203 research outputs found
Frodo Links Dishevelled to the p120-Catenin/Kaiso Pathway: Distinct Catenin Subfamilies Promote Wnt Signals
Summaryp120-catenin is an Arm repeat protein that interacts with varied components such as cadherin, small GĀ proteins, kinases, and the Kaiso transcriptional repressor. Despite recent advances in understanding the roles that p120-catenin and Kaiso play in downstream modulation of Wnt/Ī²-catenin signaling, the identity of the upstream regulators of the p120-catenin/Kaiso pathway have remained unclear. Here, we find that p120-catenin binds Frodo, which itself interacts with the Wnt pathway protein Dishevelled (Dsh). In Xenopus laevis, we demonstrate that Wnt signals result in Frodo-mediated stabilization of p120-catenin, which, in turn, promotes Kaiso sequestration or removal from the nucleus. Our results point to Dsh and Frodo as upstream regulators of the p120-catenin/Kaiso signaling pathway. Importantly, this suggests that Wnt signals acting through Dsh regulate the stability of p120-catenin in addition to that of Ī²-catenin, and that each catenin promotes its respective signal in parallel to regulate distinct, as well as shared, direct downstream gene targets
PAF-Mediated MAPK Signaling Hyperactivation via LAMTOR3 Induces Pancreatic Tumorigenesis
SummaryDeregulation of mitogen-activated protein kinase (MAPK) signaling leads to development of pancreatic cancer. Although Ras-mutation-driven pancreatic tumorigenesis is well understood, the underlying mechanism of Ras-independent MAPK hyperactivation remains elusive. Here, we have identified a distinct function of PCNA-associated factor (PAF) in modulating MAPK signaling. PAF is overexpressed in pancreatic cancer and required for pancreatic cancer cell proliferation. In mouse models, PAF expression induced pancreatic intraepithelial neoplasiaĀ with expression of pancreatic cancer stem cell markers. PAF-induced ductal epithelial cell hyperproliferation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation independently of Ras or Raf mutations. Intriguingly, PAF transcriptionally activated the expression of late endosomal/lysosomal adaptor, MAPK and mTOR activator 3 (LAMTOR3), which hyperphosphorylates MEK and ERK and is necessary for pancreatic cancerĀ cell proliferation. Our results reveal an unsuspected mechanism of mitogenic signaling activationĀ via LAMTOR3 and suggest that PAF-induced MAPK hyperactivation contributes to pancreatic tumorigenesis
Zebrafish EEG predicts the efficacy of antiepileptic drugs
Background: Pharmacological evaluation of antiepileptic drugs (AEDs) using mammalian animals takes long time and is expensive. The zebrafish is a species commonly used to study brain functions, neurological diseases, and drug toxicity, and attracts more attention as an alternative animal model to substitute or supplement mammalian animals in drug development. Electroencephalogram (EEG) is a key indicator for diagnosing brain diseases such as epilepsy, by directly measuring the brain activity. We propose a novel method for pharmacological evaluation of AEDs based on EEG from adult zebrafish, which allows researchers to select more clinically valuable drugs at the early stage of AED screening.Methods: To evaluate the efficacy of AEDs, zebrafish EEG signals were measured after administering six AEDs (valproate acid, gabapentin, ethosuximide, oxcarbazepine, tiagabine, and topiramate) at various doses to pentylenetetrazol (PTZ)-induced seizure models. The change in seizure activity was investigated according to doses. The antiepileptic effect was determined by observing a significant decrease in at least one out of three indicators of the number, total duration, and mean duration of ictal events.Results: Using EEG signals from adult zebrafish, antiepileptic effects were observed with all six AEDs. Among them, antiepileptic effects depending on dose were confirmed with valproate acid, gabapentin, ethosuximide, and tiagabine. Moreover, the 50% effective doses (ED50) of valproate acid and tiagabine were determined based on zebrafish EEG for the first time, indicating that the quantitative inter-species comparison of the AED efficacy is possible between zebrafish and mammals such as rodents.Significance: The results show that zebrafish can be used to effectively and quantitatively evaluate the efficacy of AEDs based on EEG, the same method to evaluate antiepileptic effects in mammals, suggesting that the proposed method can contribute in reducing the cost and duration of search for AEDs and thus accelerate the drug development cycles
TERT Promotes Epithelial Proliferation through Transcriptional Control of a Myc- and Wnt-Related Developmental Program
Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERTci) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERTci retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways
Impulsivity and compulsivity in Internet gaming disorder: A comparison with obsessiveācompulsive disorder and alcohol use disorder
Internet gaming disorder (IGD) is characterized by a loss of control and a preoccupation with Internet games leading to repetitive behavior. We aimed to compare the baseline neuropsychological profiles in IGD, alcohol use disorder (AUD), and obsessiveācompulsive disorder (OCD) in the spectrum of impulsivity and compulsivity. Methods A total of 225 subjects (IGD, Nā=ā86; AUD, Nā=ā39; OCD, Nā=ā23; healthy controls, Nā=ā77) were administered traditional neuropsychological tests including Korean version of the Stroop ColorāWord test and computerized neuropsychological tests, including the stop signal test (SST) and the intraāextra dimensional set shift test (IED). Results Within the domain of impulsivity, the IGD and OCD groups made significantly more direction errors in SST (pā=ā.003, pā=ā.001) and showed significantly delayed reaction times in the colorāword reading condition of the Stroop test (pā=ā.049, pā=ā.001). The OCD group showed the slowest reading time in the colorāword condition among the four groups. Within the domain of compulsivity, IGD patients showed the worst performance in IED total trials measuring attentional set shifting ability among the groups. Conclusions Both the IGD and OCD groups shared impairment in inhibitory control functions as well as cognitive inflexibility. Neurocognitive dysfunction in IGD is linked to feature of impulsivity and compulsivity of behavioral addiction rather than impulse dyscontrol by itself
Posterior condylar offset changes and its effect on clinical outcomes after posterior-substituting, fixed-bearing total knee arthroplasty: anterior versus posterior referencing
Background
We sought to determine whether there was a difference in the posterior condylar offset (PCO), posterior condylar offset ratio (PCOR) and clinical outcomes following total knee arthroplasty (TKA) with anterior referencing (AR) or posterior referencing (PR) systems. We also assessed whether the PCO and PCOR changes, as well as patient factors were related to range of motion (ROM) in each referencing system.
Methods
This retrospective study included 130 consecutive patients (184 knees) with osteoarthritis who underwent primary posterior cruciate ligament (PCL)-substituting fixed-bearing TKA. The difference between preoperative and postoperative PCO and PCOR values were calculated. Clinical outcomes including ROM and Western Ontario and McMaster University (WOMAC) scores were evaluated. Furthermore, multiple linear regression analysis was performed to determine the factors related to postoperative ROM in each referencing system.
Results
The postoperative PCO was greater in the AR group (28.4āmm) than in the PR group (27.4āmm), whereas the PCO was more consistently preserved in the PR group. The mean postoperative ROM after TKA was greater in the AR group (129Ā°) than in the PR group (122Ā°), whereas improvement in WOMAC score did not differ between the two groups. Preoperative ROM was the only factor related to postoperative ROM in both groups.
Conclusions
There was no difference in postoperative PCO in AR and PR group and the PCO was not associated with postoperative ROM. PCO was more consistently preserved after surgery in the PR group. The postoperative PCO and PCOR changes did not affect the postoperative ROM. Furthermore, similar clinical outcomes were achieved in the AR and PR groups.
Trial registration
Retrospectively registered (Trial registration number: 06-2010-110).This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (2017M3A9D8063538)
Long-term cardiovascular outcomes of gestational diabetes mellitus: a prospective UK Biobank study
Background
Previous studies showed that gestational diabetes mellitus (GDM) can be a risk factor for subsequent atherosclerotic cardiovascular disease. However, there is a paucity of information regarding diverse cardiovascular outcomes in elderly women after GDM. In the current study, we examined whether women with a history of GDM have an increased risk for long-term overall cardiovascular outcomes.
Methods
Among the UK participants, we included 219,330 women aged 40 to 69Ā years who reported at least one live birth. The new incidence of diverse cardiovascular outcomes was compared according to GDM history by multivariable Cox proportional hazard models. In addition, causal mediation analysis was performed to examine the contribution of well-known risk factors to observed risk.
Results
After enrollment, 13,094 women (6.0%) developed new overall cardiovascular outcomes. Women with GDM history had an increased risk for overall cardiovascular outcomes [adjusted HR (aHR) 1.36 (95% CI 1.18ā1.55)], including coronary artery disease [aHR 1.31 (1.08ā1.59)], myocardial infarction [aHR 1.65 (1.27ā2.15)], ischemic stroke [aHR 1.68 (1.18ā2.39)], peripheral artery disease [aHR 1.69 (1.14ā2.51)], heart failure [aHR 1.41 (1.06ā1.87)], mitral regurgitation [aHR 2.25 (1.51ā3.34)], and atrial fibrillation/flutter [aHR 1.47 (1.18ā1.84)], after adjustment for age, race, BMI, smoking, early menopause, hysterectomy, prevalent disease, and medication. In mediation analysis, overt diabetes explained 23%, hypertension explained 11%, and dyslipidemia explained 10% of the association between GDM and overall cardiovascular outcome.
Conclusions
GDM was associated with more diverse cardiovascular outcomes than previously considered, and conventional risk factors such as diabetes, hypertension, and dyslipidemia partially contributed to this relationship.This work was supported by NIGMS R01 GM138597 and by National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No.NRF-2021R1F1A1046707, NRF-2022R1F1A1072279)
Nanosilver Colloids-Filled Photonic Crystal Arrays for Photoluminescence Enhancement
For the improved surface plasmon-coupled photoluminescence emission, a more accessible fabrication method of a controlled nanosilver pattern array was developed by effectively filling the predefined hole array with nanosilver colloid in a UV-curable resin via direct nanoimprinting. When applied to a glass substrate for light emittance with an oxide spacer layer on top of the nanosilver pattern, hybrid emission enhancements were produced from both the localized surface plasmon resonance-coupled emission enhancement and the guided light extraction from the photonic crystal array. When CdSe/ZnS nanocrystal quantum dots were deposited as an active emitter, a total photoluminescence intensity improvement of 84% was observed. This was attributed to contributions from both the silver nanoparticle filling and the nanoimprinted photonic crystal array
Ultraviolet nanoimprinted polymer nanostructure for organic light emitting diode application
Light extraction efficiency of a conventional organic light emitting diode (OLED) remains limited to approximately 20% as most of the emission is trapped in the waveguide and glass modes. An etchless simple method was developed to fabricate two-dimensional nanostructures on glass substrate directly by using ultraviolet (UV) curable polymer resin and UV nanoimprint lithography in order to improve output coupling efficiency of OLEDs. The enhancement of the light extraction was predicted by the three-dimensional finite difference time domain method. OLEDs integrated on nanoimprinted substrates enhanced electroluminance intensity by up to 50% compared to the conventional device
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