Evidence suggests that fasting exerts extensive antitumor effects in various cancers, including colorectal cancer (CRC). However, the mechanism behind this response is unclear. We investigate the ...effect of fasting on glucose metabolism and malignancy in CRC. We find that fasting upregulates the expression of a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during the inhibition of CRC cell aerobic glycolysis and proliferation. In addition, the downregulation of FDFT1 is correlated with malignant progression and poor prognosis in CRC. Moreover, FDFT1 acts as a critical tumor suppressor in CRC. Mechanistically, FDFT1 performs its tumor-inhibitory function by negatively regulating AKT/mTOR/HIF1α signaling. Furthermore, mTOR inhibitor can synergize with fasting in inhibiting the proliferation of CRC. These results indicate that FDFT1 is a key downstream target of the fasting response and may be involved in CRC cell glucose metabolism. Our results suggest therapeutic implications in CRC and potential crosstalk between a cholesterogenic gene and glycolysis.
Prior studies in patients with chronic obstructive pulmonary disease (COPD) had indicated a potential correlation between cadmium (Cd) exposure and reduction in lung function. Nevertheless, the ...influence of Cd exposure on the progression of COPD remained unknown. Exploring the relationship between Cd exposure and the progression of COPD was the aim of this investigation.
Stable COPD patients were enrolled. Blood samples were collected and lung function was evaluated. Regular professional follow-ups were conducted through telephone communications, outpatient services, and patients' hospitalization records.
Each additional unit of blood Cd was associated with upward trend in acute exacerbation, hospitalization, longer hospital stay, and death within 2 years. Even after adjusting for potential confounding factors, each 1 unit rise in blood Cd still correlated with a rise in the frequencies of acute exacerbation, longer hospital stay, and death. Moreover, COPD patients with less smoking amount, lower lung function and without comorbidities were more vulnerable to Cd-induced disease deterioration.
Patients with COPD who have higher blood Cd concentration are susceptible to worse disease progression.
Soft dielectric elastomer actuators (DEAs) exhibit interesting muscle-like behavior for the development of soft robots. However, it is challenging to model these soft actuators due to their material ...nonlinearity, nonlinear electromechanical coupling, and time-dependent viscoelastic behavior. Most recent studies on DEAs focus on issues of mechanics, physics, and material science, while much less importance is given to quantitative characterization of DEAs. In this paper, we present a detailed experimental investigation probing the voltage-induced electromechanical response of a soft DEA that is subjected to cyclic loading and propose a general constitutive modeling approach to characterize the time-dependent response, based on the principles of nonequilibrium thermodynamics. In this paper, some of the key observations are found as follows: 1) Creep exhibits the drift phenomenon, and is dominant during the first three cycles. The creep decreases over time and becomes less dominant after the first few cycles; 2) a significant amount of hysteresis is observed during all cycles and it becomes repeatable after the first few cycles; 3) the peak of the displacement is shifted from the peak of the voltage signal and occurs after it. To account for these viscoelastic phenomena, a constitutive model is developed by employing several dissipative nonequilibrium mechanisms. The quantitative comparisons of the experimental and simulation results demonstrate the effectiveness of the developed model. This modeling approach can be useful for control of a viscoelastic DEA and paves the way to emerging applications of soft robots.
This paper considers the nature of returns to scale in active management following Pástor et al. (2015) who fail to establish diseconomies of scale at the fund level. Using an enhanced empirical ...strategy, we find a significant negative impact of fund size on performance. This empirical evidence indicates that fund alpha and fund size are not independent entities. Consequently, skill, rather than being measured by the fund alpha, should be measured by the value that a fund extracts from capital markets. We also show that there exist sophisticated investors who correctly exploit positive net present value investment opportunities.
Abstract
Single-atom catalysts (SACs) are promising candidates to catalyze electrochemical CO
2
reduction (ECR) due to maximized atomic utilization. However, products are usually limited to CO ...instead of hydrocarbons or oxygenates due to unfavorable high energy barrier for further electron transfer on synthesized single atom catalytic sites. Here we report a novel partial-carbonization strategy to modify the electronic structures of center atoms on SACs for lowering the overall endothermic energy of key intermediates. A carbon-dots-based SAC margined with unique CuN
2
O
2
sites was synthesized for the first time. The introduction of oxygen ligands brings remarkably high Faradaic efficiency (78%) and selectivity (99% of ECR products) for electrochemical converting CO
2
to CH
4
with current density of 40 mA·cm
-2
in aqueous electrolytes, surpassing most reported SACs which stop at two-electron reduction. Theoretical calculations further revealed that the high selectivity and activity on CuN
2
O
2
active sites are due to the proper elevated CH
4
and H
2
energy barrier and fine-tuned electronic structure of Cu active sites.
Several previous studies have demonstrated the excellent antioxidant activity of fucoxanthin against oxidative stress which is closely related to the pathogenesis of liver diseases. The present work ...was to investigate whether fucoxanthin could protect human hepatic L02 cells against hydrogen peroxide- (H2O2-) induced oxidative damage. Its effects on H2O2-induced cell viability, lactate dehydrogenase (LDH) leakage, intracellular reduced glutathione, and reactive oxygen species (ROS) contents, along with mRNA and protein relative levels of the cytoprotective genes including Nrf2, HO-1, and NQO1, were investigated. The results showed that fucoxanthin could upregulate the mRNA and protein levels of the cytoprotective genes and promote the nuclear translocation of Nrf2, which could be inhibited by the PI3K inhibitor of LY294002. Pretreatment of fucoxanthin resulted in decreased LDH leakage and intracellular ROS content but enhanced intracellular reduced glutathione. Interestingly, pretreatment using fucoxanthin protected against the oxidative damage in a nonconcentration-dependent manner, with fucoxanthin of 5 μM demonstrating the optimal effects. The results suggest that fucoxanthin exerts cytoprotective effects against H2O2-induced oxidative damage in L02 cells, which may be through the PI3K-dependent activation of Nrf2 signaling.
Cereal straw is one of the most abundant biomass burned in China but its contribution to fine particulates is not adequately understood. In this study, three main kinds of cereal straws were ...collected from five grain producing areas in China. Fine particulate matters （PMzs） from the cereal straws subjected to control burnings, both under smoldering and flaming status, were sampled by using a custom made dilution chamber and sampling system in the laboratory. Element carbon （EC） and organic carbon （OC） was analyzed. 141 compounds of organic matters were measured by gas chromatography-mass spectrum （GC-MS）. Source profiles of particulate organic matters emitted from cereal straw burnings were obtained. The results indicated that organic matters contribute a large fraction in fine particulate matters. Levoglucosan had the highest contributions with averagely 4.5% in mass of fine particulates and can be considered as the tracer of biomass burnings. Methyloxylated phenols from lignin degradation also had high concentrations in PM2.5, and contained approximately equal amounts of guaiacyl and syringyl compounds. 13-Sitostrol also made up relatively a large fraction of PMz5 compared with the other sterols （0.18%-0.63% of the total fine particle mass）. Normal alkanes, PAHs, fatty acids, as well as normal alkanols had relatively lower concentrations compared with the compounds mentioned above. Carbon preference index （CPI） of normal alkanes and alkanoic acids showed characteristics of biogenic fuel burnings. Burning status significantly influenced the formations of EC and PAHs. The differences between the emission profiles of straw and wood combustions were displayed by the fingerprint compounds, which may be used to identify the contributions between wood and straw burnings in source apportionment researches.
Plant immunity often penalizes growth and yield. The transcription factor Ideal Plant Architecture 1 (IPA1) reduces unproductive tillers and increases grains per panicle, which results in improved ...rice yield. Here we report that higher IPA1 levels enhance immunity. Mechanistically, phosphorylation of IPA1 at amino acid Ser
within its DNA binding domain occurs in response to infection by the fungus
and alters the DNA binding specificity of IPA1. Phosphorylated IPA1 binds to the promoter of the pathogen defense gene
and activates its expression, leading to enhanced disease resistance. IPA1 returns to a nonphosphorylated state within 48 hours after infection, resuming support of the growth needed for high yield. Thus, IPA1 promotes both yield and disease resistance by sustaining a balance between growth and immunity.
Patients with relapsed/refractory early T-cell precursor lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) respond poorly to traditional therapy and have dismal prognosis. CD7 is a promising therapeutic ...targets for chimeric antigen receptor modified T cell therapy (CART) due to its widely expression in almost all T-cell malignancies. Here we present the anti-CD7 CART therapy in a 11-year-old male with TP53 mutated relapsed/refractory ETP-ALL/LBL. The patient suffered second relapse after haploidentical hematopoietic stem cell transplantation, showing resistance to 4 lines salvage therapies including venetoclax. Nanobody derived CD7-CART cells were manufactured by co-transducing CAR-T cells with a CD7 protein expression blocker. 70.5% of blasts (CD7 expression: 92.6%) and extensive extramedullary disease (mediastinal mass, enlarged lymph nodes and spleen) were observed prior to CD7-CART-cell therapy. A total of 5 × 10
/kg donor-derived CD7-CART-cells were infused. Hematological and extramedullary remission were both achieved, with persistence of CD7-CART-cells be detected until the last followup at 96th days after the infusion. Reversible adverse effects including grade 3 cytokine release syndrome and macrophage activation syndrome were observed. This case demonstrated that CD7-CART was a potent and safe salvage therapy in relapsed/refractory ETP-ALL/LBL patient with high tumor burden.Trial registration: ClinicalTrials. gov, NCT04785833 , Registered on March 8, 2021, prospectively registered.
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After surgical treatment of osteoarticular tuberculosis (TB), it is necessary to fill the surgical defect with an implant, which combines the merits of osseous regeneration and local ...multi-drug therapy so as to avoid drug resistance and side effects. In this study, a 3D-printed macro/meso-porous composite scaffold is fabricated. High dosages of isoniazid (INH)/rifampin (RFP) anti-TB drugs are loaded into chemically modified mesoporous bioactive ceramics in advance, which are then bound with poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) through a 3D printing procedure. The composite scaffolds show greatly prolonged drug release time compared to commercial calcium phosphate scaffolds either in vitro or in vivo. In addition, the drug concentrations on the periphery tissues of defect are maintained above INH/RFP minimal inhibitory concentrations even up to 12weeks post-surgery, while they are extremely low in blood. Examinations of certain serum enzymes suggest no harm to hepatic or renal functions. Micro-CT evaluations and histology results also indicate partly degradation of the composite scaffolds and new bone growth in the cavity. These results suggest promising applications of our hierarchical composite scaffold in bone regeneration and local anti-TB therapy after osteoarticular TB debridement surgery.
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