Stimuli-responsive intelligent molecular machines/devices are of current research interest due to their potential application in minimized devices. Constructing molecular machines/devices capable of ...accomplishing complex missions is challenging, demanding coalescence of various functions into one molecule. Here we report the construction of intelligent molecular chiroptical photoswitches based on azobenzene-fused bicyclic pillarnarene derivatives, which we defined as molecular universal joints (MUJs). The Z/E photoisomerization of the azobenzene moiety of MUJs induces rolling in/out conformational switching of the azobenzene-bearing side-ring and consequently leads to planar chirality switching of MUJs. Meanwhile, temperature variation was demonstrated to also cause conformational/chiroptical inversion due to the significant entropy change during the ring-flipping. As a result, photo-induced chiroptical switching could be prohibited when the temperature exceeded an upper limit, demonstrating an intelligent molecular photoswitch having over-temperature protection function, which is in stark contrast to the low-temperature-gating effect commonly encountered.
Triple-negative breast Cancer (TNBC) is an aggressive subtype lacking estrogen, progesterone, and HER2 receptors. Known for limited targeted therapies, it poses challenges and requires personalized ...treatment strategies. Differential analysis revealed a significant decrease in keratin 81 (KRT81) expression in non-TNBC samples and an increase in TNBC samples, lower KRT81 expression correlated with better TNBC patient outcomes. It emerged as an independent predictive factor for TNBC, with associations found between its expression and clinically relevant features. We further developed a nomogram for survival probability assessment based on Cox regression results, demonstrating its accuracy through calibration curves. Gene annotation analysis indicated that KRT81 is involved in immune-related pathways and tumor cell adhesion. KRT81 is associated with immune cell infiltration of Follicular helper T cells (Tfh) and CD8 + T cells, suggesting its potential impact on the immunological microenvironment. The study delved into KRT81's predictive value for immunotherapy responses, high expression of KRT81 was associated with greater potential for immune evasion. Single-cell RNA sequencing analysis pinpointed KRT81 expression within a specific malignant subtype which was a risk factor for TNBC. Furthermore, KRT81 promoted TNBC cell proliferation, migration, invasion, and adhesion was confirmed by gene knockout or overexpression assay. Co-culture experiments further indicated KRT81's potential role in inhibiting CD8 + T cells, and correlation analysis implied KRT81 was highly correlated with immune checkpoint CD276, providing insights into its involvement in the immune microenvironment via CD276. In conclusion, this comprehensive study positions KRT81 as a promising prognostic marker for predicting tumor progression and immunotherapy responses in TNBC.
The present study was conducted to investigate the relative effect of structured input, referential activities, and affective activities on the acquisition of English causative forms. The processing ...of English causative structures is hindered by The First Noun Principle. Forty-one school-age Chinese learners of English as a second language were assigned to three treatment groups: (1) Structured input group; (2) Referential-only group; (3) Affective-only group. This classroom-based study adopted a pretest-posttest design. The test in the study assessed the interpretation and production of the target feature at the sentence level. Results showed that the structured input group, and the referential-only group made significant improvements in both the interpretation and production of English causative structure, while the affective-only group yielded almost no learning gains from pre-test to post-test.
Humans with ALS and transgenic rodents expressing ALS-associated superoxide dismutase (SOD1) mutations develop spontaneous blood-spinal cord barrier (BSCB) breakdown, causing microvascular ...spinal-cord lesions. The role of BSCB breakdown in ALS disease pathogenesis in humans and mice remains, however, unclear, although chronic blood-brain barrier opening has been shown to facilitate accumulation of toxic blood-derived products in the central nervous system, resulting in secondary neurodegenerative changes. By repairing the BSCB and/or removing the BSCB-derived injurious stimuli, we now identify that accumulation of blood-derived neurotoxic hemoglobin and iron in the spinal cord leads to early motor-neuron degeneration in SOD1(G93A) mice at least in part through iron-dependent oxidant stress. Using spontaneous or warfarin-accelerated microvascular lesions, motor-neuron dysfunction and injury were found to be proportional to the degree of BSCB disruption at early disease stages in SOD1(G93A) mice. Early treatment with an activated protein C analog restored BSCB integrity that developed from spontaneous or warfarin-accelerated microvascular lesions in SOD1(G93A) mice and eliminated neurotoxic hemoglobin and iron deposits. Restoration of BSCB integrity delayed onset of motor-neuron impairment and degeneration. Early chelation of blood-derived iron and antioxidant treatment mitigated early motor-neuronal injury. Our data suggest that BSCB breakdown contributes to early motor-neuron degeneration in ALS mice and that restoring BSCB integrity during an early disease phase retards the disease process.
In this paper, a nonlinear deformation modulus method is proposed for foundation settlement calculation. In the proposed method, the nonlinear deformation modulus under different stress levels is ...obtained from the load-settlement curve of in situ loading test, which are then applied to the layerwise summation method for calculating foundation settlement. On this basis and referring to the Duncan-Chang model, a variable modulus constitutive model suitable for numerical calculation of foundation settlement is further proposed. The required parameters of this model are the same as those of the nonlinear deformation modulus method and can be determined by the in situ loading test. The validity of the proposed calculation methods of foundation settlement is verified by the in situ loading tests under different plate sizes. The results illustrate that both the nonlinear deformation modulus method and the variable modulus constitutive model compare quite well with the test results, and the deduced results can better reflect the nonlinearity of foundation settlement.
Water‐soluble 9,10‐diphenylanthracene‐modified γ‐cyclodextrin derivatives A1 and A2, in which the γ‐cyclodextrin unit serves as a molecular host for a binding sensitizer, and the ...9,10‐diphenylanthracene moiety plays a role as an emitter/annihilator, were synthesized to investigate the supramolecular triplet–triplet annihilation (TTA) upconversion in aqueous solution. Both A1 and A2 readily aggregate and form nanoscale assemblies in water as a combined result of host–guest complexation and π–π stacking among the 9,10‐diphenylanthracenes. The aggregation behavior of the supramolecular emitters was fully characterized by using a diversity of methods, including dynamic light scattering (DLS), SEM, NMR, fluorescence, and circular dichroism studies. Fluorescence spectroscopic analysis reveals that the emitters have high fluorescence quantum yields in water (82 and 90 % for A1 and A2, respectively), thus demonstrating that aggregation does not quench the fluorescence. By using a coordinated ruthenium sensitizer, a high TTA upconversion quantum yield of up to 6.9 % was observed for this supramolecular TTA system, which is significantly higher than the value (<0.5 %) obtained with nonassembled emitters in organic solvent and in contrast to the fact that TTA upconversion emission in aqueous solution is usually low or negligible. We ascribe the strong TTA upconversion emission in the present supramolecular assembly system to an efficient TTA process, which is facilitated along the stacked emitters by triplet energy migration and improved triplet–triplet energy transfer through host–guest complexation.
Passing upwards: The aggregates of 9,10‐diphenylanthracene‐modified γ‐cyclodextrin derivatives form complexes with a ruthenium sensitizer in aqueous solution, thus significantly facilitating a triplet energy transfer among the sensitizer and emitters (see figure; TTA=triplet–triplet annihilation). The triplet–triplet annihilation‐based upconverted emission in such a supramolecular assembly shows high emission quantum yields of up to 6.9 %, versus <0.5 % obtained with the nonassembly system.
Cancer stem cells (CSCs) are the origin of many malignant tumours, including osteosarcoma that mainly affects adolescents and is accompanied by a poor prognosis. However, little is known about the ...intrinsic biological information of osteosarcoma stem cells, particularly for the metabolomics features. Hence, an ultra-high performance liquid chromatography coupled with tandem Q-Exactive Orbitrap mass spectrometer (UHPLC-QE-MS)-based metabolomics approach was developed to investigate the metabolism changes in the human osteosarcoma (HOS) cell line in order to understand its possible mechanism. HMDB, METLIN and m/z Cloud databases were used to identify the metabolic markers. Additionally, the compounds were further identified using standards of the metabolites. Comparing HOS-CSCs with non-CSCs, 154 different metabolites were identified in both the positive and negative modes. Based on the clearly distinct metabolites, the changed metabolic pathways were analysed using MetaboAnalyst. The top five altered pathways included alanine, aspartate and glutamate metabolism; arginine and proline metabolism; glutathione metabolism; cysteine and methionine metabolism; and the citrate cycle (TCA cycle). The downregulation of the TCA cycle and elevation of oxidized glutathione levels suggested a decline of mitochondrial metabolism, while most of the amino acid metabolisms were upregulated. Further biological experiments including an analysis of mitochondrial activity confirmed the above hypotheses that were deduced from metabolomics results. These findings not only enhance our understanding of the altered metabolome in osteosarcoma stem cells but also demonstrate the great potential of such a metabolomics method based on UHPLC-QE-MS in large-scale cell studies.
In this work, a UHPLC-QE-MS based-metabolomics approach has been developed to investigate the metabolic profiling of osteosarcoma HOS-CSCs and non-CSCs in order to reveal the corresponding mechanism. Display omitted
•A new methodology of metabolomics was developed.•The wide range of metabolites and corresponding pathways were identified and confirmed.•Significant metabolism alteration from osteosarcoma stem cells were found.•Results may enhance understanding of osteosarcoma and benefit new treatment.
We report here that amyotrophic lateral sclerosis-linked superoxide dismutase 1 (SOD1) mutants with different biochemical characteristics disrupted the blood-spinal cord barrier in mice by reducing ...the levels of the tight junction proteins ZO-1, occludin and claudin-5 between endothelial cells. This resulted in microhemorrhages with release of neurotoxic hemoglobin-derived products, reductions in microcirculation and hypoperfusion. SOD1 mutant-mediated endothelial damage accumulated before motor neuron degeneration and the neurovascular inflammatory response occurred, indicating that it was a central contributor to disease initiation.
Abstract Using the Stream Interaction Regions list from the Tianwen-1/Mars Orbiter Magnetometer (MOMAG) data between 2021 November and 2021 December and from Wind observations, we present an accurate ...prediction for the arrival time and in situ parameters of corotating interaction regions (CIRs) when the Earth and Mars have large longitudinal separations. Since CIRs were detected earlier at Earth than at Mars during the period examined, we employ Earth-based CIR detections for predicting CIR observations at Mars. The arrival time is calculated by the Parker spiral model under the assumption of steady corotation of the Sun and coronal holes, while the in situ parameters are derived from Wind data through radial dependent scaling laws. The CIR prediction results are compared to the actual observations obtained from the MOMAG and Mars Ion and Neutral Particle Analyzer instruments onboard Tianwen-1, as well as the Magnetometer and Solar Wind Ion Analyzer instruments onboard MAVEN. The predicted arrival time is close to the observed values with relative errors less than 10%, and the expected in situ data show a good consistency with the Martian measurements. The comparison results indicate that the prediction method has good performance and will be helpful for comparative analysis with Tianwen-1 observations at Mars in the future.
Abstract
Background
Renal tubular epithelial–myofibroblast transdifferentiation (EMT) plays a key role in the regulation of renal fibrosis. Exosomes derived from human umbilical cord mesenchymal stem ...cells (hucMSCs) play a crucial role in alleviating renal fibrosis and injury. Additionally, hucMSC-derived exosomes contain numerous microRNAs (miRNAs). However, it is unclear whether mesenchymal stem cells can regulate the transforming growth factor (TGF)-β1-induced EMT of human renal tubular epithelial cells (RTECs) through exosomal miRNAs.
Method
HK-2, a human RTEC line, was co-treated with TGF-β1 and hucMSC-derived exosomes. Additionally, TGF-β1-treated HK-2 cells were transfected with a miR-335-5p mimic and disintegrin and metalloproteinase domain-containing protein 19 (ADAM19)-overexpression plasmid. miR-335-5p expression and ADAM19 protein and inflammation levels were measured via quantitative reverse transcription polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assays, respectively.
Results
TGF-β1 treatment changed the shape of HK-2 cells from a cobblestone morphology to a long spindle shape, accompanied by an increase in interleukin (IL)-6, tumor necrosis factor-α, IL-1β, collagen I, collagen III, α-smooth muscle actin, vimentin, and N-cadherin protein levels, whereas E-cadherin protein levels were reduced in these HK-2 cells, suggesting that TGF-β1 treatment induced the inflammation and EMT of HK-2 cells. HucMSC-exosomes improved the inflammation and EMT phenotype of TGF-β1-induced HK-2 cells by transferring miR-335-5p. miR-335-5p was found to bind the
ADAM19
3′-untranslated region to reduce ADAM19 protein levels. Additionally, miR-335-5p improved the inflammation and EMT phenotype of HK-2 cells by reducing ADAM19 protein levels with TGF-β1 induction.
Conclusions
HucMSC-derived exosomal miR-335-5p attenuates the inflammation and EMT of HK-2 cells by reducing ADAM19 protein levels upon TGF-β1 induction. This study provides a potential therapeutic strategy and identifies targets for clinically treating renal fibrosis.
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