The hypoxia of the tumor microenvironment (TME) seriously restricts the photodynamic therapy (PDT) effect of conventional type‐II photosensitizers, which are highly dependent on O2. In this work, a ...new type‐I photosensitizer (TPE‐TeV‐PPh3) consisting of a tetraphenylethylene group (TPE) as a bioimaging moiety, triphenyl‐phosphine (PPh3) as a mitochondria‐targeting group, and telluroviologen (TeV2+) as a reactive oxygen species (O2•−, •OH) generating moiety is developed. The luminescence intensity of TPE‐TeV‐PPh3 increased significantly after specific oxidation by excess H2O2 in the TME without responding to normal tissues via the formation of Te═O bond, which can be used for monitoring abnormal H2O2, positioning, and imaging of tumors. TPE‐TeV‐PPh3 with highly reactive radicals generation and stronger hypoxia tolerance realizes efficient cancer cell killing under hypoxic conditions, achieving 88% tumor growth inhibition. Therefore, TPE‐TeV‐PPh3 with low phototoxicity in normal tissue achieves tumor imaging and effective PDT toward solid tumors in response to high concentrations of H2O2 in the TME, which provides a new strategy for the development of type‐I photosensitizers.
A new type‐I photosensitizer, TPE‐TeV‐PPh3, based on telluroviologen was synthesized. The luminescence intensity of TPE‐TeV‐PPh3 increased significantly after specific oxidation by excess H2O2 in the tumor microenvironment without responding to normal tissues, which can be used for the positioning and imaging of tumors. The light‐reduced generation of telluroviologen cationic radicals which could react with O2 to form ROS (O2•−, •OH) efficiently via electron transfer mechanism, realizes efficient cancer cell killing under hypoxic conditions, achieving 88% tumor growth inhibition.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Follicular helper T (T
) cells are a specialized subset of CD4
T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The ...regulation of T
cell survival remains unclear. Here we report that T
cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for T
cell survival. The deletion of GPX4 in T cells selectively abrogated T
cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased T
cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium-GPX4-ferroptosis axis in regulating T
homeostasis, which can be targeted to enhance T
cell function in infection and following vaccination.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The mechanical property and hydrogen transport characteristics of selective laser melting (SLM) 304L stainless steel were investigated by tensile tests and thermal desorption spectroscopy (TDS). The ...heat treatment affected the hydrogen embrittlement (HE) susceptibility and the treatment at 950 °C showed the larger HE effects. Cellular structures and melt-pool boundaries were dissolved at 850 and 950 °C, respectively. TDS results indicate that the hydrogen diffusivity of the as-received SLM 304L was lower than that of wrought 304L and the hydrogen diffusion activation energy increased with the recrystallisation degree, which was related to the dislocation density. Dislocations, rather than strain-induced martensite, were the main cause of HE owing to the high austenite stability of the samples. The pre-existing dislocations in the SLM 304L sample heat-treated at 950 °C for 4 h affected the hydrogen transport behaviour during sample stretching and led to severe HE.
•The segregation of elements affects the thermal stability of the structure.•The SLM 304L steel has a low apparent hydrogen diffusivity at room temperature.•The activation energy of hydrogen diffusion increases with the dislocation density in pure austenitic steel.•Pre-existing dislocations affect the HE susceptibility of the SLM sample by controlling hydrogen transport.•The SLM 304L steel has high resistance to hydrogen embrittlement on the basis of high-strength.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In recent years, decabromodiphenyl ethane (DBDPE), a new alternative flame retardant to the decabrominated diphenyl ethers (BDE-209), is widely used in a variety of products. Previous studies have ...indicated that DBDPE, like BDE-209, could disrupt thyroid function. However, compared with BDE-209, the degrees of thyrotoxicosis induced by DBDPE were not clear. In addition, the mechanism of thyrotoxicosis induced by DBDPE or BDE-209 was still under further investigation. In this study, male rats as a model were orally exposed to DBDPE or BDE-209 by 5, 50, 500 mg/kg bw/day for 28 days. Then, we assessed the thyrotoxicosis of DBDPE versus BDE-209 and explored the mechanisms of DBDPE and BDE-209-induced thyrotoxicosis. Results showed that decreased free triiodothyronine (FT3) and increased thyroid-stimulating hormone (TSH) and thyrotropin-releasing hormone (TRH) in serum were observed in both 500 mg/kg bw/day BDE-209 and DBDPE group. Decreased total thyroxine (TT4), total T3 (TT3), and free T4 (FT4) were only observed in BDE-209 group but not in DBDPE group. Histological examination and transmission electron microscope examination showed that high level exposure to BDE-209 and DBDPE both caused significant changes in histological structure and ultrastructure of the thyroid gland. Additionally, oxidative damages of thyroid gland (decreased SOD and GSH activities, and increased MDA content) were also observed in both BDE-209 and DBDPE groups. TG contents in the thyroid gland was reduced in BDE-209 group but not in DBDPE group. Both BDE-209 and DBDPE affected the expression of hypothalamic-pituitary-thyroid (HPT) axis related genes. These findings suggested that both BDE-209 and DBDPE exposure could disrupt thyroid function in the direction of hypothyroidism and the underlying mechanism was likely to be oxidative stress and perturbations of HPT axis. However, DBDPE was found to be less toxic than BDE-209.
•Thyroid disruption induced by BDE-209 and DBDPE in rats was studied and compared.•Both BDE-209 and DBDPE can disrupt thyroid function in the direction of hypothyroidism.•Both BDE-209 and DBDPE induced oxidative stress but DBDPE is less toxic than BDE-209.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Recently the mask-based beamforming approach received tremendous interest and is widely studied for multi-channel noise robust automatic speech recognition (ASR). Among the known mask estimation ...models, the neural network based mask estimation approach has received the most attention, resulting in a competitive performance. However this approach still suffers from training-testing mismatch between the simulated training and real test data. This paper proposes a new unsupervised scheme that can utilize the real data during NN-based mask estimator training. The clustering-based approach is applied on the real data first to generate the soft masks, which are then taken as the labels for NN-mask modeling. Moreover, acoustic adaptation technologies are borrowed from usual back-end acoustic modeling to the front-end NN-mask based beamformer, further reducing the training-testing acoustic mismatch. The proposed methods are evaluated on the CHIME-4 dataset. Experimental results show that the mismatch can be reduced significantly by the proposed strategies, leading to relative ∼ 15.0% WER reduction compared to the conventional NN-mask beamforming for the real data under noisy conditions.
Abstract
Aging in mammals is accompanied by an imbalance of intestinal homeostasis and accumulation of mitochondrial DNA (mtDNA) mutations. However, little is known about how accumulated mtDNA ...mutations modulate intestinal homeostasis. We observe the accumulation of mtDNA mutations in the small intestine of aged male mice, suggesting an association with physiological intestinal aging. Using polymerase gamma (POLG) mutator mice and wild-type mice, we generate male mice with progressive mtDNA mutation burdens. Investigation utilizing organoid technology and in vivo intestinal stem cell labeling reveals decreased colony formation efficiency of intestinal crypts and LGR5-expressing intestinal stem cells in response to a threshold mtDNA mutation burden. Mechanistically, increased mtDNA mutation burden exacerbates the aging phenotype of the small intestine through ATF5 dependent mitochondrial unfolded protein response (UPR
mt
) activation. This aging phenotype is reversed by supplementation with the NAD
+
precursor, NMN. Thus, we uncover a NAD
+
dependent UPR
mt
triggered by mtDNA mutations that regulates the intestinal aging.
Proanthocyanidins (PA), also known as condensed tannins, contribute to important forage legumes traits including disease resistance and forage quality. PA in forage plants has both positive and ...negative effects on feed digestibility and animal performance. The analytical methods and their applicability in measuring the contents of PA in forage plants are essential to studies on their nutritional effects. In spite of important breakthroughs in our understanding of the PA biosynthesis, important questions still remain to be answered such as the PA polymerization and transport. Recent advances in the understanding of transcription factor-mediated gene regulation mechanisms in anthocyanin and PA biosynthetic pathway in model plants suggest new approaches for the metabolic engineering of PA in forage plants. The present review will attempt to present the state-of-the-art of research in these areas and provide an update on the production and metabolic engineering of PA in forage plants. We hope that this will contribute to a better understanding of the ways in which PA production to manipulate the content of PA for beneficial effects in forage plants.
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CEKLJ, DOBA, EMUNI, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
After the World Health Organization declared coronavirus disease 2019 (COVID-19), as a global pandemic, global health workers have been facing an unprecedented and severe challenge. Currently, a ...mixturetion to inhibit the exacerbation of pulmonary inflammation caused by COVID-19, Fuzheng Yugan Mixture (FZYGM), has been approved for medical institution mixturetion notification. However, the mechanism of FZYGM remains poorly defined. This study aimed to elucidate the molecular and related physiological pathways of FZYGM as a potential therapeutic agent for COVID-19. Active molecules of FZYGM were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), while potential target genes of COVID-19 were identified by DrugBank and GeneCards. Compound-target networks and protein-protein interactions (PPI) were established by Cytoscape_v3.8.2 and String databases, respectively. The gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. Finally, a more in-depth study was performed using molecular docking. Our study identified 7 active compounds and 3 corresponding core targets. The main potentially acting signaling pathways include the interleukin (IL)-17 signaling pathway, tumor necrosis factor (TNF) signaling pathway, Toll-like receptor signaling pathway, Th17 cell differentiation, and coronavirus disease-COVID-19. This study shows that FZYGM can exhibit anti-COVID-19 effects through multiple targets and pathways. Therefore, FZYGM can be considered a drug candidate for the treatment of COVID-19, and it provides good theoretical support for subsequent experiments and clinical applications of COVID-19.
Based on summarizing the latest research of vehicle exhaust thermoelectric generator (TEG), this paper proposes a newly designed TEG with cylindrical shell and straight fins. A two-dimensional heat ...transfer numerical model using finite difference method is established under steady-state conditions. This model is used to predict the output performance of TEG in different simulation conditions. The average contribution rate to the output power CRvar is given in this paper to evaluate the influence level of different input parameters. Simulation results show that increasing the inlet temperature and the inlet mass flow rate of the exhaust, as well as reducing the inlet temperature of the coolant are useful methods to improve the performance of TEG in a certain extent. The heat transfer numerical model presented in this paper can be also applied to the numerical simulations and the optimization work on early designing stages of other types of TEG.
•Proposed a new structure of TEG with cylindrical shell and straight fins.•Validating the numerical model with a finite elements model in ANSYS Workbench.•The average contribution rate to the output power can be utilised to evaluate the influence level of the input parameters.•Obtaining the relevant conclusions that can be as reference to the early stages of future TEG designing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Follicular helper T (T
FH
) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate T
FH
function has been found in individuals with ...ineffective responses to vaccines, but the mechanism underlying T
FH
regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human T
FH
differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs T
FH
generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of T
FH
cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.
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