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Background: Cerebral autosomal-dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) is an inherited small-vessel disease that affects the white matter of the brain. Recent studies have confirmed that the deposition of NOTCH3ECD is the main pathological basis of CADASIL; however, whether different mutations present the same pathological characteristics remains to be further studied. Some studies have found that mitochondrial dysfunction is related to CADASIL; however, the specific effects of NOTCH3ECD on mitochondrial remain to be determined. Objective: We aimed to explore the role of mitochondrial dysfunction in CADASIL. Methods: We established transgenic human embryonic kidney-293T cell models (involving alterations in cysteine and non-cysteine residues) via lentiviral transfection. Mitochondrial function and structure were assessed using flow cytometry and transmission electron microscopy, respectively. Mitophagy was assessed using western blotting and immunofluorescence. Results: We demonstrated that NOTCH3ECD deposition affects mitochondrial morphology and function, and that its protein levels are significantly correlated with mitochondrial quality and can directly bind to mitochondria. Moreover, NOTCH3ECD deposition promoted the induction of autophagy and mitophagy. However, these processes were impaired, leading to abnormal mitochondrial accumulation. Conclusions: This study revealed a common pathological feature of NOTCH3ECD deposition caused by different NOTCH3 mutations and provided new insights into the role of NOTCH3ECD in mitochondrial dysfunction and mitophagy.
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CADASIL , Mitocôndrias , Mitofagia , Receptor Notch3 , Humanos , CADASIL/genética , CADASIL/patologia , CADASIL/metabolismo , Receptor Notch3/genética , Receptor Notch3/metabolismo , Mitofagia/fisiologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Células HEK293 , Mutação , Autofagia/fisiologiaRESUMO
The global spread of monkeypox has become a worldwide public healthcare issue. Therefore, there is an urgent need for accurate and sensitive detection methods to effectively control its spreading. Herein, we screened by phage display two peptides M4 (sequence: DPCGERICSIAL) and M6 (sequence: SCSSFLCSLKVG) with good affinity and specificity to monkeypox virus (MPXV) B21R protein. To simulate the state of the peptide in the phage and to avoid spatial obstacles of the peptide, GGGSK was added at the C terminus of M4 and named as M4a. Molecular docking shows that peptide M4a and peptide M6 are bound to different epitopes of B21R by hydrogen bonds and salt-bridge interactions, respectively. Then, peptide M4a was selected as the capture probe, phage M6 as the detection probe, and carbonized polymer dots (CPDs) as the fluorescent probe, and a colorimetric and fluorescent double-signal capture peptide/antigen/signal peptide-displayed phage sandwich ELISA triggered by horseradish peroxidase (HRP) through a simple internal filtration effect (IFE) was constructed. HRP catalyzes H2O2 to oxidize 3,3',5,5'-tetramethylbenzidine (TMB) to generate blue oxidized TMB, which can further quench the fluorescence of CPDs through IFE, enabling to detect MPXV B21R in colorimetric and fluorescent modes. The proposed simple immunoassay platform shows good sensitivity and reliability in MPXV B21R detection. The limit of detection for colorimetric and fluorescent modes was 27.8 and 9.14 pg/mL MPXV B21R, respectively. Thus, the established double-peptide sandwich-based dual-signal immunoassay provides guidance for the development of reliable and sensitive antigen detection capable of mutual confirmation, which also has great potential for exploring various analytical strategies for other respiratory virus surveillance.
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Ensaio de Imunoadsorção Enzimática , Peptídeos , Ensaio de Imunoadsorção Enzimática/métodos , Peptídeos/química , Antígenos Virais/imunologia , Antígenos Virais/análise , Antígenos Virais/química , Simulação de Acoplamento Molecular , Peroxidase do Rábano Silvestre/química , Peroxidase do Rábano Silvestre/metabolismo , Limite de Detecção , Corantes Fluorescentes/química , Biblioteca de Peptídeos , Benzidinas/química , Colorimetria/métodosRESUMO
BACKGROUND: Robot-assisted kidney transplantation (RAKT) surgery is an advanced minimally invasive technique, albeit with extended surgical and kidney ischemia time. To safeguard kidney function, the authors have devised a continuous surface cooling method (CSCT) for intraoperative kidney cooling. MATERIALS AND METHODS: Patients receiving RAKT were divided into CSCT group and conventional group. The CSCT is a custom-designed apparatus composed of a single-layer plastic bag, featuring an inflow and an outflow that create a closed circuit for the continuous flow of cooling saline. The conventional group utilized ice slush for kidney graft cooling (Vattikuti Urology Institute-Medanta Technique, VUIMT). Patients who underwent open renal transplantation during the same period were also included in the study. All patients were subject to a minimum 2-month follow-up. And 1:3 propensity score matching was used to minimize selection bias. RESULTS: A total of 144 patients underwent CSCT, 47 underwent VUIMT, and 196 underwent open surgery were included in the study, while after matching, 129, 43, 129 patients were included in the three groups, respectively. The median follow-up time was 19 months. None of the patients experienced delayed graft function, patient mortality, or graft loss. After introducing the kidney into the abdominal cavity for 20 minutes, the surface temperature of the kidney in the CSCT group was notably lower compared to the VUIMT group (15.42±0.88 vs. 21.74±2.53°C, P =0.001). This temperature disparity became more pronounced at 65 min (19.74±1.61 vs. 29.82±1.63°C, P <0.001). At both 3 and 7 days post-transplantation, creatinine levels in the VUIMT group were significantly higher than those in the CSCT and open surgery groups (at 3 days, 244.13±45.61 vs. 182.51±55.47 in CSCT group, P <0.001, or vs. 182.77±61.32 in the open surgery group, P <0.001; at 7 days, 162.42±54.86 vs. 143.11±44.32 in the CSCT group, P <0.001, or vs. 135.23±45.27 in the open surgery group, P <0.001). No differences were observed in blood creatinine, estimated glomerular filtration rate, and perioperative complications between the CSCT and open surgery groups. CONCLUSION: The CSCT presents a significant advantage over the traditional VUIMT method in terms of kidney cooling and early postoperative kidney function preservation. Additional research is required to ascertain whether the CSCT can enhance the long-term prognosis of kidney transplant recipients.
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Transplante de Rim , Procedimentos Cirúrgicos Robóticos , Humanos , Transplante de Rim/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Procedimentos Cirúrgicos Robóticos/métodos , Adulto , Rim/cirurgia , Hipotermia Induzida/métodos , Resultado do Tratamento , Estudos de CoortesRESUMO
Neck muscle weakness due to amyotrophic lateral sclerosis (ALS) can result in dropped head syndrome, adversely impacting the quality of life of those affected. Static neck collars are currently prescribed to hold the head in a fixed upright position. However, these braces are uncomfortable and do not allow any voluntary head-neck movements. By contrast, powered neck exoskeletons have the potential to enable head-neck movements. Our group has recently improved the mechanical structure of a state-of-the-art neck exoskeleton through a weighted optimization. To evaluate the effect of the structural changes, we conducted an experiment in which patients with ALS were asked to perform head-neck tracking tasks while using the two versions of the neck exoskeleton. We found that the neck muscle activation was significantly reduced when assisted by the structurally enhanced design compared to no assistance provided. The improved structure also improved kinematics tracking performance, allowing users to better achieve the desired head poses. In comparison, the previous design did not help reduce the muscle effort required to perform these tasks and even slightly worsened the kinematic tracking performance. It was also found that biomechanical benefits gained from using the structurally improved design were consistent across participants with both mild and severe neck weakness. Furthermore, we observed that participants preferred to use the powered neck exoskeletons to voluntarily move their heads and make eye contact during a conversation task rather than remain in a fixed upright position. Each of these findings highlights the importance of the structural design of neck exoskeletons in achieving desired biomechanical benefits and suggests that neck exoskeletons can be a viable method to improve the daily life of patients with ALS.
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Esclerose Lateral Amiotrófica , Exoesqueleto Energizado , Músculos do Pescoço , Humanos , Esclerose Lateral Amiotrófica/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , Músculos do Pescoço/fisiopatologia , Fenômenos Biomecânicos , Idoso , Eletromiografia , Movimentos da Cabeça , Pescoço/fisiopatologia , Desenho de Equipamento , Adulto , Debilidade Muscular/fisiopatologiaRESUMO
Emerging studies suggest that long non-coding RNAs (lncRNAs) participate in the mutual regulation of cells in tumor microenvironment, thereby affecting the anti-tumor immune activity of immune cells. Additionally, the intracellular pathways mediated by lncRNAs can affect the expression of immune checkpoints or change the cell functions, including cytokines secretion, of immune and stromal cells in tumor microenvironment, which further influences cancer patients' prognosis and treatment response. With the in-depth research, lncRNAs have shown great potency as a new immunotherapy target and predict immunotherapy response. The research on lncRNAs provides us with a new insight into developing new immunotherapy drugs and predicting the outcome of immunotherapy. With development of RNA sequencing technology, amounts of lncRNAs were found to be dysregulated in immune and stromal cells rather than tumor cells. These lncRNAs function through ceRNA network or regulating transcript factor activity, thus leading abnormal differentiation and activation of immune and stromal cells. Here, we review the function of lncRNAs in the immune microenvironment and focus on the alteration of lncRNAs in immune and stromal cells, and discuss how these alterations affect tumor growth, metastasis and treatment response.
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In the world's first pig-to-human cardiac cytomegalovirus (PCMV), xenotransplant and elevated levels of porcine key factors contributing to patient mortality were considered. This has renewed attention on PCMV, a virus widely prevalent in pigs. Currently, there are no effective drugs or vaccines targeting PCMV, and its high detection difficulty poses challenges for prevention and control research. In this study, antiviral small hairpin RNA (shRNA) was selected and inserted into the Rosa26 and miR-17-92 loci of pigs via a CRISPR/Cas9-mediated knock-in strategy. Further in vitro viral challenge experiments demonstrated that these genetically edited pig cells could effectively limit PCMV replication. Through this process, we constructed a PCMV-infected cell model, validated partial viral interference sites, enhanced gene knock-in efficiency, performed gene editing at two different gene loci, and ultimately demonstrated that RNA interference (RNAi) technology combined with CRISPR/Cas9 has the potential to generate pig cells with enhanced antiviral infection capabilities. This opens up possibilities for the future production of pig populations with antiviral functionalities.
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This paper introduces a novel cable-driven robotic platform that enables six degrees-of-freedom (DoF) natural head-neck movements. Poor postural control of the head-neck can be a debilitating symptom of neurological disorders such as amyotrophic lateral sclerosis and cerebral palsy. Current treatments using static neck collars are inadequate, and there is a need to develop new devices to empower movements and facilitate physical rehabilitation of the head-neck. State-of-the-art neck exoskeletons using lower DoF mechanisms with rigid linkages are limited by their hard motion constraints imposed on head-neck movements. By contrast, the cable-driven robot presented in this paper does not constrain motion and enables wide-range, 6-DoF control of the head-neck. We present the mechatronic design, validation, and control implementations of this robot, as well as a human experiment to demonstrate a potential use case of this versatile robot for rehabilitation. Participants were engaged in a target reaching task while the robot applied both assistive and resistive moments on the head during the task. Our results show that neck muscle activation increased by 19% when moving the head against resistance and decreased by 28-43% when assisted by the robot. Overall, these results provide a scientific justification for further research in enabling movement and identifying personalized rehabilitation for motor training. Beyond rehabilitation, other applications such as applying force perturbations on the head to study sensory integration and applying traction to achieve pain relief may benefit from the innovation of this robotic platform which is capable of applying controlled 6-DoF forces/moments on the head.
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Exoesqueleto Energizado , Doenças do Sistema Nervoso , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Robótica/métodos , Movimento/fisiologia , Movimentos da Cabeça/fisiologiaRESUMO
OBJECTIVES: Falls in hospitals pose a significant safety risk, leading to injuries, prolonged hospitalization, and lasting complications. This study explores the potential of augmented reality (AR) technology in healthcare facility design to mitigate fall risk. BACKGROUND: Few studies have investigated the impact of hospital room layouts on falls due to the high cost of building physical prototypes. This study introduces an innovative approach using AR technology to advance methods for healthcare facility design efficiently. METHODS: Ten healthy participants enrolled in this study to examine different hospital room designs in AR. Factors of interest included room configuration, door type, exit side of the bed, toilet placement, and the presence of IV equipment. AR trackers captured trajectories of the body as participants navigated through these AR hospital layouts, providing insights into user behavior and preferences. RESULTS: Door type influenced the degree of backward and sideways movement, with the presence of an IV pole intensifying the interaction between door and room type, leading to increased sideways and backward motion. Participants displayed varying patterns of backward and sideways travel depending on the specific room configurations they encountered. CONCLUSIONS: AR can be an efficient and cost-effective method to modify room configurations to identify important design factors before conducting physical testing. The results of this study provide valuable insights into the effect of environmental factors on movement patterns in simulated hospital rooms. These results highlight the importance of considering environmental factors, such as the type of door and bathroom location, when designing healthcare facilities.
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In 2023, the National Science Foundation (NSF) and the National Institute of Health (NIH) brought together engineers, scientists, and clinicians by sponsoring a conference on computational modelling in neurorehabiilitation. To facilitate multidisciplinary collaborations and improve patient care, in this perspective piece we identify where and how computational modelling can support neurorehabilitation. To address the where, we developed a patient-in-the-loop framework that uses multiple and/or continual measurements to update diagnostic and treatment model parameters, treatment type, and treatment prescription, with the goal of maximizing clinically-relevant functional outcomes. This patient-in-the-loop framework has several key features: (i) it includes diagnostic and treatment models, (ii) it is clinically-grounded with the International Classification of Functioning, Disability and Health (ICF) and patient involvement, (iii) it uses multiple or continual data measurements over time, and (iv) it is applicable to a range of neurological and neurodevelopmental conditions. To address the how, we identify state-of-the-art and highlight promising avenues of future research across the realms of sensorimotor adaptation, neuroplasticity, musculoskeletal, and sensory & pain computational modelling. We also discuss both the importance of and how to perform model validation, as well as challenges to overcome when implementing computational models within a clinical setting. The patient-in-the-loop approach offers a unifying framework to guide multidisciplinary collaboration between computational and clinical stakeholders in the field of neurorehabilitation.
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Pessoas com Deficiência , Reabilitação Neurológica , HumanosRESUMO
Aiming at the problems of small sample size and large feature dimension in the identification of ipsilateral supraclavicular lymph node metastasis status in breast cancer using ultrasound radiomics, an optimized feature combination search algorithm is proposed to construct linear classification models with high interpretability. The genetic algorithm (GA) is used to search for feature combinations within the feature subspace using least absolute shrinkage and selection operator (LASSO) regression. The search is optimized by applying a high penalty to the L1 norm of LASSO to retain excellent features in the crossover operation of the GA. The experimental results show that the linear model constructed using this method outperforms those using the conventional LASSO regression and standard GA. Therefore, this method can be used to build linear models with higher classification performance and more robustness.
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OBJECTIVES: To evaluate the effectiveness and safety of Interferon-gamma release Assay (IGRA)-based isoniazid (INH) prophylaxis strategy to prevent tuberculosis (TB) infection in kidney transplantation (KT) with a risk of TB occurrence. METHODS: Adult KT recipients (KTRs) between June 2014 and July 2021 were retrospectively enrolled. The development of active TB after KT was evaluated. RESULTS: Of 925 KTRs, 111 (12.0%) developed active TB. Among the 501 KTRs at a risk of TB occurrence, 70 (14.0%) patients developed active TB, while 41 (9.7%) of 424 patients without risk factors developed active TB (P = 0.05). Two hundred thirty-nine KTRs received IGRA test with 62 (25.9%) were positive. None of IGRA positive patients (0/40) receiving INH prophylaxis developed active TB, whereas 8 out of 22 patients who had positive IGRA results without INH prophylaxis developed active TB (0 vs. 36.4%, P < 0.01). Of note, for those in risk group but with negative IGRA result, no active TB was found even without INH prophylaxis. Although alanine aminotransferase and aspartate aminotransferase in INH prevention group were higher than those before treatment, they did not exceed three-fold of limit of reference range. CONCLUSIONS: IGRA-based INH treatment is an effective and safe protocol to prevent the development of active TB in KTRs.
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Transplante de Rim , Tuberculose Latente , Tuberculose , Adulto , Humanos , Testes de Liberação de Interferon-gama , Estudos Retrospectivos , Transplante de Rim/efeitos adversos , Tuberculose/prevenção & controle , Protocolos ClínicosRESUMO
Blood-brain barrier (BBB) dysfunction plays a pivotal role in the pathology of chronic cerebral hypoperfusion (CCH)-related neurodegenerative diseases. Continuous endothelial cells (EC) that line the blood vessels of the brain are important components of the BBB to strictly control the flow of substances and maintain the homeostatic environment of the brain. However, the molecular mechanisms from the perspective of EC-induced BBB dysfunction after CCH are largely unknown. In this study, the BBB function was assessed using immunostaining and transmission electron microscopy. The EC dysfunction profile was screened by using EC enrichment followed by RNA sequencing. After identified the key EC dysfunction factor, C-kit, we used the C-kit inhibition drug (imatinib) and C-kit down-regulation method (AAV-BR1-C-kit shRNA) to verify the role of C-kit on BBB integrity and EC transcytosis after CCH. Furthermore, we also activated C-kit with stem cell factor (SCF) to observe the effects of C-kit on BBB following CCH. We explored that macromolecular proteins entered the brain mainly through EC transcytosis after CCH and caused neuronal loss. Additionally, we identified receptor tyrosine kinase C-kit as a key EC dysfunction molecule. Furthermore, the pharmacological inhibition of C-kit with imatinib counteracted BBB leakage by reducing caveolae-mediated transcytosis. Moreover, treatment with AAV-BR1-C-kit shRNA, which targets brain EC to inhibit C-kit expression, also ameliorated BBB leakage by reducing caveolae-mediated transcytosis. Furthermore, the SCF increased the permeability of the BBB by actively increasing caveolae-mediated transcytosis. This study provides evidence that C-kit is a key BBB permeability regulator through caveolae-mediated transcytosis in EC after CCH.
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Barreira Hematoencefálica , Isquemia Encefálica , Humanos , Barreira Hematoencefálica/metabolismo , Cavéolas/metabolismo , Células Endoteliais , Mesilato de Imatinib/farmacologia , Transcitose , Isquemia Encefálica/metabolismo , RNA Interferente Pequeno/metabolismo , PermeabilidadeRESUMO
OBJECTIVE: Pseudogenes are initially regarded as nonfunctional genomic sequences, but some pseudogenes regulate tumor initiation and progression by interacting with other genes to modulate their transcriptional activities. Olfactory receptor family 7 subfamily E member 47 pseudogene (OR7E47P) is expressed broadly in lung tissues and has been identified as a positive regulator in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD). This study aimed to elucidate the correlation between OR7E47P and tumor immunity in lung squamous cell carcinoma (LUSC). METHODS: Clinical and molecular information from The Cancer Genome Atlas (TCGA) LUSC cohort was used to identify OR7E47P-related immune genes (ORIGs) by weighted gene correlation network analysis (WGCNA). Based on the ORIGs, 2 OR7E47P clusters were identified using non-negative matrix factorization (NMF) clustering, and the stability of the clustering was tested by an extreme gradient boosting classifier (XGBoost). LASSO-Cox and stepwise regressions were applied to further select prognostic ORIGs and to construct a predictive model (ORPScore) for immunotherapy. The Botling cohorts and 8 immunotherapy cohorts (the Samstein, Braun, Jung, Gide, IMvigor210, Lauss, Van Allen, and Cho cohorts) were included as independent validation cohorts. RESULTS: OR7E47P expression was positively correlated with immune cell infiltration and enrichment of immune-related pathways in LUSC. A total of 57 ORIGs were identified to classify the patients into 2 OR7E47P clusters (Cluster 1 and Cluster 2) with distinct immune, mutation, and stromal programs. Compared to Cluster 1, Cluster 2 had more infiltration by immune and stromal cells, lower mutation rates of driver genes, and higher expression of immune-related proteins. The clustering performed well in the internal and 5 external validation cohorts. Based on the 7 ORIGs (HOPX, STX2, WFS, DUSP22, SLFN13, GGCT, and CCSER2), the ORPScore was constructed to predict the prognosis and the treatment response. In addition, the ORPScore was a better prognostic factor and correlated positively with the immunotherapeutic response in cancer patients. The area under the curve values ranged from 0.584 to 0.805 in the 6 independent immunotherapy cohorts. CONCLUSION: Our study suggests a significant correlation between OR7E47P and TME modulation in LUSC. ORIGs can be applied to molecularly stratify patients, and the ORPScore may serve as a biomarker for clinical decision-making regarding individualized prognostication and immunotherapy.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Pulmão , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Pseudogenes/genética , Microambiente Tumoral/genéticaRESUMO
Cancer treatment has evolved rapidly due to major advances in tumor immunity research. However, due to the complexity, heterogeneity, and immunosuppressive microenvironment of tumors, the overall efficacy of immunotherapy is only 20%. In recent years, nanoparticles have attracted more attention in the field of cancer immunotherapy because of their remarkable advantages in biocompatibility, precise targeting, and controlled drug delivery. However, the clinical application of nanomedicine also faces many problems concerning biological safety, and the synergistic mechanism of nano-drugs with immunity remains to be elucidated. Our study summarizes the functional characteristics and regulatory mechanisms of nanoparticles in the cancer immune microenvironment and how nanoparticles activate and long-term stimulate innate immunity and adaptive immunity. Finally, the current problems and future development trends regarding the application of nanoparticles are fully discussed and prospected to promote the transformation and application of nanomedicine used in cancer treatment.
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Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Imunoterapia , Nanomedicina , Sistemas de Liberação de Medicamentos , Imunidade Adaptativa , Microambiente TumoralRESUMO
YG8 is a common cemented carbide material with excellent mechanical properties and mechanical properties, so it is widely used in the actual industry. However, due to the active chemical properties and strong affinity of tungsten alloy steel, it is easy to produce bonding and peeling in application, resulting in an unstable process and short service life. In order to control and reduce the surface wear of YG8 cemented carbide, groove-textured surface (GS) and flocking surface (FS) were prepared on smooth surface (SS). The friction characteristics of the samples were studied under different applied load conditions. The results show that the average friction coefficient of SS, GS and FS is inversely proportional to the load in dry/oil environment. Compared with SS, FS exhibits the lowest friction coefficient, which is reduced by 30.78% (dry friction) and 13.13% (oil lubrication). FS effectively improves the tooth jump phenomenon of the sample and the amplitude of the friction coefficient, friction force and load, and has the best anti-friction characteristics. At the same time, the FS with the fastest contact angle drop at any time also showed excellent wetting ability, and the wear rate decreased by an order of magnitude. The implantation of fibers in the groove inhibits the spalling and furrow of wear track, which is attributed to the effect of fibers on damage repair. In the friction process, FS increases the content of the O element and induces the formation of oxides. The friction mechanism is mainly chemical wear. The excellent tribological properties of FS have a good guiding significance and theoretical support for improving the tribological properties of high hardness material surfaces.
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Introduction: Spinocerebellar ataxias 36 (SCA36) is the neurodegenerative disease caused by the GGCCTG Hexanucleotide repeat expansions in NOP56, which is too long to sequence using short-read sequencing. Single molecule real time (SMRT) sequencing can sequence across disease-causing repeat expansion. We report the first long-read sequencing data across the expansion region in SCA36. Methods: We collected and described the clinical manifestations and imaging features of Han Chinese pedigree with three generations of SCA36. Also, we focused on structural variation analysis for intron 1 of the NOP56 gene by SMRT sequencing in the assembled genome. Results: The main clinical features of this pedigree are late-onset ataxia symptoms, with a presymptomatic presence of affective and sleep disorders. In addition, the results of SMRT sequencing showed the specific repeat expansion region and demonstrated that the region was not composed of single GGCCTG hexanucleotides and there were random interruptions. Discussion: We extended the phenotypic spectrum of SCA36. We applied SMRT sequencing to reveal the correlation between genotype and phenotype of SCA36. Our findings indicated that long-read sequencing is well suited to characterize known repeat expansion.
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BACKGROUND: Chronic cerebral hypoperfusion (CCH) is associated with neuronal loss and blood-brain barrier (BBB) impairment in vascular dementia (VaD). However, the relationship and the molecular mechanisms between BBB dysfunction and neuronal loss remain elusive. OBJECTIVE: We explored the reasons for neuron loss following CCH. METHODS: Using permanent bilateral common carotid artery occlusion (2VO) rat model, we observed the pathological changes of cortical neurons and BBB in the sham group as well as rats 3d, 7d, 14d and 28d post 2VO. In order to further explore the factors influencing neuron loss following CCH with regard to cortical blood vessels, we extracted cortical brain microvessels at five time points for transcriptome sequencing. Finally, integrin receptor a4ß1 (VLA-4) inhibitor was injected into the tail vein, and cortical neuron loss was detected again. RESULTS: We found that cortical neuron loss following CCH is a continuous process, but damage to the BBB is acute and transient. Results of cortical microvessel transcriptome analysis showed that biological processes related to vascular inflammation mainly occurred in the chronic phase. Meanwhile, cell adhesion molecules, cytokine-cytokine receptor interaction were significantly changed at this phase. Among them, the adhesion molecule VCAM1 plays an important role. Using VLA-4 inhibitor to block VCAM1-VLA-4 interaction, cortical neuron damage was ameliorated at 14d post 2VO. CONCLUSION: Injury of the BBB may not be the main reason for persistent loss of cortical neurons following CCH. The continuous inflammatory response within blood vessels maybe an important factor in the continuous loss of cortical neurons following CCH.
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Isquemia Encefálica , Demência Vascular , Molécula 1 de Adesão de Célula Vascular , Animais , Ratos , Encéfalo/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Demência Vascular/metabolismo , Demência Vascular/patologia , Modelos Animais de Doenças , Inflamação/complicações , Inflamação/metabolismo , Integrina alfa4beta1/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
The optimization of a broach surface is of great significance to improve the cutting performance of the tool. However, the traditional optimization method (surface texture, coating, etc.) destroys the stress distribution of the tool and reduces the service life of the tool. To avoid these problems, four kinds of flocking surfaces (FB1, FB2, FB3, and FB4), imitating the biological structure of Daphniphyllum calycinum Benth (DCB), were fabricated on the rake face of the broach by electrostatic flocking. The broaching experiment, wettability, and spreading experiment were then conducted. Moreover, the mathematical model of the friction coefficient of the bionic broach was built. The effect of broaches with different flocking surfaces on the broaching force, chip morphology, and surface quality of workpieces was studied. The results indicate that the flocked broaches (FB) with good lubricity and capacity of microchips removal (CMR) present a smaller cutting force (Fc) and positive pressure (Ft) compared to the unflocked broach (NB), and reduce the friction coefficient (COF). The chip curl was decreased, and the shear angle was increased by FB, which were attributed to the function of absorbing lubricant, storing, and sweeping microchips. Its vibration suppression effect enhanced the stability in the broaching process and improved the surface quality of the workpiece. More importantly, the FB2 with the most reasonable fluff area and spacing exhibited the best cutting performance. The experimental conclusions and methods of this paper can provide a new research idea for functional structure tools.
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OBJECTIVE: This study aims to investigate the expression, prognostic value, and function of kinesin superfamily 4A (KIF4A) in cervical cancer. METHODS: Cervical cancer cell lines (Hela and SiHa) and TCGA data were used for experimental and bioinformatic analyses. Overall survival (OS) and progression free survival (PFS) were compared between patients with high or low KIF4A expression. Copy number variation (CNV) and somatic mutations of patients were visualized and GISTIC 2.0 was used to identify significantly altered sites. The function of KIF4A was also explored based on transcriptome analysis and validated by experimental methods. Chemotherapeutic and immunotherapeutic benefits were inferred using multiple reference databases and algorithms. RESULTS: Patients with high KIF4A expression had better OS and PFS. KIF4A could inhibit proliferation and migration and induce G1 arrest of cervical cancer cells. Higher CNV load was observed in patients with low KIF4A expression, while the group with low KIF4A expression displayed more significantly altered sites. A total of 13 genes were found to mutate more in the low KIF4A expression group, including NOTCH1 and PUM1. The analysis revealed that low KIF4A expression may indicate an immune escape phenotype, and patients in this group may benefit more from immunotherapy. With respect to chemotherapy, cisplatin and gemcitabine may respond better in patients with high KIF4A expression, while 5-fluorouracil etc. may be responded better in patients with low KIF4A expression CONCLUSION: KIF4A is a tumor suppressor gene in cervical cancer, and it can be used as a prognostic and therapeutic biomarker in cervical cancer.