RESUMO
Yoshida et al. (2020) report in this issue of Molecular Cell that a paternal low-protein diet elevates ROS in the testicular germ cells, altering ATF7 activity and H3K9me2 abundance on target genes, including tRNA loci. These changes are maintained in spermatozoa, regulating tsRNA biogenesis, and together transmit intergenerational effects.
Assuntos
Dieta com Restrição de Proteínas , Hereditariedade , Epigênese Genética , Masculino , Espécies Reativas de Oxigênio , EspermatozoidesRESUMO
The human neck is a unique mechanical structure, highly flexible but fatigue prone. The rising prevalence of neck pain and chronic injuries has been attributed to increasing exposure to fatigue loading in activities such as prolonged sedentary work and overuse of electronic devices. However, a causal relationship between fatigue and musculoskeletal mechanical changes remains elusive. This work aimed to establish this relationship through a unique experiment design, inspired by a cantilever beam mechanical model of the neck, and an orchestrated deployment of advanced motion-force measurement technologies including dynamic stereo-radiographic imaging. As a group of 24 subjects performed sustained-till-exhaustion neck exertions in varied positions-neutral, extended, and flexed, their cervical spine musculoskeletal responses were measured. Data verified the occurrence of fatigue and revealed fatigue-induced neck deflection which increased cervical lordosis or kyphosis by 4-5° to 11°, depending on the neck position. This finding and its interpretations render a renewed understanding of muscle fatigue from a more unified motor control perspective as well as profound implications on neck pain and injury prevention.
Assuntos
Fadiga Muscular , Cervicalgia , Pescoço , Humanos , Masculino , Adulto , Feminino , Fadiga Muscular/fisiologia , Cervicalgia/fisiopatologia , Cervicalgia/etiologia , Vértebras Cervicais/diagnóstico por imagem , Fenômenos Biomecânicos , Músculos do Pescoço/fisiologia , Amplitude de Movimento Articular , Adulto Jovem , Lordose/fisiopatologiaRESUMO
BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.
Assuntos
Catepsina D , Diabetes Mellitus Tipo 2 , Monócitos , Animais , Humanos , Camundongos , Encéfalo/metabolismo , Catepsina D/metabolismo , Catepsina D/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Precursores Enzimáticos , Camundongos Transgênicos , Monócitos/metabolismo , Transcitose/fisiologiaRESUMO
Transfer RNA (tRNA)-derived small RNAs (tsRNAs) are among the most ancient small RNAs in all domains of life and are generated by the cleavage of tRNAs. Emerging studies have begun to reveal the versatile roles of tsRNAs in fundamental biological processes, including gene silencing, ribosome biogenesis, retrotransposition, and epigenetic inheritance, which are rooted in tsRNA sequence conservation, RNA modifications, and protein-binding abilities. We summarize the mechanisms of tsRNA biogenesis and the impact of RNA modifications, and propose how thinking of tsRNA functionality from an evolutionary perspective urges the expansion of tsRNA research into a wider spectrum, including cross-tissue/cross-species regulation and harnessing of the 'tsRNA code' for precision medicine.
Assuntos
Inativação Gênica , RNA de Transferência , RNA de Transferência/genéticaRESUMO
Light scattered or radiated from a material carries valuable information on the said material. Such information can be uncovered by measuring the light field at different angles and frequencies. However, this technique typically requires a large optical apparatus, hampering the widespread use of angle-resolved spectroscopy beyond the lab. Here we demonstrate compact angle-resolved spectral imaging by combining a tunable metasurface-based spectrometer array and a metalens. With this approach, even with a miniaturized spectrometer footprint of only 4 × 4 µm2, we demonstrate a wavelength accuracy of 0.17 nm, spectral resolution of 0.4 nm and a linear dynamic range of 149 dB. Moreover, our spectrometer has a detection limit of 1.2 fJ, and can be patterned to an array for spectral imaging. Placing such a spectrometer array directly at the back focal plane of a metalens, we achieve an angular resolution of 4.88 × 10-3 rad. Our angle-resolved spectrometers empowered by metalenses can be employed towards enhancing advanced optical imaging and spectral analysis applications.
RESUMO
BACKGROUND: Although chimeric antigen receptor T (CAR-T) cells have been proven to be an effective way of treating B cell malignancies, a lot of patients could not benefit from it because of failure in CAR-T cell manufacturing, disease progression, and unaffordable price. The study aimed to explore universal CAR-T cell products to extend the clinical accessibility. METHODS: The antitumor activity of CRISPR/Cas9-edited allogeneic anti-CD19 CAR-T (CAR-T19) cells was assessed in vitro, in animal models, and in patients with relapsed/refractory (R/R) acute B cell lymphoblastic leukemia (B-ALL) or diffuse large B cell lymphoma. RESULTS: B2M-/TRAC- universal CAR-T19 (U-CAR-T19) cells exhibited powerful anti-leukemia abilities both in vitro and in animal models, as did primary CD19+ leukemia cells from leukemia patients. However, expansion, antitumor efficacy, or graft-versus-host-disease (GvHD) was not observed in six patients with R/R B cell malignancies after U-CAR-T19 cell infusion. Accordingly, significant activation of natural killer (NK) cells by U-CAR-T19 cells was proven both clinically and in vitro. HLA-A-/B-/TRAC- novel CAR-T19 (nU-CAR-T19) cells were constructed with similar tumoricidal capacity but resistance to NK cells in vitro. Surprisingly, robust expansion of nU-CAR-T19 cells, along with rapid eradication of CD19+ abnormal B cells, was observed in the peripheral blood and bone marrow of another three patients with R/R B-ALL. The patients achieved complete remission with no detectable minimal residual disease 14 days after the infusion of nU-CAR-T19 cells. Two of the three patients had grade 2 cytokine release syndrome, which were managed using an IL-6 receptor blocker. Most importantly, GvHD was not observed in any patient, suggesting the safety of TRAC-disrupted CAR-T cells generated using the CRISPR/Cas9 method for clinical application. CONCLUSIONS: The nU-CAR-T19 cells showed a strong response in R/R B-ALL. nU-CAR-T19 cells have the potential to be a promising new approach for treating R/R B cell malignancies.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Linfocítica Crônica de Células B , Leucemia , Receptores de Antígenos Quiméricos , Animais , Humanos , Receptores de Antígenos Quiméricos/genética , Anticorpos , Antígenos CD19 , Linfócitos T , Antígenos HLA-ARESUMO
The properties of the drug may be altered by the combination, which may cause unexpected drug-drug interactions (DDIs). Prediction of DDIs provides combination strategies of drugs for systematic and effective treatment. In most of deep learning-based methods for predicting DDI, encoded information about the drugs is insufficient in some extent, which limits the performances of DDIs prediction. In this work, we propose a novel attention-mechanism-based multidimensional feature encoder for DDIs prediction, namely attention-based multidimensional feature encoder (AMDE). Specifically, in AMDE, we encode drug features from multiple dimensions, including information from both Simplified Molecular-Input Line-Entry System sequence and atomic graph of the drug. Data experiments are conducted on DDI data set selected from Drugbank, involving a total of 34 282 DDI relationships with 17 141 positive DDI samples and 17 141 negative samples. Experimental results show that our AMDE performs better than some state-of-the-art baseline methods, including Random Forest, One-Dimension Convolutional Neural Networks, DeepDrug, Long Short-Term Memory, Seq2seq, Deepconv, DeepDDI, Graph Attention Networks and Knowledge Graph Neural Networks. In practice, we select a set of 150 drugs with 3723 DDIs, which are never appeared in training, validation and test sets. AMDE performs well in DDIs prediction task, with AUROC and AUPRC 0.981 and 0.975. As well, we use Torasemide (DB00214) as an example and predict the most likely drug to interact with it. The top 15 scores all have been reported with clear interactions in literatures.
Assuntos
Interações Medicamentosas , Aprendizado Profundo , Humanos , Redes Neurais de Computação , Preparações FarmacêuticasRESUMO
Multi-drug combinations for the treatment of complex diseases are gradually becoming an important treatment, and this type of treatment can take advantage of the synergistic effects among drugs. However, drug-drug interactions (DDIs) are not just all beneficial. Accurate and rapid identifications of the DDIs are essential to enhance the effectiveness of combination therapy and avoid unintended side effects. Traditional DDIs prediction methods use only drug sequence information or drug graph information, which ignores information about the position of atoms and edges in the spatial structure. In this paper, we propose Molormer, a method based on a lightweight attention mechanism for DDIs prediction. Molormer takes the two-dimension (2D) structures of drugs as input and encodes the molecular graph with spatial information. Besides, Molormer uses lightweight-based attention mechanism and self-attention distilling to process spatially the encoded molecular graph, which not only retains the multi-headed attention mechanism but also reduces the computational and storage costs. Finally, we use the Siamese network architecture to serve as the architecture of Molormer, which can make full use of the limited data to train the model for better performance and also limit the differences to some extent between networks dealing with drug features. Experiments show that our proposed method outperforms state-of-the-art methods in Accuracy, Precision, Recall and F1 on multi-label DDIs dataset. In the case study section, we used Molormer to make predictions of new interactions for the drugs Aliskiren, Selexipag and Vorapaxar and validated parts of the predictions. Code and models are available at https://github.com/IsXudongZhang/Molormer.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Interações Medicamentosas , HumanosRESUMO
BACKGROUND: Identifying precise biomarkers of immunotherapy response for non-small cell lung carcinoma (NSCLC) before treatment is challenging. This study aimed to construct and investigate the potential performance of a sub-regional radiomics model (SRRM) as a novel tumor biomarker in predicting the response of patients with NSCLC treated with immune checkpoint inhibitors, and test whether its predictive performance is superior to that of conventional radiomics, tumor mutational burden (TMB) score and programmed death ligand-1 (PD-L1) expression. METHODS: We categorized 264 patients from retrospective databases of two centers into training (n = 159) and validation (n = 105) cohorts. Radiomic features were extracted from three sub-regions of the tumor region of interest using the K-means method. We extracted 1,896 features from each sub-region, resulting in 5688 features per sample. The least absolute shrinkage and selection operator regression method was used to select sub-regional radiomic features. The SRRM was constructed and validated using the support vector machine algorithm. We used next-generation sequencing to classify patients from the two cohorts into high TMB (≥ 10 muts/Mb) and low TMB (< 10 muts/Mb) groups; immunohistochemistry was performed to assess PD-L1 expression in formalin-fixed, paraffin-embedded tumor sections, with high expression defined as ≥ 50% of tumor cells being positive. Associations between the SRRM and progression-free survival (PFS) and variant genes were assessed. RESULTS: Eleven sub-regional radiomic features were employed to develop the SRRM. The areas under the receiver operating characteristic curve (AUCs) of the proposed SRRM were 0.90 (95% confidence interval [CI] 0.84-0.96) and 0.86 (95% CI 0.76-0.95) in the training and validation cohorts, respectively. The SRRM (low vs. high; cutoff value = 0.936) was significantly associated with PFS in the training (hazard ratio [HR] = 0.35 [0.24-0.50], P < 0.001) and validation (HR = 0.42 [0.26-0.67], P = 0.001) cohorts. A significant correlation between the SRRM and three variant genes (H3C4, PAX5, and EGFR) was observed. In the validation cohort, the SRRM demonstrated a higher AUC (0.86, P < 0.001) than that for PD-L1 expression (0.66, P = 0.034) and TMB score (0.54, P = 0.552). CONCLUSIONS: The SRRM had better predictive performance and was superior to conventional radiomics, PD-L1 expression, and TMB score. The SRRM effectively stratified the progression-free survival (PFS) risk among patients with NSCLC receiving immunotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Antígeno B7-H1/genética , Radiômica , Estudos Retrospectivos , Imunoterapia , Biomarcadores Tumorais , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapiaRESUMO
For a certain number of mAbs, bispecific antibodies (bsAbs) and Fc-fusion proteins that we worked on, the Protein A capture step experienced low yield (i.e., â¼80%). A previous case study suggested that non-binding aggregate formed in cell culture was the root cause of low Protein A step yield. In the current work, we selected five projects with the low Protein A yield issue to further illustrate this phenomenon. In all cases, existence of non-binding aggregates was confirmed by size-exclusion chromatography-high performance liquid chromatography (SEC-HPLC) analysis of Protein A load and flow-through. In addition, we demonstrated that aggregates failed to bind to Protein A resin mainly due to their large sizes, which prevented them from entering the resin beads. As the data suggested, SEC-HPLC analysis of Protein A load and flow-through, although not a standard procedure, can provide information that is critical for understanding the unexpected performance of Protein A chromatography in cases like those being presented here. Thus, SEC-HPLC analysis of Protein A load and flow-through is highly recommended for antibodies/Fc-fusions suffering from low Protein A yield.
Assuntos
Anticorpos Biespecíficos , Técnicas de Cultura de Células , Cromatografia Líquida de Alta Pressão , Cromatografia em Gel , Anticorpos Monoclonais/química , Anticorpos Biespecíficos/química , Proteína Estafilocócica A/químicaRESUMO
Clenbuterol (CLB) as an illegal feed additive may cause a great security risk to food safety. However, convenient and efficient detection means for CLB in practical application remain a formidable challenge. Herein, a stable Eu-based organic framework {[H2N(CH3)2]2[Eu2(ttca)2]·H2O}n (compound 1) (H4ttca = [1,1':2',1â³-terphenyl]-4,4',4â³,5'-tetracarboxylic acid) has been harvested, exhibiting excellent chemical stability and thermal stability. Luminescence investigation reveals that compound 1 can sensitively and selectively detect CLB without being affected by different components from simulated serum and urine (limit detection: 22.7 nM). Furthermore, sensor 1 can also be applicable to CLB recognition in real swine feeds, presenting excellent anti-interference performance. The good cyclicity of compound 1 endows CLB determination with many advantages: low cost, high stability, and simplicity. Importantly, in view of the indication of the luminescence color (red to blue), test membranes were fabricated and employed for convenient and fast CLB detection, providing a valuable scheme for the visual monitoring of CLB in meat products. This work enriches rare earth metal compounds and luminescence sensor portfolios and breaks the concentration record (nM) for detecting CLB compared with reported complex materials, providing an effective monitoring platform for CLB visually.
Assuntos
Clembuterol , Animais , Suínos , Luminescência , TiazolidinasRESUMO
Electrosorption (ES) is a research frontier in electrochemical separation, with proven potential applications in desalination, wastewater treatment, and selective resource extraction. However, due to the limited adsorption capacity of film electrodes, ES requires short circuiting or circuit reversal, accompanied by a solution switch between the feed solution and receiving solution, to sustain desalination over many charge-discharge cycles. In previously reported studies, solution switches have been commonly ignored to simplify experimental procedures, and their impacts on separation performance are thus not well understood. This study aims to provide a quantitative analysis of the impacts of mixing due to a solution switch on the performance of ES-based desalination. A numerical model of ES has been employed to evaluate the adverse effects of the solution switch on the desalination performance in three commonly used operation modes. The analysis reveals that the impacts of mixing due to solution-switch are more severe with a larger concentration difference between the desalinated water and the brine and provides insights into the effectiveness of increasing electrode loading or specific capacity in mitigating the detrimental impacts of mixing. Even with state-of-the-art systems, producing freshwater from seawater or even brackish water with medium-to-high salinity is practically challenging due to the presence of solution switch.
Assuntos
Salinidade , Purificação da Água , Purificação da Água/métodos , Água do Mar/química , Adsorção , Eletrodos , SoluçõesRESUMO
Aim: This multicenter retrospective study aimed to develop a novel prognostic system for extranodal natural killer/T-cell lymphoma (ENKTL) patients in the era of pegaspargase/L-asparaginase. Materials & methods: A total of 844 newly diagnosed ENKTL patients were included. Results: Multivariable analysis confirmed that Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, Chinese Southwest Oncology Group and Asia Lymphoma Study Group ENKTL (CA) system, and albumin were independent prognostic factors. By rounding up the hazard ratios from four significant variables, a maximum of 7 points were assigned. The model of Huaihai Lymphoma Working Group-Natural killer/T-cell Lymphoma prognostic index (NPI) was identified with four risk groups and the 5-year overall survival was 88.2, 66.7, 54.3 and 30.5%, respectively. Conclusion: Huaihai Lymphoma Working Group-NPI provides a feasible stratification system for patients with ENKTL in the era of pegaspargase/L-asparaginase.
[Box: see text].
RESUMO
Sludge incineration is the main strategy for sludge reduction in China. The combined conditioning of lime and chemical agents has been proven to achieve sludge dewatering by disrupting the extracellular polymeric substances (EPS) of sludge and reducing its compressibility. However, when incineration is the intended disposal purpose, this method poses challenges such as incomplete combustion, equipment corrosion, secondary pollution, and decreased calorific value of sludge cake. In contrast, freeze-thaw conditioning, coupled with sawdust as a high-calorific-value bio-waste, emerges as an efficient and clean alternative. The research investigates the synergistic effects of freeze-thaw and sawdust co-conditioning on various sludge properties, including dewaterability, compressibility, consolidation, permeability, microscopicity, and calorific value. The study reveals that the combined conditioning significantly reduces water content and compressibility while increasing void ratio, consolidation, permeability, and enhancing the calorific value of the sludge cake. Specifically, sludge cake conditioned with 60% dried solids (DS) sawdust and freeze-thaw achieved a water content (Wc) of 49.07% and a calorific value of 1422.3 kcal/kg, meeting standards for self-sustained incineration. With heat recovery, the combined conditioning generates an economic revenue of 25.1 $/t DS after deducting costs, thereby reducing the overall cost of sludge reduction treatment. This research offers a clean and practical solution for sludge incineration and reduction, demonstrating great economic value and application potential.
Assuntos
Congelamento , Incineração , Esgotos , Esgotos/química , Incineração/métodos , Madeira/química , Estudos de Viabilidade , ÁguaRESUMO
Cancer therapeutic resistance remains a significant challenge in the pursuit of effective treatment strategies. Circular RNAs (circRNAs), a class of non-coding RNAs, have recently emerged as key regulators of various biological processes, including cancer progression and drug resistance. This review highlights the emerging role of circRNAs-mediated autophagy in cancer therapeutic resistance, a cellular process that plays a dual role in cancer by promoting both cell survival and death. Increasing evidence suggests that circRNAs can modulate autophagy pathways, thereby influencing the response of cancer cells to therapeutic agents. In this context, the intricate interplay between circRNAs, autophagy, and therapeutic resistance is explored. Various mechanisms are discussed through which circRNAs can impact autophagy, including direct interactions with autophagy-related genes, modulation of signaling pathways, and cross-talk with other non-coding RNAs. Furthermore, the review delves into specific examples of how circRNA-mediated autophagy regulation can contribute to resistance against chemotherapy and radiotherapy. Understanding these intricate molecular interactions provides valuable insights into potential strategies for overcoming therapeutic resistance in cancer. Exploiting circRNAs as therapeutic targets or utilizing them as diagnostic and predictive biomarkers opens new avenues for developing personalized treatment approaches. In summary, this review underscores the importance of circRNA-mediated autophagy in cancer therapeutic resistance and proposes future directions for research in this exciting and rapidly evolving field.
Assuntos
Autofagia , Resistencia a Medicamentos Antineoplásicos , Neoplasias , RNA Circular , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Autofagia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias/genética , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Transdução de Sinais/genética , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
Despite the associations of dietary patterns and air pollution with human reproductive health have been demonstrated, the interaction of maternal preconception diet and PM2.5 and its components exposure on in vitro fertilization (IVF) treatment outcomes has not been investigated. A total of 2688 couples from an ongoing prospective cohort were included. Principle component analysis with varimax rotation was performed to determine dietary patterns. One-year and 85-day average PM2.5 and its components exposure levels before oocyte retrieval were estimated. Generalized linear regression models were conducted to assess the association of dietary patterns and PM2.5 and its components exposure with IVF outcomes. Interactive effects of dietary patterns on the association between PM2.5 and its components and IVF outcomes were evaluated by stratified analyses based on different dietary patterns. A positive association between the "Fruits-Vegetables-Dairy" pattern and normal fertilization (p-trend = 0.009), Day 3 available embryos (p-trend = 0.048), and top-quality embryos (p-trend = 0.041) was detected. Conversely, women with higher adherence to the "Puffed food-Bakery-Candy" pattern were less likely to achieve Day 3 available embryos (p-trend = 0.042) and top-quality embryos (p-trend = 0.030), clinical pregnancy (p-trend = 0.049), and live birth (p-trend = 0.020). Additionally, increased intake of animal organs and seafood improved the odds of live birth (p-trend = 0.048). Exposure to PM2.5, SO42-, organic matter (OM), and black carbon (BC) had adverse effects on embryo development and pregnancy outcomes. Furthermore, our findings indicated that the effects of PM2.5 components exposure on normal fertilization and embryo quality were modified by the "Grains-Tubers-Legumes". Moreover, moderate intake of animal organs and seafood appeared to attenuate the effect of NO3- and NH4+ on the risk of early abortion. Our findings provide human evidence of the interaction between dietary patterns and PM2.5 exposure on IVF outcomes during preconception, implicating the potential for dietary interventions in infertile women to improve reproductive outcomes under conditions of unavoidable ambient air-pollutant exposure.
Assuntos
Poluentes Atmosféricos , Dieta , Fertilização in vitro , Material Particulado , Feminino , Humanos , Material Particulado/análise , Adulto , Gravidez , Dieta/estatística & dados numéricos , Estudos Prospectivos , Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , Exposição Materna/estatística & dados numéricos , Masculino , Padrões DietéticosRESUMO
Diminished testosterone levels have been documented as a key factor in numerous male health disorders. Both human and animal studies have consistently demonstrated that cadmium (Cd), a pervasive environmental heavy metal, results in decreased testosterone levels. However, the exact mechanism through which Cd interferes with testosterone synthesis remains incompletely elucidated. This research sought to examine the impact of cellular senescence on Cd-suppressed testosterone synthesis. We also investigated the related m6A modification mechanism. The results demonstrated that Cd (100â¯mg/L) led to a decrease in testosterone levels, along with downregulated expression of testosterone synthase in C57BL/6â¯N male mice. Furthermore, Cd significantly increased ß-galactosidase staining intensity, senescence-related proteins, and senescence-related secretory phenotypes in mouse testicular Leydig cells. Subsequent investigations revealed that Cd decreased the mRNA and protein levels of NAD-dependent deacetylase Sirtuin-1 (SIRT1) in Leydig cells. Mechanistically, mice treated with resveratrol (50â¯mg/kg), a specific SIRT1 activator, mitigated Leydig cell senescence and reversed Cd-reduced testosterone levels in mouse testes. These effects were also restored by SIRT1 overexpression in Leydig cells. Additionally, we found that Cd increased the level of methyltransferase enzyme METTL3 and Sirt1 m6A modification in Leydig cells. Mettl3 siRNA effectively restored Cd-enhanced Sirt1 m6A level and reversed Cd-downregulated Sirt1 mRNA expression in Leydig cells. Overall, our findings suggest that Cd exposure inhibits testosterone synthesis via Sirt1 m6A modification-mediated senescence in mouse testes. These results offer an experimental basis for investigating the causes and potential treatments of hypotestosteronemia induced by environmental factors.
RESUMO
Waste cooking oil's (WCO's) potential as a rejuvenator of aged asphalt has received attention in recent years, with the acid value of WCO affecting its rejuvenation effect. This study explored the rejuvenation effect of WCO with a high acid value on aged asphalt by using molecular dynamics simulation. First, the representative molecules of WCO with a high acid value and asphalt were determined. The rejuvenation effect of WCO on aged asphalt was analyzed by adding different contents of WCO to an aged asphalt model. The effect of WCO on the thermodynamic properties of the aged asphalt was analyzed. The results show that WCO can restore the thermodynamic properties of aged asphalt binder to a certain extent. Regarding the microstructure of rejuvenated asphalt, WCO molecules dispersed around asphaltenes weakened the latter's aggregation and improved the colloidal structure of the aged asphalt. In terms of interface adhesion properties, WCO can improve the adhesion properties between asphalt binder and SiO2, but it has limited influence on water sensitivity. The results allowed us to comprehensively evaluate the rejuvenation effect of WCO with a high acid value on aged asphalt and to explore its rejuvenation mechanism.
RESUMO
This study aimed to establish an ambulatory field-friendly system based on miniaturised wireless flexible sensors for studying the biomechanics of human-exoskeleton interactions. Twelve healthy adults performed symmetric lifting with and without a passive low-back exoskeleton, while their movements were tracked using both a flexible sensor system and a conventional motion capture (MoCap) system synchronously. Novel algorithms were developed to convert the raw acceleration, gyroscope, and biopotential signals from the flexible sensors into kinematic and dynamic measures. Results showed that these measures were highly correlated with those obtained from the MoCap system and discerned the effects of the exoskeleton, including increased peak lumbar flexion, decreased peak hip flexion, and decreased lumbar flexion moment and back muscle activities. The study demonstrated the promise of an integrated flexible sensor-based system for biomechanics and ergonomics field studies as well as the efficacy of exoskeleton in relieving the low-back stress associated with manual lifting.
This study established and tested a flexible sensor-based ambulatory system for biomechanical evaluation of human-exoskeleton interactions and as a promising new tool for field ergonomics studies in practical or naturalistic settings.Abbreviations: MoCap: motion capture; WMSD: Work-related musculoskeletal disorders; EMG: electromyography; IMU: inertial measurement unit; TES: thoracic erector spinae; LES: lumbar erector spinae; WITH: tasks performed with wearing the exoskeleton; WITHOUT: tasks performed without wearing the exoskeleton; RMS: root mean square; RMSE: root-mean-square error; r: Pearson's correlation coefficient; ASIS: anterior superior iliac spine.
Assuntos
Músculos do Dorso , Exoesqueleto Energizado , Organotiofosfatos , Adulto , Humanos , Músculo Esquelético/fisiologia , Eletromiografia/métodos , Remoção , Músculos do Dorso/fisiologia , Fenômenos BiomecânicosRESUMO
Recent data suggest that most genotoxic agents in cancer therapy can lead to shock of genome and increase in cell size, which leads whole genome duplication or multiplication, formation of polyploid giant cancer cells, activation of an early embryonic program, and dedifferentiation of somatic cells. This process is achieved via the giant cell life cycle, a recently proposed mechanism for malignant transformation of somatic cells. Increase in both cell size and ploidy allows cells to completely or partially restructures the genome and develop into a blastocyst-like structure, similar to that observed in blastomere-stage embryogenesis. Although blastocyst-like structures with reprogrammed genome can generate resistant or metastatic daughter cells or benign cells of different lineages, they also acquired ability to undergo embryonic diapause, a reversible state of suspended embryonic development in which cells enter dormancy for survival in response to environmental stress. Therapeutic agents can activate this evolutionarily conserved developmental program, and when cells awaken from embryonic diapause, this leads to recurrence or metastasis. Understanding of the key mechanisms that regulate the different stages of the giant cell life cycle offers new opportunities for therapeutic intervention.