72 research outputs found
Regulation of GSK-3 Activity as A Shared Mechanism in Psychiatric Disorders
Serin/Treonin kinaz ailesinin ΓΌyelerinden bir kinaz olarak ilk kez glikojen sentazβΔ± inhibe ettiΔi keΕfedilen glikojen sentaz kinaz-3 (GSK-3), gΓΌnΓΌmΓΌzde bilinen 50βden fazla substratΔ± ile birΓ§ok hΓΌcre iΓ§i dΓΌzenleyici mekanizmada gΓΆrev alan geniΕ etki spektrumlu bir enzim olarak kabul edilmektedir. GSK-3βΓΌn memelilerde GSK-3Ξ± ve GSK-3Ξ² olmak ΓΌzere yapΔ±sal olarak yΓΌksek homoloji gΓΆsteren iki izoformu bulunmaktadΔ±r. Her iki izoform birΓ§ok dokuda yaygΔ±n daΔΔ±lΔ±m gΓΆstermekle beraber, en yΓΌksek oranda beyinde bulunmakta ve genellikle benzer fonksiyonlar gΓΆstermektedirler. DiΔer protein kinazlarΔ±n aksine GSK-3 uyarΔ±lmamΔ±Ε hΓΌcrede yapΔ±sal olarak aktif yani defosforile halde bulur. Protein kinaz A (PKA), protein kinaz B (PKB;AKT) ve protein kinaz C (PKC) gibi diΔer protein kinazlarla fosforilasyona uΔrayarak olarak inaktive edilir. GΓΌnΓΌmΓΌzde artmΔ±Ε GSK-3 aktivitesinin major depresyon, bipolar bozukluk, hiperaktivite bozukluklarΔ± gibi hastalΔ±klar ve Εizofreni oluΕumunda rol oynayabileceΔine iliΕkin ΓΆnemli bulgular mevcuttur. Bu nedenle sΓΆz konusu psikiyatrik hastalΔ±klarda arttΔ±ΔΔ± gΓΆsterilen GSK-3 aktivitesinin azaltΔ±lmasΔ±nΔ±n tedavide umut verici bir yaklaΕΔ±m olabileceΔi kabul edilebilir. Bu gΓΆzden geΓ§irme Γ§alΔ±ΕmasΔ±nda yukarΔ±da sΓΆzΓΌ edilen psikiyatrik hastalΔ±klarΔ±n oluΕmasΔ±nda gΓΆrev alan GSK-3 aracΔ±lΔ± mekanizmalara kΔ±saca deΔinilerek GSK-3βΓΌn aktivitesinin dΓΌzenlenmesinde rol oynadΔ±ΔΔ± gΓΆsterilen klinikte kullanΔ±lan ilaΓ§lara yer verilmiΕtir. Anahtar sΓΆzcΓΌkler: GSK-3, depresyon, bipolar bozukluk, Εizofren
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Development and characterisation of a novel, megakaryocyte NF-ΞΊB reporter cell line for investigating inflammatory responses
Background
Due to the difficulties in acquiring large numbers of megakaryocytes, the impact of inflammatory responses on these cells and their ability to produce fully functional platelets under various pathological conditions has not been investigated in detail.
Objectives
The primary objective of this study is to develop and functionally characterise a novel megakaryocyte NF-ΞΊB reporter cell line in order to determine the effects of various inflammatory molecules on megakaryocytes and their signalling pathways.
Methods
A Meg-01-NF-ΞΊB-GFP-Luc (Meg-01R) cell line was developed by inserting a reporter NF-ΞΊB-GFP-Luc cassette into normal Meg-01 cells to produce luciferase following activation of NF-ΞΊB to enable easy detection of pro-inflammatory and reparative signalling.
Results and conclusions
Meg-01 and Meg-01R cells have comparable characteristics including the expression of both GPIb and integrin Ξ²3. Meg-01R cells responded to various inflammatory molecules as measured by NF-ΞΊB-dependent bioluminescence. For example, inflammatory molecules such as TNFΞ± and Pam3CSK4 increased NF-ΞΊB activity, whereas an antimicrobial peptide, LL37, reduced its activity. Meg-01R cells were also found to be sensitive to inhibitors (IMD0354 and C87) of inflammatory pathways. Notably, Meg-01R cells were able to respond to LPS (non-ultrapure) although it was not able to react to ultrapure LPS due to the lack of sufficient TLR4 molecules on their surface.
For the first time, we report the development and characterisation of a novel megakaryocyte NF-ΞΊB reporter cell line (Meg-01R) as a robust tool to study the inflammatory responses/signalling of megakaryocytes upon stimulation with a broad range of inflammatory molecules that can affect NF-ΞΊB activity
Liquid-gas phase transition in nuclear multifragmentation
The equation of state of nuclear matter suggests that at suitable beam
energies the disassembling hot system formed in heavy ion collisions will pass
through a liquid-gas coexistence region. Searching for the signatures of the
phase transition has been a very important focal point of experimental
endeavours in heavy ion collisions, in the last fifteen years. Simultaneously
theoretical models have been developed to provide information about the
equation of state and reaction mechanisms consistent with the experimental
observables. This article is a review of this endeavour.Comment: 63 pages, 27 figures, submitted to Adv. Nucl. Phys. Some typos
corrected, minor text change
What Every Reader Should Know About Studies Using Electronic Health Record Data but May Be Afraid to Ask
Coincident with the tsunami of COVID-19-related publications, there has been a surge of studies using real-world data, including those obtained from the electronic health record (EHR). Unfortunately, several of these high-profile publications were retracted because of concerns regarding the soundness and quality of the studies and the EHR data they purported to analyze. These retractions highlight that although a small community of EHR informatics experts can readily identify strengths and flaws in EHR-derived studies, many medical editorial teams and otherwise sophisticated medical readers lack the framework to fully critically appraise these studies. In addition, conventional statistical analyses cannot overcome the need for an understanding of the opportunities and limitations of EHR-derived studies. We distill here from the broader informatics literature six key considerations that are crucial for appraising studies utilizing EHR data: data completeness, data collection and handling (eg, transformation), data type (ie, codified, textual), robustness of methods against EHR variability (within and across institutions, countries, and time), transparency of data and analytic code, and the multidisciplinary approach. These considerations will inform researchers, clinicians, and other stakeholders as to the recommended best practices in reviewing manuscripts, grants, and other outputs from EHR-data derived studies, and thereby promote and foster rigor, quality, and reliability of this rapidly growing field
International comparisons of laboratory values from the 4CE collaborative to predict COVID-19 mortality
Given the growing number of prediction algorithms developed to predict COVID-19 mortality, we evaluated the transportability of a mortality prediction algorithm using a multi-national network of healthcare systems. We predicted COVID-19 mortality using baseline commonly measured laboratory values and standard demographic and clinical covariates across healthcare systems, countries, and continents. Specifically, we trained a Cox regression model with nine measured laboratory test values, standard demographics at admission, and comorbidity burden pre-admission. These models were compared at site, country, and continent level. Of the 39,969 hospitalized patients with COVID-19 (68.6% male), 5717 (14.3%) died. In the Cox model, age, albumin, AST, creatine, CRP, and white blood cell count are most predictive of mortality. The baseline covariates are more predictive of mortality during the early days of COVID-19 hospitalization. Models trained at healthcare systems with larger cohort size largely retain good transportability performance when porting to different sites. The combination of routine laboratory test values at admission along with basic demographic features can predict mortality in patients hospitalized with COVID-19. Importantly, this potentially deployable model differs from prior work by demonstrating not only consistent performance but also reliable transportability across healthcare systems in the US and Europe, highlighting the generalizability of this model and the overall approach
Long-term kidney function recovery and mortality after COVID-19-associated acute kidney injury: An international multi-centre observational cohort study
Background: While acute kidney injury (AKI) is a common complication in COVID-19, data on post-AKI kidney function recovery and the clinical factors associated with poor kidney function recovery is lacking. Methods: A retrospective multi-centre observational cohort study comprising 12,891 hospitalized patients aged 18 years or older with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction from 1 January 2020 to 10 September 2020, and with at least one serum creatinine value 1β365 days prior to admission. Mortality and serum creatinine values were obtained up to 10 September 2021. Findings: Advanced age (HR 2.77, 95%CI 2.53β3.04, p < 0.0001), severe COVID-19 (HR 2.91, 95%CI 2.03β4.17, p < 0.0001), severe AKI (KDIGO stage 3: HR 4.22, 95%CI 3.55β5.00, p < 0.0001), and ischemic heart disease (HR 1.26, 95%CI 1.14β1.39, p < 0.0001) were associated with worse mortality outcomes. AKI severity (KDIGO stage 3: HR 0.41, 95%CI 0.37β0.46, p < 0.0001) was associated with worse kidney function recovery, whereas remdesivir use (HR 1.34, 95%CI 1.17β1.54, p < 0.0001) was associated with better kidney function recovery. In a subset of patients without chronic kidney disease, advanced age (HR 1.38, 95%CI 1.20β1.58, p < 0.0001), male sex (HR 1.67, 95%CI 1.45β1.93, p < 0.0001), severe AKI (KDIGO stage 3: HR 11.68, 95%CI 9.80β13.91, p < 0.0001), and hypertension (HR 1.22, 95%CI 1.10β1.36, p = 0.0002) were associated with post-AKI kidney function impairment. Furthermore, patients with COVID-19-associated AKI had significant and persistent elevations of baseline serum creatinine 125% or more at 180 days (RR 1.49, 95%CI 1.32β1.67) and 365 days (RR 1.54, 95%CI 1.21β1.96) compared to COVID-19 patients with no AKI. Interpretation: COVID-19-associated AKI was associated with higher mortality, and severe COVID-19-associated AKI was associated with worse long-term post-AKI kidney function recovery. Funding: Authors are supported by various funders, with full details stated in the acknowledgement section
PABPN1 gene therapy for oculopharyngeal muscular dystrophy
International audienceOculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus-based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome. The efficacy of the combined treatment is further confirmed in cells derived from OPMD patients. These results pave the way towards a gene replacement approach for OPMD treatment
Adolescent Brain Development and the Risk for Alcohol and Other Drug Problems
Dynamic changes in neurochemistry, fiber architecture, and tissue composition occur in the adolescent brain. The course of these maturational processes is being charted with greater specificity, owing to advances in neuroimaging and indicate grey matter volume reductions and protracted development of white matter in regions known to support complex cognition and behavior. Though fronto-subcortical circuitry development is notable during adolescence, asynchronous maturation of prefrontal and limbic systems may render youth more vulnerable to risky behaviors such as substance use. Indeed, binge-pattern alcohol consumption and comorbid marijuana use are common among adolescents, and are associated with neural consequences. This review summarizes the unique characteristics of adolescent brain development, particularly aspects that predispose individuals to reward seeking and risky choices during this phase of life, and discusses the influence of substance use on neuromaturation. Together, findings in this arena underscore the importance of refined research and programming efforts in adolescent health and interventional needs
Culture of human intestinal epithelial cell using the dissociating enzyme thermolysin and endothelin-3
Clinical, humanistic, and economic burden of chronic obstructive pulmonary disease (COPD) in Canada: a systematic review
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