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Dysregulation of the DNA/RNA-binding protein FUS causes certain subtypes of ALS/FTD by largely unknown mechanisms. Recent evidence has shown that FUS toxic gain of function due either to mutations or to increased expression can disrupt critical cellular processes, including mitochondrial functions. Here, we demonstrate that in human cells overexpressing wild-type FUS or expressing mutant derivatives, the protein associates with multiple mRNAs, and these are enriched in mRNAs encoding mitochondrial respiratory chain components. Notably, this sequestration leads to reduced levels of the encoded proteins, which is sufficient to bring about disorganized mitochondrial networks, reduced aerobic respiration and increased reactive oxygen species. We further show that mutant FUS associates with mitochondria and with mRNAs encoded by the mitochondrial genome. Importantly, similar results were also observed in fibroblasts derived from ALS patients with FUS mutations. Finally, we demonstrate that FUS loss of function does not underlie the observed mitochondrial dysfunction, and also provides a mechanism for the preferential sequestration of the respiratory chain complex mRNAs by FUS that does not involve sequence-specific binding. Together, our data reveal that respiratory chain complex mRNA sequestration underlies the mitochondrial defects characteristic of ALS/FTD and contributes to the FUS toxic gain of function linked to this disease spectrum.
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Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/fisiopatologia , Regulação da Expressão Gênica/genética , Mitocôndrias/patologia , RNA Mensageiro/metabolismo , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Linhagem Celular , Respiração Celular/genética , Células Cultivadas , Transporte de Elétrons/genética , Genoma Mitocondrial , Humanos , Mitocôndrias/genética , Mutação , Agregação Patológica de Proteínas/genética , Ligação Proteica/genéticaRESUMO
The activation and mobilization of immune cells play a crucial role in immunotherapy. Existing therapeutic interventions, such as cytokines administration, aim to enhance immune cell activity. However, these approaches usually result in modest effectiveness and toxic side effects, thereby restricting their clinical application. Protease-activated receptors (PARs), a subfamily of G protein-coupled receptors, actively participate in the immune system by directly activating immune cells. The activation of PARs by proteases or synthetic ligands can modulate immune cell behavior, signaling, and responses to treat immune-related diseases, suggesting the significance of PARs agonism in immunotherapy. However, the agonism of PARs in therapeutical applications remains rarely discussed, since it has been traditionally considered that PARs activation facilitates disease progressions. This review aims to comprehensively summarize the activation, rather than inhibition, of PARs in immune-related physiological responses and diseases. Additionally, we will discuss the emerging immunotherapeutic potential of PARs agonism, providing a new strategic direction for PARs-mediated immunotherapy.
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Imunoterapia , Receptores Ativados por Proteinase , Peptídeo Hidrolases/metabolismo , Receptores Acoplados a Proteínas G , Receptores Ativados por Proteinase/agonistas , Receptores Ativados por Proteinase/metabolismo , Transdução de Sinais , Neoplasias/imunologia , Neoplasias/terapia , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Humanos , AnimaisRESUMO
Adipose tissue is the second most important site of estrogen production, where androgens are converted into estrogen by aromatase. While gastric cancer patients often develop adipocyte-rich peritoneal metastasis, the underlying mechanism remains unclear. In this study, we identified the G-protein-coupled estrogen receptor (GPER1) as a promoter of gastric cancer peritoneal metastasis. Functional in vitro studies revealed that ß-Estradiol (E2) or the GPER1 agonist G1 inhibited anoikis in gastric cancer cells. Additionally, genetic overexpression or knockout of GPER1 significantly inhibited or enhanced gastric cancer cell anoikis in vitro and peritoneal metastasis in vivo, respectively. Mechanically, GPER1 knockout disrupted the NADPH pool and increased reactive oxygen species (ROS) generation. Conversely, overexpression of GPER1 had the opposite effects. GPER1 suppressed nicotinamide adenine dinucleotide kinase 1(NADK1) ubiquitination and promoted its phosphorylation, which were responsible for the elevated expression of NADK1 at protein levels and activity, respectively. Moreover, genetic inhibition of NADK1 disrupted NADPH and redox homeostasis, leading to high levels of ROS and significant anoikis, which inhibited lung and peritoneal metastasis in cell-based xenograft models. In summary, our study suggests that inhibiting GPER1-mediated NADK1 activity and its ubiquitination may be a promising therapeutic strategy for peritoneal metastasis of gastric cancer.
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Neoplasias Peritoneais , Receptores de Estrogênio , Receptores Acoplados a Proteínas G , Neoplasias Gástricas , Humanos , Estrogênios/metabolismo , NAD/metabolismo , NADP/metabolismo , Oxirredução , Neoplasias Peritoneais/secundário , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Gástricas/patologia , AnimaisRESUMO
The prostate is a vital accessory gonad in the mammalian male reproductive system. With the ever-increasing proportion of the population over 60 years of age worldwide, the incidence of prostate diseases, such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa), is on the rise and is gradually becoming a significant medical problem globally. The notch signaling pathway is essential in regulating prostate early development. However, the potential regulatory mechanism of Notch signaling in prostatic enlargement and hyperplasia remains unclear. In this study, we proved that overactivation of Notch1 signaling in mouse prostatic epithelial cells (OEx) led to prostatic enlargement via enhancing proliferation and inhibiting apoptosis of prostatic epithelial cells. Further study showed that N1ICD/RBPJ directly up-regulated the androgen receptor (AR) and enhanced prostatic sensitivity to androgens. Hyper-proliferation was not found in orchidectomized OEx mice without androgen supply but was observed after Dihydrotestosterone (DHT) supplementation. Our data showed that the number of mitochondrion in prostatic epithelial cells of OEx mice was increased, but the mitochondrial function was impaired, and the essential activity of the mitochondrial respiratory electron transport chain was significantly weakened. Disordered mitochondrial number and metabolic function further resulted in excessive accumulation of reactive oxygen species (ROS). Importantly, anti-oxidant N-Acetyl-L-Cysteine (NAC) therapy could alleviate prostatic hyperplasia caused by the over-activation of Notch1 signaling. Furthermore, we observed the incremental Notch signaling activity in progenitor-like club cells in the scRNA-seq data set of human BPH patients. Moreover, the increased number of TROP2+ progenitors and Club cells was also confirmed in our OEx mice. In conclusion, our study revealed that over-activated Notch1 signaling induces prostatic enlargement by increasing androgen receptor sensitivity, disrupting cellular mitochondrial metabolism, increasing ROS, and a higher number of progenitor cells, all of which can be effectively rescued by NAC treatment.
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Hiperplasia Prostática , Animais , Humanos , Masculino , Camundongos , Androgênios/metabolismo , Mamíferos/metabolismo , Mitocôndrias/metabolismo , Próstata/metabolismo , Hiperplasia Prostática/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de SinaisRESUMO
Materials containing heterogeneous nanostructures hold great promise for achieving superior mechanical properties. However, the strengthening effect due to plastically inhomogeneous deformation in heterogeneous nanostructures has not been clearly understood. Here, we investigate a prototypical heterogeneous nanostructured material of gradient nanotwinned (GNT) Cu to unravel the origin of its extra strength arising from gradient nanotwin structures relative to uniform nanotwin counterparts. We measure the back and effective stresses of GNT Cu with different nanotwin thickness gradients and compare them with those of homogeneous nanotwinned Cu with different uniform nanotwin thicknesses. We find that the extra strength of GNT Cu is caused predominantly by the extra back stress resulting from nanotwin thickness gradient, while the effective stress is almost independent of the gradient structures. The combined experiment and strain gradient plasticity modeling show that an increasing structural gradient in GNT Cu produces an increasing plastic strain gradient, thereby raising the extra back stress. The plastic strain gradient is accommodated by the accumulation of geometrically necessary dislocations inside an unusual type of heterogeneous dislocation structure in the form of bundles of concentrated dislocations. Such a heterogeneous dislocation structure produces microscale internal stresses leading to the extra back stress in GNT Cu. Altogether, this work establishes a fundamental connection between the gradient structure and extra strength in GNT Cu through the mechanistic linkages of plastic strain gradient, heterogeneous dislocation structure, microscale internal stress, and extra back stress. Broadly, this work exemplifies a general approach to unraveling the strengthening mechanisms in heterogeneous nanostructured materials.
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Arl13b, an ARF/Arl-family GTPase, is highly enriched in the cilium. Recent studies have established Arl13b as one of the most crucial regulators for ciliary organization, trafficking, and signaling. The ciliary localization of Arl13b is known to require the RVEP motif. However, its cognate ciliary transport adaptor has been elusive. Here, by imaging the ciliary localization of truncation and point mutations, we defined the ciliary targeting sequence (CTS) of Arl13b as a C-terminal stretch of 17 amino acids containing the RVEP motif. We found Rab8-GDP, but not Rab8-GTP, and TNPO1 simultaneously and directly bind to the CTS of Arl13b in pull-down assays using cell lysates or purified recombinant proteins. Furthermore, Rab8-GDP substantially enhances the interaction between TNPO1 and CTS. Additionally, we determined that the RVEP motif is an essential element as its mutation abolishes the interaction of the CTS with Rab8-GDP and TNPO1 in pull-down and TurboID-based proximity ligation assays. Finally, the knockdown of endogenous Rab8 or TNPO1 decreases the ciliary localization of endogenous Arl13b. Therefore, our results suggest Rab8 and TNPO1 might function together as a ciliary transport adaptor for Arl13b by interacting with its RVEP-containing CTS.
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Cílios , GTP Fosfo-Hidrolases , Fatores de Ribosilação do ADP/metabolismo , Cílios/genética , Cílios/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Transporte Proteico , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , Transdução de Sinais , Humanos , Linhagem CelularRESUMO
A key step in the activation of canonical Wnt signaling is the interaction between ß-catenin and Tcf/Lefs that forms the transcription activation complex and facilitates the expression of target genes. Eukaryotic initiation factor 4A3 (EIF4A3) is an ATP-dependent DEAD box-family RNA helicase and acts as a core subunit of the exon junction complex (EJC) to control a series of RNA post-transcriptional processes. In this study, we uncover that EIF4A3 functions as a Wnt inhibitor by interfering with the formation of ß-catenin/Tcf transcription activation complex. As Wnt stimulation increases, accumulated ß-catenin displaces EIF4A3 from a transcriptional complex with Tcf/Lef, allowing the active complex to facilitate the expression of target genes. In zebrafish embryos, eif4a3 depletion inhibited the development of the dorsal organizer and pattern formation of the anterior neuroectoderm by increasing Wnt/ß-catenin signaling. Conversely, overexpression of eif4a3 decreased Wnt/ß-catenin signaling and inhibited the formation of the dorsal organizer before gastrulation. Our results reveal previously unreported roles of EIF4A3 in the inhibition of Wnt signaling and the regulation of embryonic development in zebrafish.
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Fator de Iniciação 4A em Eucariotos/metabolismo , Via de Sinalização Wnt/fisiologia , Peixe-Zebra/embriologia , Animais , Embrião não Mamífero/metabolismo , Fator de Iniciação 4A em Eucariotos/genética , Regulação da Expressão Gênica no Desenvolvimento , Ativação Transcricional , Proteínas Wnt/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Phase shifting profilometry is an important technique for reconstructing the three-dimensional (3D) geometry of objects with purely diffuse surfaces. However, it is challenging to measure the transparent objects due to the pattern aliasing caused by light refraction and multiple reflections inside the object. In this work, we analyze the aliasing fringe pattern formation for transparent objects and then, propose to learn the front surface light intensity distribution based on the formation principle by using the diffusion models for generating the non-aliased fringe patterns reflected from the front surface only. With the generated fringe patterns, the 3D shape of the transparent objects can be reconstructed via the conventional structured light. We show the feasibility and performance of the proposed method on the data of purely transparent objects that are not seen in the training stage. Moreover, we found it could be generalized to other cases with local-transparent and translucent objects, showing the potential capability of the diffusion based learnable framework in tackling the problems of transparent object reconstruction.
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In mammals, the endometrium undergoes dynamic changes in response to estrogen and progesterone to prepare for blastocyst implantation. Two distinct types of endometrial epithelial cells, the luminal (LE) and glandular (GE) epithelial cells play different functional roles during this physiological process. Previously, we have reported that Notch signaling plays multiple roles in embryo implantation, decidualization, and postpartum repair. Here, using the uterine epithelial-specific Ltf-iCre, we showed that Notch1 signaling over-activation in the endometrial epithelium caused dysfunction of the epithelium during the estrous cycle, resulting in hyper-proliferation. During pregnancy, it further led to dysregulation of estrogen and progesterone signaling, resulting in infertility in these animals. Using 3D organoids, we showed that over-activation of Notch1 signaling increased the proliferative potential of both LE and GE cells and reduced the difference in transcription profiles between them, suggesting disrupted differentiation of the uterine epithelium. In addition, we demonstrated that both canonical and non-canonical Notch signaling contributed to the hyper-proliferation of GE cells, but only the non-canonical pathway was involved with estrogen sensitivity in the GE cells. These findings provided insights into the effects of Notch1 signaling on the proliferation, differentiation, and function of the uterine epithelium. This study demonstrated the important roles of Notch1 signaling in regulating hormone response and differentiation of endometrial epithelial cells and provides an opportunity for future studies in estrogen-dependent diseases, such as endometriosis.
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Progesterona , Útero , Animais , Feminino , Camundongos , Gravidez , Proliferação de Células , Implantação do Embrião/fisiologia , Endométrio/metabolismo , Epitélio/metabolismo , Estrogênios/farmacologia , Estrogênios/metabolismo , Progesterona/farmacologia , Progesterona/metabolismo , Útero/metabolismoRESUMO
Targeting selective CO2 photoreduction into CH4 remains a challenge due to the sluggish reaction kinetics and poor hydrogenation ability of the unstable intermediate. Here, the active Pt2+ sites were photodeposited on the SrTiO3 photocatalyst, which was well demonstrated to manipulate the CH4 product selectivity. The results showed that SrTiO3 mainly yielded the CO (6.98 µmol g-1) product with poor CH4 (0.17 µmol g-1). With the Pt2+ modification, 100% CH4 selectivity could be obtained with an optimized yield rate of 8.07 µmol g-1. The prominent enhancement resulted from the following roles: (1) the strong electronic interaction between the Pt2+ cocatalyst and SrTiO3 could prompt efficient separation of the photoelectron-hole pairs. (2) The Pt2+ sites were active to capture and activate inert CO2 into HCO3- and CO32- species and allowed fast *COOH formation with the lowered reaction barrier. (3) Compared with SrTiO3, the formed *CO species could be captured tightly on the Pt2+ cocatalyst surface for generating the *CH2 intermediate by the following electron-proton coupling reaction, thus leading to the CH4 product with 100% selectivity.
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Advanced photocatalysts are highly desired to activate the photocatalytic CO2reduction reaction (CO2RR) with low concentration. Herein, the NiSn(OH)6with rich surface lattice hydroxyls was synthesized to boost the activity directly under the natural air. Results showed that terminal Ni-OH could serve as donors to feed protons and generate oxygen vacancies (VO), thus beneficial to convert the activated CO2(HCO3-) mainly into CO (5.60µmol g-1) in the atmosphere. It was flexible and widely applicable for a stable CO2RR from high pure to air level free of additionally adding H2O reactant, and higher than the traditional gas-liquid-solid (1.58µmol g-1) and gas-solid (4.07µmol g-1) reaction system both using high pure CO2and plenty of H2O. The strong hydrophilia by the rich surface hydroxyls allowed robust H2O molecule adsorption and dissociation at VOsites to achieve the Ni-OH regeneration, leading to a stable CO yield (11.61µmol g-1) with the enriched renewable VOregardless of the poor CO2and H2O in air. This work opens up new possibilities for the practical application of natural photosynthesis.
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Indium oxide (In2O3) is a promising channel material for thin-film transistors (TFTs). In this work, we develop an atomic layer deposition (ALD) process of using trimethylindium and ozone (O3) to deposit In2O3films and fabricate ultrathin In2O3TFTs. The In2O3TFTs with 4 nm channel thickness show generally good switching characteristics with a highIon/Ioffof 108, a high mobility (µFE) of 16.2cm2V-1s-1and a positive threshold voltage (Vth) of 0.48 V. Although the 4 nm In2O3TFTs exhibit short channel effect, it can be improved by adding an ALD Ga2O3capping layer to afford the bilayer In2O3/Ga2O3channel structure. The afforded In2O3/Ga2O3TFTs exhibit improved immunity to the short channel effect, with good TFT characteristics ofIon/Ioffof 107,µFEof 9.3cm2V-1s-1, and positiveVthof 2.23 V. Overall, the thermal budget of the entire process is only 400 °C, which is suitable for the display and CMOS back-end-of-line-compatible applications.
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OBJECTIVE: To compare the risks of gastric cancer and other gastric diseases in patients with type-2 diabetes mellitus (T2DM) exposed to sodium-glucose cotransporter 2 inhibitors (SGLT2I), dipeptidyl peptidase-4 inhibitors (DPP4I) or glucagon-like peptide-1 receptor agonists (GLP1a). DESIGN: This was a population-based cohort study of prospectively collected data on patients with T2DM prescribed SGLT2I, DPP4I or GLP1a between January 1st 2015 and December 31st 2020 from Hong Kong. The outcomes were new-onset gastric cancer, peptic ulcer (PU), acute gastritis, non-acute gastritis, and gastroesophageal reflux disease (GERD). Propensity score matching (1:1) using the nearest neighbour search was performed, and multivariable Cox regression was applied. A three-arm comparison between SGLT2I, DPP4I and GLP1a was conducted using propensity scores with inverse probability of treatment weighting. RESULTS: A total of 62,858 patients (median age: 62.2 years old [SD: 12.8]; 55.93% males; SGLT2I: n = 23,442; DPP4I: n = 39,416) were included. In the matched cohort, the incidence of gastric cancer was lower in SGLT2I (Incidence rate per 1000 person-year, IR: 0.32; 95% confidence interval, CI 0.23-0.43) than in DPP4I (IR per 1000 person-year: 1.22; CI 1.03-1.42) users. Multivariable Cox regression found that SGLT2I use was associated with lower risks of gastric cancer (HR 0.30; 95% CI 0.19-0.48), PU, acute gastritis, non-acute gastritis, and GERD (p < 0.05) compared to DPP4I use. In the three-arm analysis, GLP1a use was associated with higher risks of gastric cancer and GERD compared to SGLT2I use. CONCLUSIONS: The use of SGLT2I was associated with lower risks of new-onset gastric cancer, PU, acute gastritis, non-acute gastritis, and GERD after matching and adjustments compared to DPP4I use. SGLT2I use was associated with lower risks of GERD and gastric cancer compared to GLP1a use.
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Identification of O-glycopeptides from tandem mass spectrometry data is complicated by the near complete dissociation of O-glycans from the peptide during collisional activation and by the combinatorial explosion of possible glycoforms when glycans are retained intact in electron-based activation. The recent O-Pair search method provides an elegant solution to these problems, using a collisional activation scan to identify the peptide sequence and total glycan mass, and a follow-up electron-based activation scan to localize the glycosite(s) using a graph-based algorithm in a reduced search space. Our previous O-glycoproteomics methods with MSFragger-Glyco allowed for extremely fast and sensitive identification of O-glycopeptides from collisional activation data but had limited support for site localization of glycans and quantification of glycopeptides. Here, we report an improved pipeline for O-glycoproteomics analysis that provides proteome-wide, site-specific, quantitative results by incorporating the O-Pair method as a module within FragPipe. In addition to improved search speed and sensitivity, we add flexible options for oxonium ion-based filtering of glycans and support for a variety of MS acquisition methods and provide a comparison between all software tools currently capable of O-glycosite localization in proteome-wide searches.
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Accurate branching ratios of the H-abstraction reactions from dimethylamine (DMA) by OH radicals are important in understanding the atmospheric fate of DMA. In this work, the reaction kinetics of the water-free, water-assisted, and self-assisted H-abstraction reactions between DMA and OH radicals are accurately determined using the multipath canonical variational theory with the small-curvature tunneling correction, to explore the catalytic effects of the reactant (DMA) and product (water). To choose a suitable method that well describes the current reaction systems, various combinations with seven DFT methods and six basis sets are first evaluated, and the M08-HX/ma-TZVP method is identified as the most appropriate, with a mean unsigned deviation of 0.9 kcal mol-1 against the gold-standard CCSD(T)/CBS(T-Q) method. Based on the determined potential energy surfaces with the considerations of ground-state structures and specific-reaction parameters of zero-point energies, rate constants and branching ratios are calculated in a wide temperature range. The calculations show that the participation of water and DMA can lead to three-body complexes with a lower energy and influence the energy barriers, but neither of them shows the catalytic effect on the H-abstraction reactions in terms of kinetics. Additionally, the branching ratio analysis demonstrates that the product distribution is significantly altered in the presence of DMA and water.
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INTRODUCTION: Dorsal root ganglion stimulation (DRG-S) is a viable interventional option for intractable pain management. Although systematic data are lacking regarding the immediate neurologic complications of this procedure, intraoperative neurophysiological monitoring (IONM) can be a valuable tool to detect real-time neurologic changes and prompt intervention(s) during DRG-S performed under general anesthesia and deep sedation. MATERIALS AND METHODS: In our single-center case series, we performed multimodal IONM, including peripheral nerve somatosensory evoked potentials (pnSSEPs) and dermatomal somatosensory evoked potentials (dSSEPs), spontaneous electromyography (EMG), transcranial motor evoked potentials (MEPs), and electroencephalogram (EEG) for some trials and all permanent DRG-S lead placement per surgeon preference. Alert criteria for each IONM modality were established before data acquisition and collection. An IONM alert was used to implement an immediate repositioning of the lead to reduce any possible postoperative neurologic deficits. We reviewed the literature and summarized the current IONM modalities commonly applied during DRG-S, including somatosensory evoked potentials and EMG. Because DRG-S targets the dorsal roots, we hypothesized that including dSSEP would allow more sensitivity as a proxy for potential sensory changes under generalized anesthesia than would including standard pnSSEPs. RESULTS: From our case series of 22 consecutive procedures with 45 lead placements, one case had an alert immediately after DRG-S lead positioning. In this case, dSSEP attenuation was seen, indicating changes in the S1 dermatome, which occurred despite ipsilateral pnSSEP from the posterior tibial nerve remaining at baselines. The dSSEP alert prompted the surgeon to reposition the S1 lead, resulting in immediate recovery of the dSSEP to baseline status. The rate of IONM alerts reported intraoperatively was 4.55% per procedure and 2.22% per lead (n = 1). No neurologic deficits were reported after the procedure, resulting in no postoperative neurologic complications or deficits. No other IONM changes or alerts were observed from pnSSEP, spontaneous EMG, MEPs, or EEG modalities. Reviewing the literature, we noted challenges and potential deficiencies when using current IONM modalities for DRG-S procedures. CONCLUSIONS: Our case series suggests dSSEPs offer greater reliability than do pnSSEPs in quickly detecting neurologic changes, and subsequent neural injury, during DRG-S cases. We encourage future studies to focus on adding dSSEP to standard pnSSEP to provide a comprehensive, real-time neurophysiological assessment during lead placement for DRG-S. More investigation, collaboration, and evidence are required to evaluate, compare, and standardize comprehensive IONM protocols for DRG-S.
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Monitorização Neurofisiológica Intraoperatória , Humanos , Monitorização Neurofisiológica Intraoperatória/métodos , Gânglios Espinais , Reprodutibilidade dos Testes , Potencial Evocado Motor/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Complicações Pós-Operatórias/etiologiaRESUMO
BACKGROUND: Syndecan 4 (SDC4), a type I transmembrane proteoglycan, serves as a critical link between chondrocytes and the extracellular matrix. OBJECTIVE: This study aimed to explore the role of SDC4 in cartilage degeneration of temporomandibular joint osteoathritis (TMJOA). METHODS: Condylar chondrocytes were stimulated with varying concentrations of recombinant rat interleukin-1ß (rrIL-1ß) and SDC4 small interfering RNA (si-SDC4). Anti-SDC4 ectodomain-specific antibodies or IgG were intra-articularly administrated in a TMJOA model rats. SDC4 conditional knockout (SDC4-cKO) and Sdc4flox/flox mice were induced TMJOA. Cartilage degeneration was assessed using haematoxylin & eosin (H&E) and safranin O (SO) staining. Protein levels of SDC4, matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with a thrombospondin motifs 5 (ADAMTS5), tumour necrosis factor α (TNFα), type II collagen (Col-II), aggrecan (ACAN), cleaved caspase 3 (CASP3), Ki67 and related pathways in condylar cartilage were evaluated by immunohistochemical (IHC) staining or western blot assays. RESULTS: SDC4 expression was evidently increased in MIA-model animals compared to control groups. rrIL-1ß stimulation increased the expression of SDC4, MMP3 and ADAMTS5 expression in chondrocytes, while decreasing the expression of Col-II. These effects were reversed by si-SDC4 in vitro. In vivo, SDC4 blockade reduced the death of chondrocytes and the loss of cartilage matrix, which was evidenced by increased expression of Col-II and ACAN, and a decrease in SDC4, MMP13 and cleaved-CASP3-positive cells. Furthermore, the protein levels of ACAN and Ki67 were elevated, and the ERK1/2 and P38 signalling pathways were activated following SDC4 inhibition. CONCLUSIONS: SDC4 inhibition significantly ameliorates condylar cartilage degeneration, which was mediated, at least partly, through P38 and ERK1/2 signalling. Inhibition of SDC4 may be of great value for the treatment of TMJOA.
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BACKGROUND: The present study is to evaluate the clinical characteristics of patients with temporomandibular disorders (TMD). METHODS: A total of 3362 TMD patients were included. Each participant had complete medical records according to the diagnostic criteria for temporomandibular disorders (DC/TMD). The clinical characteristics including symptoms and signs in relation to age and gender were analyzed. RESULTS: The mean age of the patients seeking care was 29.89 ± 13.73Y, and 68.6% of patients were aged 16-35 years. The female-to-male ratio of patients was 2.2: 1, and the average age of males was significantly lower than that of females. The prevalence of clicking symptoms decreased with age, while the prevalence of pain symptoms and limitations in jaw movement increased with age. Females were more likely to have limitations in jaw movement than males. Among the patients with pain, the average visual analogue scale (VAS) was 2.96 ± 1.23. The average VAS score of acute TMD patients (≤ 3 months) was significantly higher than that of chronic TMD patients (> 3 months). CONCLUSIONS: The majority of TMD patients seeking care were young people. The number and average age of female patients was higher than the males. Female patients were more likely to have limitations in jaw movement than males.
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Transtornos da Articulação Temporomandibular , Humanos , Masculino , Feminino , Transtornos da Articulação Temporomandibular/epidemiologia , Adulto , Estudos Retrospectivos , Adolescente , Fatores Sexuais , Fatores Etários , Adulto Jovem , Dor Facial , Pessoa de Meia-Idade , Medição da Dor , PrevalênciaRESUMO
Objective: To explore the clinical effect of laser acupuncture combined with Schroth therapy on adolescent idiopathic scoliosis (AIS). Method: This was a retrospective study. Eighty AIS patients were admitted to The Second People's Hospital of Dalian from March 2021 to March 2022 and divided into control group and experimental group according to the treatment method, with 40 cases in each group. The control group received Schroth therapy, and the experimental group received Schroth therapy and laser acupuncture therapy (MLS® laser). All treatments are performed five times a week for four consecutive weeks we compared the clinical effects of the two groups before treatment, six months and 12 months after treatment, and compared the improvement of Cobb angle, axial trunk rotation (ATR), musculoskeletal stiffness(The PulStarG3 system), and gait evaluation (Micro-Electro-Mechanical System(MEMS) between the two groups of patients. Result: After four weeks of treatment, the spinal condition of both groups of patients improved. After treatment, the experimental group showed greater improvement in Cobb angle, ATR, spinal range of motion, gait parameters, and clinical efficacy compared to the control group (p<0.05). Conclusion: Laser acupuncture combined with Schroth therapy is safe and effective in the treatment of AIS, and is more effective in correcting scoliosis and related problems of AIS.
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Solid electrolytes (SEs) are central components that enable high-performance, all-solid-state lithium batteries (ASSLBs). Amorphous SEs hold great potential for ASSLBs because their grain-boundary-free characteristics facilitate intact solid-solid contact and uniform Li-ion conduction for high-performance cathodes. However, amorphous oxide SEs with limited ionic conductivities and glassy sulfide SEs with narrow electrochemical windows cannot sustain high-nickel cathodes. Herein, we report a class of amorphous Li-Ta-Cl-based chloride SEs possessing high Li-ion conductivity (up to 7.16 mS cm-1) and low Young's modulus (approximately 3 GPa) to enable excellent Li-ion conduction and intact physical contact among rigid components in ASSLBs. We reveal that the amorphous Li-Ta-Cl matrix is composed of LiCl43-, LiCl54-, LiCl65- polyhedra, and TaCl6- octahedra via machine-learning simulation, solid-state 7Li nuclear magnetic resonance, and X-ray absorption analysis. Attractively, our amorphous chloride SEs exhibit excellent compatibility with high-nickel cathodes. We demonstrate that ASSLBs comprising amorphous chloride SEs and high-nickel single-crystal cathodes (LiNi0.88Co0.07Mn0.05O2) exhibit â¼99% capacity retention after 800 cycles at â¼3 C under 1 mA h cm-2 and â¼80% capacity retention after 75 cycles at 0.2 C under a high areal capacity of 5 mA h cm-2. Most importantly, a stable operation of up to 9800 cycles with a capacity retention of â¼77% at a high rate of 3.4 C can be achieved in a freezing environment of -10 °C. Our amorphous chloride SEs will pave the way to realize high-performance high-nickel cathodes for high-energy-density ASSLBs.