•Early expression of EVI-1 is localised to the pharyngeal arches and intermediate mesoderm of chicken embryos.•EVI-1 expression in the limb is limited to the mesenchyme with the most prominent ...expression in the anterior margin.•Knocking down the EVI-1 expression in limb micromass cultures by siRNA reduced chondrogenesis in micromass cultures.•Application of FGFRs inhibitors (PD161570 and SU5402) into the wing mesenchyme leads to downregulation of EVI-1 expression.
Ecotropical viral integration site 1 (Evi-1) is a transcription factor essential for vascularisation and cell proliferation during embryonic development. The chimeric transcription factor AML1-EVI-1 is activated in leukaemia where it plays a role as a differentiation block and stimulator of proliferation. Here, we cloned chicken Evi-1 and analysed its expression during embryonic development. There was early expression in the pharyngeal arches, in the brain and intermediate mesoderm of chicken embryos at stage 15. Later at stage 20, Evi-1 mesenchymal expression was concentrated in the second pharyngeal arch, and weaker expression was found in the mandibular and maxillary prominences. Facial expression decreased in intensity during development. Evi-1 expression in the limb was also limited to the mesenchyme with the most prominent expression in the anterior margin. Evi-1 was not detectable in the posterior limb bud. At later stages, Evi-1 was expressed in the peripheral mesenchyme of the limb but not in the developing precartilage blastema. At stage 29, the expression became restricted to the perichondrium and interdigital areas; however, the cartilage condensations themselves were negative. To study the function of Evi-1 in chondrogenesis, we knocked down expression in limb micromass cultures using siRNA. Chondrogenesis was significantly reduced in both anterior and posterior cultures. Since Evi-1 was expressed adjacent to the apical ectodermal ridge and this area is a source of FGFs, we tested whether endogenous FGF receptor signalling was necessary to maintain its expression. Inhibitors of FGFRs (PD161570 and SU5402) were applied to wing mesenchyme, and downregulation of Evi-1 expression was observed after treatment with both inhibitors. Therefore, Evi-1 may be a transcription factor mediating the effects of FGF and may also be defining the size of cartilage elements in the limb.
Myeloid neoplasms represent a broad spectrum of hematological disorders for which somatic mutation status in key driver genes is important for diagnosis, prognosis and treatment. Here we summarize ...the findings of a targeted, next generation sequencing laboratory developed test in 24,639 clinical myeloid samples. Data were analyzed comprehensively and as part of individual cohorts specific to acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN). Overall, 48,015 variants were detected, and variants were found in all 50 genes in the panel. The mean number of mutations per patient was 1.95. Mutation number increased with age (Spearman's rank correlation coefficient, ρ = 0.29, P < 0.0001) and was higher in patients with AML than MDS or MPN (Student's t-test, P < 0.0001). TET2 was the most common mutation detected (19.1% of samples; 4,695/24,639) including 7.7% (1,908/24,639) with multi-hit TET2 mutations. Mutation frequency was correlated between patients with cytopenias and MDS (Spearman's, ρ = 0.97, P < 2.2×10-16) with the MDS diagnostic gene SF3B1 being the only notable outlier. This large retrospective study shows the utility of NGS testing to inform clinical decisions during routine clinical care and highlights the mutational landscape of a broad population of myeloid patients.
Huntington's disease (HD) is an incurable neuropsychiatric disease associated with CAG repeat expansion within a widely expressed gene that causes selective neuronal death. To understand its normal ...function, we have created a targeted disruption in exon 5 of
Hdh (
Hdh
ex5
), the murine homolog of the HD gene. Homozygotes die before embryonic day 8.5, initiate gastrulation, but do not proceed to the formation of somites or to organogenesis. Mice heterozygous for the
Hdh
ex5
mutation display increased motor activity and cognitive deficits. Neuropathological assessment of two heterozygous mice shows significant neuronal loss in the subthalamic nucleus. These studies show that the HD gene is essential for postimplantation development and that it may play an important role in normal functioning of the basal ganglia.
Abstract
Motivated by the potential of oceanic mesoscale eddies to drive intrinsic low-frequency variability, this paper examines geostrophic turbulence in the frequency–wavenumber domain. ...Frequency–wavenumber spectra, spectral fluxes, and spectral transfers are computed from an idealized two-layer quasigeostrophic (QG) turbulence model, a realistic high-resolution global ocean general circulation model, and gridded satellite altimeter products. In the idealized QG model, energy in low wavenumbers, arising from nonlinear interactions via the well-known inverse cascade, is associated with energy in low frequencies and vice versa, although not in a simple way. The range of frequencies that are highly energized and engaged in nonlinear transfer is much greater than the range of highly energized and engaged wavenumbers. Low-frequency, low-wavenumber energy is maintained primarily by nonlinearities in the QG model, with forcing and friction playing important but secondary roles. In the high-resolution ocean model, nonlinearities also generally drive kinetic energy to low frequencies as well as to low wavenumbers. Implications for the maintenance of low-frequency oceanic variability are discussed. The cascade of surface kinetic energy to low frequencies that predominates in idealized and realistic models is seen in some regions of the gridded altimeter product, but not in others. Exercises conducted with the general circulation model suggest that the spatial and temporal filtering inherent in the construction of gridded satellite altimeter maps may contribute to the discrepancies between the direction of the frequency cascade in models versus gridded altimeter maps seen in some regions. Of course, another potential reason for the discrepancy is missing physics in the models utilized here.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sputum from patients with cystic fibrosis, bronchiectasis, and chronic bronchitis contains neutrophils and neutrophil proteases, which have been implicated in the pathophysiology of mucus ...hypersecretion in airways. We asked whether interleukin-8 (IL-8), a potent neutrophil chemoattractant, might be involved in recruiting neutrophils into airways of patients with cystic fibrosis, bronchiectasis, and chronic bronchitis. We found significant neutrophil chemotactic activity in sputum obtained from these patients. The IL-8 concentrations that we measured in sputum of patients with cystic fibrosis (7.1 +/- 1.0 x 10(-9) M, mean +/- SE), bronchiectasis (9.6 +/- 2.9 x 10(-9) M), and chronic bronchitis (2.8 +/- 1.0 x 10(-9) M) have been reported to cause significant chemotaxis in vitro and in airways in vivo, whereas concentrations measured in induced sputum from healthy subjects (1.1 +/- 0.3 x 10(-10) M) do not. A monoclonal antibody to IL-8 significantly inhibited the chemotactic activity in patients' sputum by 75-98%, but not in induced sputum from healthy subjects (9%). We conclude that IL-8 is an important chemotactic factor in sputum of patients with cystic fibrosis, bronchiectasis, and chronic bronchitis, and we suggest that IL-8 accounts, at least in part, for neutrophil recruitment into airways of patients with these diseases.
In recent years, drug prevention networks and drug education programs have started using Web-based or mobile phone apps as novel prevention tools, testing their efficacy compared with face-to-face ...prevention.
The aim of this study was to assess the potential of an interactive app called Once Upon a High (VoltEgySzer).
The app approaches drug prevention from 6 different aspects, and it addresses youngsters with 6 different modules: (1) interactive comics/cartoons, telling stories of recovery; (2) quiz game; (3) roleplay game; (4) introduction of psychoactive drugs; (5) information on the somatic and psychological effects of psychoactive substances; (6) list of available treatment units, rehabs, and self-support groups in Hungary. Students of 2 vocational schools and 2 high schools filled out a questionnaire at a baseline (T0) and a 2-month follow-up (T1) data collection session. Students of 1 vocational school and 1 high school downloaded the Once Upon a High app (app group), whereas students from the other vocational school and high school did not (nonapp group). The time points of T0 and T1 questionnaires contained demographic variables, items with regard to substance use characteristics for both legal and illegal substances, including novel psychoactive substance, exercise habits, knowledge about psychoactive substances, attitudes toward substance users and validated instruments measuring the severity of tobacco (Fagerström Test for Nicotine Dependence), alcohol (Alcohol Use Disorder Identification Test), cannabis (Cannabis Abuse Screening Test), and synthetic cannabinoid consumption. Beliefs about substance use (Beliefs About Substance Abuse) and perceived self-efficacy (General Perceived Self-Efficacy) were also measured. At T1, members of the app group provided additional evaluation of the app.
There were 386 students who participated in the T0 session. After dropout, 246 students took part in T1 data collection procedure. Alcohol was the most frequently consumed psychoactive substance (334/364, 91.8% lifetime use), followed by tobacco (252/386, 65.3%, lifetime use) and cannabis (43/323, 13.3% lifetime use). Decreased self-efficacy (beta=-.29, P=.04) and increased daily physical exercise frequencies (beta=.04, P<.001) predicted higher frequencies of past month energy drink consumption, whereas elevated past month alcohol consumption was mainly predicted by a decrease in negative attitudes toward substance users (beta=-.13, P=.04) in the regression models. Once Upon a High was found to be effective only in reducing energy drink consumption (beta=-1.13, P=.04) after controlling for design effect, whereas perceived utility of the app showed correlation with a decreasing alcohol use (r
=.32, P=.03). The roleplay module of the app was found to be the most preferred aspect of the app by the respondents.
The Once Upon a High app can be a useful tool to assist preventive intervention programs by increasing knowledge and self-efficacy; however, its efficacy in reducing or preventing substance use needs to be improved and further studied. Additional potential impacts of the app need further testing.
The Cdc42p GTPase is involved in the signal transduction cascades controlling bud emergence and polarized cell growth in S. cerevisiae . Cells expressing the cdc42
V44A effector domain mutant allele ...displayed morphological defects of highly elongated and multielongated budded cells indicative
of a defect in the apical-isotropic switch in bud growth. In addition, these cells contained one, two, or multiple nuclei
indicative of a G 2 /M delay in nuclear division and also a defect in cytokinesis and/or cell separation. Actin and chitin were delocalized, and
septin ring structure was aberrant and partially delocalized to the tips of elongated cdc42
V44A cells; however, Cdc42 V44A p localization was normal. Two-hybrid protein analyses showed that the V44A mutation interfered with Cdc42pâs interactions
with Cla4p, a p21(Cdc42/Rac)-activated kinase (PAK)-like kinase, and the novel effectors Gic1p and Gic2p, but not with the
Ste20p or Skm1p PAK-like kinases, the Bni1p formin, or the Iqg1p IQGAP homolog. Furthermore, the cdc42
V44A morphological defects were suppressed by deletion of the Swe1p cyclin-dependent kinase inhibitory kinase and by overexpression
of Cla4p, Ste20p, the Cdc12 septin protein, or the guanine nucleotide exchange factor Cdc24p. In sum, these results suggest
that proper Cdc42p function is essential for timely progression through the apical-isotropic switch and G 2 /M transition and that Cdc42 V44A p differentially interacts with a number of effectors and regulators.
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