Presenilin-1 processing of ErbB4 in fetal type II cells is necessary for control of fetal lung maturation

AbstractMaturation of pulmonary fetal type II cells to initiate adequate surfactant production is crucial for postnatal respiratory function. Little is known about specific mechanisms of signal transduction controlling type II cell maturation. The ErbB4 receptor and its ligand neuregulin (NRG) are critical for lung development. ErbB4 is cleaved at the cell membrane by the γ-secretase enzyme complex whose active component is either presenilin-1 (PSEN-1) or presenilin-2. ErbB4 cleavage releases the 80kDa intracellular domain (4ICD), which associates with chaperone proteins such as YAP (Yes-associated protein) and translocates to the nucleus to regulate gene expression. We hypothesized that PSEN-1 and YAP have a development-specific expression in fetal type II cells and are important for ErbB4 signaling in surfactant production. In primary fetal mouse E16, E17, and E18 type II cells, PSEN-1 and YAP expression increased at E17 and E18 over E16. Subcellular fractionation showed a strong cytosolic and a weaker membrane location of both PSEN-1 and YAP. This was enhanced by NRG stimulation. Co-immunoprecipitations showed ErbB4 associated separately with PSEN-1 and with YAP. Their association, phosphorylation, and co-localization were induced by NRG. Confocal immunofluorescence and nuclear fractionation confirmed these associations in a time-dependent manner after NRG stimulation. Primary ErbB4-deleted E17 type II cells were transfected with a mutant ErbB4 lacking the γ-secretase binding site. When compared to transfection with wild-type ErbB4, the stimulatory effect of NRG on surfactant protein mRNA expression was lost. We conclude that PSEN-1 and YAP have crucial roles in ErbB4 signal transduction during type II cell maturation

Permeability and conductivity of platelet-reinforced membranes and composites

We present large scale simulations of the diffusion constant $D$ of a random composite consisting of aligned platelets with aspect ratio $a/b>>1$ in a matrix (with diffusion constant $D_0$) and find that $D/D_0 = 1/(1+ c_1 x + c_2 x^2)$, where $x= a v_f/b$ and $v_f$ is the platelet volume fraction. We demonstrate that for large aspect ratio platelets the pair term ($x^2$) dominates suggesting large property enhancements for these materials. However a small amount of face-to-face ordering of the platelets markedly degrades the efficiency of platelet reinforcement.Comment: RevTeX, 5 pages, 4 figures, submitted to PR

Incompatibility Systems in Switchgrass

Switchgrass (Panicum virgatum L.), a cross-pollinated perennial, produces very little or no seed when self-pollinated, indicating the presence of self-incompatibility mechanisms. Knowledge of self-incompatibility mechanisms is required to use germplasm effectively in a breeding program. The objective of this study was to characterize features of the incompatibility systems in switchgrass. Seed set and seed characteristics of reciprocal matings of tetraploid, octaploid, and tetraploid x octaploid plants were used as measures of incompatibility. Both bagged mutual pollination and manual emasculation and pollination methods were used to make crosses. The percentages of self-compatibility in the tetraploid and octaploid parent plants were 0.35 and 1.39%, respectively. Prefertilization incompatibility in switchgrass is apparently under gametophytic control, since there were significant differences in percentage of compatible pollen as measured by percentage of total seed set between reciprocal matings within ploidy levels. Results indicated that the prefertilization incompatibility system in switchgrass is similar to the S-Z incompatibility system found in other members of the Poaceae. A postfertilization incompatibility system also exists that inhibits intermatings among octaploid and tetraploid plants. In these interploidy crosses, two very distinctive types of abnormal seed were found. When the female parent was the tetraploid plant, the resulting seed was small and shriveled, while when the female parent was the octaploid, small seed with floury endosperm was obtained. These results are similar to those obtained for endosperm incompatibility due to the endosperm balance number system found in other species

ErbB4 regulates the timely progression of late fetal lung development

AbstractThe ErbB4 receptor has an important function in fetal lung maturation. Deletion of ErbB4 leads to alveolar hypoplasia and hyperreactive airways similar to the changes in bronchopulmonary dysplasia (BPD). BPD is a chronic pulmonary disorder affecting premature infants as a consequence of lung immaturity, lung damage, and abnormal repair. We hypothesized that proper ErbB4 function is needed for the timely progression of fetal lung development. An ErbB4 transgenic cardiac rescue mouse model was used to study the effect of ErbB4 deletion on fetal lung structure, surfactant protein (SP) expression, and synthesis, and inflammation. Morphometric analyses revealed a delayed structural development with a significant decrease in saccular size at E18 and more pronounced changes at E17, keeping these lungs in the canalicular stage. SP-B mRNA expression was significantly down regulated at E17 with a subsequent decrease in SP-B protein expression at E18. SP-D protein expression was significantly decreased at E18. Surfactant phospholipid synthesis was significantly decreased on both days, and secretion was down regulated at E18. We conclude that pulmonary ErbB4 deletion results in a structural and functional delay in fetal lung development, indicating a crucial regulatory role of ErbB4 in the timely progression of fetal lung development

Coherent manipulation of atomic qubits in optical micropotentials

We experimentally demonstrate the coherent manipulation of atomic states in far-detuned dipole traps and registers of dipole traps based on two-dimensional arrays of microlenses. By applying Rabi, Ramsey, and spin-echo techniques, we systematically investigate the dephasing mechanisms and determine the coherence time. Simultaneous Ramsey measurements in up to 16 dipole traps are performed and proves the scalability of our approach. This represents an important step in the application of scalable registers of atomic qubits for quantum information processing. In addition, this system can serve as the basis for novel atomic clocks making use of the parallel operation of a large number of individual clocks each remaining separately addressable.Comment: to be published in Appl. Phys.

Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation

Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD

An Effective-Medium Tight-Binding Model for Silicon

A new method for calculating the total energy of Si systems is presented. The method is based on the effective-medium theory concept of a reference system. Instead of calculating the energy of an atom in the system of interest a reference system is introduced where the local surroundings are similar. The energy of the reference system can be calculated selfconsistently once and for all while the energy difference to the reference system can be obtained approximately. We propose to calculate it using the tight-binding LMTO scheme with the Atomic-Sphere Approximation(ASA) for the potential, and by using the ASA with charge-conserving spheres we are able to treat open system without introducing empty spheres. All steps in the calculational method is {\em ab initio} in the sense that all quantities entering are calculated from first principles without any fitting to experiment. A complete and detailed description of the method is given together with test calculations of the energies of phonons, elastic constants, different structures, surfaces and surface reconstructions. We compare the results to calculations using an empirical tight-binding scheme.Comment: 26 pages (11 uuencoded Postscript figures appended), LaTeX, CAMP-090594-

Nonequilibrium Transport through a Kondo Dot in a Magnetic Field: Perturbation Theory

Using nonequilibrium perturbation theory, we investigate the nonlinear transport through a quantum dot in the Kondo regime in the presence of a magnetic field. We calculate the leading logarithmic corrections to the local magnetization and the differential conductance, which are characteristic of the Kondo effect out of equilibrium. By solving a quantum Boltzmann equation, we determine the nonequilibrium magnetization on the dot and show that the application of both a finite bias voltage and a magnetic field induces a novel structure of logarithmic corrections not present in equilibrium. These corrections lead to more pronounced features in the conductance, and their form calls for a modification of the perturbative renormalization group.Comment: 16 pages, 7 figure