Tendon injuries cause prolonged disability and never recover completely. Current mechanistic understanding of tendon regeneration is limited. Here, we use single-cell transcriptomics to identify a ...tubulin polymerization-promoting protein family member 3-expressing (Tppp3
) cell population as potential tendon stem cells. Through inducible lineage tracing, we demonstrate that these cells can generate new tenocytes and self-renew upon injury. A fraction of Tppp3
cells expresses platelet-derived growth factor receptor alpha (Pdfgra). Ectopic platelet-derived growth factor-AA (PDGF-AA) protein induces new tenocyte production while inactivation of Pdgfra in Tppp3
cells blocks tendon regeneration. These results support Tppp3
Pdgfra
cells as tendon stem cells. Unexpectedly, Tppp3
Pdgfra
fibro-adipogenic progenitors coexist in the tendon stem cell niche and give rise to fibrotic cells, revealing a clandestine origin of fibrotic scars in healing tendons. Our results explain why fibrosis occurs in injured tendons and present clinical challenges to enhance tendon regeneration without a concurrent increase in fibrosis by PDGF application.
Hepatocellular cancer (HCC) has been reported to belong to one of the highly vascularized solid tumours accompanied with angiogenesis of human umbilical vein endothelial cells (HUVECs). KDM5A, an ...attractive drug target, plays a critical role in diverse physiological processes. Thus, this study aims to investigate its role in angiogenesis and underlying mechanisms in HCC. ChIP‐qPCR was utilized to validate enrichment of H3K4me3 and KDM5A on the promotor region of miR‐433, while dual luciferase assay was carried out to confirm the targeting relationship between miR‐433 and FXYD3. Scratch assay, transwell assay, Edu assay, pseudo‐tube formation assay and mice with xenografted tumours were conducted to investigate the physiological function of KDM5A‐miR‐433‐FXYD3‐PI3K‐AKT axis in the progression of HCC after loss‐ and gain‐function assays. KDM5A p‐p85 and p‐AKT were highly expressed but miR‐433 was down‐regulated in HCC tissues and cell lines. Depletion of KDM5A led to reduced migrative, invasive and proliferative capacities in HCC cells, including growth and a lowered HUVEC angiogenic capacity in vitro. Furthermore, KDM5A suppressed the expression of miR‐433 by demethylating H3K4me3 on its promoterregion. miR‐433 negatively targeted FXYD3. Depleting miR‐433 or re‐expressing FXYD3 restores the reduced migrative, invasive and proliferative capacities, and lowers the HUVEC angiogenic capacity caused by silencing KDM5A. Therefore, KDM5A silencing significantly suppresses HCC tumorigenesis in vivo, accompanied with down‐regulated miR‐433 and up‐regulated FXYD3‐PI3K‐AKT axis in tumour tissues. Lastly, KDM5A activates the FXYD3‐PI3K‐AKT axis to enhance angiogenesis in HCC by suppressing miR‐433.
In this study, the polyphenols composition and antioxidant properties of 12 blue highland barley varieties planted on the Qinghai-Tibet Plateau area were measured. The contents of the free, bound and ...total phenolic acids varied between 166.20-237.60, 170.10-240.75 and 336.29-453.94 mg of gallic acid equivalents per 100 g of dry weight (DW) blue highland barley grains, while the free and bound phenolic acids accounted for 50.09% and 49.91% of the total phenolic acids, respectively. The contents of the free, bound and total flavones varied among 20.61-25.59, 14.91-22.38 and 37.91-47.98 mg of catechin equivalents per 100 g of dry weight (DW) of blue highland barley grains, while the free and bound flavones accounted for 55.90% and 44.10% of the total flavones, respectively. The prominent phenolic compounds in the blue hulless barley grains were gallic acid, benzoic acid, syringic acid, 4-coumaric acid, naringenin, hesperidin, rutin, (+)-catechin and quercetin. Among these, protocatechuic acid, chlorogenic acid and (+)-catechin were the major phenolic compounds in the free phenolics extract. The most abundant bound phenolics were gallic acid, benzoic acid, syringic acid, 4-coumaric acid, benzoic acid, dimethoxybenzoic acid, naringenin, hesperidin, quercetin and rutin. The average contribution of the bound phenolic extract to the DPPH
free radical scavenging capacity was higher than 86%, that of free phenolic extract to the ABTS
free radical scavenging capacity was higher than 79%, and that of free phenolic (53%) to the FRAP antioxidant activity was equivalent to that of the bound phenol extract (47%). In addition, the planting environment exerts a very important influence on the polyphenol composition, content and antioxidant activity of blue highland barley. The correlation analysis showed that 2,4-hydroxybenzoic acid and protocatechuic acid were the main contributors to the DPPH
and ABTS
free radical scavenging capacity in the free phenolic extract, while chlorogenic acid, vanillic acid, ferulic acid and quercetin were the main contributors to the free radical scavenging capacity in the bound phenol extract. The study results show that the blue highland barley grains have rich phenolic compounds and high antioxidant activity, as well as significant varietal differences. The free and bound phenolic extracts in the blue hulless barley grains have an equivalent proportion in the total phenol, and co-exist in two forms. They can be used as a potential valuable source of natural antioxidants, and can aid in enhancing the development and daily consumption of foods relating to blue highland barley.
The localized method of fundamental solutions (LMFS) is an efficient meshless collocation method that combines the concept of localization and the method of fundamental solutions (MFS). The resultant ...system of linear algebraic equations in the LMFS is sparse and banded and thus, drastically reduces the storage and computational burden of the MFS. In the LMFS, the moving least square (MLS) approximation, based on fundamental solutions, is used to construct approximate solution at each node. In this paper, this fundamental solutions-based MLS approximation, named as an augmented MLS (AMLS) approximation, is generalized to any point in the computational domain. Computational formulas, theoretical properties and error estimates of the AMLS approximation are derived. Then, taking Laplace equation as an example, this paper sets up a framework for the theoretical error analysis of the LMFS. Finally, numerical results are presented to verify the efficiency and theoretical results of the AMLS approximation and the LMFS. Convergence and comparison researches are conducted to validate the accuracy, convergence and efficiency.
Multidrug resistance (MDR) resulting from the overexpression of drug transporters such as P‐glycoprotein (Pgp) increases the efflux of drugs and thereby limits the effectiveness of chemotherapy. To ...address this issue, this work develops an injectable hollow microsphere (HM) system that carries the anticancer agent irinotecan (CPT‐11) and a NO‐releasing donor (NONOate). Upon injection of this system into acidic tumor tissue, environmental protons infiltrate the shell of the HMs and react with their encapsulated NONOate to form NO bubbles that trigger localized drug release and serve as a Pgp‐mediated MDR reversal agent. The site‐specific drug release and the NO‐reduced Pgp‐mediated transport can cause the intracellular accumulation of the drug at a concentration that exceeds the cell‐killing threshold, eventually inducing its antitumor activity. These results reveal that this pH‐responsive HM carrier system provides a potentially effective method for treating cancers that develop MDR.
Two is better than one: A carrier system is developed that can generate NO bubbles in the acidic environment of tumor tissues to trigger localized drug release (specifically irinotecan, denoted CPT‐11) and to reverse Pgp‐mediated multidrug resistance (Pgp=P‐glycoprotein). The combined system enhances intracellular drug accumulation in cancer cells so that the concentration exceeds the therapeutic threshold, eventually leading to antitumor activity.
In this paper, we develop a game theoretic model to study the pricing of e-books and e-readers under two pricing models: wholesale and agency. We analyze pricing strategies for a publisher and a ...retailer. We identify the complementary relationship between e-books and e-readers as the main reason for the retailer to set a low e-book price in the wholesale model. Comparing the wholesale and the agency models, we find, in a wide range of market conditions, the price for e-book readers is lower in the agency model, leading to a higher e-book market share. However, a higher e-book price in the agency model lowers e-book consumption. Overall social welfare is lower in the agency model than in the wholesale model. While total consumer surplus is slightly higher in the agency model, largely because of a lower e-reader price, business profit is lower. The publisher, surprisingly, is worse off under the agency model.
Skeletal muscle tissue provides mechanical force for locomotion of all vertebrate animals. It is prone to damage from acute physical trauma and physiological stress. To cope with this, it possesses a ...tremendous capacity for rapid and effective repair that is widely held to be accomplished by the satellite cells lying between the muscle fiber plasmalemma and the basement membrane. Cell transplantation and lineage-tracing studies have demonstrated that Pax7-expressing (Pax7(+)) satellite cells can repair damaged muscle tissue repeatedly after several bouts of acute injury. These findings provided evidence that Pax7(+) cells are muscle stem cells. However, stem cells from a variety of other origins are also reported to contribute to myofibers upon engraftment into muscles, questioning whether satellite cells are the only stem cell source for muscle regeneration. Here, we have engineered genetic ablation of Pax7(+) cells to test whether there is any significant contribution to muscle regeneration after acute injury from cells other than this source. We find that such elimination of Pax7(+) cells completely blocks regenerative myogenesis either following injury to the tibialis anterior (TA) muscle or after transplantation of extensor digitorum longus (EDL) muscles into nude mice. As Pax7 is specifically expressed in satellite cells, we conclude that they are essential for acute injury-induced muscle regeneration. It remains to be established whether there is any significant role for stem cells of other origins. The implications of our results for muscle stem cell-based therapy are discussed.
Aiming for increased nickel and lower cobalt content in layered transition metal oxide cathodes (NCM) is a feasible strategy for achieving increased energy density and cost competitiveness in ...commercial lithium‐ion batteries. However, the practical long‐term cycling of NCM cathodes suffers from severe capacity degradation due to irreversible interface phase transformation and unavoidable crack formation. Herein, an in situ modification strategy is used to form a uniform and conformal Li1.8Sc0.8Ti1.2(PO4)3 (LSTP) protective layer by interconnecting the single‐crystal‐layered LiNi0.6Co0.1Mn0.3O2 (SC‐NCM) particles. LSTP surface modification helps to construct a robust cathode‐electrolyte interphase thin film between the cathode and the electrolyte, which can prevent SC‐NCM corrosion by electrolyte, and the stability of the mechanics can improve the intergranular cracks caused by long cycles under harsh conditions. Moreover, the LSTP conductive modification layer facilitates the lithium‐ion transport among cathode particles, effectively enhancing the rate capability. Impressively, the LSTP modified SC‐NCM exhibits a high reversible capacity of 144.3 mAh g−1 at the high discharge rate of 5 C and maintains a capacity retention of 90.27% even at the ultrahigh charge voltage of 4.6 V operation after 500 cycles. Moreover, in a pouch‐type full battery, the graphite/LSTP modified SC‐NCM maintains a capacity retention of 89.6% after 1700 cycles.
An innovative surface modification is developed to improve the long‐term cyclability and rate capability of a single‐crystalline Ni‐rich cathode. The surface modification strategy improves the mechanical stability and lithium‐ion transport, which creates a strong CEI interface to prevent electrolyte corrosion and improve the intergranular cracks caused by long cycles under harsh conditions.
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