Físico/fisiología , Adulto Joven , Músculo Esquelético/fisiología , Hiperventilación/fisiopatología , Adulto , Fentanilo/farmacología , Neuronas Aferentes/fisiología
10.
J Physiol ; 602(5): 855-873, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38376957

RESUMEN

Myoglobin (Mb) plays an important role at rest and during exercise as a reservoir of oxygen and has been suggested to regulate NO• bioavailability under hypoxic/acidic conditions. However, its ultimate role during exercise is still a subject of debate. We aimed to study the effect of Mb deficiency on maximal oxygen uptake ( V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ ) and exercise performance in myoglobin knockout mice (Mb-/- ) when compared to control mice (Mb+/+ ). Furthermore, we also studied NO• bioavailability, assessed as nitrite (NO2 - ) and nitrate (NO3 - ) in the heart, locomotory muscle and in plasma, at rest and during exercise at exhaustion both in Mb-/- and in Mb+/+ mice. The mice performed maximal running incremental exercise on a treadmill with whole-body gas exchange measurements. The Mb-/- mice had lower body mass, heart and hind limb muscle mass (P < 0.001). Mb-/- mice had significantly reduced maximal running performance (P < 0.001). V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ expressed in ml min-1 in Mb-/ - mice was 37% lower than in Mb+/+ mice (P < 0.001) and 13% lower when expressed in ml min-1  kg body mass-1 (P = 0.001). Additionally, Mb-/- mice had significantly lower plasma, heart and locomotory muscle NO2 - levels at rest. During exercise NO2 - increased significantly in the heart and locomotory muscles of Mb-/- and Mb+/+ mice, whereas no significant changes in NO2 - were found in plasma. Our study showed that, contrary to recent suggestions, Mb deficiency significantly impairs V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ and maximal running performance in mice. KEY POINTS: Myoglobin knockout mice (Mb-/- ) possess lower maximal oxygen uptake ( V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ ) and poorer maximal running performance than control mice (Mb+/+ ). Respiratory exchange ratio values at high running velocities in Mb-/- mice are higher than in control mice suggesting a shift in substrate utilization towards glucose metabolism in Mb-/- mice at the same running velocities. Lack of myoglobin lowers basal systemic and muscle NO• bioavailability, but does not affect exercise-induced NO2 - changes in plasma, heart and locomotory muscles. The present study demonstrates that myoglobin is of vital importance for V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_2}\max }}$ and maximal running performance as well as explains why previous studies have failed to prove such a role of myoglobin when using the Mb-/- mouse model.


Asunto(s)
Mioglobina , Carrera , Ratones , Animales , Mioglobina/genética , Dióxido de Nitrógeno , Carrera/fisiología , Oxígeno , Prueba de Esfuerzo , Ratones Noqueados , Consumo de Oxígeno/fisiología
11.
Plant J ; 116(1): 87-99, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37340958

RESUMEN

Nitrogen (N) is a vital major nutrient for rice (Oryza sativa). Rice responds to different applications of N by altering its root morphology, including root elongation. Although ammonium ( NH 4 + ) is the primary source of N for rice, NH 4 + is toxic to rice roots and inhibits root elongation. However, the precise molecular mechanism that NH 4 + -inhibited root elongation of rice is not well understood. Here, we identified a rice T-DNA insert mutant of OsMADS5 with a longer seminal root (SR) under sufficient N conditions. Reverse-transcription quantitative PCR analysis revealed that the expression level of OsMADS5 was increased under NH 4 + compared with NO 3 - supply. Under NH 4 + conditions, knocking out OsMADS5 (cas9) produced a longer SR, phenocopying osmads5, while there was no significant difference in SR length between wild-type and cas9 under NO 3 - supply. Moreover, OsMADS5-overexpression plants displayed the opposite SR phenotype. Further study demonstrated that enhancement of OsMADS5 by NH 4 + supply inhibited rice SR elongation, likely by reducing root meristem activity of root tip, with the involvement of OsCYCB1;1. We also found that OsMADS5 interacted with OsSPL14 and OsSPL17 (OsSPL14/17) to repress their transcriptional activation by attenuating DNA binding ability. Moreover, loss of OsSPL14/17 function in osmads5 eliminated its stimulative effect on SR elongation under NH 4 + conditions, implying OsSPL14/17 may function downstream of OsMADS5 to mediate rice SR elongation under NH 4 + supply. Overall, our results indicate the existence of a novel modulatory pathway in which enhancement of OsMADS5 by NH 4 + supply represses the transcriptional activities of OsSPL14/17 to restrict SR elongation of rice.


Asunto(s)
Compuestos de Amonio , Oryza , Meristema/metabolismo , Oryza/metabolismo , Raíces de Plantas/metabolismo , Compuestos de Amonio/metabolismo , Proliferación Celular , Regulación de la Expresión Génica de las Plantas
12.
BMC Genomics ; 25(1): 885, 2024 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-39304826

RESUMEN

MicroRNAs (miRNAs) have been demonstrated to be closely related to human diseases. Studying the potential associations between miRNAs and diseases contributes to our understanding of disease pathogenic mechanisms. As traditional biological experiments are costly and time-consuming, computational models can be considered as effective complementary tools. In this study, we propose a novel model of robust orthogonal non-negative matrix tri-factorization (NMTF) with self-paced learning and dual hypergraph regularization, named SPLHRNMTF, to predict miRNA-disease associations. More specifically, SPLHRNMTF first uses a non-linear fusion method to obtain miRNA and disease comprehensive similarity. Subsequently, the improved miRNA-disease association matrix is reformulated based on weighted k-nearest neighbor profiles to correct false-negative associations. In addition, we utilize L 2 , 1 norm to replace Frobenius norm to calculate residual error, alleviating the impact of noise and outliers on prediction performance. Then, we integrate self-paced learning into NMTF to alleviate the model from falling into bad local optimal solutions by gradually including samples from easy to complex. Finally, hypergraph regularization is introduced to capture high-order complex relations from hypergraphs related to miRNAs and diseases. In 5-fold cross-validation five times experiments, SPLHRNMTF obtains higher average AUC values than other baseline models. Moreover, the case studies on breast neoplasms and lung neoplasms further demonstrate the accuracy of SPLHRNMTF. Meanwhile, the potential associations discovered are of biological significance.


Asunto(s)
Biología Computacional , MicroARNs , MicroARNs/genética , Humanos , Biología Computacional/métodos , Algoritmos , Predisposición Genética a la Enfermedad , Aprendizaje Automático , Neoplasias Pulmonares/genética
13.
Eur J Neurosci ; 60(7): 5750-5763, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39210784

RESUMEN

Virtual reality (VR)-guided motor imagery (MI) is a widely used approach for motor rehabilitation, especially for patients with severe motor impairments. Most approaches provide visual guidance from the first-person perspective (1PP). MI training with visual guidance from the third-person perspective (3PP) remains largely unexplored. We argue that 3PP MI training has its own advantages and can supplement 1PP MI. For some movements beyond the view of 1PP, such as shoulder shrugging and other axial movements, MI are suitable performed under 3PP. However, the efficiency of existing paradigms for 3PP MI is unsatisfactory. We speculate that the absence of sense of body ownership (SOO) from 3PP could be one possible factor and hypothesize that 3PP MI could be enhanced by eliciting SOO over a 3PP avatar. Based on our hypothesis, a novel paradigm was proposed to enhance 3PP MI by inducing full-body illusion (FBI) from 3PP, which is similar to the so-called out-of-body experience (OBE), using synchronous visuo-tactile stimulus with VR. The event-related Electroencephalograph (EEG) desynchronization (ERD) at motor-related regions from 31 healthy participants were calculated and compared with a control paradigm without "OBE" FBI induction. This study attempts to enhance 3PP MI with FBI induction. It offers an opportunity to perform MI guided by action observation from 3PP with elicited SOO to the observed avatar. We believe that 3PP MI could provide more possibilities for effective rehabilitation training, when SOO could be elicited to a virtual avatar and the present work demonstrates its viability and effectiveness.


Asunto(s)
Imaginación , Realidad Virtual , Humanos , Masculino , Femenino , Adulto , Imaginación/fisiología , Adulto Joven , Ilusiones/fisiología , Imagen Corporal , Electroencefalografía/métodos , Movimiento/fisiología
14.
Br J Haematol ; 205(2): 568-579, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38877874

RESUMEN

MLL-rearranged (MLL-r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL-r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI-503, a potent menin-MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI-503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-targeted therapy for MLL::AF9 AML.


Asunto(s)
Sinergismo Farmacológico , Leucemia Mieloide Aguda , Proteína de la Leucemia Mieloide-Linfoide , Proteínas Proto-Oncogénicas , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Animales , Ratones , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral
15.
Mol Genet Genomics ; 299(1): 97, 2024 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-39395039

RESUMEN

The food industry has incurred substantial losses from contamination by Pseudomonas fluorescens, emphasizing the critical importance of implementing effective control strategies. Phages are potential sterilizers due to their specific killing abilities and the difficulty bacteria face in developing resistance. However, a significant barrier to their development is the lack of diversity among phage types. In this study, we characterized a novel lytic P. fluorescens phage, named vB_PF_Y1-MI. Phage vB_PF_Y1-MI displayed a latent period of nearly 10 min and a high burst size of 1493 PFU/cell. This phage showed good activity over a wide range of temperature (up to 70 °C) and pH (3-12). The genome of phage vB_PF_Y1-MI spans 93,233 bp with a GC content of 45%. It encompasses 174 open-reading frames and 19 tRNA genes, while no lysogeny or virulence-associated genes were detected. Phylogenetic analysis positions it as a novel unassigned evolutionary lineage within the Caudoviricetes class among related dsDNA phages. Our study provides foundational insights into vB_PF_Y1-MI and emphasizes its potential as an effective biological control agent against P. fluorescens. This research offers crucial theoretical groundwork and technical support for subsequent efforts in preventing and controlling P. fluorescens contamination.


Asunto(s)
Genoma Viral , Leche , Filogenia , Pseudomonas fluorescens , Pseudomonas fluorescens/virología , Pseudomonas fluorescens/genética , Leche/microbiología , Leche/virología , Animales , Genoma Viral/genética , Fagos Pseudomonas/genética , Fagos Pseudomonas/aislamiento & purificación , Composición de Base/genética , Contaminación de Alimentos/prevención & control , Microbiología de Alimentos , Bacteriófagos/genética , Bacteriófagos/aislamiento & purificación , Bacteriófagos/clasificación , Sistemas de Lectura Abierta/genética
16.
Small ; : e2406829, 2024 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-39370665

RESUMEN

The nickel hydroxide-based (Ni(OH)2) methanol-to-formate electrooxidation reaction (MOR) performance is greatly related to the d x 2 - y 2 ${{d}_{{{x}^2} - {{y}^2}}}$ orbital electronic states. Hence, optimizing the d x 2 - y 2 ${{d}_{{{x}^2} - {{y}^2}}}$ orbital electronic states to achieve enhanced MOR activities are highly desired. Here, cobalt (Co) and iron (Fe) doping are used to modify the d x 2 - y 2 ${{d}_{{{x}^2} - {{y}^2}}}$ orbital electronic states. Although both dopants can broaden the d x 2 - y 2 ${{d}_{{{x}^2} - {{y}^2}}}$ orbital; however, Co doping leads to an elevation in the energy level of d x 2 - y 2 ${{d}_{{{x}^2} - {{y}^2}}}$ highest occupied crystal orbital (HOCO), whereas Fe doping results in its reduction. Such a discrepancy in the regulation of d x 2 - y 2 ${{d}_{{{x}^2} - {{y}^2}}}$ orbital electronic states stems from the disparate partial electron transfer mechanisms amongst these transition metal ions, which possess distinct energy level and occupancy of d orbitals. Motivated by this finding, the NiCoFe hydroxide is prepared and exhibited an excellent MOR performance. The results showed that the Co dopants effectively suppress the partial electron transfer from Ni to Fe, combined with the d x 2 - y 2 ${{d}_{{{x}^2} - {{y}^2}}}$ orbital broadening induced by NiO6 octahedra distortion, endowing NiCoFe hydroxide with high d x 2 - y 2 ${{d}_{{{x}^2} - {{y}^2}}}$ HOCO and broad d x 2 - y 2 ${{d}_{{{x}^2} - {{y}^2}}}$ orbital. It is believed that the work gives an in-depth understanding on d x 2 - y 2 ${{d}_{{{x}^2} - {{y}^2}}}$ orbital electronic states regulation in Ni(OH)2, which is beneficial for designing Ni(OH)2-based catalysts with high MOR performance.

17.
Magn Reson Med ; 91(6): 2508-2518, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38321602

RESUMEN

PURPOSE: The purpose of this study is to improve the image quality of diffusion-weighted images obtained with a single RF transmit channel 7 T MRI setup using time-resampled frequency-offset corrected inversion (TR-FOCI) pulses to refocus the spins in a twice-refocused spin-echo readout scheme. METHODS: We replaced the conventional Shinnar-Le Roux-pulses in the twice refocused diffusion sequence with TR-FOCI pulses. The slice profiles were evaluated in simulation and experimentally in phantoms. The image quality was evaluated in vivo comparing the Shinnar-Le Roux and TR-FOCI implementation using a b value of 0 and of 1000 s/mm2. RESULTS: The b0 and diffusion-weighted images acquired using the modified sequence improved the image quality across the whole brain. A region of interest-based analysis showed an SNR increase of 113% and 66% for the nondiffusion-weighted (b0) and the diffusion-weighted (b = 1000 s/mm2) images in the temporal lobes, respectively. Investigation of all slices showed that the adiabatic pulses mitigated B 1 + $$ {B}_1^{+} $$ inhomogeneity globally using a conventional single-channel transmission setup. CONCLUSION: The TR-FOCI pulse can be used in a twice-refocused spin-echo diffusion pulse sequence to mitigate the impact of B 1 + $$ {B}_1^{+} $$ inhomogeneity on the signal intensity across the brain at 7 T. However, further work is needed to address SAR limitations.


Asunto(s)
Algoritmos , Imagen de Difusión por Resonancia Magnética , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , Fantasmas de Imagen
18.
Magn Reson Med ; 91(4): 1598-1607, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38156827

RESUMEN

PURPOSE: To show that B 0 $$ {\mathrm{B}}_0 $$ variations through slice and slice profile effects are two major confounders affecting 2D dual angle B 1 + $$ {\mathrm{B}}_1^{+} $$ maps using gradient-echo signals and thus need to be corrected to obtain accurate B 1 + $$ {\mathrm{B}}_1^{+} $$ maps. METHODS: The 2D gradient-echo transverse complex signal was Bloch-simulated and integrated across the slice dimension including nonlinear variations in B 0 $$ {\mathrm{B}}_0 $$ inhomogeneities through slice. A nonlinear least squares fit was used to find the B 1 + $$ {\mathrm{B}}_1^{+} $$ factor corresponding to the best match between the two gradient-echo signals experimental ratio and the Bloch-simulated ratio. The correction was validated in phantom and in vivo at 3T. RESULTS: For our RF excitation pulse, the error in the B 1 + $$ {\mathrm{B}}_1^{+} $$ factor scales by approximately 3.8% for every 10 Hz/cm variation in B 0 $$ {\mathrm{B}}_0 $$ along the slice direction. Higher accuracy phantom B 1 + $$ {\mathrm{B}}_1^{+} $$ maps were obtained after applying the proposed correction; the root mean square B 1 + $$ {\mathrm{B}}_1^{+} $$ error relative to the gold standard B 1 + $$ {\mathrm{B}}_1^{+} $$ decreased from 6.4% to 2.6%. In vivo whole-liver T 1 $$ {\mathrm{T}}_1 $$ maps using the corrected B 1 + $$ {\mathrm{B}}_1^{+} $$ map registered a significant decrease in T 1 $$ {\mathrm{T}}_1 $$ gradient through slice. CONCLUSION: B 0 $$ {\mathrm{B}}_0 $$ inhomogeneities varying through slice were seen to have an impact on the accuracy of 2D double angle B 1 + $$ {\mathrm{B}}_1^{+} $$ maps using gradient-echo sequences. Consideration of this confounder is crucial for research relying on accurate knowledge of the true excitation flip angles, as is the case of T 1 $$ {\mathrm{T}}_1 $$ mapping using a spoiled gradient recalled echo sequence.


Asunto(s)
Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Fantasmas de Imagen , Análisis de los Mínimos Cuadrados , Frecuencia Cardíaca
19.
Magn Reson Med ; 2024 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-39462464

RESUMEN

PURPOSE: Demonstration of a high dynamic-range and high SNR method for acquiring absolute B 1 + $$ {\mathrm{B}}_1^{+} $$ maps from a combination of gradient echo and actual-flip-angle measurements that is especially useful during the construction of parallel-transmit arrays. METHODS: Low flip angle gradient echo images, acquired when transmitting with each channel individually, are used to compute relative B 1 + $$ {\mathrm{B}}_1^{+} $$ maps. Instead of computing these in a conventional manner, the equivalence of the problem to the ESPIRiT parallel image reconstruction method is used to compute B 1 + $$ {\mathrm{B}}_1^{+} $$ maps with a higher SNR. Absolute maps are generated by calibration against a single actual flip-angle acquisition when transmitting on all channels simultaneously. RESULTS: Depending on the number of receiver channels and the location of the receive elements with respect to the subject being investigated, moderate to high gains in the SNR of the acquired B 1 + $$ {\mathrm{B}}_1^{+} $$ maps can be achieved. CONCLUSIONS: The proposed method is especially suited for the acquisition of B 1 + $$ {\mathrm{B}}_1^{+} $$ maps during the construction of transceiver arrays. Compared to the original method, maps with higher SNR can be computed without the need for additional measurements, and maps can also be generated using previously acquired data. Furthermore, easy adoption and fast estimation of receiver channels is possible because of existing highly optimized open-source implementations of ESPIRiT, such as in the BART toolbox.

20.
Magn Reson Med ; 92(4): 1525-1539, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38725149

RESUMEN

PURPOSE: To accelerate whole-brain quantitative T 2 $$ {\mathrm{T}}_2 $$ mapping in preclinical imaging setting. METHODS: A three-dimensional (3D) multi-echo spin echo sequence was highly undersampled with a variable density Poisson distribution to reduce the acquisition time. Advanced iterative reconstruction based on linear subspace constraints was employed to recover high-quality raw images. Different subspaces, generated using exponential or extended-phase graph (EPG) simulations or from low-resolution calibration images, were compared. The subspace dimension was investigated in terms of T 2 $$ {\mathrm{T}}_2 $$ precision. The method was validated on a phantom containing a wide range of T 2 $$ {\mathrm{T}}_2 $$ and was then applied to monitor metastasis growth in the mouse brain at 4.7T. Image quality and T 2 $$ {\mathrm{T}}_2 $$ estimation were assessed for 3 acceleration factors (6/8/10). RESULTS: The EPG-based dictionary gave robust estimations of a large range of T 2 $$ {\mathrm{T}}_2 $$ . A subspace dimension of 6 was the best compromise between T 2 $$ {\mathrm{T}}_2 $$ precision and image quality. Combining the subspace constrained reconstruction with a highly undersampled dataset enabled the acquisition of whole-brain T 2 $$ {\mathrm{T}}_2 $$ maps, the detection and the monitoring of metastasis growth of less than 500 µ m 3 $$ \mu {\mathrm{m}}^3 $$ . CONCLUSION: Subspace-based reconstruction is suitable for 3D T 2 $$ {\mathrm{T}}_2 $$ mapping. This method can be used to reach an acceleration factor up to 8, corresponding to an acquisition time of 25 min for an isotropic 3D acquisition of 156 µ $$ \mu $$ m on the mouse brain, used here for monitoring metastases growth.


Asunto(s)
Algoritmos , Encéfalo , Imagenología Tridimensional , Fantasmas de Imagen , Animales , Ratones , Encéfalo/diagnóstico por imagen , Imagenología Tridimensional/métodos , Neoplasias Encefálicas/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Reproducibilidad de los Resultados , Procesamiento de Imagen Asistido por Computador/métodos
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