Autophagy is a highly conserved catabolic process that mediates degradation of pernicious or dysfunctional cellular components, such as invasive pathogens, senescent proteins, and organelles. It can ...promote or suppress tumor development, so it is a "double-edged sword" in tumors that depends on the cell and tissue types and the stages of tumor. The epithelial-mesenchymal transition (EMT) is a complex biological trans-differentiation process that allows epithelial cells to transiently obtain mesenchymal features, including motility and metastatic potential. EMT is considered as an important contributor to the invasion and metastasis of cancers. Thus, clarifying the crosstalk between autophagy and EMT will provide novel targets for cancer therapy. It was reported that EMT-related signal pathways have an impact on autophagy; conversely, autophagy activation can suppress or strengthen EMT by regulating various signaling pathways. On one hand, autophagy activation provides energy and basic nutrients for EMT during metastatic spreading, which assists cells to survive in stressful environmental and intracellular conditions. On the other hand, autophagy, acting as a cancer-suppressive function, is inclined to hinder metastasis by selectively down-regulating critical transcription factors of EMT in the early phases. Therefore, the inhibition of EMT by autophagy inhibitors or activators might be a novel strategy that provides thought and enlightenment for the treatment of cancer. In this article, we discuss in detail the role of autophagy and EMT in the development of cancers, the regulatory mechanisms between autophagy and EMT, the effects of autophagy inhibition or activation on EMT, and the potential applications in anticancer therapy.
The mechanical response of interpenetrating phase composites (IPCs) with stochastic spinodal topologies is investigated experimentally and numerically. Model polymeric systems are fabricated by ...Polyjet multi-material printing, with the reinforcing phase taking the topology of a spinodal shell, and the remaining volume filled by a softer matrix. We show that spinodal shell IPCs have comparable compressive strength and stiffness to IPCs with two well-established periodic reinforcements, the Schwarz P triply periodic minimal surface (TPMS) and the octet truss-lattice, while exhibiting far less catastrophic failure and greater damage resistance, particularly at high volume fraction of reinforcing phase. The combination of high stiffness and strength and a long flat plateau after yielding makes spinodal shell IPCs a promising candidate for energy absorption and impact protection applications, where the lack of material softening upon large compressive strains can prevent sudden collapse. Importantly, in contrast with all IPCs with periodic reinforcements, spinodal shell IPCs are amenable to scalable manufacturing via self-assembly techniques.
Sirtuin 3 (SIRT3) is a potential therapeutic target for cardiovascular, metabolic, and other aging-related diseases. In this study, we investigated the role of SIRT3 in diabetic cardiomyopathy (DCM). ...Mice were injected with streptozotocin (STZ, 60 mg/kg, ip) to induce diabetes mellitus. Our proteomics analysis revealed that SIRT3 expression in the myocardium of diabetic mice was lower than that of control mice, as subsequently confirmed by real-time PCR and Western blotting. To explore the role of SIRT3 in DCM, SIRT3-knockout mice and 129S1/SvImJ wild-type mice were injected with STZ. We found that diabetic mice with SIRT3 deficiency exhibited aggravated cardiac dysfunction, increased lactate dehydrogenase (LDH) level in the serum, decreased adenosine triphosphate (ATP) level in the myocardium, exacerbated myocardial injury, and promoted myocardial reactive oxygen species (ROS) accumulation. Neonatal rat cardiomyocytes were transfected with SIRT3 siRNA, then exposed to high glucose (HG, 25.5 mM). We found that downregulation of SIRT3 further increased LDH release, decreased ATP level, suppressed the mitochondrial membrane potential, and elevated oxidative stress in HG-treated cardiomyocytes. SIRT3 deficiency further raised expression of necroptosis-related proteins including receptor-interacting protein kinase 1 (RIPK1), RIPK3, and cleaved caspase 3, and upregulated the expression of inflammation-related proteins including NLR family pyrin domain-containing protein 3 (NLRP3), caspase 1 p20, and interleukin-1β both in vitro and in vivo. Collectively, SIRT3 deficiency aggravated hyperglycemia-induced mitochondrial damage, increased ROS accumulation, promoted necroptosis, possibly activated the NLRP3 inflammasome, and ultimately exacerbated DCM in the mice. These results suggest that SIRT3 can be a molecular intervention target for the prevention and treatment of DCM.
Resistance to chemotherapy is a major challenge for the treatment of patients with colorectal cancer (CRC). Previous studies have found that microRNAs (miRNAs) play key roles in drug resistance; ...however, the role of miRNA‐373‐3p (miR‐375‐3p) in CRC remains unclear. The current study aimed to explore the potential function of miR‐375‐3p in 5‐fluorouracil (5‐FU) resistance. MicroRNA‐375‐3p was found to be widely downregulated in human CRC cell lines and tissues and to promote the sensitivity of CRC cells to 5‐FU by inducing colon cancer cell apoptosis and cycle arrest and by inhibiting cell growth, migration, and invasion in vitro. Thymidylate synthase (TYMS) was found to be a direct target of miR‐375‐3p, and TYMS knockdown exerted similar effects as miR‐375‐3p overexpression on the CRC cellular response to 5‐FU. Lipid‐coated calcium carbonate nanoparticles (NPs) were designed to cotransport 5‐FU and miR‐375‐3p into cells efficiently and rapidly and to release the drugs in a weakly acidic tumor microenvironment. The therapeutic effect of combined miR‐375 + 5‐FU/NPs was significantly higher than that of the individual treatments in mouse s.c. xenografts derived from HCT116 cells. Our results suggest that restoring miR‐375‐3p levels could be a future novel therapeutic strategy to enhance chemosensitivity to 5‐FU.
Resistance to chemotherapy is a major challenge for the treatment of patients with colorectal cancer (CRC). Our results suggest that the restoration of microRNA‐375‐3p levels could be a future novel therapeutic strategy to modulate and enhance chemosensitivity to 5‐fluorouracil treatment in CRC.
This cross-sectional study evaluated and quantified the possible association of psychological symptoms and health status ratings on the burnout of healthcare workers from a tertiary medical center. ...Demographic data were obtained through a questionnaire survey. We evaluated their psychological symptoms using a 5-item Brief Symptom Rating Scale (BSRS-5) and burnout was measured using the Chinese version of the Maslach Burnout Inventory-Health Services Survey. The study began in Nov. 2018 and ended in Nov. 2020. A total of 2813 participants (men = 296, 10.5%; women = 2517, 89.5%) completed the questionnaires between December 2018 and March 2019. The response rate and complete rate were 71.7% and 93.2%. The multivariate analysis showed that, as the BSRS-5 level added, the odds ratio (OR) of burnout increased (BSRS-5 scores 6-9, 10-14, and 15-20; OR = 1.83, 3.23, and 9.15, separately; p value < 0.05). Overall, men (≥ 30 years of age) and women staffs with BSRS-5 scores ≥ 6; women with longer working hours (more than 46 h/week), men and women (≥ 30 years of age) working night shifts, and poor health status ratings were highly associated with burnout. The findings highlight the importance of screening for the BSRS-5 scores and health status ratings level for healthcare professionals at high risk of burnout, especially men ≥ 30 years of age and women with stressful working conditions.
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•Beam- and surface-based lattice topologies are all suitable for bone implant design.•In surface-based topologies, specific area and implant stiffness can be decoupled.•Surface-based ...topologies are more efficient at promoting bone growth than beam-based topologies.•Stochastic spinodal shell topologies require the smallest safety factor.
Large bone fractures often require porous implants for complete healing. In this work, we numerically investigate the suitability of three topologically very different architected materials for long bone implants: the octet truss-based lattice, the Schwartz P minimal surface-based lattice and the spinodal stochastic surface-based lattice. Each implant topology (reinforcement) and its surrounding tissue (soft matrix) are modeled as a composite system via finite element analysis. Performance metrics are defined based on the Young’s modulus, the peak stress under service conditions, the interfacial surface area per unit volume and the relative bone growth rate (estimated based on the strain transferred to the soft matrix). We show that surface-based topologies are less prone to fatigue failure and may promote superior bone growth than conventional truss-based designs. Spinodal surface-based architected materials have the best performance, and can be fabricated via self-assembly approaches followed by material conversion, potentially allowing scalable fabrication of implants with unit cell sizes at the micro-scale, thus dramatically amplifying surface area per unit volume and bone growth efficiency.
Using an intensive longitudinal design, this study investigated the predictive role of and interaction between competence beliefs and task value in relation to four achievement emotions (enthusiasm, ...excitement, anxiety, and irritation) as well as cognitive engagement. Data were collected using an experience sampling method to capture the momentary experiences of 81 university students over 14 days. Using a multilevel modeling approach, the study disentangled variations between and within individuals across learning situations. The results indicated that associations between competence and value beliefs and emotions were primarily observed at the situational level. Both competence and value beliefs played important roles in predicting cognitive engagement. In addition, high competence beliefs acted as a buffer, mitigating the positive association between opportunity cost and anxiety and reducing the negative impact of low intrinsic value on irritation. Positive value beliefs emerged as instrumental in fostering cognitive engagement, particularly in situations characterized by limited competence beliefs.
The motivation and engagement displayed by university students in diverse learning events offer valuable insights into their dedication and academic involvement in pursuing their degrees. This study highlights the importance of perceiving both high competence beliefs and intrinsic value, which results in stronger associations with enthusiasm and excitement during learning. Conversely, high opportunity cost is linked to greater anxiety, but high competence beliefs act as a protective factor, mitigating this effect. High competence beliefs also counteract the negative impact of low intrinsic value on irritation. Value beliefs, particularly importance and intrinsic value, have a compensatory effect on cognitive engagement. Positive value beliefs play a crucial role in driving cognitive engagement, especially when competence beliefs are lacking. Gaining insight into changes within individuals and variations between students enables educators to effectively tailor instructional strategies and provide support, which in turn fosters students' motivation and engagement.
•Substantial intrapersonal fluctuations in emotions and cognitive engagement•Competence beliefs interact with value beliefs affecting emotions.•High competence beliefs mitigate the positive association between cost and anxiety.•High competence beliefs reduce negative impact of low intrinsic value on irritation.•Positive value beliefs play a crucial role in driving cognitive engagement.
Abstract Background The motivation and emotions of students are context dependent. There are specific moments when students may find their coursework more or less motivating, resulting in stronger or ...milder emotional responses. Identifying factors directly controllable by teachers empowers them to effectively address challenging situations characterized by lower motivation and increased negative emotions. Aims We aimed to investigate how learning activities and students' perception of teaching practices fostering autonomy relate to competence and value beliefs, and emotions in the context of course participation within higher education. Sample Seventy‐seven Taiwanese university students provided 762 learning reports associated with their course participation experiences. Methods The experience sampling method (ESM) was used. Participants responded to ESM surveys on their phones for 14 days, reporting motivational beliefs, emotions and contextual characteristics of the course if they indicated active participation in a course upon receiving notifications from their phones. Results A significant portion of the variation is attributed to situational fluctuation, suggesting that academic emotions and competence and value beliefs vary within students across measurements. An increase in students' perception of an autonomy‐supportive learning climate correlates with higher competence beliefs, intrinsic value and positive emotions, coupled with reduced perceived costs and negative emotions. In contrast to lectures, engaging in independent hands‐on work, participating in group collaborative projects or interactive discussions appear to inspire motivation or evoke stronger emotional responses in students. Conclusions Teachers' teaching practices and classroom learning activities play a pivotal role in shaping students' situational motivation and emotions.
•Spinodal shell-based metamaterials are stochastic yet stretching-dominated.•Spinodal shell-based metamaterials are imperfection-insensitive.•Spinodal shell-based metamaterials have superior specific ...stiffness and strength.•Spinodal shell materials are isotropic in three dimensions.•Spinodal decomposition provides a route for scalable nanomanufacturing of metamaterials.
The mechanical response of cellular materials with spinodal topologies is numerically and experimentally investigated. Spinodal microstructures are generated by the numerical solution of the Cahn-Hilliard equation. Two different topologies are investigated: ‘solid models,’ where one of the two phases is modeled as a solid material and the remaining volume is void space; and ‘shell models,’ where the interface between the two phases is assumed to be a solid shell, with the rest of the volume modeled as void space. In both cases, a wide range of relative densities and spinodal characteristic feature sizes are investigated. The topology and morphology of all the numerically generated models are carefully characterized to extract key geometrical features and ensure that the distribution of curvatures and the aging law are consistent with the physics of spinodal decomposition. Finite element meshes are generated for each model, and the uniaxial compressive stiffness and strength are extracted. We show that while solid spinodal models in the density range of 30–70% are relatively inefficient (i.e., their strength and stiffness exhibit a high-power scaling with relative density), shell spinodal models in the density range of 0.01–1% are exceptionally stiff and strong. Spinodal shell materials are also shown to be remarkably imperfection insensitive. These findings are verified experimentally by in-situ uniaxial compression of polymeric samples printed at the microscale by Direct Laser Writing (DLW). At low relative densities, the strength and stiffness of shell spinodal models outperform those of most lattice materials and approach theoretical bounds for isotropic cellular materials. Most importantly, these materials can be produced by self-assembly techniques over a range of length scales, providing unique scalability.
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