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MOTIVATION: Deep learning models have achieved remarkable success in a wide range of natural-world tasks, such as vision, language, and speech recognition. These accomplishments are largely attributed to the availability of open-source large-scale datasets. More importantly, pre-trained foundational modellearnings exhibit a surprising degree of transferability to downstream tasks, enabling efficient learning even with limited training examples. However, the application of such natural-domain models to the domain of tiny Cryo-Electron Tomography (Cryo-ET) images has been a relatively unexplored frontier. This research is motivated by the intuition that 3D Cryo-ET voxel data can be conceptually viewed as a sequence of progressively evolving video frames. RESULTS: Leveraging the above insight, we propose a novel approach that involves the utilization of 3D models pre-trained on large-scale video datasets to enhance Cryo-ET subtomogram classification. Our experiments, conducted on both simulated and real Cryo-ET datasets, reveal compelling results. The use of video initialization not only demonstrates improvements in classification accuracy but also substantially reduces training costs. Further analyses provide additional evidence of the value of video initialization in enhancing subtomogram feature extraction. Additionally, we observe that video initialization yields similar positive effects when applied to medical 3D classification tasks, underscoring the potential of cross-domain knowledge transfer from video-based models to advance the state-of-the-art in a wide range of biological and medical data types. AVAILABILITY AND IMPLEMENTATION: https://github.com/xulabs/aitom.
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In this contribution, the concept of spatial modulation (SM) is firstly integrated into the structure of space-time block codes (STBC)-aided vertical Bell-labs layered space-time (VBLAST) systems, in order to strike a balanced tradeoff among bit error ratio (BER), spectral efficiency and computational complexity. First of all, in order to enhance the BER performance of STBC-VBLAST, we advocate an effective transmit power allocation (TPA) scheme with negligible implementation costs, while dividing the STBC and VBLAST layers with alleviated interference, so as to facilitate combination with SM. Then, we further utilize the unique structure of SM for enhancing the spectral efficiency of original STBC-VBLAST, wherein the information is conveyed by not only the amplitude/phase modulation (APM) symbols but also the antenna indices. In addition, constellation sets of STBC symbols are specifically designed to be rotated to make full use of the degrees of freedom. Finally, the performance advantages of the above-mentioned structures over traditional STBC-VBLAST are demonstrated by the theoretical derivation of a closed-form expression for the union bound on the bit error probability for various spectral efficiencies, and they are supported by simulation results.
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α-Synuclein (α-syn)-induced neurotoxicity has been generally accepted as a key step in the pathogenesis of Parkinson's disease (PD). Microtubule-associated protein tau, which is considered second only to α-syn, has been repeatedly linked with PD in association studies. However, the underlying interaction between these two PD-related proteins in vivo remains unclear. To investigate how the expression of tau affects α-syn-induced neurodegeneration in vivo, we generated triple transgenic mice that overexpressed α-syn A53T mutation in the midbrain dopaminergic neurons (mDANs) with different expression levels of tau. Here, we found that tau had no significant effect on the A53T α-syn-mediated mDANs degeneration. However, tau knockout could modestly promote the formation of α-syn aggregates, accelerate the severe and progressive degeneration of parvalbumin-positive (PV+) neurons in substantia nigra pars reticulata (SNR), accompanied with anxiety-like behavior in aged PD-related α-syn A53T mice. The mechanisms may be associated with A53T α-syn-mediated specifically successive impairment of N-methyl-d-aspartate receptor subunit 2B (NR2B), postsynaptic density-95 (PSD-95) and microtubule-associated protein 1A (MAP1A) in PV+ neurons. Our study indicates that MAP1A may play a beneficial role in preserving the survival of PV+ neurons, and that inhibition of the impairment of NR2B/PSD-95/MAP1A pathway, may be a novel and preferential option to ameliorate α-syn-induced neurodegeneration.
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Mutação , Degeneração Neural , Doença de Parkinson/etiologia , Parvalbuminas/análise , Substância Negra/patologia , alfa-Sinucleína/genética , Proteínas tau/fisiologia , Animais , Proteína 4 Homóloga a Disks-Large/fisiologia , Proteínas de Homeodomínio/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/fisiologia , Doença de Parkinson/patologia , Fragmentos de Peptídeos/fisiologia , Agregados Proteicos , Receptores de N-Metil-D-Aspartato/fisiologia , Fatores de Transcrição/fisiologia , alfa-Sinucleína/fisiologia , Proteínas tau/química , Proteínas tau/genéticaRESUMO
Banks can potentially reduce the variability of their revenue by diversifying beyond traditional lending activities into noninterest revenue sources. We investigate the effect of the COVID-19 pandemic on the relation between the use of noninterest income and bank profit and risk. The economic effect of the pandemic resulted in tightened credit standards and reduced demand for many types of loans. We find that noninterest revenue sources are positively related to performance but inversely related to risk. These results are consistent with a beneficial diversification effect during the pandemic from banks expanding beyond traditional lending sources of revenue.
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Parthenolide exhibits anti-leukaemia activity, whilst its synthetic modification to impart improve drug-like properties, including 1,4-conjugate addition of primary and secondary amines, have previously been used, 1,4-addition of aniline derivatives to parthenolide has not been fully explored. A protocol for such additions to parthenolide is outlined herein. Reaction conditions were determined using tulipane as a model Michael acceptor. Subsequently, aniline-containing parthenolide derivatives were prepared under the optimised conditions and single crystal X-ray diffraction structures were resolved for three of the compounds synthesised. The synthesised derivatives, along with compounds resulting from a side reaction, were tested for their in vitro anti-leukaemia activity using the chronic lymphocytic leukaemia (CLL) MEC1 cell line. Computational studies with the 2RAM protein structure suggested that the activity of the derivatives was independent of their in silico ability to dock with the Cys38 residue of NF-κB.
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Homozygous tau knockout (Mapt-/-) mice develop age-dependent dopaminergic (DA) neuronal loss in the substantia nigra (SN) and ventral tegmental area (VTA), supporting an important function of tau in maintaining the survival of midbrain dopaminergic neurons (mDANs) during aging. However, it remains to be determined whether the microtubule-associated protein tau regulates the differentiation and survival of mDANs during embryonic developmental stages. Here, we show that tau haploinsufficiency in postnatal day 0 (P0) heterozygous (Mapt+/-) pups, but not a complete loss of tau in the Mapt-/- littermates, led to a significant reduction of DA neurons in the VTA. This selective loss of DA neurons correlated with a similar reduction in orthodenticle homeobox 2 (Otx2), which is restricted to VTA neurons at the postmitotic stage and selectively controls the neurogenesis and survival of specific neuronal subtypes of VTA. Moreover, the prenatal developmental cell death in the Mapt+/- VTA specifically increased, and the expression of microtubule-associated protein (MAP)-1A was significantly up-regulated in the P0 Mapt-/- , but not the Mapt+/- , pups. These results suggest that tau haploinsufficiency, without the compensation effect of MAP1A, induces reduction of Otx2 expression, increases prenatal cell death, and accordingly leads to selective loss of VTA DA neurons in the early postnatal stage. Our findings highlight the impact of tau haploinsufficiency on the survival of mDANs and indicate that tau may participate in midbrain development in a dose-dependent way.-Zheng, M., Jiao, L., Tang, X., Xiang, X., Wan, X., Yan, Y., Li, X., Zhang, G., Li, Y., Jiang, B., Cai, H., Lin, X. Tau haploinsufficiency causes prenatal loss of dopaminergic neurons in the ventral tegmental area and reduction of transcription factor orthodenticle homeobox 2 expression.
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Neurônios Dopaminérgicos/fisiologia , Haplótipos , Fatores de Transcrição Otx/metabolismo , Área Tegmentar Ventral/citologia , Proteínas tau/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Camundongos , Camundongos Knockout , Neurogênese , Fatores de Transcrição Otx/genética , Transcriptoma , Proteínas tau/genéticaRESUMO
Many of the unique properties of a conventionally crosslinked shape memory network are not found at the same time, and this is a large challenge for the development of advanced shape memory functional materials. In this work, a topologically well-controlled network shape memory poly(ethyl methacrylate) (CN-SMPEMA) is designed and fabricated by introducing two tetra-armed functional structures simultaneously as well-defined structure units to promote switch segment and net-point uniform distribution via the combined technology of the unique controllable atom transfer radical polymerization (ATRP) and copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC). Compared with conventionally crosslinked networks, the as-prepared CN-SMPEMA not only exhibits a combination of excellent mechanical properties, shape fixity, shape recovery ratios and outstanding cycling stability, but also displays rapid recoverability. Additionally, a feasible molecular mechanism for the shape memory effect of the CN-SMPEMA system is analyzed and proposed. We anticipate that such a topologically well-defined network shape memory material with multiple excellent properties will broaden the practical application range of acrylate-based shape memory polymer materials.
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Fabricating a single polymer network with no need to design complex structures to achieve an ideal combination of tunable high-strain multiple-shape memory effects and highly recoverable shape memory property is a great challenge for the real applications of advanced shape memory devices. Here, a facile and general approach to recoverable high-strain multishape shape memory polymers is presented via a random copolymerization of acrylate monomers and a chain-extended multiblock copolymer crosslinker. As-prepared shape memory networks show a large width at the half-peak height of the glass transition, far wider than current classical multishape shape memory polymers. A combination of tunable high-strain multishape memory effect and as high as 1000% recoverable strain in a single chemical-crosslinking network can be obtained. To the best of our knowledge, this is the first thermosetting material with a combination of highly recoverable strain and tunable high-strain multiple-shape memory effects.
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Materiais Biocompatíveis/química , Polímeros/química , Acrilatos/química , Teste de Materiais , TemperaturaRESUMO
BACKGROUND: We explored the prevalence of and risk factors for type 2 diabetes in the adult population of Shanghai (China) with and without dyslipidemia. MATERIAL AND METHODS: We conducted a cross-sectional survey including 14 385 adults (aged 16 to 88 years) in Shanghai using a stratified, multistage cluster sampling approach. RESULTS: Type 2 diabetes and hyperlipidemia were found in 1456 (10.1%) and 4583 (31.9%) subjects, respectively. Type 2 diabetes was more common in males (11.4%) than in females (9.2%, P<0.01), in the elderly (> or =65 years, 22.5%) than in younger (<55 years, <10%, P<0.01) individuals, and in urban (12.8%) than in rural populations (5.2%, P<0.01). Diabetes incidence was higher among patients with hyperlipidemia than in controls (16.9% vs. 7.0%, P<0.01; OR=2.72, 95% CI 2.44-3.03). Compared with controls, the risk for diabetes in subjects with isolated hypertriglyceridemia, isolated hypercholesterolemia, and mixed hyperlipidemia increased 1.75-fold (95% CI 1.53-1.99), 1.53-fold (95% CI 1.17-2.01), and 2.93-fold (95% CI 2.37-3.63), respectively. The fasting plasma glucose (FPG) and 2h-postprandial plasma glucose (2h-PG) increased with age in both sexes. The age- and sex-adjusted FPG and 2h-PG levels in hyperlipidemia were significantly higher than in controls (P<0.01). CONCLUSIONS: A high prevalence of type 2 diabetes in hyperlipidemia patients exists in Shanghai. Hyperlipidemia is associated with elevated blood glucose levels and therefore requires prompt intervention for prevention and treatment of diabetes in patients with dyslipidemia.
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Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Hiperlipidemias/complicações , Adolescente , Adulto , Idoso , Glicemia/metabolismo , China/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Jejum/sangue , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hiperlipidemias/sangue , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Prevalência , Fatores de Risco , Adulto JovemRESUMO
OBJECTIVE: To investigate the role of albumin-to-globulin ratio (AGR) in systemic lupus erythematosus (SLE) and its relationship with disease activity. METHODS: This retrospective study consecutively selected patients with SLE and healthy controls. Patients were divided into three groups according to the SLE Disease Activity Index 2000 (SLEDAI-2K): group 1 (mild disease activity, SLEDAI-2K ≤ 6), group 2 (moderate disease activity, SLEDAI-2K 7-12) and group 3 (severe disease activity, SLEDAI-2K > 12). Predictors of SLE disease activity were analysed by ordinal logistical regression. RESULTS: A total of 101 Chinese patients with SLE and 75 healthy Chinese controls were included. Patients with SLE had lower AGR values than healthy individuals, and group 3 patients with SLE displayed lower AGR values than those in group 1, but similar values to group 2. AGR was inversely correlated with SLEDAI-2K (r = -0.543). Ordinal logistic regression analysis showed that lower AGR (ß = -1.319) and lower complement C4 (ß = -1.073) were independent risk factors for SLE disease activity. CONCLUSIONS: AGR was decreased in patients with SLE and may be utilized as a useful inflammatory biomarker for monitoring SLE disease activity.
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Lúpus Eritematoso Sistêmico , Albumina Sérica , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores/sangue , Estudos de Casos e Controles , Complemento C4/metabolismo , Complemento C4/análise , Modelos Logísticos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica/análise , Albumina Sérica/metabolismo , Soroglobulinas/análise , Soroglobulinas/metabolismo , Índice de Gravidade de DoençaRESUMO
Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of RAB GTPases, and the phosphorylation levels are elevated by Parkinson's disease (PD)-linked mutations of LRRK2. However, the precise function of the specific RAB GTPase targeted by LRRK2 signaling in the brain remains to be elucidated. Here, we identify RAB12 as a robust LRRK2 substrate in the mouse brains through phosphoproteomics profiling and solve the structure of RAB12-LRRK2 protein complex through Cryo-EM analysis. Mechanistically, RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes through enhancing the phosphorylation of RAB10 and recruiting Rab interacting lysosomal protein like 1 (RILPL1), while the functions of RAB12 require a direct interaction with LRRK2 and LRRK2 kinase activity. Furthermore, the ciliary deficits and centrosome alteration caused by the PD-linked LRRK2-G2019S mutation are prevented by the deletion of Rab12 in astrocytes. Thus, our study reveals a physiological function of the RAB12-LRRK2 complex in regulating ciliogenesis and centrosome homeostasis. The RAB12-LRRK2 structure offers a guidance in the therapeutic development of PD by targeting the RAB12-LRRK2 interaction.
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Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling. Here, we focused on the role of Semaphorin 3A (Sema3A), expressed by sensory nerves, in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement (OTM) model. Firstly, bone formation was activated after the 3rd day of OTM, coinciding with a decrease in sensory nerves and an increase in pain threshold. Sema3A, rather than nerve growth factor (NGF), highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM. Moreover, in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells (hPDLCs) within 24 hours. Furthermore, exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload. Mechanistically, Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway, maintaining mitochondrial dynamics as mitochondrial fusion. Therefore, Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation, both as a pain-sensitive analgesic and a positive regulator for bone formation.
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Osteogênese , Semaforina-3A , Humanos , Remodelação Óssea , Diferenciação Celular , Semaforina-3A/metabolismo , Semaforina-3A/farmacologia , Gânglio Trigeminal/metabolismoRESUMO
OBJECTIVE: To identify the long non-coding RNA (lncRNA) expression profiling in exosomes derived from synovial fluid of rheumatoid arthritis (RA) patients, and carry out bioinformatics analysis on target genes of differentially expressed lncRNAs. METHODS: Exosomes were isolated from synovial fluid via ultracentrifugation. RNAs were extracted from exosomes by using HiPure Liquid RNA/miRNA kits, followed by lncRNA sequencing. Differentially expressed lncRNAs in RA were screened, and bioinformatics analysis of their target genes was carried out. qRT-PCR was used to verify the lncRNA expression levels. RESULTS: Compared with osteoarthritis (OA), 347 lncRNAs were found differentially expressed in RA. Compared with gout, 805 lncRNAs were found differentially expressed in RA. Compared with both OA and gout, 85 lncRNAs were found specially expressed in RA (65 were upregulated (including ENST00000433825.1)). Functional analysis of target genes of the specially expressed lncRNAs revealed significant enrichment of "autophagy" and "mTOR signaling pathway". The qRT-PCR results indicated that ENST00000433825.1 was highly expressed in RA, compared with both OA and gout (P < 0.05), which matched the lncRNA sequencing results. Correlation analysis showed that the level of ENST00000433825.1 in RA patients was significantly and positively correlated with the level of C-reactive protein (CRP) (P < 0.001). CONCLUSIONS: The lncRNA expression profiling in exosomes derived from synovial fluid of RA was significantly different from OA and gout. ENST00000433825.1 was highly and uniquely expressed in RA and significantly and positively correlated with CRP, which might provide a diagnostic and therapeutic biomarker for RA.
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Artrite Reumatoide , Exossomos , Gota , Osteoartrite , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Líquido Sinovial/metabolismo , Exossomos/genética , Exossomos/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismoRESUMO
Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10.6 million new cases and 1.4 million deaths in 2021. This global emergency is exacerbated by the emergence of multidrug-resistant MDR-TB and extensively drug-resistant XDR-TB; therefore, new drugs and new drug targets are urgently required. From a whole cell phenotypic screen, a series of azetidines derivatives termed BGAz, which elicit potent bactericidal activity with MIC99 values <10 µM against drug-sensitive Mycobacterium tuberculosis and MDR-TB, were identified. These compounds demonstrate no detectable drug resistance. The mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from the existing mycobacterial cell wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as antitubercular chemotherapies.
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Azetidinas , Tuberculose Extensivamente Resistente a Medicamentos , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Testes de Sensibilidade MicrobianaRESUMO
Contamination of leafy vegetables grown in heavy metal(loid)-polluted mining areas pose serious health risks. This study aimed to explore the heavy metal(loid) contamination of leafy vegetables near two mining areas, by collecting samples from 14 different leafy vegetable species in Yunnan Province, China. The lead (Pb), cadmium (Cd), arsenic (As), and copper (Cu) contents of the samples were determined, and risks to human health were calculated using the hazard quotient and hazard index (HI). Moreover, Malabar spinach was identified as a leafy vegetable that exhibits low accumulation of heavy metal(loid)s. The accumulation capacity of different Malabar spinach varieties was verified, and a Cd soil safety threshold was determined using a pot experiment. Overall, Pb and Cd were the main soil and vegetable contaminants found in both study sites. The HI values for all leafy vegetables, apart from Malabar spinach, were greater than 1, indicating the presence of risks to human health; moreover, the health risks were greater for children than adults. The Malabar spinach pot experiment results showed that only some Cd forms exceeded China's maximum permissible standards. Furthermore, Malabar spinach varieties A (instant Malabar spinach), C (extra-large leaf green vine Malabar spinach), and F (large leaf Malabar spinach) displayed the lowest Cd accumulation. We calculated Cd total and bioavailable soil safety thresholds of 4.75 and 0.77 mg kg-1, respectively. However, further research is required to validate soil heavy metal safety thresholds for different vegetables. Ultimately, the heavy metal(loid) contamination of leafy vegetables described here was more serious than anticipated. Finally, the results of this study can inform residents living near these mining areas of a low-risk leafy vegetable, which will reduce the harm caused by heavy metal(loid) contamination in the area.
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Metais Pesados , Poluentes do Solo , Criança , Adulto , Humanos , Cádmio/análise , Verduras , Spinacia oleracea , Bioacumulação , Chumbo , Contaminação de Alimentos/análise , Poluentes do Solo/análise , China , Metais Pesados/análise , Solo , Folhas de Planta/química , Medição de Risco , Monitoramento Ambiental/métodosRESUMO
The advent of large-scale pretrained language models (PLMs) has contributed greatly to the progress in natural language processing (NLP). Despite its recent success and wide adoption, fine-tuning a PLM often suffers from overfitting, which leads to poor generalizability due to the extremely high complexity of the model and the limited training samples from downstream tasks. To address this problem, we propose a novel and effective fine-tuning framework, named layerwise noise stability regularization (LNSR). Specifically, our method perturbs the input of neural networks with the standard Gaussian or in-manifold noise in the representation space and regularizes each layer's output of the language model. We provide theoretical and experimental analyses to prove the effectiveness of our method. The empirical results show that our proposed method outperforms several state-of-the-art algorithms, such as [Formula: see text] norm and start point (L2-SP), Mixout, FreeLB, and smoothness inducing adversarial regularization and Bregman proximal point optimization (SMART). In addition to evaluating the proposed method on relatively simple text classification tasks, similar to the prior works, we further evaluate the effectiveness of our method on more challenging question-answering (QA) tasks. These tasks present a higher level of difficulty, and they provide a larger amount of training examples for tuning a well-generalized model. Furthermore, the empirical results indicate that our proposed method can improve the ability of language models to domain generalization.
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Background: The mechanisms and effects of the interplay between the nerves and skeleton remain a popular research topic. This study aimed to analyze and evaluate publications on nerve-bone interactions using bibliometrics and to identify the state of the art of current research, hotspots, and future directions. Methods: This study included 1989 articles and reviews from the Web of Science Core Collection (WoSCC) published from January 1, 1991, to June 22, 2022. The Bibliometrix package of R 4.2.0 (The R Foundation for Statistical Computing, Vienna, Austria) was used to analyze basic information about the publications, including the annual number of publications, institution analysis, author influence analysis, journal analysis, and the national cooperation network. We also used CiteSpace 5.8.R3 for bibliometric analysis, including co-occurrence, co-citation, and cluster analysis. Results: We discovered a significant increase in the number of articles on nerve-bone interactions published over the last 10 years. The most active country and institution were the United States and the University of Minnesota, respectively. In terms of journals and cocited journals, Bone was ranked highest with respect to the number of publications, while Journal of Bone and Mineral Research was ranked highest among cited journals. Wang Lei was the author with the most publications, and Bjurholm A was the most cited author. The analysis of references and keywords revealed that the impact of nerve- and neuromodulation-related factors on stem cell differentiation was a persistently hot topic. Osteoarthritis, neuropeptide Y, and osteoclastogenic process are likely to be the next era of research hotspots. The neurovascular crosstalk within bone has received great attention, especially in skeletal diseases, which may provide potential targets for future treatments. Conclusions: We used a bibliometric method to provide an efficient, objective, and comprehensive assessment of existing research about the interplay between the skeletal and nervous systems and to accurately identify hotspots and research frontiers, providing valuable information for future research.
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BACKGROUND: The overexpression, accumulation, and cell-to-cell transmission of α-synuclein leads to the deterioration of Parkinson's disease (PD). Previous studies suggest that Baicalein (BAI) can bind to α-synuclein and inhibit α-synuclein aggregation and secretion. However, it is still unclear whether BAI can intervene with the pathogenic molecules in α-synuclein-mediated PD pathways beyond directly targeting α-synuclein per se. METHODS: This study aimed to systematically investigate BAI's potential targets in PD-related A53T mutant α-synuclein-mediated pathways by integrating data mining, network pharmacological analysis, and molecular docking simulation techniques. RESULTS: The results suggest that BAI may target genes that are dysregulated in synaptic transmission, vesicle trafficking, gene transcription, protein binding, extracellular matrix formation, and kinase activity in α-synucleinmediated pathways. NFKB1, STAT3, and CDKN1A are BAI's potential hub targets in these pathways. CONCLUSION: Our findings highlight BAI's potentiality to modulate α-synuclein-mediated pathways beyond directly targeting α-synuclein per se.
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Flavanonas , Doença de Parkinson , Humanos , alfa-Sinucleína/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Simulação de Acoplamento Molecular , Flavanonas/farmacologia , Subunidade p50 de NF-kappa B/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
Due to their unique surface structures and physicochemical properties, microplastics (MPs) can adsorb other contaminants, thus impacting their toxicity and fate in aquatic ecosystems. In the present study, the adsorption and transportation of copper ions (Cu2+) in polyethylene (PE, 5 and 150 µm) and their combined effects on four submerged macrophyte species were assessed. Results demonstrated that the addition of PE reduced the Cu2+ concentration in copper sulfate (CuSO4) solution and the adsorption of Cu2+ in PE (10 mg/L) increased with CuSO4 concentration (100-600 µmol/L). PE alone exhibited no inhibitory effects on macrophytes, while Cu2+ showed fatal toxicity toward the macrophytes. However, the combination of PE and Cu2+ showed lower inhibitory effects on macrophytes and the toxicity attenuation varied among species. Additionally, PE may act as a carrier (like a Trojan horse) for the environmental transfer of Cu2+, thereby hosting Cu2+ toxicity against macrophytes in the imported environment. Our findings indicate that PE acts as both an antidote to and carrier of Cu2+ toxicity in macrophytes. This study should help in clarifying the combined effects and risk assessments of MPs and heavy metals in future studies.
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Microplásticos , Poluentes Químicos da Água , Antídotos , Cobre/toxicidade , Ecossistema , Plásticos/toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidadeRESUMO
BACKGROUND: The development of the mandible largely determines the sagittal and vertical lateral appearance. The gonial angle (Articulare-Gonion-Menton, Ar-Go'-Me), as a composite indicator, represents the growth direction of the mandible. We proposed a method based on the Frankfort horizontal (FH) plane and its vertical plane (VFH) to divide the gonial angle into sagittal and vertical components (Articulare-Gonion-VFH / Menton-Gonion-FH, Ar-Go'-VFH / Me-Go'-FH) and to compare the accuracy of diagnosing the development of the mandible and maxillofacial structures with other methods. METHODS: Lateral cephalometric films from 736 volunteers aged 6-30 years were collected and analyzed for cephalometric measurements. Four groups of segmentation-based angle, including the FH-based segmentation (Ar-Go'-VFH / Me-Go'-FH), the SN-based segmentation (Articulare-Gonion- Sellion-Nasion plane' vertical plane/ Menton-Gonion- Sellion-Nasion plane, Ar-Go'-VSN / Me-Go'-SN), the Go'-S based segmentation(Articulare-Gonion-Sellion / Menton-Gonion-Sellion, Ar-Go'-S / Me-Go'-S), and the Go'-N based segmentation (Articulare-Gonion-Nasion / Menton-Gonion-Nasion, Ar-Go'-N / Me-Go'-N), as well as commonly used sagittal and vertical indices were measured. Pearson correlation analysis was used to show the representativeness of different segmentation methods on the mandibular growth direction. RESULTS: As the gonial angle decreased with age, all the segmentation-based metrics decreased. The plane-based segmentation metrics, including Ar-Go'-VFH / Me-Go'-FH, Ar-Go'-VSN / Me-Go'-SN, were superior to the point-based segmentation metrics (Ar-Go'-S / Me-Go'-S, and Ar-Go'-N / Me-Go '-N) in evaluating vertical and sagittal development of the mandible. The sagittal indicators displayed alteration of ramus and condyle, while these vertical indicators responded to the alteration of the mandibular corpus and gonial angle. CONCLUSIONS: The gonial angle should be clinically segmented with planes (including SN plane and FH plane) rather than points (including Go'-S and Go'-N) to assess mandibular development. The FH plane-based segmentation method facilitated chair-side diagnosis of the mandibular growth direction.