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Klotho is an anti-aging protein and can be divided into three types: full-length transmembrane Klotho, soluble Klotho and secreted Klotho. Many studies have shown that Klotho is closely related to oxidative stress, inflammatory response, myocardial hypertrophy, fibrosis, autophagy, and mitochondrial dysfunction. It is also involved in the occurrence and development of heart failure. It is expected to provide a new target and direction for the treatment of heart failure.

With-no-lysine kinase (WNK) is a unique serine/threonine kinase family member. WNK differs from other protein kinases by not having a standard lysine in subdomain II of the universally preserved kinase catalytic region. Conversely, the amino acid lysine located in subdomain I plays a crucial role in its phosphorylation. The WNK family has been reported to regulate Arabidopsis flowering, circadian rhythm, and abiotic stress. Eighteen members of the WNK gene family were discovered in apples in this research, and they were primarily grouped into five categories on the phylogenetic tree. Conserved domains and motifs also confirmed their identity as members of the WNK family. Promoter cis-acting element analysis indicated their potential role in responses to both abiotic stress and phytohormones. Furthermore, qRT-PCR analysis showed that the expression of MdWNK family genes was stimulated to different extents by Colletotrichum siamense, NaCl, mannitol, ABA, JA, and SA, with Colletotrichum siamense being the most prominent stimulant. MdWNK family genes were expressed across all apple tissues, with young fruits showing the greatest expression and roots showing the least expression. The research offered detailed insights into the MdWNK gene family, serving as a crucial basis for investigating the biological roles of MdWNK genes. [ABSTRACT FROM AUTHOR]

The online-to-offline (O2O) business mode has on-demand features to offer consumers instant fulfillment from a local store upon their online order. The O2O mode has attracted many more consumers recently. Using empirical evidence from a leading O2O platform in China, our study focuses on the market entry issue in the O2O context. Upon the new entrant entering the market, existing listed sellers implement a higher overall promotion to their consumers by enlarging the direct promotion extent but reducing the other types of promotions, including coupon, bundle, quantity, and gift promotions. However, the O2O platforms reduce the promotions level to the consumer orders from the existing listed sellers. The platform's and existing listed sellers' promotions increase consumers' purchase frequency but lower their purchase amount per order. The extent of these impacts depends on the geographic location of the new entrant. Our findings provide guidelines for the O2O platforms and listed providers to implement appropriate promotion strategies to attract consumers when considering the impact of certain new providers entering the O2O market. [ABSTRACT FROM AUTHOR]

Key message: MdERF023 is a transcription factor that can reduce salt tolerance by inhibiting ABA signaling and Na+/H+ homeostasis. Salt stress is one of the principal environmental stresses limiting the growth and productivity of apple (Malus × domestica). The APETALA2/ethylene response factor (AP2/ERF) family plays key roles in plant growth and various stress responses; however, the regulatory mechanism involved has not been fully elucidated. In the present study, we identified an AP2/ERF transcription factor (TF), MdERF023, which plays a negative role in apple salt tolerance. Stable overexpression of MdERF023 in apple plants and calli significantly decreased salt tolerance. Biochemical and molecular analyses revealed that MdERF023 directly binds to the promoter of MdMYB44-like, a positive modulator of ABA signaling-mediated salt tolerance, and suppresses its transcription. In addition, MdERF023 downregulated the transcription of MdSOS2 and MdAKT1, thereby reducing the Na+ expulsion, K+ absorption, and salt tolerance of apple plants. Taken together, these results suggest that MdERF023 reduces apple salt tolerance by inhibiting ABA signaling and ion transport, and that it could be used as a potential target for breeding new varieties of salt-tolerant apple plants via genetic engineering. [ABSTRACT FROM AUTHOR]

Papillary hemangioma (PH) is a recently described vascular tumor with a predilection for the skin of the head and neck. Histopathologically, it is characterized by a bland endothelial proliferation arranged in a papillary configuration, bearing resemblance to glomeruloid hemangioma seen in the context of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes syndrome. The largest cutaneous PH reported to date measured 1.5 cm in greatest dimension. Here, we report a case of PH with an alarming size of 10 cm. We present this case to add to the limited literature on this rare tumor, highlight the histopathologic differences between PH and its mimics, and emphasize the variable nature of PH tumor size. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose stands as the primary cause of acute liver failure in the United States. APAP hepatotoxicity involves hepatic glutathione (GSH) depletion and mitochondrial damage. To counteract the toxicity of APAP, the nuclear factor erythroid 2 like 2 (Nrf2) activates the expression of genes responsible for drug detoxification and GSH synthesis. In this study, we present evidence that the elimination of hepatocyte small heterodimer partner, a critical transcriptional repressor for liver metabolism, results in Nrf2 activation and protects mice from APAP-induced acute liver injury. Initial investigations conducted on wildtype (WT) mice revealed a swift downregulation of Shp mRNA within the first 24 h after APAP administration. Subsequent treatment of hepatocyte-specific Shp knockout (Shp Hep−/−) mice with 300 mg/kg APAP for 2 h exhibited comparable bioactivation of APAP with that observed in the WT controls. However, a significant reduction in liver injury was observed in Shp Hep−/− after APAP treatment for 6 and 24 h. The decreased liver injury correlated with a faster recovery of GSH, attributable to heightened expression of Nrf2 target genes involved in APAP detoxification and GSH synthesis. Moreover, in vitro studies revealed that SHP protein interacted with NRF2 protein, inhibiting the transcription of Nrf2 target genes. These findings hold relevance for humans, as overexpression of SHP hindered APAP-induced NRF2 activation in primary human hepatocytes. In conclusion, our studies have unveiled a novel regulatory axis involving SHP and NRF2 in APAP-induced acute liver injury, emphasizing SHP as a promising therapeutic target in APAP overdose-induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

O2O (Online to Offline) services enable customers to place orders online and receive products/services offline. In addition to traditional in-house drivers, the emergence of crowd-sourced drivers provides an opportunity to re-organise offline delivery services. In practice, three types of workforce, namely, in-house, full-time, and part-time crowd-sourced drivers, coexist in the system while exhibiting different characteristics. This situation creates challenges for the management of order assignment and routing. In particular, we study three settings in response to different driver preferences: the guaranteed minimum daily number of orders for full-time drivers; the maximally allowed number of orders per trip; and the detour proportion for part-time drivers. This paper aims to provide a method for O2O platforms to optimise order assignment and routing, considering these designs about driver preferences. We further validate our model and study managerial insights using real datasets. Specifically, the results show that among all designed parameters for the O2O on-demand delivery system, two parameters – the maximally allowed number of orders per trip and the detour proportion – are critical for the design. Moreover, we find that incentive mechanisms for inexperienced and experienced drivers are different because of their service capacities. The managerial insights are expected to guide practitioners. [ABSTRACT FROM AUTHOR]