Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 184
Filtrar
1.
Biomed Opt Express ; 15(3): 1474-1485, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38495699

RESUMO

The kidney is an important organ for excreting metabolic waste and maintaining the stability of the body's internal environment. The renal function involves multiple complex and fine structures in the whole kidney, and any change in these structures may cause impaired nephric function. Consequently, achieving three-dimensional (3D) reconstruction of the entire kidney at a single-cell resolution is of significant importance for understanding the kidney's structural characteristics and exploring the pathogenesis of kidney diseases. In this paper, we propose a pipeline from sample preparation to optical microscopic imaging of the entire kidney, followed by data processing for 3D reconstruction of the whole mouse kidney. We employed transgenic fluorescent labeling and propidium iodide (PI) labeling to obtain detailed information about the vascular structure and cytoarchitecture of the kidney. Subsequently, the entire mouse kidney was imaged at submicron-resolution using high-definition fluorescent micro-optical sectioning tomography (HD-fMOST). Finally, we reconstructed the structures of interest through various data processing methods on the original images. This included detecting glomeruli throughout the entire kidney, as well as the segmentation and visualization of the renal arteries, veins, and three different types of nephrons. Our method provides a powerful tool for studying the renal microstructure and its spatial relationships throughout the entire kidney.

2.
Cell Death Dis ; 15(3): 235, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38531846

RESUMO

Ubiquitin-specific protease 3 (USP3) plays an important role in the progression of various tumors. However, the role of USP3 in osteosarcoma (OS) remains poorly understood. The aim of this study was to explore the biological function of USP3 in OS and the underlying molecular mechanism. We found that OS had higher USP3 expression compared with that of normal bone tissue, and high expression of USP3 was associated with poor prognosis in patients with OS. Overexpression of USP3 significantly increased OS cell proliferation, migration, and invasion. Mechanistically, USP3 led to the activation of the PI3K/AKT signaling pathway in OS by binding to EPHA2 and then reducing its protein degradation. Notably, the truncation mutant USP3-F2 (159-520) interacted with EPHA2, and amino acid 203 was found to play an important role in this process. And knockdown of EPHA2 expression reversed the pro-tumour effects of USP3-upregulating. Thus, our study indicates the USP3/EPHA2 axis may be a novel potential target for OS treatment.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais , Proliferação de Células , Osteossarcoma/patologia , Neoplasias Ósseas/patologia , Movimento Celular , Proteases Específicas de Ubiquitina/metabolismo
3.
Science ; 383(6682): eadj9198, 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38300992

RESUMO

Mapping single-neuron projections is essential for understanding brain-wide connectivity and diverse functions of the hippocampus (HIP). Here, we reconstructed 10,100 single-neuron projectomes of mouse HIP and classified 43 projectome subtypes with distinct projection patterns. The number of projection targets and axon-tip distribution depended on the soma location along HIP longitudinal and transverse axes. Many projectome subtypes were enriched in specific HIP subdomains defined by spatial transcriptomic profiles. Furthermore, we delineated comprehensive wiring diagrams for HIP neurons projecting exclusively within the HIP formation (HPF) and for those projecting to both intra- and extra-HPF targets. Bihemispheric projecting neurons generally projected to one pair of homologous targets with ipsilateral preference. These organization principles of single-neuron projectomes provide a structural basis for understanding the function of HIP neurons.


Assuntos
Axônios , Mapeamento Encefálico , Hipocampo , Neurônios , Animais , Camundongos , Axônios/fisiologia , Axônios/ultraestrutura , Hipocampo/ultraestrutura , Neurônios/classificação , Neurônios/ultraestrutura , Análise de Célula Única/métodos , Rede Nervosa , Masculino , Camundongos Endogâmicos C57BL
4.
Comput Biol Med ; 171: 108102, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38350398

RESUMO

The morphological analysis of cells from optical images is vital for interpreting brain function in disease states. Extracting comprehensive cell morphology from intricate backgrounds, common in neural and some medical images, poses a significant challenge. Due to the huge workload of manual recognition, automated neuron cell segmentation using deep learning algorithms with labeled data is integral to neural image analysis tools. To combat the high cost of acquiring labeled data, we propose a novel semi-supervised cell segmentation algorithm for immunofluorescence-stained cell image datasets (ISC), utilizing a mean-teacher semi-supervised learning framework. We include a "cross comparison representation learning block" to enhance the teacher-student model comparison on high-dimensional channels, thereby improving feature compactness and separability, which results in the extraction of higher-dimensional features from unlabeled data. We also suggest a new network, the Multi Pooling Layer Attention Dense Network (MPAD-Net), serving as the backbone of the student model to augment segmentation accuracy. Evaluations on the immunofluorescence staining datasets and the public CRAG dataset illustrate our method surpasses other top semi-supervised learning methods, achieving average Jaccard, Dice and Normalized Surface Dice (NSD) indicators of 83.22%, 90.95% and 81.90% with only 20% labeled data. The datasets and code are available on the website at https://github.com/Brainsmatics/CCRL.


Assuntos
Algoritmos , Núcleo Celular , Humanos , Processamento de Imagem Assistida por Computador , Coloração e Rotulagem , Aprendizado de Máquina Supervisionado
5.
Physiol Behav ; 277: 114499, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38378074

RESUMO

An increasing body of evidence suggests that the state of hyperalgesia could be socially transferred from one individual to another through a brief empathetic social contact. However, how the social transfer of pain develops during social contact is not well-known. Utilizing a well-established mouse model, the present study aims to study the functional role of visual and olfactory cues in the development of socially-transferred mechanical hypersensitivity. Behavioral tests demonstrated that one hour of brief social contact with a conspecific mouse injected with complete Freund's adjuvant (CFA) was both sufficient and necessary for developing socially-transferred mechanical hypersensitivity. One hour of social contact with visual deprivation could not prevent the development of socially-transferred mechanical hypersensitivity, and screen observation of a CFA cagemate was not sufficient to develop socially-transferred mechanical hypersensitivity in bystanders. Methimazole-induced olfactory deprivation, a compound with reversible toxicity on the nasal olfactory epithelium, was sufficient to prevent the development of socially-transferred mechanical hypersensitivity. Intriguingly, repeated but not acute olfactory exposure to the CFA mouse bedding induced a robust decrease in 50 % paw withdrawal thresholds (50 %PWTs) to mechanical stimuli, an effect returned to the baseline level after two days of washout with clean bedding. The findings strongly indicate that the normal olfactory function is crucial for the induction of mechanical hypersensitivity through brief empathetic contact, offering valuable insights for animal housing in future pain research.


Assuntos
Hiperalgesia , Dor , Camundongos , Masculino , Animais , Camundongos Endogâmicos C57BL , Hiperalgesia/induzido quimicamente , Modelos Animais de Doenças , Inflamação
6.
Neuron ; 112(7): 1081-1099.e7, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38290516

RESUMO

Oxytocin (OXT) plays important roles in autonomic control and behavioral modulation. However, it is unknown how the projection patterns of OXT neurons align with underlying physiological functions. Here, we present the reconstructed single-neuron, whole-brain projectomes of 264 OXT neurons of the mouse paraventricular hypothalamic nucleus (PVH) at submicron resolution. These neurons hierarchically clustered into two groups, with distinct morphological and transcriptional characteristics and mutually exclusive projection patterns. Cluster 1 (177 neurons) axons terminated exclusively in the median eminence (ME) and have few collaterals terminating within hypothalamic regions. By contrast, cluster 2 (87 neurons) sent wide-spread axons to multiple brain regions, but excluding ME. Dendritic arbors of OXT neurons also extended outside of the PVH, suggesting capability to sense signals and modulate target regions. These single-neuron resolution observations reveal distinct OXT subpopulations, provide comprehensive analysis of their morphology, and lay the structural foundation for better understanding the functional heterogeneity of OXT neurons.


Assuntos
Ocitocina , Núcleo Hipotalâmico Paraventricular , Animais , Camundongos , Hipotálamo , Neurônios/fisiologia , Ocitocina/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia
7.
Nat Neurosci ; 27(2): 249-258, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38238430

RESUMO

Sleep interacts reciprocally with immune system activity, but its specific relationship with microglia-the resident immune cells in the brain-remains poorly understood. Here, we show in mice that microglia can regulate sleep through a mechanism involving Gi-coupled GPCRs, intracellular Ca2+ signaling and suppression of norepinephrine transmission. Chemogenetic activation of microglia Gi signaling strongly promoted sleep, whereas pharmacological blockade of Gi-coupled P2Y12 receptors decreased sleep. Two-photon imaging in the cortex showed that P2Y12-Gi activation elevated microglia intracellular Ca2+, and blockade of this Ca2+ elevation largely abolished the Gi-induced sleep increase. Microglia Ca2+ level also increased at natural wake-to-sleep transitions, caused partly by reduced norepinephrine levels. Furthermore, imaging of norepinephrine with its biosensor in the cortex showed that microglia P2Y12-Gi activation significantly reduced norepinephrine levels, partly by increasing the adenosine concentration. These findings indicate that microglia can regulate sleep through reciprocal interactions with norepinephrine transmission.


Assuntos
Cálcio , Microglia , Camundongos , Animais , Norepinefrina , Transdução de Sinais/fisiologia , Sono
8.
Transplant Cell Ther ; 30(2): 207.e1-207.e7, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37931801

RESUMO

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare form of plasma cell dyscrasia often treated with high-dose chemotherapy and autologous stem cell transplantation (ASCT). ASCT has resulted in satisfactory and sustained therapeutic outcomes. However, a substantial number of patients eventually experience disease progression, requiring second-line treatment. Therefore, it would be of further benefit to identify patients who will acquire the best long-term survival after ASCT. The aim of this study was to fully reveal the outcomes of patients undergoing ASCT in a large series with long-term follow-up. Long-term outcomes of 239 patients with newly diagnosed POEMS syndrome undergoing ASCT at a single center were evaluated retrospectively. Rates of hematologic complete response (CRH) and vascular endothelial growth factor (VEGF) complete response (CRV) were 57.3% and 68.6%, respectively, with 90.5% of patients achieving an overall clinical response. At a median follow-up of 94 months, the 5-year overall survival (OS) rate was 92.8%, and the 5-year time to next-line treatment (TTNT) rate was 72.2% (median TTNT, 96 months). Patients achieving CRH (5-year TTNT rate, 82.5% versus 60.7%; P < .0001) or CRV (5-year TTNT rate 83.7% versus 54.2%; P < .0001) had better survival outcomes compared to non-CR group patients. Dual hematologic and VEGF complete responses carry further benefit for survival (median TTNT, 129 months versus 68 months; P < .0001). Seven cases of second primary malignancy were recorded, all of which were solid tumors. Front-line ASCT resulted in excellent long-term survival in patients with POEMS syndrome, with the best survival observed in those achieving dual hematologic and VEGF CRs.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome POEMS , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Síndrome POEMS/terapia , Síndrome POEMS/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Transplante Autólogo/métodos
9.
J Neural Eng ; 20(6)2023 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-37972395

RESUMO

Objective. The OSort algorithm, a pivotal unsupervised spike sorting method, has been implemented in dedicated hardware devices for real-time spike sorting. However, due to the inherent complexity of neural recording environments, OSort still grapples with numerous transient cluster occurrences during the practical sorting process. This leads to substantial memory usage, heavy computational load, and complex hardware architectures, especially in noisy recordings and multi-channel systems.Approach. This study introduces an optimized OSort algorithm (opt-OSort) which utilizes correlation coefficient (CC), instead of Euclidean distance as classification criterion. TheCCmethod not only bolsters the robustness of spike classification amidst the diverse and ever-changing conditions of physiological and recording noise environments, but also can finish the entire sorting procedure within a fixed number of cluster slots, thus preventing a large number of transient clusters. Moreover, the opt-OSort incorporates two configurable validation loops to efficiently reject cluster outliers and track recording variations caused by electrode drifting in real-time.Main results. The opt-OSort significantly reduces transient cluster occurrences by two orders of magnitude and decreases memory usage by 2.5-80 times in the number of pre-allocated transient clusters compared with other hardware implementations of OSort. The opt-OSort maintains an accuracy comparable to offline OSort and other commonly-used algorithms, with a sorting time of 0.68µs as measured by the hardware-implemented system in both simulated datasets and experimental data. The opt-OSort's ability to handle variations in neural activity caused by electrode drifting is also demonstrated.Significance. These results present a rapid, precise, and robust spike sorting solution suitable for integration into low-power, portable, closed-loop neural control systems and brain-computer interfaces.


Assuntos
Neurônios , Processamento de Sinais Assistido por Computador , Neurônios/fisiologia , Algoritmos , Eletrodos , Sistemas Computacionais , Potenciais de Ação/fisiologia
10.
J Cardiovasc Nurs ; 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-38019028

RESUMO

BACKGROUND: Adequate energy intake is essential for good clinical outcomes. The association between energy intake and readmission burden of patients with heart failure (HF) still needs to be clarified. OBJECTIVE: In this study, our aim was to determine the association between energy intake and readmission in patients with HF. METHODS: A total of 311 inpatients with HF were recruited. Demographic and clinical information were collected during hospitalization; the daily diets of the participants were collected in the second week after discharge using the 3-day diet record, and the energy intake was calculated using a standardized nutrition calculator. The inadequate energy intake was defined as <70% × 25 kcal/kg of ideal body weight. The participants were followed up for 12 weeks after discharge. The number, reasons, and length of stay of unplanned readmissions were collected. Regression analyses were used to evaluate the associations between inadequate energy intake, and readmission rate and readmission days. RESULTS: The median of the energy intake of participants was 1032 (interquartile range, 809-1266) kcal/d. The prevalence of inadequate energy intake was 40%. Patients with inadequate energy intake had a higher risk of unplanned readmission (odds ratio, 5.616; 95% confidence interval, 3.015-10.462; P < .001) and more readmission days (incidence rate ratio, 5.226; 95% confidence interval, 3.829-7.134, P < .001) after adjusting for potential confounders. CONCLUSIONS: Patients with HF had a high incidence of inadequate dietary energy intake, and it increases the burden of readmission.

11.
Cell ; 186(24): 5394-5410.e18, 2023 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-37922901

RESUMO

Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or dopamine receptor agonists, but its action lacks specificity due to the wide distribution of dopamine receptors in the central nervous system and periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient retrograde adeno-associated virus (AAV), promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans.


Assuntos
Terapia Genética , Doença de Parkinson , Animais , Humanos , Camundongos , Corpo Estriado/metabolismo , Levodopa/uso terapêutico , Levodopa/genética , Neurônios/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/terapia , Primatas , Receptores de Dopamina D1/metabolismo , Modelos Animais de Doenças
12.
Cell Rep ; 42(10): 113204, 2023 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-37804511

RESUMO

Olfactory learning is widely regarded as a substrate for animal survival. The exact brain areas involved in olfactory learning and how they function at various stages during learning remain elusive. Here, we investigate the role of the lateral entorhinal cortex (LEC) and the posterior piriform cortex (PPC), two important olfactory areas, in aversive olfactory learning. We find that the LEC is involved in the acquisition of negative odor value during olfactory fear conditioning, whereas the PPC is involved in the memory-retrieval phase. Furthermore, inhibition of LEC CaMKIIα+ neurons affects fear encoding, fear memory recall, and PPC responses to a conditioned odor. These findings provide direct evidence for the involvement of LEC CaMKIIα+ neurons in negative valence encoding.


Assuntos
Córtex Entorrinal , Olfato , Animais , Córtex Entorrinal/fisiologia , Olfato/fisiologia , Odorantes , Memória/fisiologia , Neurônios/fisiologia
13.
Neuron ; 111(23): 3837-3853.e5, 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-37734380

RESUMO

Reward devaluation adaptively controls reward intake. It remains unclear how cortical circuits causally encode reward devaluation in healthy and depressed states. Here, we show that the neural pathway from the anterior cingulate cortex (ACC) to the basolateral amygdala (BLA) employs a dynamic inhibition code to control reward devaluation and depression. Fiber photometry and imaging of ACC pyramidal neurons reveal reward-induced inhibition, which weakens during satiation and becomes further attenuated in depression mouse models. Ablating or inhibiting these neurons desensitizes reward devaluation, causes reward intake increase and ultimate obesity, and ameliorates depression, whereas activating the cells sensitizes reward devaluation, suppresses reward consumption, and produces depression-like behaviors. Among various ACC neuron subpopulations, the BLA-projecting subset bidirectionally regulates reward devaluation and depression-like behaviors. Our study thus uncovers a corticoamygdalar circuit that encodes reward devaluation via blunted inhibition and suggests that enhancing inhibition within this circuit may offer a therapeutic approach for treating depression.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Condicionamento Operante , Animais , Camundongos , Condicionamento Operante/fisiologia , Depressão , Recompensa , Complexo Nuclear Basolateral da Amígdala/fisiologia , Saciação/fisiologia
14.
Aging (Albany NY) ; 15(18): 9590-9613, 2023 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-37724907

RESUMO

YY1 affects tumorigenesis and metastasis in multiple ways. However, the function of YY1 and the potential mechanisms through which it operates in gastric cancer (GC) progression by regulating autophagy remains poorly understood. This study aimed to assess the essential transcription factors (TFs) involved in autophagy regulation in GC. Western blot, RFP-GFP-LC3 double fluorescence and transmission electron microscopy (TEM) assays were used to probe autophagy activity in GC cells. Methylated RNA immunoprecipitation (MeRIP) was utilized to evaluate the ALKBH5-regulated m6A levels of YY1. Gain- and loss-of-function assays were employed in the scrutiny of the biological effects of the ALKBH5/YY1/ATG4B axis on cancer cell proliferation and invasion abilities in vitro. Per the findings, YY1 was identified as a crucial transcriptional activator of cancer autophagy-related genes and promoted the proliferation and aggressiveness of cancer cells associated with enhanced ATG4B-mediated autophagy. However, ectopic ALKBH5 expression abolished the YY1-induced effect via m6A modification. Importantly, YTHDF1 facilitated the mRNA stability of YY1 through m6A recognition. Collectively, this study found that YY1 was regulated by ALKBH5 and YTHDF1-mediated m6A modification and served as an autophagy-dependent tumor driver to accelerate cancer progression through ATG4B transactivation, providing an exploitable therapeutic target for GC.

15.
Eur J Prev Cardiol ; 30(17): 1906-1921, 2023 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-37652032

RESUMO

AIMS: To perform a systematic review and meta-analysis to evaluate the impact of weight loss (WL) on the prognosis of overweight and obese patients with heart failure (HF). METHODS AND RESULTS: We reviewed the literature up to 1 February 2023 from PubMed, Web of Science, Embase, Cochrane Library, and Chinese databases for cohort studies, and randomized controlled trials (RCTs). Data from eligible studies were extracted, and statistical analyses were performed using Review Manager 5.3. A total of 19 studies (involving 449 882 patients) were included in the systematic review and meta-analyses. The results showed that WL did not reduce the mortality and rehospitalization rates in overweight and obese HF patients, but could improve the quality of life (P = 0.002), cardiac function (P = 0.0001), and exercise capacity (P = 0.03). The subgroup analysis showed that WL from bariatric surgery (BS) reduced the risk of death (P < 0.00001), WL from medication or exercise was not significantly associated with the risk of death (P = 0.18), and WL was associated with a higher mortality in the subgroup with unspecified WL modality or unintentional WL (P < 0.00001). In addition, it did not reduce the risk of short-term rehospitalization (P = 0.11), but reduced the rehospitalization rates over the long-term (P = 0.03). CONCLUSION: WL improves the long-term rehospitalization (>3 months), quality of life, cardiac function, and exercise capacity in overweight and obese HF patients. Although overall WL is not proven effective, subgroup analysis shows that BS can reduce mortality.


We used mortality, rehospitalization rates, quality of life, the New York Heart Association (NYHA), and 6-min walk test (6 MWT) to assess the impact of weight loss (WL) on the prognosis of overweight and obese heart failure (HF) patients. Key findings: WL is associated with improvements in long-term rehospitalization rates, quality of life, cardiac function, and exercise capacity.Bariatric surgery (BS) may reduce mortality in overweight and obese HF patients. Unintentional WL of more than 5% may mean a bad condition and could increase mortality.


Assuntos
Insuficiência Cardíaca , Sobrepeso , Humanos , Sobrepeso/complicações , Sobrepeso/diagnóstico , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/epidemiologia , Redução de Peso , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Qualidade de Vida
16.
Light Sci Appl ; 12(1): 204, 2023 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-37640721

RESUMO

One intrinsic yet critical issue that troubles the field of fluorescence microscopy ever since its introduction is the unmatched resolution in the lateral and axial directions (i.e., resolution anisotropy), which severely deteriorates the quality, reconstruction, and analysis of 3D volume images. By leveraging the natural anisotropy, we present a deep self-learning method termed Self-Net that significantly improves the resolution of axial images by using the lateral images from the same raw dataset as rational targets. By incorporating unsupervised learning for realistic anisotropic degradation and supervised learning for high-fidelity isotropic recovery, our method can effectively suppress the hallucination with substantially enhanced image quality compared to previously reported methods. In the experiments, we show that Self-Net can reconstruct high-fidelity isotropic 3D images from organelle to tissue levels via raw images from various microscopy platforms, e.g., wide-field, laser-scanning, or super-resolution microscopy. For the first time, Self-Net enables isotropic whole-brain imaging at a voxel resolution of 0.2 × 0.2 × 0.2 µm3, which addresses the last-mile problem of data quality in single-neuron morphology visualization and reconstruction with minimal effort and cost. Overall, Self-Net is a promising approach to overcoming the inherent resolution anisotropy for all classes of 3D fluorescence microscopy.

17.
Cell Commun Signal ; 21(1): 199, 2023 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-37563688

RESUMO

The study was design to investigate the functional roles of Wilms tumor 1-associated protein (WTAP), an enzyme catalyzes m6A modification, in the pathogenesis of osteoarthritis (OA) and further elucidate its possible regulatory mechanism. Herein, we discovered that WTAP was outstandingly upregulated in chondrocyte stimulated with Lipopolysaccharide (LPS) and cartilage tissue of patients with OA. Functional studies have demonstrated that WTAP knockdown enhances proliferation ability, suppresses apoptosis, and reduces extracellular matrix (ECM) degradation in an LPS-induced OA chondrocyte injury model and ameliorates cartilage damage in a destabilizing the medial meniscus (DMM)-induced OA mice model. Conversely, overexpression of WTAP contributes to the opposite effects. Mechanistically, our data has demonstrated that m6A modification mediated by WTAP promotes the maturation of pri-miR-92b to miR-92b-5p, thereby enhancing the targeted inhibitory function of miR-92b-5p on TIMP4. Furthermore, we have discovered that WTAP can directly facilitate the degradation of TIMP4 mRNAs in a YTHDF2-dependent manner. In a nutshell, our findings suggested that WTAP knockdown alleviated OA progression by modulating the miR-92b-5p/TIMP4 axis in an m6A-dependent manner. Our study disclosed that WTAP-mediated m6A modification displayed a crucial role in OA development and suggested that targeting WTAP could be a promising preventive and therapeutic target for patients with OA. Video Abstract.


Assuntos
MicroRNAs , Osteoartrite , Animais , Camundongos , Apoptose , Condrócitos/metabolismo , Lipopolissacarídeos/farmacologia , Metiltransferases/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Humanos
18.
Nat Neurosci ; 26(8): 1394-1406, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37474638

RESUMO

The brain generates predictive motor commands to control the spatiotemporal precision of high-velocity movements. Yet, how the brain organizes automated internal feedback to coordinate the kinematics of such fast movements is unclear. Here we unveil a unique nucleo-olivary loop in the cerebellum and its involvement in coordinating high-velocity movements. Activating the excitatory nucleo-olivary pathway induces well-timed internal feedback complex spike signals in Purkinje cells to shape cerebellar outputs. Anatomical tracing reveals extensive axonal collaterals from the excitatory nucleo-olivary neurons to downstream motor regions, supporting integration of motor output and internal feedback signals within the cerebellum. This pathway directly drives saccades and head movements with a converging direction, while curtailing their amplitude and velocity via the powerful internal feedback mechanism. Our finding challenges the long-standing dogma that the cerebellum inhibits the inferior olivary pathway and provides a new circuit mechanism for the cerebellar control of high-velocity movements.


Assuntos
Cerebelo , Núcleo Olivar , Núcleo Olivar/fisiologia , Cerebelo/fisiologia , Neurônios/fisiologia , Células de Purkinje/fisiologia , Axônios
20.
BMC Biol ; 21(1): 135, 2023 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-37280580

RESUMO

BACKGROUND: Based on their anatomical location, rostral projections of nuclei are classified as ascending circuits, while caudal projections are classified as descending circuits. Upper brainstem neurons participate in complex information processing and specific sub-populations preferentially project to participating ascending or descending circuits. Cholinergic neurons in the upper brainstem have extensive collateralizations in both ascending and descending circuits; however, their single-cell projection patterns remain unclear because of the lack of comprehensive characterization of individual neurons. RESULTS: By combining fluorescent micro-optical sectional tomography with sparse labeling, we acquired a high-resolution whole-brain dataset of pontine-tegmental cholinergic neurons (PTCNs) and reconstructed their detailed morphology using semi-automatic reconstruction methods. As the main source of acetylcholine in some subcortical areas, individual PTCNs had abundant axons with lengths up to 60 cm and 5000 terminals and innervated multiple brain regions from the spinal cord to the cortex in both hemispheres. Based on various collaterals in the ascending and descending circuits, individual PTCNs were grouped into four subtypes. The morphology of cholinergic neurons in the pedunculopontine nucleus was more divergent, whereas the laterodorsal tegmental nucleus neurons contained richer axonal branches and dendrites. In the ascending circuits, individual PTCNs innervated the thalamus in three different patterns and projected to the cortex via two separate pathways. Moreover, PTCNs targeting the ventral tegmental area and substantia nigra had abundant collaterals in the pontine reticular nuclei, and these two circuits contributed oppositely to locomotion. CONCLUSIONS: Our results suggest that individual PTCNs have abundant axons, and most project to various collaterals in the ascending and descending circuits simultaneously. They target regions with multiple patterns, such as the thalamus and cortex. These results provide a detailed organizational characterization of cholinergic neurons to understand the connexional logic of the upper brainstem.


Assuntos
Axônios , Tronco Encefálico , Tronco Encefálico/fisiologia , Axônios/fisiologia , Ponte/anatomia & histologia , Ponte/fisiologia , Encéfalo , Neurônios Colinérgicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...