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1.
Blood Sci ; 6(3): e00192, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38994525

RESUMEN

Acute myeloid leukemia (AML) is a common hematological malignancy with overall poor prognosis. Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory (RR) AML patients. Through clinical specimens, animal models and cell-level studies, we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1) in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation, increase chemotherapy sensitivity and improve the occurrence and development of AML. Here, we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival (OS). Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity, while stable overexpression of HMGCS1 had the opposite effects. Mechanistically, we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase (MAPK) pathway activity, while overexpression of HMGCS1 could remarkably enhance the pathway. U0126, a MEK1 inhibitor, offset the effects of HMGCS1 overexpression, indicating that HMGCS1 promotes RR AML through the MAPK pathway. Further, we verified that hymeglusin, a specific inhibitor of HMGCS1, decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients. Furthermore, combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin (ADR) had synergistic toxic effects on AML cells. Our study demonstrates the important role of HMGCS1 in AML, and targeting this protein is promising for the treatment of RR AML.

2.
Artículo en Inglés | MEDLINE | ID: mdl-38976473

RESUMEN

Learning with little data is challenging but often inevitable in various application scenarios where the labeled data are limited and costly. Recently, few-shot learning (FSL) gained increasing attention because of its generalizability of prior knowledge to new tasks that contain only a few samples. However, for data-intensive models such as vision transformer (ViT), current fine-tuning-based FSL approaches are inefficient in knowledge generalization and, thus, degenerate the downstream task performances. In this article, we propose a novel mask-guided ViT (MG-ViT) to achieve an effective and efficient FSL on the ViT model. The key idea is to apply a mask on image patches to screen out the task-irrelevant ones and to guide the ViT focusing on task-relevant and discriminative patches during FSL. Particularly, MG-ViT only introduces an additional mask operation and a residual connection, enabling the inheritance of parameters from pretrained ViT without any other cost. To optimally select representative few-shot samples, we also include an active learning-based sample selection method to further improve the generalizability of MG-ViT-based FSL. We evaluate the proposed MG-ViT on classification, object detection, and segmentation tasks using gradient-weighted class activation mapping (Grad-CAM) to generate masks. The experimental results show that the MG-ViT model significantly improves the performance and efficiency compared with general fine-tuning-based ViT and ResNet models, providing novel insights and a concrete approach toward generalizing data-intensive and large-scale deep learning models for FSL.

3.
ACS Appl Mater Interfaces ; 16(26): 33819-33828, 2024 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-38885614

RESUMEN

Broadband photodetectors have attracted much attention due to their multispectral response properties and show great potential in the fields of optical sensing, multispectral imaging, and optical communications. Palladium telluride (PdTe2) is highly competitive in broadband detection due to its tunable bandgap and nonlinear optical properties. However, the low response speed hinders further improvement in the performance of PdTe2-based broadband photodetectors. In this work, we present island-type ZnO@PdTe2 composites on Si as a heterojunction photodetector exhibiting highly sensitive photodetection capabilities in a wide band from the solar-blind region (254 nm) to the short-infrared (1.55 µm). Due to the island-type morphology of the ZnO@PdTe2 composites effectively enhancing light absorption and the ZnO@PdTe2/Si stacks forming a type-II heterojunction accelerating carrier separation, the devices have an ultrafast response (1.58/1.34 µs), a detectivity of up to 1.56 × 1013 Jones, and a sensitivity of up to 107 cm2/W. A triple-channel color imaging system and a dual-channel data transmission system were developed based on the excellent and stable performance of the device. This study demonstrates the great potential of ZnO@PdTe2/Si vertical heterojunction photodetectors for high-speed, wide-band, multiscenario optical communication.

4.
Compr Rev Food Sci Food Saf ; 23(4): e13364, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38847746

RESUMEN

Kefir milk, known for its high nutritional value and health benefits, is traditionally produced by fermenting milk with kefir grains. These grains are a complex symbiotic community of lactic acid bacteria, acetic acid bacteria, yeasts, and other microorganisms. However, the intricate coexistence mechanisms within these microbial colonies remain a mystery, posing challenges in predicting their biological and functional traits. This uncertainty often leads to variability in kefir milk's quality and safety. This review delves into the unique structural characteristics of kefir grains, particularly their distinctive hollow structure. We propose hypotheses on their formation, which appears to be influenced by the aggregation behaviors of the community members and their alliances. In kefir milk, a systematic colonization process is driven by metabolite release, orchestrating the spatiotemporal rearrangement of ecological niches. We place special emphasis on the dynamic spatiotemporal changes within the kefir microbial community. Spatially, we observe variations in species morphology and distribution across different locations within the grain structure. Temporally, the review highlights the succession patterns of the microbial community, shedding light on their evolving interactions.Furthermore, we explore the ecological mechanisms underpinning the formation of a stable community composition. The interplay of cooperative and competitive species within these microorganisms ensures a dynamic balance, contributing to the community's richness and stability. In kefir community, competitive species foster diversity and stability, whereas cooperative species bolster mutualistic symbiosis. By deepening our understanding of the behaviors of these complex microbial communities, we can pave the way for future advancements in the development and diversification of starter cultures for food fermentation processes.


Asunto(s)
Kéfir , Simbiosis , Kéfir/microbiología , Simbiosis/fisiología , Microbiota/fisiología , Fermentación , Microbiología de Alimentos
5.
Theriogenology ; 225: 152-161, 2024 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-38805997

RESUMEN

Oocytes and embryos are highly sensitive to environmental stress in vivo and in vitro. During in vitro culture, many stressful conditions can affect embryo quality and viability, leading to adverse clinical outcomes such as abortion and congenital abnormalities. In this study, we found that valeric acid (VA) increased the mitochondrial membrane potential and ATP content, decreased the level of reactive oxygen species that the mitochondria generate, and thus improved mitochondrial function during early embryonic development in pigs. VA decreased expression of the autophagy-related factors LC3B and BECLIN1. Interestingly, VA inhibited expression of autophagy-associated phosphorylation-adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylation-UNC-51-like autophagy-activated kinase 1 (p-ULK1, Ser555), and ATG13, which reduced apoptosis. Short-chain fatty acids (SCFAs) can signal through G-protein-coupled receptors on the cell membrane or enter the cell directly through transporters. We further show that the monocarboxylate transporter 1 (MCT1) was necessary for the effects of VA on embryo quality, which provides a new molecular perspective of the pathway by which SCFAs affect embryos. Importantly, VA significantly inhibited the AMPK-ULK1 autophagic signaling pathway through MCT1, decreased apoptosis, increased expression of embryonic pluripotency genes, and improved embryo quality.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Homólogo de la Proteína 1 Relacionada con la Autofagia , Autofagia , Desarrollo Embrionario , Mitocondrias , Transportadores de Ácidos Monocarboxílicos , Animales , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Porcinos/embriología , Desarrollo Embrionario/efectos de los fármacos , Autofagia/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transducción de Señal/efectos de los fármacos , Blastocisto/efectos de los fármacos , Blastocisto/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Técnicas de Cultivo de Embriones/veterinaria , Simportadores
6.
Cell Mol Life Sci ; 81(1): 221, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38763964

RESUMEN

In females, the pathophysiological mechanism of poor ovarian response (POR) is not fully understood. Considering the expression level of p62 was significantly reduced in the granulosa cells (GCs) of POR patients, this study focused on identifying the role of the selective autophagy receptor p62 in conducting the effect of follicle-stimulating hormone (FSH) on antral follicles (AFs) formation in female mice. The results showed that p62 in GCs was FSH responsive and that its level increased to a peak and then decreased time-dependently either in ovaries or in GCs after gonadotropin induction in vivo. GC-specific deletion of p62 resulted in subfertility, a significantly reduced number of AFs and irregular estrous cycles, which were same as pathophysiological symptom of POR. By conducting mass spectrum analysis, we found the ubiquitination of proteins was decreased, and autophagic flux was blocked in GCs. Specifically, the level of nonubiquitinated Wilms tumor 1 homolog (WT1), a transcription factor and negative controller of GC differentiation, increased steadily. Co-IP results showed that p62 deletion increased the level of ubiquitin-specific peptidase 5 (USP5), which blocked the ubiquitination of WT1. Furthermore, a joint analysis of RNA-seq and the spatial transcriptome sequencing data showed the expression of steroid metabolic genes and FSH receptors pivotal for GCs differentiation decreased unanimously. Accordingly, the accumulation of WT1 in GCs deficient of p62 decreased steroid hormone levels and reduced FSH responsiveness, while the availability of p62 in GCs simultaneously ensured the degradation of WT1 through the ubiquitin‒proteasome system and autophagolysosomal system. Therefore, p62 in GCs participates in GC differentiation and AF formation in FSH induction by dynamically controlling the degradation of WT1. The findings of the study contributes to further study the pathology of POR.


Asunto(s)
Hormona Folículo Estimulante , Células de la Granulosa , Folículo Ovárico , Proteína Sequestosoma-1 , Ubiquitinación , Proteínas WT1 , Animales , Hormona Folículo Estimulante/metabolismo , Hormona Folículo Estimulante/farmacología , Femenino , Proteínas WT1/metabolismo , Proteínas WT1/genética , Ratones , Folículo Ovárico/metabolismo , Folículo Ovárico/efectos de los fármacos , Células de la Granulosa/metabolismo , Células de la Granulosa/efectos de los fármacos , Proteína Sequestosoma-1/metabolismo , Proteína Sequestosoma-1/genética , Ratones Endogámicos C57BL , Autofagia/efectos de los fármacos , Proteolisis/efectos de los fármacos , Humanos , Ratones Noqueados
7.
J Agric Food Chem ; 72(21): 11885-11899, 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38747409

RESUMEN

Actin, a multifunctional protein highly expressed in eukaryotes, is widely distributed throughout cells and serves as a crucial component of the cytoskeleton. Its presence is integral to maintaining cell morphology and participating in various biological processes. As an irreplaceable component of myofibrillar proteins, actin, including G-actin and F-actin, is highly related to food quality. Up to now, purification of actin at a moderate level remains to be overcome. In this paper, we have reviewed the structures and functions of actin, the methods to obtain actin, and the relationships between actin and food texture, color, and flavor. Moreover, actin finds applications in diverse fields such as food safety, bioengineering, and nanomaterials. Developing an actin preparation method at the industrial level will help promote its further applications in food science, nutrition, and safety.


Asunto(s)
Actinas , Calidad de los Alimentos , Actinas/metabolismo , Actinas/química , Animales , Humanos
9.
Elife ; 122024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38635322

RESUMEN

Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, our research defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. Shared and unique gyral peaks in human and macaque are identified in this study, and their similarities and differences in spatial distribution, anatomical morphology, and functional connectivity were also dicussed.


Asunto(s)
Encéfalo , Macaca , Animales , Humanos
10.
Environ Sci Technol ; 58(17): 7469-7479, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38557082

RESUMEN

Trivalent arsenicals such as arsenite (AsIII) and methylarsenite (MAsIII) are thought to be ubiquitous in flooded paddy soils and have higher toxicity than pentavalent forms. Fungi are widely prevalent in the rice rhizosphere, and the latter is considered a hotspot for As uptake. However, few studies have focused on alleviating As toxicity in paddy soils using fungi. In this study, we investigated the mechanism by which the protein TaGlo1, derived from the As-resistant fungal strain Trichoderma asperellum SM-12F1, mitigates AsIII and MAsIII toxicity in paddy soils. Taglo1 gene expression in Escherichia coli BL21 conferred strong resistance to AsIII and MAsIII, while purified TaGlo1 showed a high affinity for AsIII and MAsIII. Three cysteine residues (Cys13, Cys18, and Cys71) play crucial roles in binding with AsIII, while only two (Cys13 and Cys18) play crucial roles for MAsIII binding. TaGlo1 had a stronger binding strength for MAsIII than AsIII. Importantly, up to 90.2% of the homologous TaGlo1 proteins originate from fungi by GenBank searching. In the rhizospheres of 14 Chinese paddy soils, Taglo1 was widely distributed and its gene abundance increased with porewater As. This study highlights the potential of fungi to mitigate As toxicity and availability in the soil-rice continuum and suggests future microbial strategies for bioremediation.


Asunto(s)
Contaminantes del Suelo , Suelo , Suelo/química , Arsenitos , Microbiología del Suelo , Oryza
11.
Theranostics ; 14(6): 2345-2366, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38646645

RESUMEN

Rationale: Primordial follicles are limited in number and cannot be regenerated, dormant primordial follicles cannot be reversed once they enter a growth state. Therefore, the length of the female reproductive lifespan depends on the orderly progression and selective activation of primordial follicles, the mechanism of which remains unclear. Methods: We used human ovarian cortical biopsy specimens, granulosa cells from diminished ovarian reserve (DOR) patients, Hdac6-overexpressing transgenic mouse model, and RNA sequencing to analyze the crucial roles of histone deacetylase 6 (HDAC6) in fertility preservation and primordial follicle activation. Results: In the present study, we found that HDAC6 was highly expressed in most dormant primordial follicles. The HDAC6 expression was reduced accompanying reproductive senescence in human and mouse ovaries. Overexpression of Hdac6 delayed the rate of primordial follicle activation, thereby prolonging the mouse reproductive lifespan. Short-term inhibition of HDAC6 promoted primordial follicle activation and follicular development in humans and mice. Mechanism studies revealed that HDAC6 directly interacted with NGF, reducing acetylation modification of NGF and thereby accelerating its ubiquitination degradation. Consequently, the reduced NGF protein level maintained the dormancy of primordial follicles. Conclusions: The physiological significance of the high expression of HDAC6 in most primordial follicles is to reduce NGF expression and prevent primordial follicle activation to maintain female fertility. Reduced HDAC6 expression increases NGF expression in primordial follicles, activating their development and contributing to reproduction. Our study provides a clinical reference value for fertility preservation.


Asunto(s)
Histona Desacetilasa 6 , Ratones Transgénicos , Factor de Crecimiento Nervioso , Folículo Ovárico , Ubiquitinación , Animales , Femenino , Humanos , Ratones , Acetilación , Células de la Granulosa/metabolismo , Histona Desacetilasa 6/metabolismo , Histona Desacetilasa 6/genética , Factor de Crecimiento Nervioso/metabolismo , Folículo Ovárico/metabolismo
12.
Biochim Biophys Acta Mol Basis Dis ; 1870(5): 167161, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38599260

RESUMEN

The tongue epithelium is maintained by a proliferative basal layer. This layer contains long-lived stem cells (SCs), which produce progeny cells that move up to the surface as they differentiate. B-lymphoma Mo-MLV insertion region 1 (BMI1), a protein in mammalian Polycomb Repressive Complex 1 (PRC1) and a biomarker of oral squamous cell carcinoma, is expressed in almost all basal epithelial SCs of the tongue, and single, Bmi1-labelled SCs give rise to cells in all epithelial layers. We previously developed a transgenic mouse model (KrTB) containing a doxycycline- (dox) controlled, Tet-responsive element system to selectively overexpress Bmi1 in the tongue basal epithelial SCs. Here, we used this model to assess BMI1 actions in tongue epithelia. Genome-wide transcriptomics revealed increased levels of transcripts involved in the cellular response to hypoxia in Bmi1-overexpressing (KrTB+DOX) oral epithelia even though these mice were not subjected to hypoxia conditions. Ectopic Bmi1 expression in tongue epithelia increased the levels of hypoxia inducible factor-1 alpha (HIF1α) and HIF1α targets linked to metabolic reprogramming during hypoxia. We used chromatin immunoprecipitation (ChIP) to demonstrate that Bmi1 associates with the promoters of HIF1A and HIF1A-activator RELA (p65) in tongue epithelia. We also detected increased SC proliferation and oxidative stress in Bmi1-overexpressing tongue epithelia. Finally, using a human oral keratinocyte line (OKF6-TERT1R), we showed that ectopic BMI1 overexpression decreases the oxygen consumption rate while increasing the extracellular acidification rate, indicative of elevated glycolysis. Thus, our data demonstrate that high BMI1 expression drives hypoxic signaling, including metabolic reprogramming, in normal oral cavity epithelia.


Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia , Ratones Transgénicos , Complejo Represivo Polycomb 1 , Transducción de Señal , Complejo Represivo Polycomb 1/metabolismo , Complejo Represivo Polycomb 1/genética , Animales , Ratones , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Humanos , Lengua/metabolismo , Lengua/patología , Mucosa Bucal/metabolismo , Mucosa Bucal/patología , Hipoxia de la Célula , Epitelio/metabolismo , Boca/metabolismo , Boca/patología , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Neoplasias de la Boca/genética , Proteínas Proto-Oncogénicas
13.
Cereb Cortex ; 34(3)2024 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-38483143

RESUMEN

Gyri and sulci are 2 fundamental cortical folding patterns of the human brain. Recent studies have suggested that gyri and sulci may play different functional roles given their structural and functional heterogeneity. However, our understanding of the functional differences between gyri and sulci remains limited due to several factors. Firstly, previous studies have typically focused on either the spatial or temporal domain, neglecting the inherently spatiotemporal nature of brain functions. Secondly, analyses have often been restricted to either local or global scales, leaving the question of hierarchical functional differences unresolved. Lastly, there has been a lack of appropriate analytical tools for interpreting the hierarchical spatiotemporal features that could provide insights into these differences. To overcome these limitations, in this paper, we proposed a novel hierarchical interpretable autoencoder (HIAE) to explore the hierarchical functional difference between gyri and sulci. Central to our approach is its capability to extract hierarchical features via a deep convolutional autoencoder and then to map these features into an embedding vector using a carefully designed feature interpreter. This process transforms the features into interpretable spatiotemporal patterns, which are pivotal in investigating the functional disparities between gyri and sulci. We evaluate the proposed framework on Human Connectome Project task functional magnetic resonance imaging dataset. The experiments demonstrate that the HIAE model can effectively extract and interpret hierarchical spatiotemporal features that are neuroscientifically meaningful. The analyses based on the interpreted features suggest that gyri are more globally activated, whereas sulci are more locally activated, demonstrating a distinct transition in activation patterns as the scale shifts from local to global. Overall, our study provides novel insights into the brain's anatomy-function relationship.


Asunto(s)
Corteza Cerebral , Conectoma , Humanos , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiología , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Conectoma/métodos , Cabeza
14.
Clin Nutr ; 43(4): 1013-1020, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38503020

RESUMEN

BACKGROUND & AIMS: While obesity has been reported as a protective factor in septic patients, little is known about the potential modifying effects of age and sex. The objective of this study is to investigate age and sex-specific associations between obesity and the prognosis of septic patients. METHODS: A retrospective analysis was conducted on a cohort of 15,464 septic patients, categorized by body mass index (BMI) into four groups: underweight (<18.5 kg/m2, n = 483), normal (18.5-24.9 kg/m2, n = 4344), overweight (25-29.9 kg/m2, n = 4949) and obese (≥30 kg/m2, n = 5688). Multivariable logistic regression and inverse probability weighting were employed to robustly confirm the protective effect of a higher BMI on 28-day mortality, with normal weight serving as the reference category. Subgroup analyses based on age (young: 18-39, middle-aged: 40-64 and elderly: ≥65) and sex were performed. RESULTS: The findings demonstrate that high BMI independently confers a protective effect against 28-day mortality in septic patients. However, the relationship between BMI and 28-day mortality exhibits a non-linear trend, with a BMI of 34.5 kg/m2 displaying the lowest odds ratio. Notably, the survival benefits associated with a high BMI were not observed in the young group. Moreover, being underweight emerges as an independent risk factor for middle-aged and elderly female patients, while in males it is only a risk factor in the elderly group. Interestingly, being overweight and obese were identified as independent protective factors in middle-aged and elderly male patients, but not in females. CONCLUSIONS: The effect of BMI on mortality in septic patients varies according to age and sex. Elderly individuals with sepsis may derive more prognostic benefits from obesity.


Asunto(s)
Sobrepeso , Sepsis , Persona de Mediana Edad , Anciano , Humanos , Masculino , Femenino , Sobrepeso/complicaciones , Estudios Retrospectivos , Delgadez/complicaciones , Delgadez/epidemiología , Obesidad/complicaciones , Obesidad/epidemiología , Factores de Riesgo , Sepsis/epidemiología , Índice de Masa Corporal
15.
Sci Bull (Beijing) ; 69(8): 1122-1136, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38302330

RESUMEN

In a growing follicle, the survival and maturation of the oocyte largely depend on support from somatic cells to facilitate FSH-induced mutual signaling and chemical communication. Although apoptosis and autophagy in somatic cells are involved in the process of FSH-induced follicular development, the underlying mechanisms require substantial study. According to our study, along with FSH-induced antral follicles (AFs) formation, both lysine-specific demethylase 1 (LSD1) protein levels and autophagy increased simultaneously in granulosa cells (GCs) in a time-dependent manner, we therefore evaluated the importance of LSD1 upon facilitating the formation of AFs correlated to autophagy in GCs. Conditional knockout of Lsd1 in GCs resulted in significantly decreased AF number and subfertility in females, accompanied by marked suppression of the autophagy in GCs. On the one hand, depletion of Lsd1 resulted in accumulation of Wilms tumor 1 homolog (WT1), at both the protein and mRNA levels. WT1 prevented the expression of FSH receptor (Fshr) in GCs and thus reduced the responsiveness of the secondary follicles to FSH induction. On the other hand, depletion of LSD1 resulted in suppressed level of autophagy by upregulation of ATG16L2 in GCs. We finally approved that LSD1 contributed to these sequential activities in GCs through its H3K4me2 demethylase activity. Therefore, the importance of LSD1 in GCs is attributable to its roles in both accelerating autophagy and suppressing WT1 expression to ensure the responsiveness of GCs to FSH during AFs formation.


Asunto(s)
Células de la Granulosa , Folículo Ovárico , Femenino , Autofagia/genética , Hormona Folículo Estimulante/farmacología , Células de la Granulosa/metabolismo , Folículo Ovárico/metabolismo , Transducción de Señal
16.
Theranostics ; 14(4): 1371-1389, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38389850

RESUMEN

Rationale: Premature ovarian insufficiency (POI) is an accelerated reduction in ovarian function inducing infertility. Folliculogenesis defects have been reported to trigger POI as a consequence of ovulation failure. However, the underlying mechanisms remain unclear due to the genetic complexity and heterogeneity of POI. Methods: We used whole genome sequencing (WGS), conditional knockout mouse models combined with laser capture microdissection (LCM), and RNA/ChIP sequencing to analyze the crucial roles of polycomb repressive complex 1 (PRC1) in clinical POI and mammalian folliculogenesis. Results: A deletion mutation of MEL18, the key component of PRC1, was identified in a 17-year-old patient. However, deleting Mel18 in granulosa cells (GCs) did not induce infertility until its homolog, Bmi1, was deleted simultaneously. Double deficiency of BMI1/MEL18 eliminated PRC1 catalytic activity, upregulating cyclin-dependent kinase inhibitors (CDKIs) and thus blocking GC proliferation during primary-to-secondary follicle transition. This defect led to damaged intercellular crosstalk, eventually resulting in gonadotropin response failure and infertility. Conclusions: Our findings highlighted the pivotal role of PRC1 as an epigenetic regulator of gene transcription networks in GC proliferation during early folliculogenesis. In the future, a better understanding of molecular details of PRC1 structural and functional abnormalities may contribute to POI diagnosis and therapeutic options.


Asunto(s)
Infertilidad , Insuficiencia Ovárica Primaria , Adolescente , Animales , Femenino , Humanos , Ratones , Núcleo Celular , Proliferación Celular/genética , Mamíferos , Complejo Represivo Polycomb 1/genética , Insuficiencia Ovárica Primaria/genética , Reproducción , Modelos Animales de Enfermedad , Ratones Noqueados
17.
Inorg Chem ; 63(7): 3359-3365, 2024 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-38315811

RESUMEN

The Fe(II) oxidation mechanism in the ferroxidase center of heavy chain ferritin has been studied extensively. However, the actual production of H2O2 was found to be substantially lower than expected at low flux of Fe(II) to ferritin subunits. Here, we demonstrated that H2O2 could interact with the di-iron nuclear center, leading to the production of hydroxyl radicals and oxygen. Two reaction intermediates were captured in the ferroxidase center by using the time-lapse crystallographic techniques in a shellfish ferritin. The crystal structures revealed the binding of H2O2 as a µ -1,2-peroxo-diferric species and the binding of O2 to the diferric structure. This investigation sheds light on the reaction between the di-iron nuclear center and H2O2 and provides insights for the exploitation of metalloenzymes.


Asunto(s)
Ferritinas , Hierro , Hierro/química , Ferritinas/química , Peróxido de Hidrógeno/química , Ceruloplasmina/química , Oxidación-Reducción , Compuestos Ferrosos/química
18.
Cell Stem Cell ; 31(2): 196-211.e6, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-38237586

RESUMEN

COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response. High-throughput screening in hPSC-derived DA neurons identified several FDA-approved drugs that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection. We also identified the inflammatory and cellular senescence signature and low levels of SARS-CoV-2 transcripts in human substantia nigra tissue of COVID-19 patients. Furthermore, we observed reduced numbers of neuromelanin+ and tyrosine-hydroxylase (TH)+ DA neurons and fibers in a cohort of severe COVID-19 patients. Our findings demonstrate that hPSC-derived DA neurons are susceptible to SARS-CoV-2, identify candidate neuroprotective drugs for COVID-19 patients, and suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.


Asunto(s)
COVID-19 , Células Madre Pluripotentes , Humanos , SARS-CoV-2 , Neuronas Dopaminérgicas , Sistema Nervioso Central
19.
IEEE J Biomed Health Inform ; 28(4): 2223-2234, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38285570

RESUMEN

Preterm birth is the leading cause of death in children under five years old, and is associated with a wide sequence of complications in both short and long term. In view of rapid neurodevelopment during the neonatal period, preterm neonates may exhibit considerable functional alterations compared to term ones. However, the identified functional alterations in previous studies merely achieve moderate classification performance, while more accurate functional characteristics with satisfying discrimination ability for better diagnosis and therapeutic treatment is underexplored. To address this problem, we propose a novel brain structural connectivity (SC) guided Vision Transformer (SCG-ViT) to identify functional connectivity (FC) differences among three neonatal groups: preterm, preterm with early postnatal experience, and term. Particularly, inspired by the neuroscience-derived information, a novel patch token of SC/FC matrix is defined, and the SC matrix is then adopted as an effective mask into the ViT model to screen out input FC patch embeddings with weaker SC, and to focus on stronger ones for better classification and identification of FC differences among the three groups. The experimental results on multi-modal MRI data of 437 neonatal brains from publicly released Developing Human Connectome Project (dHCP) demonstrate that SCG-ViT achieves superior classification ability compared to baseline models, and successfully identifies holistically different FC patterns among the three groups. Moreover, these different FCs are significantly correlated with the differential gene expressions of the three groups. In summary, SCG-ViT provides a powerfully brain-guided pipeline of adopting large-scale and data-intensive deep learning models for medical imaging-based diagnosis.


Asunto(s)
Conectoma , Nacimiento Prematuro , Femenino , Niño , Humanos , Recién Nacido , Preescolar , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Conectoma/métodos , Suministros de Energía Eléctrica
20.
ACS Appl Mater Interfaces ; 16(6): 8119-8129, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38293896

RESUMEN

Metamaterial has received widespread research in the fields of electromagnetic stealth due to its characteristics of strong resonance and flexible designability. However, a lack of a comprehensive understanding of the internal physical mechanism still imposes certain limitations on broadband absorption designs. Hence, this work proposes a new strategy for the broadening of the working frequency band of metamaterial absorbers by constructing local-chiral features to regulate the amplitude and phase information. The absorber consists of staggered cut-wire metal patterns with lumped resistors placed at the center position determined by characteristic mode analysis. Combining the modal significance, equivalent circuit, surface current, electric field distribution, and symmetry model theory, the working mechanism for wideband absorption performance has been analyzed in detail. The experimental results are in good agreement with the simulation results; the absorption rate exceeds 82% in the frequency range of 4.5-11.7 GHz and surpasses about 90% in the frequency range of 4.7-10.8 GHz under transverse electric (TE) or transverse-magnetic (TM) polarizations. Compared to the case without chiral features, the proposed design can achieve a 28% increase in operating bandwidth. The proposed design method is applicable for the optimization of various typical dipole-type metamaterial absorbers and provides a novel strategy for future wideband metamaterial absorption.

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