Linking specification to differentiation:From proneural genes to the regulation of ciliogenesis

Much of developmental biology is concerned with the processes by which cells become committed to particular fates in a regulated fashion, whereas cell biology addresses, among other things, the variety of differentiated forms and functions that cells can acquire. One open question is how the regulators of the former process lead to attainment of the latter. “High-level” regulators of cell fate specification include the proneural factors, which drive cells to commit as precursors in the sensory nervous system. Recent research has concentrated on the gene expression events downstream of proneural factor function. Here we summarize this research and describe our own research that has provided clear links between a proneural factor, atonal and the cell biological program of ciliogenesis, which is a central aspect of sensory neuron differentiation

The function and regulation of the bHLH gene, cato, in Drosophila neurogenesis

Abstract Background bHLH transcription factors play many roles in neural development. cousin of atonal (cato) encodes one such factor that is expressed widely in the developing sensory nervous system of Drosophila. However, nothing definitive was known of its function owing to the lack of specific mutations. Results We characterised the expression pattern of cato in detail using newly raised antibodies and GFP reporter gene constructs. Expression is predominantly in sensory lineages that depend on the atonal and amos proneural genes. In lineages that depend on the scute proneural gene, cato is expressed later and seems to be particularly associated with the type II neurons. Consistent with this, we find evidence that cato is a direct target gene of Atonal and Amos, but not of Scute. We generated two specific mutations of cato. Mutant embryos show several defects in chordotonal sensory lineages, most notably the duplication of the sensory neuron, which appears to be caused by an extra cell division. In addition, we show that cato is required to form the single chordotonal organ that persists in atonal mutant embryos. Conclusions We conclude that although widely expressed in the developing PNS, cato is expressed and regulated very differently in different sensory lineages. Mutant phenotypes correlate with cato's major expression in the chordotonal sensory lineage. In these cells, we propose that it plays roles in sense organ precursor maintenance and/or identity, and in controlling the number of cell divisions in the neuronal branch of the lineage arising from these precursors.</p

Relaxing credit constraints in emerging economies: the impact of public loans on the performance of Brazilian manufacturers

Especially in developing countries credit constraints are often perceived as one of the most important market frictions constraining firm innovation and growth. Huge amounts of public money are being devoted to the removal of such constraints but their effectiveness is still subject to an intense policy debate. This paper contributes to this debate by analysing the effects of the Brazilian Development Bank (BNDES) loans. It finds that, before receiving BNDES support, granted firms are indeed more credit constrained than comparable non-granted firms. It also finds that BNDES support allows granted firms to achieve the same level of performance as similar non-granted firms that are not credit constrained. However, it does not allow granted firms to outperform similar non-granted ones

Multiple enhancers contribute to spatial but not temporal complexity in the expression of the proneural gene, amos

BACKGROUND: The regulation of proneural gene expression is an important aspect of neurogenesis. In the study of the Drosophila proneural genes, scute and atonal, several themes have emerged that contribute to our understanding of the mechanism of neurogenesis. First, spatial complexity in proneural expression results from regulation by arrays of enhancer elements. Secondly, regulation of proneural gene expression occurs in distinct temporal phases, which tend to be under the control of separate enhancers. Thirdly, the later phase of proneural expression often relies on positive autoregulation. The control of these phases and the transition between them appear to be central to the mechanism of neurogenesis. We present the first investigation of the regulation of the proneural gene, amos. RESULTS: Amos protein expression has a complex pattern and shows temporally distinct phases, in common with previously characterised proneural genes. GFP reporter gene constructs were used to demonstrate that amos has an array of enhancer elements up- and downstream of the gene, which are required for different locations of amos expression. However, unlike other proneural genes, there is no evidence for separable enhancers for the different temporal phases of amos expression. Using mutant analysis and site-directed mutagenesis of potential Amos binding sites, we find no evidence for positive autoregulation as an important part of amos control during neurogenesis. CONCLUSION: For amos, as for other proneural genes, a complex expression pattern results from the sum of a number of simpler sub-patterns driven by specific enhancers. There is, however, no apparent separation of enhancers for distinct temporal phases of expression, and this correlates with a lack of positive autoregulation. For scute and atonal, both these features are thought to be important in the mechanism of neurogenesis. Despite similarities in function and expression between the Drosophila proneural genes, amos is regulated in a fundamentally different way from scute and atonal

Disfagia e Disartria. Forma Invulgar de Apresentação da Miastenia Gravis

Myasthenia Gravis is an autoimmune disorder that generally presents with ocular symptoms, specially diplopia and ptosis. Dysphagia may be a manifestation of the generalised type of the disease, but rarely is its presenting feature. The authors describe a case of Myasthenia Gravis in an old patient complaining of dysphagia and dysarthria. Because Myasthenia Gravis is a potentially serious but treatable disease, we emphasize the need to consider it in the differential diagnosis of dysphagia, namely in the elderly. In fact, the disorder is probably underdiagnosed in this population group, because clinicians tend to accept other more frequent diagnosis to explain these symptoms

Solvable Kinetic Gaussian Model in External Field

In this paper, the single-spin transition dynamics is used to investigate the kinetic Gaussian model in a periodic external field. We first derive the fundamental dynamic equations, and then treat an isotropic d-dimensional hypercubic lattice Gaussian spin system with Fourier's transformation method. We obtain exactly the local magnetization and the equal-time pair correlation function. The critical characteristics of the dynamical, the complex susceptibility, and the dynamical response are discussed. The results show that the time evolution of the dynamical quantities and the dynamical responses of the system strongly depend on the frequency and the wave vector of the external field.Comment: 11 page

Brain Natriuretic Peptide Levels Predict Morbidity and Mortality in Haemodialysis Patients

Background: Brain natriuretic peptide is a predictor of mortality in multiple cardiovascular diseases but its value in patients with chronic kidney disease is still a matter of debate. Patients and methods: We studied 48 haemodialysis patients with mean age 70.0±13.9 years,62.5% female, 43.8% diabetics, with a mean haemodialysis time of 38.1±29.3 months. To evaluate the role of brain natriuretic peptide as a prognostic factor in this population we performed a two-session evaluation of pre- and postmid-week haemodialysis plasma brain natriuretic peptide concentrations and correlated them with hospitalisation and overall and cardiovascular mortality over a two-year period. Results: There were no significant variations in pre– and post-haemodialysis plasma brain natriuretic peptide concentrations. Pre- and post-haemodialysis brain natriuretic peptide concentrations were significantly greater in patients who died from all causes(p=0.034 and p=0.001, respectively) and from cardiovascular causes (p=0.043 and p=0.001, respectively). Patients who were hospitalised in the two-year study period also presented greater pre- and posthaemodialysis brain natriuretic peptide concentrations(p=0.03 and p=0.036, respectively). Patients with mean brain natriuretic peptide concentrations ≥ 390 pg/mL showed a significantly lower survival at the end of the two-year study period. Conclusion: Brain natriuretic peptide was a good predictor of morbidity and mortality (overall and cardiovascular) in our population

Forkhead Transcription Factor Fd3F Cooperates with Rfx to Regulate a Gene Expression Program for Mechanosensory Cilia Specialization

Cilia have evolved hugely diverse structures and functions to participate in a wide variety of developmental and physiological processes. Ciliary specialization requires differences in gene expression, but few transcription factors are known to regulate this, and their molecular function is unclear. Here, we show that the Drosophila Forkhead box (Fox) gene, fd3F, is required for specialization of the mechanosensory cilium of chordotonal (Ch) neurons. fd3F regulates genes for Ch-specific axonemal dyneins and TRPV ion channels, which are required for sensory transduction, and retrograde transport genes, which are required to differentiate their distinct motile and sensory ciliary zones. fd3F is reminiscent of vertebrate Foxj1, a motile cilia regulator, but fd3F regulates motility genes as part of a broader sensory regulation program. Fd3F cooperates with the pan-ciliary transcription factor, Rfx, to regulate its targets directly. This illuminates pathways involved in ciliary specialization and the molecular mechanism of transcription factors that regulate them

AAV-mediated Sirt1 overexpression in skeletal muscle activates oxidative capacity but does not prevent insulin resistance

Type 2 diabetes is characterized by triglyceride accumulation and reduced lipid oxidation capacity in skeletal muscle. SIRT1 is a key protein in the regulation of lipid oxidation and its expression is reduced in the skeletal muscle of insulin resistant mice. In this tissue, Sirt1 up-regulates the expression of genes involved in oxidative metabolism and improves mitochondrial function mainly through PPARGC1 deacetylation. Here we examined whether Sirt1 overexpression mediated by adeno-associated viral vectors of serotype 1 (AAV1) specifically in skeletal muscle can counteract the development of insulin resistance induced by a high fat diet in mice. AAV1- Sirt1 -treated mice showed up-regulated expression of key genes related to β-oxidation together with increased levels of phosphorylated AMP protein kinase. Moreover, SIRT1 overexpression in skeletal muscle also increased basal phosphorylated levels of AKT. However, AAV1- Sirt1 treatment was not enough to prevent high fat diet-induced obesity and insulin resistance. Although Sirt1 gene transfer to skeletal muscle induced changes at the muscular level related with lipid and glucose homeostasis, our data indicate that overexpression of SIRT1 in skeletal muscle is not enough to improve whole-body insulin resistance and that suggests that SIRT1 has to be increased in other metabolic tissues to prevent insulin resistance