Differential Palmit(e)oylation of Wnt1 on C93 and S224 Residues Has Overlapping and Distinct Consequences

Though the mechanisms by which cytosolic/intracellular proteins are regulated by the post-translational addition of palmitate adducts is well understood, little is known about how this lipid modification affects secreted ligands, such as Wnts. Here we use mutational analysis to show that differential modification of the two known palmit(e)oylated residues of Wnt1, C93 and S224, has both overlapping and distinct consequences. Though the relative roles of each residue are similar with respect to stability and secretion, two distinct biological assays in L cells show that modification of C93 primarily modulates signaling via a ß-catenin independent pathway while S224 is crucial for ß-catenin dependent signaling. In addition, pharmacological inhibition of Porcupine (Porcn), an upstream regulator of Wnt, by IWP1, specifically inhibited ß-catenin dependent signaling. Consistent with these observations, mapping of amino acids in peptide domains containing C93 and S224 demonstrate that acylation of C93 is likely to be Porcn-independent while that of S224 is Porcn-dependent. Cumulatively, our data strongly suggest that C93 and S224 are modified by distinct enzymes and that the differential modification of these sites has the potential to influence Wnt signaling pathway choice

Age-related glomerulosclerosis and interstitial fibrosis in Milan normotensive rats: A podocyte disease

Age-related glomerulosclerosis and interstitial fibrosis in Milan normotensive rats: A podocyte disease. In Milan normotensive (MNS) rats glomerulosclerosis and interstitial fibrosis develop spontaneously in the absence of hypertension. Renal changes were sequentially assessed in these rats between 2 and 10 months of age. At 10 months, rats were characterized by heavy proteinuria, increased serum creatinine, focal or global glomerulosclerosis in 51 ± 12% of the glomeruli as well as tubulointerstitial injury involving > 25% of the section area. Cell injury in podocytes (evidenced as increased expression of desmin and by electron microscopy) and interstitial fibroblasts (increased expression of α-smooth muscle actin) and mild glomerular hypertrophy were witnessed as early as three to four months of age and preceded glomerulosclerosis and interstitial fibrosis. Only minor evidence of mesangial cell activation (as assessed by glomerular de novo α-smooth muscle actin or type I collagen expression or increased cell proliferation) was noted throughout the observation period. Later stages of the disease were characterized by glomerular and/or tubulointerstitial macrophage influx and osteopontin expression (a chemoattractant), mild accumulation of lymphocytes, platelets, fibrinogen, as well as by a progressive accumulation of various matrix proteins. Progressive renal disease in MNS rats is thus noteworthy for the relative lack of mesangial cell activation. Rather, early podocyte damage, induced by yet unknown mechanisms, may underlie the development of glomerulosclerosis and subsequent interstitial fibrosis

Software "Proasu"

The paper describes software for automation of ASCTP project documentation development ("ProASU"). This software is implemented for development of text documentation in automate mode way that for every of document type (TS, MS, PS, IS, SS, OS) there are predefined individual scenarios of creation

The role of ongoing dendritic oscillations in single-neuron dynamics

The dendritic tree contributes significantly to the elementary computations a neuron performs while converting its synaptic inputs into action potential output. Traditionally, these computations have been characterized as temporally local, near-instantaneous mappings from the current input of the cell to its current output, brought about by somatic summation of dendritic contributions that are generated in spatially localized functional compartments. However, recent evidence about the presence of oscillations in dendrites suggests a qualitatively different mode of operation: the instantaneous phase of such oscillations can depend on a long history of inputs, and under appropriate conditions, even dendritic oscillators that are remote may interact through synchronization. Here, we develop a mathematical framework to analyze the interactions of local dendritic oscillations, and the way these interactions influence single cell computations. Combining weakly coupled oscillator methods with cable theoretic arguments, we derive phase-locking states for multiple oscillating dendritic compartments. We characterize how the phase-locking properties depend on key parameters of the oscillating dendrite: the electrotonic properties of the (active) dendritic segment, and the intrinsic properties of the dendritic oscillators. As a direct consequence, we show how input to the dendrites can modulate phase-locking behavior and hence global dendritic coherence. In turn, dendritic coherence is able to gate the integration and propagation of synaptic signals to the soma, ultimately leading to an effective control of somatic spike generation. Our results suggest that dendritic oscillations enable the dendritic tree to operate on more global temporal and spatial scales than previously thought

Conserved nematode signalling molecules elicit plant defenses and pathogen resistance

Plant-defense responses are triggered by perception of conserved microbe-associated molecular patterns (MAMPs), for example, flagellin or peptidoglycan. However, it remained unknown whether plants can detect conserved molecular patterns derived from plant-parasitic animals, including nematodes. Here we show that several genera of plant-parasitic nematodes produce small molecules called ascarosides, an evolutionarily conserved family of nematode pheromones. Picomolar to micromolar concentrations of ascr#18, the major ascaroside in plant-parasitic nematodes, induce hallmark defense responses including the expression of genes associated with MAMP-triggered immunity, activation of mitogen-activated protein kinases, as well as salicylic acid- and jasmonic acid-mediated defense signalling pathways. Ascr#18 perception increases resistance in Arabidopsis, tomato, potato and barley to viral, bacterial, oomycete, fungal and nematode infections. These results indicate that plants recognize ascarosides as a conserved molecular signature of nematodes. Using small-molecule signals such as ascarosides to activate plant immune responses has potential utility to improve economic and environmental sustainability of agriculture

The Panchromatic Hubble Andromeda Treasury: Triangulum Extended Region (PHATTER) I. Ultraviolet to Infrared Photometry of 22 Million Stars in M33

We present panchromatic resolved stellar photometry for 22 million stars in the Local Group dwarf spiral Triangulum (M33), derived from Hubble Space Telescope (HST) observations with the Advanced Camera for Surveys (ACS) in the optical (F475W, F814W), and the Wide Field Camera 3 (WFC3) in the near ultraviolet (F275W, F336W) and near-infrared (F110W, F160W) bands. The large, contiguous survey area covers $\sim$14 square kpc and extends to 3.5 kpc (14 arcmin, or 1.5-2 scale lengths) from the center of M33. The PHATTER observing strategy and photometry technique closely mimic those of the Panchromatic Hubble Andromeda Treasury (PHAT), but with updated photometry techniques that take full advantage of all overlapping pointings (aligned to within $<$5-10 milliarcseconds) and improved treatment of spatially-varying point spread functions. The photometry reaches a completeness-limited depth of F475W$\sim$28.5 in the lowest surface density regions observed in M33 and F475W$\sim$26.5 in the most crowded regions found near the center of M33. We find the young populations trace several relatively tight arms, while the old populations show a clear, looser two-armed structure. We present extensive analysis of the data quality including artificial star tests to quantify completeness, photometric uncertainties, and flux biases. This stellar catalog is the largest ever produced for M33, and is publicly available for download by the community.Comment: 38 pages, 6 tables, 25 figures, accepted for publication in ApJ