The emergence of platform‐based entrepreneurial firms (PBEFs) and their rapid scaling holds considerable implications for the theory and practice of firm growth in the digital economy. Building on ...the resource‐based view, we seek deeper insights into the question of how PBEFs orchestrate resources to scale up in the context of platform ecosystems. We conduct an in‐depth longitudinal case study of Tencent, one of the largest PBEFs in the world, and develop an inductive process model based on the logic of ‘dialectic tuning’. We uncover the specific actions and capabilities that PBEFs possess and employ to scale up a platform ecosystem, as manifested in a complementary set of concrete organizational practices enacted at different stages of the growth trajectory. We unveil an important boundary condition that has hitherto remained implicit in the literature on firm growth driven by platform‐based business models. Our findings diverge from the conventional perspective which predominantly associates firm growth with the characteristics of internal resources and capabilities. We argue that the relational properties of interaction and integration between internal and external resources are what gives rise to the capabilities needed to scale up a platform. Thus, we extend and refine the resource‐based view by explaining the evolving patterns of resource orchestration and management of PBEFs in terms of the interplay between the focal platform and its ecosystem partners.
Hydrangea serrata (THUNB.) SER. (Hydrangeaceae) leaves have been used as herbal teas in Korea and Japan. The objective of this study was to identify anti-photoaging compounds in aqueous EtOH extract ...prepared from leaves of H. serrata and their effects on UVB-irradiated Hs68 human foreskin fibroblasts. Phytochemical study on H. serrata leaves led to the isolation and characterization of ten compounds: hydrangenol, thunberginol A, thunberginol C, hydrangenoside A, hydrangenoside C, cudrabibenzyl A, 2,3,4′-trihydroxystilbene, thunberginol F, quercetin 3-O-β-D-xylopyranosyl (1-2)-β-D-galactopyranoside, quercetin 3-O-β-D-xylopyranosyl (1-2)-β-D-glucopyranoside. Cudrabibenzyl A, 2,3,4′-trihydroxystilbene, quercetin 3-O-β-D-xylopyranosyl (1-2)-β-D-galactopyranoside, quercetin 3-O-β-D-xylopyranosyl (1-2)-β-D-glucopyranoside were firstly isolated from H. serrata. We estimated the effects of 10 compounds on cell viability and production of pro-collagen Type I, matrix metalloproteinase (MMP)-1, and hyaluronic acid (HA) after UVB irradiation. Of these compounds, hydrangenol showed potent preventive activities against reduced cell viability and degradation of pro-collagen Type I in UVB-irradiated Hs68 fibroblasts. Hydrangenol had outstanding inductive activities on HA production. It suppressed mRNA expression levels of MMP-1, MMP-3, hyaluronidase (HYAL)-1, HYAL-2, cyclooxygenase-2 (COX-2), interleukin (IL)-6, IL-8, and IL-1β in UVB-irradiated Hs68 fibroblasts. When Hs68 fibroblasts were exposed to hydrangenol after UVB irradiation, UVB-induced reactive oxygen species (ROS) production was suppressed. Hydrangenol also inhibited the activation of activator protein-1 (AP-1) and signal transduction and activation of transcription 1 (STAT-1) by downregulating phosphorylation of p38 and extracellular signal-regulated kinase (ERK). Our data indicate that hydrangenol isolated from H. serrata leaves has potential protective effects on UVB-induced skin photoaging.
Calcium is an abundant intracellular ion, and calcium homeostasis plays crucial roles in several cellular processes. The calcineurin signaling cascade is one of the major pathways governed by ...intracellular calcium. Calcineurin, a conserved protein from yeast to humans, is a calcium-calmodulin-dependent serine-threonine-specific phosphatase that orchestrates cellular stress responses. In eukaryotic microbial pathogens, calcineurin controls essential virulence pathways, such as the ability to grow at host temperature, morphogenesis to enable invasive hyphal growth, drug tolerance and resistance, cell wall integrity, and sexual development. Therefore, the calcineurin cascade is an attractive target in drug development against eukaryotic pathogens. In the present review, we summarize and discuss the current knowledge on the roles of calcineurin in eukaryotic microbial pathogens, focusing on fungi and parasitic protists.
In this Review, Park et al. provide an overview of the calcium-calmodulin-calcineurin signaling pathways in eukaryotic microbial pathogens, with a focus on fungal pathogens and parasitic protists. They highlight both the conserved and unique aspects of this important pathway and explore their potential role as therapeutic targets against such pathogens.
Reducing the duration of intraoperative hypoxemia in pediatric patients by means of rapid detection and early intervention is considered crucial by clinicians. We aimed to develop and validate a ...machine learning model that can predict intraoperative hypoxemia events 1 min ahead in children undergoing general anesthesia.
This retrospective study used prospectively collected intraoperative vital signs and parameters from the anesthesia ventilator machine extracted every 2 s in pediatric patients undergoing surgery under general anesthesia between January 2019 and October 2020 in a tertiary academic hospital. Intraoperative hypoxemia was defined as oxygen saturation <95% at any point during surgery. Three common machine learning techniques were employed to develop models using the training dataset: gradient-boosting machine (GBM), long short-term memory (LSTM), and transformer. The performances of the models were compared using the area under the receiver operating characteristics curve using randomly assigned internal testing dataset. We also validated the developed models using temporal holdout dataset. Pediatric patient surgery cases between November 2020 and January 2021 were used. The performances of the models were compared using the area under the receiver operating characteristic curve (AUROC).
In total, 1,540 (11.73%) patients with intraoperative hypoxemia out of 13,130 patients' records with 2,367 episodes were included for developing the model dataset. After model development, 200 (13.25%) of the 1,510 patients' records with 289 episodes were used for holdout validation. Among the models developed, the GBM had the highest AUROC of 0.904 (95% confidence interval CI 0.902 to 0.906), which was significantly higher than that of the LSTM (0.843, 95% CI 0.840 to 0.846 P < .001) and the transformer model (0.885, 95% CI, 0.882-0.887, P < .001). In holdout validation, GBM also demonstrated best performance with an AUROC of 0.939 (95% CI 0.936 to 0.941) which was better than LSTM (0.904, 95% CI 0.900 to 0.907, P < .001) and the transformer model (0.929, 95% CI 0.926 to 0.932, P < .001).
Machine learning models can be used to predict upcoming intraoperative hypoxemia in real-time based on the biosignals acquired by patient monitors, which can be useful for clinicians for prediction and proactive treatment of hypoxemia in an intraoperative setting.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic exposure to ultraviolet B (UVB) is a major cause of skin aging. The aim of the present study was to determine the photoprotective effect of a 30% ethanol extract of
(Kjellman) Setchell (EEB) ...against UVB-induced skin aging. By treating human dermal fibroblasts (Hs68) with EEB after UVB irradiation, we found that EEB had a cytoprotective effect. EEB treatment significantly decreased UVB-induced matrix metalloproteinase-1 (MMP-1) production by suppressing the activation of mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling and enhancing the protein expression of tissue inhibitors of metalloproteinases (TIMPs). EEB was also found to recover the UVB-induced degradation of pro-collagen by upregulating Smad signaling. Moreover, EEB increased the mRNA expression of filaggrin, involucrin, and loricrin in UVB-irradiated human epidermal keratinocytes (HaCaT). EEB decreased UVB-induced reactive oxygen species (ROS) generation by upregulating glutathione peroxidase 1 (GPx1) and heme oxygenase-1 (HO-1) expression via nuclear factor erythroid-2-related factor 2 (Nrf2) activation in Hs68 cells. In a UVB-induced HR-1 hairless mouse model, the oral administration of EEB mitigated photoaging lesions including wrinkle formation, skin thickness, and skin dryness by downregulating MMP-1 production and upregulating the expression of pro-collagen type I alpha 1 chain (pro-COL1A1). Collectively, our findings revealed that EEB prevents UVB-induced skin damage by regulating MMP-1 and pro-collagen type I production through MAPK/AP-1 and Smad pathways.
Background and Purpose
Paracetamol (acetaminophen)‐induced hepatotoxicity is the leading cause of drug‐induced liver injury worldwide. Autophagy is a degradative process by which various cargoes are ...collected by the autophagic receptors such as p62/SQSTM1/Sequestosome‐1 for lysosomal degradation. Here, we investigated the protective role of p62‐dependent autophagy in paracetamol‐induced liver injury.
Experimental Approach
Paracetamol‐induced hepatotoxicity was induced by a single i.p. injection of paracetamol (500 mg·kg−1) in C57/BL6 male mice. YTK‐2205 (20 mg·kg−1), a p62 agonist targeting ZZ domain, was co‐ or post‐administered with paracetamol. Western blotting and immunocytochemistry were performed to explore the mechanism.
Key Results
N‐terminal arginylation of the molecular chaperone calreticulin retro‐translocated from the endoplasmic reticulum (ER) was induced in the livers undergoing paracetamol‐induced hepatotoxicity, and YTK‐2205 exhibited notable therapeutic efficacy in acute hepatotoxicity as assessed by the levels of serum alanine aminotransferase and hepatic necrosis. This efficacy was significantly attributed to accelerated degradation of ubiquitin (Ub) conjugates as well as damaged mitochondria (mitophagy) and endoplasmic reticulum (ER‐phagy). In primary murine hepatocytes treated with paracetamol, YTK‐2205 induced the co‐localization of p62+LC3+ phagophores to the sites of mitophagy and ER‐phagy. A similar activity of YTK‐2205 was observed with N‐acetyl‐p‐benzoquinone imine, a putative toxic metabolite of paracetamol in Hep3B cells.
Conclusion and Implications
Our results elucidated that p62‐dependent autophagy plays a key role in the removal of cytotoxic materials such as damaged mitochondria in paracetamol‐induced hepatotoxicity. Small molecule ligands to p62 may be developed into drugs to treat this pathological condition.
The pharmacological profile of fimasartan, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{2-(1H-tetrazole-5-yl)biphenyl-4-ylmethyl}-pyrimidin-4(3H)-one, a new non-peptide angiotensin type ...1 (AT1)-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, fimasartan showed slow dissociation and irreversible binding to AT1 subtype receptors in membrane fractions of HEK-293 cells with a Kd of 0.03 nM and a T1/2 of 63.7 min. The inhibitory effect of fimasartan on angiotensin II (Ang II)-induced contraction persisted longer after washout than that of losartan or candesartan. In conscious rats, a single dose of fimasartan (0.3, 1, or 3 mg/kg; per os (p.o.)) dose-dependently antagonized Ang II-induced pressor responses. Both orally administrated fimasartan and losartan dose-dependently decreased mean arterial pressure in furosemide-treated rats and dogs, and fimasartan administered orally at 1, 3, or 10 mg/kg reduced blood pressure in conscious spontaneously hypertensive rats. Taken together, these findings indicate that fimasartan has potent and sustained binding affinity at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in various conscious rats and dogs models after its oral administration.
Sugammadex, a selective antagonist of steroidal non‐depolarizing neuromuscular blocking agents, has been used in children in limited circumstances. However, neither pharmacokinetics (PKs) nor ...recovery profile of sugammadex for intense neuromuscular blockade reversal in children have been reported. This prospective study aimed to obtain a PK model of sugammadex and evaluate its efficacy and safety for intense neuromuscular blockade reversal in children. Forty children (age, 2–17 years) who underwent surgery that required early neuromuscular blockade reversal were enrolled. After neuromuscular blockade with 1 mg∙kg−1 of rocuronium, sugammadex (2, 4, and 8 mg∙kg−1) or a conventional dose of neostigmine (0.03 mg∙kg−1) was administered randomly after confirmation of zero post‐tetanic count. The plasma concentrations of rocuronium and sugammadex were measured 2 min after rocuronium injection; immediately before, 2, 5, 15, 60, 120, 240, and 480 min after the study drug injection. Response to train‐of‐four stimulation was continuously recorded. Noncompartmental analysis and population PK modeling were performed. For pharmacodynamics, the recovery profile was measured. Three‐compartment PK model was established for sugammadex. The median (interquartile range IQR) time from injection of 8 mg∙kg−1 of sugammadex to recovery of T4/T1greater than or equal to 0.9 at train‐of‐four stimulation was 1.1 (IQR: 0.88–1.8) min. No adverse events related to sugammadex were observed. We present a PK analysis of sugammadex for rocuronium‐induced intense neuromuscular blockade reversal in children with its recovery profile. The time to recover T4/T1 greater than or equal to 0.9 at train‐of‐four stimulation with 8 mg∙kg−1 of sugammadex was less than 3 min and comparable to that in adults.
Identification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor ...GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinase inhibitor 7a potently inhibited Lck kinase with great selectivity (IC
50
of 23.0 nM). It was found that 7a and its derivatives possessed high selectivity for Lck over even structurally conserved all Src family kinases. We also observed that 7a inhibited Lck activation in Jurkat T cells. Moreover, 7a was found to alleviate clinical symptoms in DSS-induced colitis mice. This study provides a novel insight into the design of selective type II kinase inhibitors by adopting chiral peptidomimetic moieties on the tail region.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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