Is Bursting More Effective than Spiking in Evoking Pituitary Hormone Secretion? A Spatiotemporal Simulation Study of Calcium and Granule Dynamics

This is the author accepted manuscript. The final version is available from the American Physiological Society via the DOI in this record.Endocrine cells of the pituitary gland secrete a number of hormones, and the amount of hormone released by a cell is controlled in large part by the cell's electrical activity and subsequent Ca2+ influx. Typical electrical behaviors of pituitary cells include continuous spiking and so-called pseudo-plateau bursting. It has been shown that the amplitude of Ca2+ fluctuations is greater in bursting cells, leading to the hypothesis that bursting cells release more hormone than spiking cells. In this work, we apply computer simulations to test this hypothesis. We use experimental recordings of electrical activity as input to mathematical models of Ca2+ channel activity, buffered Ca2+ diffusion, and Ca2+-driven exocytosis. To compare the efficacy of spiking and bursting on the same cell, we pharmacologically block the large conductance potassium (BK) current from a bursting cell, or add a BK current to a spiking cell via dynamic clamp. We find that bursting is generally at least as effective as spiking at evoking hormone release, and is often considerably more effective, even when normalizing to Ca2+ influx. Our hybrid experimental/modeling approach confirms that adding a BK-type K+ current, which is typically associated with decreased cell activity and reduced secretion, can actually produce an increase in hormone secretion, as suggested earlier.JT and RB were partially supported by grant DMS1220063 from the National Science Foundation

Isochrone-cloud fitting of the extended main-sequence turn-off of young clusters

Context. Extended main-sequence turn-offs (eMSTOs) are a commonly observed property of young clusters. A global theoretical interpretation for eMSTOs is still lacking, but stellar rotation is considered a necessary ingredient to explain eMSTOs. Aims. We aim to assess the importance of core-boundary and envelope mixing in stellar interiors for the interpretation of eMSTOs in terms of one coeval population. Methods. We constructed isochrone-clouds based on interior mixing profiles of stars with a convective core calibrated from asteroseismology of isolated galactic field stars. We fitted these isochrone-clouds to the measured eMSTO to estimate the age and core mass of the stars in the two young clusters NGC 1850 and NGC 884, assuming one coeval population and by fixing the metallicity to the one measured from spectroscopy. We assessed the correlations between the interior mixing properties of the cluster members and their rotational and pulsational properties. Results. We find that stellar models based on asteroseismically-calibrated interior mixing profiles lead to enhanced core masses of eMSTO stars. Additionally, these models can explain a significant fraction of the observed eMSTOs of the two considered clusters in terms of one coeval population of stars, which have similar ages to those in the literature, given the large uncertainties. The rotational and pulsational properties of the stars in NGC 884 are not sufficiently well known to perform asteroseismic modelling as it is achieved for field stars from space photometry. The stars in NGC 884 for which we have v sin i and a few pulsation frequencies show no correlation between these properties and the core masses of the stars that set the cluster age. Conclusions. Future cluster space asteroseismology may allow for the interpretation of the core masses in terms of the physical processes that cause them, based on the modelling of the interior mixing profiles for the individual member stars with suitable identified modes

The mass discrepancy in intermediate- and high-mass eclipsing binaries: The need for higher convective core masses

Context. Eclipsing, spectroscopic double-lined binary star systems are excellent laboratories for calibrating theories of stellar interior structure and evolution. Their precise and accurate masses and radii measured from binary dynamics offer model-independent constraints and challenge current theories of stellar evolution. Aims. We aim to investigate the mass discrepancy in binary stars. This is the significant difference between stellar components’ masses measured from binary dynamics and those inferred from models of stellar evolution via positions of the components in the Teff − log g Kiel diagram. We study the effect of near-core mixing on the mass of the convective core of the stars and interpret the results in the context of the mass discrepancy. Methods. We fitted stellar isochrones computed from a grid of MESA stellar evolution models to a homogeneous sample of eleven high-mass binary systems. Two scenarios are considered where individual stellar components of a binary system are treated independent of each other and where they are forced to have the same age and initial chemical composition. We also study the effect of the microturbulent velocity and turbulent pressure on the atmosphere model structure and stellar spectral lines, and its link with the mass discrepancy. Results. We find that the mass discrepancy is present in our sample and that it is anti-correlated with the surface gravity of the star. No correlations are found with other fundamental and atmospheric parameters, including the stellar mass. The mass discrepancy can be partially accounted for by increasing the amount of near-core mixing in stellar evolution models. We also find that ignoring the microturbulent velocity and turbulent pressure in stellar atmosphere models of hot evolved stars results in the overestimation of their effective temperature by up to 8%. Together with enhanced near-core mixing, this can almost entirely account for the ∼30% mass discrepancy found for the evolved primary component of V380 Cyg. Conclusions. We find a strong link between the mass discrepancy and the convective core mass. The mass discrepancy can be solved by considering the combined effect of extra near-core boundary mixing and the consistent treatment in the spectrum analysis of hot evolved stars. Our binary modelling results in convective core masses between 17 and 35% of the stellar mass, which is in excellent agreement with the results from gravity-mode asteroseismology of single stars. This implies larger helium core masses near the end of the main sequence than have been anticipated so far

Urbanization and traffic related exposures as risk factors for Schizophrenia

BACKGROUND: Urban birth or upbringing increase schizophrenia risk. Though unknown, the causes of these urban-rural differences have been hypothesized to include, e.g., infections, diet, toxic exposures, social class, or an artefact due to selective migration. METHODS: We investigated the hypothesis that traffic related exposures affect schizophrenia risk and that this potential effect is responsible for the urban-rural differences. The geographical distance from place of residence to nearest major road was used as a proxy variable for traffic related exposures. We used a large population-based sample of the Danish population (1.89 million people) including information on all permanent addresses linked with geographical information on all roads and house numbers in Denmark. Schizophrenia in cohort members (10,755 people) was identified by linkage with the Danish Psychiatric Central Register. RESULTS: The geographical distance from place of residence to nearest major road had a significant effect. The highest risk was found in children living 500–1000 metres from nearest major road (RR = 1.30 (95% Confidence Interval: 1.17–1.44). However, when we accounted for the degree of urbanization, the geographical distance to nearest major road had no significant effect. CONCLUSION: The cause(s) or exposure(s) responsible for the urban-rural differences in schizophrenia risk were closer related to the degree of urbanization than to the geographical distance to nearest major road. Traffic related exposures might thus be less likely explanations for the urban-rural differences in schizophrenia risk

Modifications of bovine prothrombin fragment 1 in the presence and absence of Ca (II) ions. Loss of positive cooperativity in Ca (II) ion binding for the modified proteins.

Chemical modification of bovine prothrombin fragment 1 according to the procedure of D. J. Welsch and G. L. Nelsestuen (1988) [Biochemistry 27, 4946-4952 and ealier papers] provided a series of fragment 1 derivatives in which various nitrogen-containing side chains were N-acetylated and/or N-2,4,6-trinitrophenylated. In addition the des-[Ala-1,Asn-2]- and des-[Ala-1,Asn-2,Lys-3]-fragment 1 derivatives were prepared by limited enzymatic hydrolysis of fragment 1 using cathepsin C and plasmin, respectively. Quantitative studies on the Ca(II) binding of these proteins have been accomplished using 45Ca(II) equilibrium dialysis. Binding of these fragment 1 derivatives to phosphatidylserine/phosphatidylcholine (PS/PC) vesicles (25:75) in the presence of Ca(II) ions has been studied using the light-scattering technique. Acylation of the 5 lysine residues of fragment 1 by the action of acetic anhydride (500-fold molar excess) in the presence of 75 mM Ca(II), pH 8.0, results in loss of positive cooperativity in Ca(II) binding (Scatchard plot) and an increase in the number of Ca(II) ions bound. The Ca(II)-dependent PS/PC binding of the acylated protein is reduced. Removal of 2 and 3 residues from the amino terminus likewise leads to loss of positive cooperativity in Ca(II) binding and reduced binding affinity to PS/PC vesicles. The important role of the amino-terminal 1-10 sequence is discussed. We conclude that positive cooperativity in Ca(II) binding is not a prerequisite for the Ca(II)-dependent binding of bovine prothrombin fragment 1 to PS/PC vesicles

The co-presence of deletion 7q, 20q and inversion 16 in therapy-related acute myeloid leukemia developed secondary to treatment of breast cancer with cyclophosphamide, doxorubicin, and radiotherapy: a case report

Introduction. Therapy-related acute myeloid leukemia occurs as a complication of treatment with chemotherapy, radiotherapy, immunosuppressive agents or exposure to environmental carcinogens. Case presentation. We report a case of therapy-related acute myeloid leukemia in a 37-year-old Turkish woman in complete remission from breast cancer. Our patient presented to our facility with fatigue, fever, sore throat, peripheral lymphadenopathy, and moderate hepatosplenomegaly. On peripheral blood and bone marrow aspirate smears, monoblasts were present. Immunophenotypic analysis of the bone marrow showed expression of CD11b, CD13, CD14, CD15, CD33, CD34, CD45 and human leukocyte antigen-DR, findings compatible with the diagnosis of acute monoblastic leukemia (French-American-British classification M5a). Therapy-related acute myeloid leukemia developed three years after adjuvant chemotherapy consisting of an alkylating agent, cyclophosphamide and DNA topoisomerase II inhibitor, doxorubicin and adjuvant radiotherapy. Cytogenetic analysis revealed a 46, XX, deletion 7 (q22q34), deletion 20 (q11.2q13.1) karyotype in five out of 20 metaphases and inversion 16 was detected by fluorescence in situ hybridization. There was no response to chemotherapy (cytarabine and idarubicin, FLAG-IDA protocol, azacitidine) and our patient died in the 11th month after diagnosis. Conclusions: The median survival in therapy-related acute myeloid leukemia is shorter compared to de novo acute myeloid leukemia. Also, the response to therapy is poor. In therapy-related acute myeloid leukemia, complex karyotypes have been associated with abnormalities of chromosome 5, rather than 7. To the best of our knowledge, this is the first case of therapy-related acute myeloid leukemia showing the co-presence of deletion 7q, 20q and the inversion 16 signal. © 2012 Yonal et al; licensee BioMed Central Ltd

Restrictions and extensions of semibounded operators

We study restriction and extension theory for semibounded Hermitian operators in the Hardy space of analytic functions on the disk D. Starting with the operator zd/dz, we show that, for every choice of a closed subset F in T=bd(D) of measure zero, there is a densely defined Hermitian restriction of zd/dz corresponding to boundary functions vanishing on F. For every such restriction operator, we classify all its selfadjoint extension, and for each we present a complete spectral picture. We prove that different sets F with the same cardinality can lead to quite different boundary-value problems, inequivalent selfadjoint extension operators, and quite different spectral configurations. As a tool in our analysis, we prove that the von Neumann deficiency spaces, for a fixed set F, have a natural presentation as reproducing kernel Hilbert spaces, with a Hurwitz zeta-function, restricted to FxF, as reproducing kernel.Comment: 63 pages, 11 figure

Shaping bursting by electrical coupling and noise

Gap-junctional coupling is an important way of communication between neurons and other excitable cells. Strong electrical coupling synchronizes activity across cell ensembles. Surprisingly, in the presence of noise synchronous oscillations generated by an electrically coupled network may differ qualitatively from the oscillations produced by uncoupled individual cells forming the network. A prominent example of such behavior is the synchronized bursting in islets of Langerhans formed by pancreatic \beta-cells, which in isolation are known to exhibit irregular spiking. At the heart of this intriguing phenomenon lies denoising, a remarkable ability of electrical coupling to diminish the effects of noise acting on individual cells. In this paper, we derive quantitative estimates characterizing denoising in electrically coupled networks of conductance-based models of square wave bursting cells. Our analysis reveals the interplay of the intrinsic properties of the individual cells and network topology and their respective contributions to this important effect. In particular, we show that networks on graphs with large algebraic connectivity or small total effective resistance are better equipped for implementing denoising. As a by-product of the analysis of denoising, we analytically estimate the rate with which trajectories converge to the synchronization subspace and the stability of the latter to random perturbations. These estimates reveal the role of the network topology in synchronization. The analysis is complemented by numerical simulations of electrically coupled conductance-based networks. Taken together, these results explain the mechanisms underlying synchronization and denoising in an important class of biological models