Study of the role of Pax6b and CREB signaling on pancreas differentiation in zebrafish (Danio rerio)

The vertebrate endocrine pancreas has the crucial function of maintaining blood sugar homeostasis. This role is dependent upon the development and maintenance of pancreatic islets comprising appropriate ratios of hormone-producing cells. Pax6 is a well-conserved transcription factor that contains two DNA-binding domains, and plays a key role in the development of eye, brain and pancreas in vertebrates. Within the endocrine progenitor pool, a variety of transcription factors influence cell fate decisions. Here we show that in zebrafish, in absence of pax6b, there is a loss of insulin-producing cells, a decrease of somatostatin-expressing cells, a decrease of glucagon-expressing cells and a strong increase of ghrelin-expressing cells. We propose a model where, in absence of pax6b, cells that should become insulin-positive become ghrelin-expressing cells. \ud In the second part of the work we describe the generation and characterization of zebrafish transgenic lines responsive to CREB signaling. These lines could represent useful tools for studying specific human pathologie

Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis, pancreas morphology, vascularization and regeneration

Type 2 diabetes (T2D) is a disease characterized by impaired insulin secretion. The Wnt signaling transcription factor Tcf7l2 is to date the T2D-associated gene with the largest effect on disease susceptibility. However, the mechanisms by which TCF7L2 variants affect insulin release from \u3b2-cells are not yet fully understood. By taking advantage of a tcf7l2 zebrafish mutant line, we first show that these animals are characterized by hyperglycemia and impaired islet development. Moreover, we demonstrate that the zebrafish tcf7l2 gene is highly expressed in the exocrine pancreas, suggesting potential bystander effects on \u3b2-cell growth, differentiation and regeneration. Finally, we describe a peculiar vascular phenotype in tcf7l2 mutant larvae, characterized by significant reduction in the average number and diameter of pancreatic islet capillaries. Overall, the zebrafish Tcf7l2 mutant, characterized by hyperglycemia, pancreatic and vascular defects, and reduced regeneration proves to be a suitable model to study the mechanism of action and the pleiotropic effects of Tcf7l2, the most relevant T2D GWAS hit in human populations

In-depth characterisation of metal-support compounds in spent Co/SiO2 Fischer-Tropsch model catalysts

Only little is known about the formation and morphology of metal-support compounds (MSCs) in heterogeneous catalysis. This fact can be mostly ascribed to the challenges in directly identifying these phases. In the present study, a series of Co/SiO2 model catalysts with different crystallite sizes was thoroughly characterised with focus on the identification of cobalt silicate, which is the expected metal-support compound for this particular catalyst system. The catalysts were exposed to simulated high conversion Fischer-Tropsch environment, i.e. water-rich conditions in the presence of hydrogen. The transformation of significant amounts of metallic cobalt to a hard-to-reduce phase has been observed. This particular MSC, Co2SiO4, was herein identified as needle- or platelet-type cobalt silicate structures by means of X-ray spectroscopy (XAS) and high-resolution scanning transmission electron microscopy (HRSTEM) in combination with elemental mapping. The metal-support compounds formed on top of fully SiO2-encapsulated nanoparticles, which are hypothesised to represent a prerequisite for the formation of cobalt silicate needles. Both, the encapsulation of cobalt nanoparticles by SiO2 via creeping, as well as the formation of these structures, were seemingly induced by high concentrations of water

SAFIR2022 Program, KYT2022 Program and SAFER2028 Draft Framework External Evaluation Report

At the request of the Ministry of Economic Affairs and Employment of Finland, an international evaluation team conducted an external review of the SAFIR2022 and KYT2022 research programs. Furthermore, feedback on the proposed framework plan of SAFER2028, a new research program that combines the previous SAFIR and KYT programs, was requested. The team found that, in general, the research programs produce a remarkable level of scientific output for a modest stream of funding. The primary, perceived value added by the research programs is that they provide a pipeline of new talent and expertise necessary for the successful regulation of nuclear power and waste management activities in Finland. The research products had, generally, a high technical quality. In some instances, however, the research aimed towards well-established, or mature fields of study where the value added in terms of increased knowledge or improved safety might be considered marginal or incremental. However, the benefit of these activities vis-à-vis the educational benefit in training new experts in relevant fields could be seen. There are opportunities for key improvements in some of the novel elements of the SAFER2028 framework plan, in particular the doctoral education network

A Novel Tropically Stable Oral Amphotericin B Formulation (iCo-010) Exhibits Efficacy against Visceral Leishmaniasis in a Murine Model

Visceral leishmaniasis (VL) is a systemic form of a vector-borne parasitic disease caused by obligate intra-macrophage protozoa of the genus Leishmania. VL is always fatal in humans if left untreated and treatment options are limited. Amphotericin B (AmB), a polyene antibiotic, is the most active antileishmanial agent that currently exists. Liposomal AmB (AmBisome) is used as first-line treatment in developed countries [1], [7], [8], [9], [10]; however, the requisite parenteral administration and the high cost of the liposomal formulation prevents this treatment from reaching the majority of patients in developing nations [3]. A stable, efficacious oral treatment for VL that is able to withstand the rigors of tropical climates would overcome many of the current barriers to treatment that exist in countries with large VL-infected patient populations. In this study we have developed an oral formulation of AmB that is stable in tropical conditions and exhibits significant antileshimanial activity in mice

Developmental and Tumor Angiogenesis Requires the Mitochondria-Shaping Protein Opa1

While endothelial cell (EC) function is influenced by mitochondrial metabolism, the role of mitochondrial dynamics in angiogenesis, the formation of new blood vessels from existing vasculature, is unknown. Here we show that the inner mitochondrial membrane mitochondrial fusion protein optic atrophy 1 (OPA1) is required for angiogenesis. In response to angiogenic stimuli, OPA1 levels rapidly increase to limit nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) signaling, ultimately allowing angiogenic genes expression and angiogenesis. Endothelial Opa1 is indeed required in an NFκB-dependent pathway essential for developmental and tumor angiogenesis, impacting tumor growth and metastatization. A first-in-class small molecule-specific OPA1 inhibitor confirms that EC Opa1 can be pharmacologically targeted to curtail tumor growth. Our data identify Opa1 as a crucial component of physiological and tumor angiogenesis

Relation of mitral valve morphology and motion to mitral regurgitation severity in patients with mitral valve prolapse

<p>Abstract</p> <p>Background</p> <p>Mitral valve thickness is used as a criterion to distinguish the classical from the non-classical form of mitral valve prolapse (MVP). Classical form of MVP has been associated with higher risk of mitral regurgitation (MR) and concomitant complications. We sought to determine the relation of mitral valve morphology and motion to mitral regurgitation severity in patients with MVP.</p> <p>Methods</p> <p>We prospectively analyzed transthoracic echocardiograms of 38 consecutive patients with MVP and various degrees of MR. In the parasternal long-axis view, leaflets length, diastolic leaflet thickness, prolapsing depth, billowing area and non-coaptation distance between both leaflets were measured.</p> <p>Results</p> <p>Twenty patients (53%) and 18 patients (47%) were identified as having moderate to severe and mild MR respectively (ERO = 45 ± 27 mm²vs. 5 ± 7 mm², p < 0.001). Diastolic leaflet thickness was similar in both groups (5.5 ± 0.9 mm vs. 5.3 ± 1 mm, p = 0.57). On multivariate analysis, the non-coaptation distance (OR 7.9 per 1 mm increase; 95% CI 1.72-37.2) was associated with significant MR. Thick mitral valve leaflet as traditionally reported (≥ 5 mm) was not associated with significant MR (OR 0.9; 95% CI 0.2-3.4).</p> <p>Conclusions</p> <p>In patients with MVP, thick mitral leaflet is not associated with significant MR. Leaflet thickness is probably not as important in risk stratification as previously reported in patients with MVP. Other anatomical and geometrical features of the mitral valve apparatus area appear to be much more closely related to MR severity.</p

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

The importance of crop growth modeling to interpret the Δ14CO2 signature of annual plants

[1] The 14C/C abundance in CO2(¿14CO2) promises to provide useful constraints on regional fossil fuel emissions and atmospheric transport through the large gradients introduced by anthropogenic activity. The currently sparse atmospheric ¿14CO2 monitoring network can potentially be augmented by using plant biomass as an integrated sample of the atmospheric ¿14CO2. But the interpretation of such an integrated sample requires knowledge about the day¿to¿day CO2 uptake of the sampled plants. We investigate here the required detail in daily plant growth variations needed to accurately interpret regional fossil fuel emissions from annual plant samples. We use a crop growth model driven by daily meteorology to reproduce daily fixation of ¿14CO2 in maize and wheat plants in the Netherlands in 2008. When comparing the integrated ¿14CO2 simulated with this detailed model to the values obtained when using simpler proxies for daily plant growth (such as radiation and temperature), we find differences that can exceed the reported measurement precision of ¿14CO2(~2‰). Furthermore, we show that even in the absence of any spatial differences in fossil fuel emissions, differences in regional weather can induce plant growth variations that result in spatial gradients of up to 3.5‰ in plant samples. These gradients are even larger when interpreting separate plant organs (leaves, stems, roots, or fruits), as they each develop during different time periods. Not accounting for these growth¿induced differences in ¿14CO2 in plant samples would introduce a substantial bias (1.5–2¿ppm) when estimating the fraction of atmospheric CO2 variations resulting from nearby fossil fuel emission

Assessment of Future Remnant Liver Function Using Hepatobiliary Scintigraphy in Patients Undergoing Major Liver Resection

Tc-99m-mebrofenin hepatobiliary scintigraphy (HBS) was used as a quantitative method to evaluate liver function. The aim of this study was to compare future remnant liver function assessed by Tc-99m-mebrofenin hepatobiliary scintigraphy with future remnant liver volume in the prediction of liver failure after major liver resection. Computed tomography (CT) volumetry and Tc-99m-mebrofenin hepatobiliary scintigraphy were performed prior to major resection in 55 high-risk patients, including 30 patients with parenchymal liver disease. Liver volume was expressed as percentage of total liver volume or as standardized future remnant liver volume. Receiver operating characteristic (ROC) curve analysis was performed to identify a cutoff value for future remnant liver function in predicting postoperative liver failure. Postoperative liver failure occurred in nine patients. A liver function cutoff value of 2.69%/min/m(2) was calculated by ROC curve analysis. Tc-99m-mebrofenin hepatobiliary scintigraphy demonstrated better sensitivity, specificity, and positive and negative predictive value compared to future remnant liver volume. Using Tc-99m-mebrofenin hepatobiliary scintigraphy, one cutoff value suffices in both compromised and noncompromised patients. Preoperative Tc-99m-mebrofenin hepatobiliary scintigraphy is a valuable technique to estimate the risk of postoperative liver failure. Especially in patients with uncertain quality of the liver parenchyma, Tc-99m-mebrofenin HBS proved of more value than CT volumetr