The Casein Kinase I Family in Wnt Signaling

AbstractThe canonical Wnt-signaling pathway is critical for many aspects of development, and mutations in components of the Wnt pathway are carcinogenic. Recently, sufficiency tests identified casein kinase Iϵ (CKIϵ) as a positive component of the canonical Wnt/β-catenin pathway, and necessity tests showed that CKIϵ is required in vertebrates to transduce Wnt signals. In addition to CKIϵ, the CKI family includes several other isoforms (α, β, γ, and δ) and their role in Wnt sufficiency tests had not yet been clarified. However, in Caenorhabditis elegans studies, loss-of-function of a CKI isoform most similar to α produced the mom phenotype, indicative of loss-of-Wnt signaling. In this report, we examine the ability of the various CKI isoforms to activate Wnt signaling and find that all the wild-type CKI isoforms do so. Dishevelled (Dsh), another positive component of the Wnt pathway, becomes phosphorylated in response to Wnt signals. All the CKI isoforms, with the exception of γ, increase the phosphorylation of Dsh in vivo. In addition, CKI directly phosphorylates Dsh in vitro. Finally, we find that CKI is required in vivo for the Wnt-dependent phosphorylation of Dsh. These studies advance our understanding of the mechanism of Wnt action and suggest that more than one CKI isoform is capable of transducing Wnt signals in vivo

The Casein Kinase I Family: Roles in Morphogenesis

AbstractWnt signals play important roles in development and oncogenesis and are transduced through at least two pathways: a canonical β-catenin-dependent and a β-catenin-independent cascade. Casein kinase I (CKI) is required in both invertebrates and vertebrates to transduce canonical Wnt signals. However, its role in the β-catenin-independent pathway was unknown. During vertebrate embryogenesis, the β-catenin-independent cascade is thought to control cell movements and has been postulated to be analogous to the Drosophila planar cell polarity pathway, which signals through the JNK cascade. Here, we report that blocking CKI function inhibits embryonic morphogenesis and activates JNK in cell lines. These studies suggest that CKI might also act in the β-catenin-independent pathway and indicate a role for CKI during convergence extension in early vertebrate development

Thiazolidinediones Regulate Adipose Lineage Dynamics

SummaryWhite adipose tissue regulates metabolism; the importance of this control is highlighted by the ongoing pandemic of obesity and associated complications such as diabetes, atherosclerosis, and cancer. White adipose tissue maintenance is a dynamic process, yet very little is known about how pharmacologic stimuli affect such plasticity. Combining in vivo lineage marking and BrdU labeling strategies, we found that rosiglitazone, a member of the thiazolidinedione class of glucose-lowering medicines, markedly increases the evolution of adipose progenitors into adipocytes. Notably, chronic rosiglitazone administration disrupts the adipogenic and self-renewal capacities of the stem cell compartment and alters its molecular characteristics. These data unravel unknown aspects of adipose dynamics and provide a basis to manipulate the adipose lineage for therapeutic ends

Brain MR Spectroscopy Changes Precede Frontotemporal Lobar Degeneration Phenoconversion in Mapt Mutation Carriers.

Background and purposeThe objective of this study was to longitudinally investigate the trajectory of change in 1 H MRS measurements in asymptomatic MAPT mutation carriers who became symptomatic during follow-up, and to determine the time at which the neurochemical alterations accelerated during disease progression.MethodsWe identified eight MAPT mutations carriers who transitioned from asymptomatic to symptomatic disease during follow-up. All participants were longitudinally followed with an average of 7.75 years (range 4-11 years) and underwent two or more single voxel 1 H MRS examinations from the posterior cingulate voxel, with a total of 60 examinations. The rate of longitudinal change for each metabolite was estimated using linear mixed models. A flex point model was used to estimate the flex time point of the change in slope.ResultsThe decrease in the NAA/mI ratio accelerated 2.09 years prior to symptom onset, and continued to decline. A similar trajectory was observed in the presumed glial marker mI/Cr ratio accelerating 1.86 years prior to symptom onset.ConclusionsOur findings support the potential use of longitudinal 1 H MRS for monitoring the neurodegenerative progression in MAPT mutation carriers starting from the asymptomatic stage

Rates of lobar atrophy in asymptomatic MAPT mutation carriers.

IntroductionThe aim of this study was to investigate the rates of lobar atrophy in the asymptomatic microtubule-associated protein tau (MAPT) mutation carriers.MethodsMAPT mutation carriers (n = 14; 10 asymptomatic, 4 converters from asymptomatic to symptomatic) and noncarriers (n = 13) underwent structural magnetic resonance imaging and were followed annually with a median of 9.2 years. Longitudinal changes in lobar atrophy were analyzed using the tensor-based morphometry with symmetric normalization algorithm.ResultsThe rate of temporal lobe atrophy in asymptomatic MAPT mutation carriers was faster than that in noncarriers. Although the greatest rate of atrophy was observed in the temporal lobe in converters, they also had increased atrophy rates in the frontal and parietal lobes compared to noncarriers.DiscussionAccelerated decline in temporal lobe volume occurs in asymptomatic MAPT mutation carriers followed by the frontal and parietal lobe in those who have become symptomatic. The findings have implications for monitoring the progression of neurodegeneration during clinical trials in asymptomatic MAPT mutation carriers

White Fat Progenitor Cells Reside in the Adipose Vasculature

White adipose (fat) tissues regulate metabolism, reproduction, and life span. Adipocytes form throughout life, with the most marked expansion of the lineage occurring during the postnatal period. Adipocytes develop in coordination with the vasculature, but the identity and location of white adipocyte progenitor cells in vivo are unknown. We used genetically marked mice to isolate proliferating and renewing adipogenic progenitors. We found that most adipocytes descend from a pool of these proliferating progenitors that are already committed, either prenatally or early in postnatal life. These progenitors reside in the mural cell compartment of the adipose vasculature, but not in the vasculature of other tissues. Thus, the adipose vasculature appears to function as a progenitor niche and may provide signals for adipocyte development

COMPARATIVO DE CUSTOS DA ALTERAÇÃO DE UM SISTEMA FOTOVOLTAICO ISOLADO PARA FOTOVOLTAICO INTERLIGADO À REDE DA CONCESSIONÁRIA – ESTUDO DE CASO

A energia elétrica pode ser gerada da conversão direta da radiação solar através de placas produzidas com materiais fotossensíveis, que possuem a característica de conversão de energia solar em energia elétrica através do efeito fotovoltaico. Parte da iluminação externa do Setor Palotina, da Universidade Federal do Paraná, é fornecida por sistemas fotovoltaicos isolados (SFI’s). Os atuais sistemas apresentam funcionamento insatisfatório e altos custos de manutenção, por esses motivos foi elaborado este estudo de caso, para analisar a viabilidade econômica e técnica de se alterar os atuais SFI’s em um sistema fotovoltaico conectado à rede (SFCR). Foram levantados os custos para a alteração dos SFI’s em SFCR, assim como a manutenção dos dois sistemas. Com os resultados obtidos, foi possível fazer uma análise dos custos unitários da energia elétrica gerada pelos dois sistemas de energia fotovoltaica e compará-los com as tarifas da energia da concessionária. Como resultado, verificou-se que a substituição dos atuais SFI’s em SFCR é tecnicamente possível e as estimativas apontam retorno de investimento em 9 anos. Caso a instituição não invista na transformação acima apontada, desconectar as luminárias dos atuais SFI’s e conectá-las na rede elétrica da concessionária, também se apresentou como uma alternativa mais econômica aos cofres públicos

Classifying LISA gravitational wave burst signals using Bayesian evidence

We consider the problem of characterisation of burst sources detected with the Laser Interferometer Space Antenna (LISA) using the multi-modal nested sampling algorithm, MultiNest. We use MultiNest as a tool to search for modelled bursts from cosmic string cusps, and compute the Bayesian evidence associated with the cosmic string model. As an alternative burst model, we consider sine-Gaussian burst signals, and show how the evidence ratio can be used to choose between these two alternatives. We present results from an application of MultiNest to the last round of the Mock LISA Data Challenge, in which we were able to successfully detect and characterise all three of the cosmic string burst sources present in the release data set. We also present results of independent trials and show that MultiNest can detect cosmic string signals with signal-to-noise ratio (SNR) as low as ~7 and sine-Gaussian signals with SNR as low as ~8. In both cases, we show that the threshold at which the sources become detectable coincides with the SNR at which the evidence ratio begins to favour the correct model over the alternative.Comment: 21 pages, 11 figures, accepted by CQG; v2 has minor changes for consistency with accepted versio

Frequency and topography of cerebral microbleeds in dementia with Lewy bodies compared to Alzheimer's disease

AbstractAimTo determine the frequency and topographic distribution of cerebral microbleeds (CMBs) in dementia with Lewy bodies (DLB) in comparison to CMBs in Alzheimer disease dementia (AD).MethodsConsecutive probable DLB (n = 23) patients who underwent 3-T T2* weighted gradient-recalled-echo MRI, and age and gender matched probable Alzheimer's disease patients (n = 46) were compared for the frequency and location of CMBs.ResultsThe frequency of one or more CMBs was similar among patients with DLB (30%) and AD (24%). Highest densities of CMBs were found in the occipital lobes of patients with both DLB and AD. Patients with AD had greater densities of CMBs in the parietal, temporal lobes and infratentorial regions compared to DLB (p < 0.05).ConclusionCMBs are as common in patients with DLB as in patients with AD, with highest densities observed in the occipital lobes, suggesting common pathophysiologic mechanisms underlying CMBs in both diseases