Immunological characterization of chromogranins A and B and secretogranin II in the bovine pancreatic islet

Antisera against chromogranin A and B and secretogranin II were used for analysing the bovine pancreas by immunoblotting and immunohistochemistry. All three antigens were found in extracts of fetal pancreas by one dimensional immunoblotting. A comparison with the soluble proteins of chromaffin granules revealed that in adrenal medulla and in pancreas antigens which migrated identically in electrophoresis were present. In immunohistochemistry, chromogranin A was found in all pancreatic endocrine cell types with the exception of most pancreatic polypeptide-(PP-) producing cells. For chromogranin B, only a faint immunostaining was obtained. For secretorgranin II, A-and B-cells were faintly positive, whereas the majority of PP-cells exhibited a strong immunostaining for this antigen. These results establish that chromogranins A and B and secretogranin II are present in the endocrine pancreas, but that they exhibit a distinct cellular localization

Renormalization of the Yang-Mills theory in the ambiguity-free gauge

The renormalization procedure for the Yang-Mills theory in the gauge free of the Gribov ambiguity is constructed. It is shown that all the ultraviolet infinities may be removed by renormalization of the parameters entering the classical Lagrangian and the local redefinition of the fields.Comment: 20 pages. Some explanations extended, one reference added. Final version published in the journa

Breaking out of biogeographical modules: range expansion and taxon cycles in the hyperdiverse ant genus Pheidole

published_or_final_versio

Patterns of primary care and mortality among patients with schizophrenia or diabetes: a cluster analysis approach to the retrospective study of healthcare utilization

Abstract Background Patients with schizophrenia have difficulty managing their medical healthcare needs, possibly resulting in delayed treatment and poor outcomes. We analyzed whether patients reduced primary care use over time, differentially by diagnosis with schizophrenia, diabetes, or both schizophrenia and diabetes. We also assessed whether such patterns of primary care use were a significant predictor of mortality over a 4-year period. Methods The Veterans Healthcare Administration (VA) is the largest integrated healthcare system in the United States. Administrative extracts of the VA's all-electronic medical records were studied. Patients over age 50 and diagnosed with schizophrenia in 2002 were age-matched 1:4 to diabetes patients. All patients were followed through 2005. Cluster analysis explored trajectories of primary care use. Proportional hazards regression modelled the impact of these primary care utilization trajectories on survival, controlling for demographic and clinical covariates. Results Patients comprised three diagnostic groups: diabetes only (n = 188,332), schizophrenia only (n = 40,109), and schizophrenia with diabetes (Scz-DM, n = 13,025). Cluster analysis revealed four distinct trajectories of primary care use: consistent over time, increasing over time, high and decreasing, low and decreasing. Patients with schizophrenia only were likely to have low-decreasing use (73% schizophrenia-only vs 54% Scz-DM vs 52% diabetes). Increasing use was least common among schizophrenia patients (4% vs 8% Scz-DM vs 7% diabetes) and was associated with improved survival. Low-decreasing primary care, compared to consistent use, was associated with shorter survival controlling for demographics and case-mix. The observational study was limited by reliance on administrative data. Conclusion Regular primary care and high levels of primary care were associated with better survival for patients with chronic illness, whether psychiatric or medical. For schizophrenia patients, with or without comorbid diabetes, primary care offers a survival benefit, suggesting that innovations in treatment retention targeting at-risk groups can offer significant promise of improving outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/78274/1/1472-6963-9-127.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78274/2/1472-6963-9-127.pdfPeer Reviewe

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

<div><p>Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in <i>Cftr^F508del</i> homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the <i>F508del-CFTR</i> mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from <i>F508del</i> homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both <i>in vivo</i>, in mice, and <i>in vitro</i>, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 <i>F508del-CFTR</i> homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells <i>in vivo</i>, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of <i>TNF/TNF-alpha (tumor necrosis factor)</i> and <i>CXCL8</i> (<i>chemokine [C-X-C motif] ligand 8</i>) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the <i>F508del-CFTR</i> mutation.</p></div

Can spacetime curvature induced corrections to Lamb shift be observable?

The Lamb shift results from the coupling of an atom to vacuum fluctuations of quantum fields, so corrections are expected to arise when the spacetime is curved since the vacuum fluctuations are modified by the presence of spacetime curvature. Here, we calculate the curvature-induced correction to the Lamb shift outside a spherically symmetric object and demonstrate that this correction can be remarkably significant outside a compact massive astrophysical body. For instance, for a neutron star or a stellar mass black hole, the correction is $\sim$ 25% at a radial distance of $4GM/c^2$, $\sim$ 16% at $10GM/c^2$ and as large as $\sim$ 1.6% even at $100GM/c^2$, where $M$ is the mass of the object, $G$ the Newtonian constant, and $c$ the speed of light. In principle, we can look at the spectra from a distant compact super-massive body to find such corrections. Therefore, our results suggest a possible way of detecting fundamental quantum effects in astronomical observations.Comment: 13 pages, 3 figures, slight title change, clarifications and more discussions added, version to be published in JHE

Mammalian Stem Cells Reprogramming in Response to Terahertz Radiation

We report that extended exposure to broad-spectrum terahertz radiation results in specific changes in cellular functions that are closely related to DNA-directed gene transcription. Our gene chip survey of gene expression shows that whereas 89% of the protein coding genes in mouse stem cells do not respond to the applied terahertz radiation, certain genes are activated, while other are repressed. RT-PCR experiments with selected gene probes corresponding to transcripts in the three groups of genes detail the gene specific effect. The response was not only gene specific but also irradiation conditions dependent. Our findings suggest that the applied terahertz irradiation accelerates cell differentiation toward adipose phenotype by activating the transcription factor peroxisome proliferator-activated receptor gamma (PPARG). Finally, our molecular dynamics computer simulations indicate that the local breathing dynamics of the PPARG promoter DNA coincides with the gene specific response to the THz radiation. We propose that THz radiation is a potential tool for cellular reprogramming

Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer

BACKGROUND: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. METHODS: Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. RESULTS: ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. CONCLUSIONS: Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression.British Journal of Cancer advance online publication, 22 December 2016; doi:10.1038/bjc.2016.402 www.bjcancer.com

Transmission Characteristics of Primate Vocalizations: Implications for Acoustic Analyses

Acoustic analyses have become a staple method in field studies of animal vocal communication, with nearly all investigations using computer-based approaches to extract specific features from sounds. Various algorithms can be used to extract acoustic variables that may then be related to variables such as individual identity, context or reproductive state. Habitat structure and recording conditions, however, have strong effects on the acoustic structure of sound signals. The purpose of this study was to identify which acoustic parameters reliably describe features of propagated sounds. We conducted broadcast experiments and examined the influence of habitat type, transmission height, and re-recording distance on the validity (deviation from the original sound) and reliability (variation within identical recording conditions) of acoustic features of different primate call types. Validity and reliability varied independently of each other in relation to habitat, transmission height, and re-recording distance, and depended strongly on the call type. The smallest deviations from the original sounds were obtained by a visually-controlled calculation of the fundamental frequency. Start- and end parameters of a sound were most susceptible to degradation in the environment. Because the recording conditions can have appreciable effects on acoustic parameters, it is advisable to validate the extraction method of acoustic variables from recordings over longer distances before using them in acoustic analyses

A hippocampal Cdk5 pathway regulates extinction of contextual fear

Treatment of emotional disorders involves the promotion of extinction processes, which are defined as the learned reduction of fear. The molecular mechanisms underlying extinction have only begun to be elucidated. By employing genetic and pharmacological approaches in mice, we show here that extinction requires downregulation of Rac-1 and cyclin-dependent kinase 5 (Cdk5), and upregulation of p21 activated kinase-1 (PAK-1) activity. This is physiologically achieved by a Rac-1–dependent relocation of the Cdk5 activator p35 from the membrane to the cytosol and dissociation of p35 from PAK-1. Moreover, our data suggest that Cdk5/p35 activity prevents extinction in part by inhibition of PAK-1 activity in a Rac-1–dependent manner. We propose that extinction of contextual fear is regulated by counteracting components of a molecular pathway involving Rac-1, Cdk5 and PAK-1. Our data suggest that this pathway could provide a suitable target for therapeutic treatment of emotional disorders.National Institutes of Health (U.S.) (Grant NS051874)Alexander von Humboldt-Stiftung (German Research Foundation Fellowship)European Neuroscience Institute Goettinge