National accounting rules in a globalized world (Pro and contra) ; contra - the best of both worlds

Grundsätze ordnungsmäßiger Buchführung, Bilanztheorie, Globalisierung, GAAP (Generally Accepted Accounting Principles), Accounting theory, Globalization

Second Messengers

Second messengers are small molecules and ions that relay signals received by cell-surface receptors to effector proteins. They include a wide variety of chemical species and have diverse properties that allow them to signal within membranes (e.g., hydrophobic molecules such as lipids and lipid derivatives), within the cytosol (e.g., polar molecules such as nucleotides and ions), or between the two (e.g., gases and free radicals). Second messengers are typically present at low concentrations in resting cells and can be rapidly produced or released when cells are stimulated. The levels of second messengers are exquisitely controlled temporally and spatially, and, during signaling, enzymatic reactions or opening of ion channels ensure that they are highly amplified. These messengers then diffuse rapidly from the source and bind to target proteins to alter their properties (activity, localization, stability, etc.) to propagate signaling

PHLPP1 counter-regulates STAT1-mediated inflammatory signaling.

Inflammation is an essential aspect of innate immunity but also contributes to diverse human diseases. Although much is known about the kinases that control inflammatory signaling, less is known about the opposing phosphatases. Here we report that deletion of the gene encoding PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) protects mice from lethal lipopolysaccharide (LPS) challenge and live Escherichia coli infection. Investigation of PHLPP1 function in macrophages reveals that it controls the magnitude and duration of inflammatory signaling by dephosphorylating the transcription factor STAT1 on Ser727 to inhibit its activity, reduce its promoter residency, and reduce the expression of target genes involved in innate immunity and cytokine signaling. This previously undescribed function of PHLPP1 depends on a bipartite nuclear localization signal in its unique N-terminal extension. Our data support a model in which nuclear PHLPP1 dephosphorylates STAT1 to control the magnitude and duration of inflammatory signaling in macrophages

Menopause induces changes to the stratum corneum ceramide profile, which are prevented by hormone replacement therapy

Abstract The menopause can lead to epidermal changes that are alleviated by hormone replacement therapy (HRT). We hypothesise that these changes could relate to altered ceramide production, and that oestrogen may have a role in keratinocyte ceramide metabolism. White Caucasian women were recruited into three groups: pre-menopausal (n = 7), post-menopausal (n = 11) and post-menopausal taking HRT (n = 10). Blood samples were assessed for hormone levels, transepidermal water loss was measured to assess skin barrier function, and stratum corneum lipids were sampled from photoprotected buttock skin. Ceramides and sphingomyelins were analysed by ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry. Post-menopausal stratum corneum contained lower levels of ceramides, with shorter average length; changes that were not evident in the HRT group. Serum oestradiol correlated with ceramide abundance and length. Ceramides had shorter sphingoid bases, indicating altered de novo ceramide biosynthesis. Additionally, post-menopausal women had higher sphingomyelin levels, suggesting a possible effect on the hydrolysis pathway. Treatment of primary human keratinocytes with oestradiol (10 nM) increased production of CER[NS] and CER[NDS] ceramides, confirming an effect of oestrogen on cutaneous ceramide metabolism. Taken together, these data show perturbed stratum corneum lipids post-menopause, and a role for oestrogen in ceramide production

Integrative annotation and knowledge discovery of kinase post-translational modifications and cancer-associated mutations through federated protein ontologies and resources.

Many bioinformatics resources with unique perspectives on the protein landscape are currently available. However, generating new knowledge from these resources requires interoperable workflows that support cross-resource queries. In this study, we employ federated queries linking information from the Protein Kinase Ontology, iPTMnet, Protein Ontology, neXtProt, and the Mouse Genome Informatics to identify key knowledge gaps in the functional coverage of the human kinome and prioritize understudied kinases, cancer variants and post-translational modifications (PTMs) for functional studies. We identify 32 functional domains enriched in cancer variants and PTMs and generate mechanistic hypotheses on overlapping variant and PTM sites by aggregating information at the residue, protein, pathway and species level from these resources. We experimentally test the hypothesis that S768 phosphorylation in the C-helix of EGFR is inhibitory by showing that oncogenic variants altering S768 phosphorylation increase basal EGFR activity. In contrast, oncogenic variants altering conserved phosphorylation sites in the \u27hydrophobic motif\u27 of PKCβII (S660F and S660C) are loss-of-function in that they reduce kinase activity and enhance membrane translocation. Our studies provide a framework for integrative, consistent, and reproducible annotation of the cancer kinomes. Sci Rep 2018 Apr 25; 8(1):6518

Active site inhibitors protect protein kinase C from dephosphorylation and stabilize its mature

Conformational changes acutely control protein kinase C (PKC). We have previously shown that the autoinhibitory pseudosubstrate must be removed from the active site in order for 1) PKC to be phosphorylated by its upstream kinase phosphoinositide-dependent kinase 1 (PDK-1), 2) the mature enzyme to bind and phosphorylate substrates, and 3) the mature enzyme to be dephosphorylated by phosphatases. Here we show an additional level of conformational control; binding of active site inhibitors locks PKC in a conformation in which the priming phosphorylation sites are resistant to dephosphorylation. Using homogeneously pure PKC, we show that the active site inhibitor Gö 6983 prevents the dephosphorylation by pure protein phosphatase 1 (PP1) or the hydrophobic motif phosphatase, pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP). Consistent with results using pure proteins, treatment of cells with the competitive inhibitors Gö 6983 or bisindolylmaleimide I, but not the uncompetitive inhibitor bisindolylmaleimide IV, prevents the dephosphorylation and down-regulation of PKC induced by phorbol esters. Pulse-chase analyses reveal that active site inhibitors do not affect the net rate of priming phosphorylations of PKC; rather, they inhibit the dephosphorylation triggered by phorbol esters. These data provide a molecular explanation for the recent studies showing that active site inhibitors stabilize the phosphorylation state of protein kinases B/Akt and C. PKC isozymes comprise a family of multidomain proteins that are under exquisite conformational control. Two major mechanisms control the conformation of PKC family members: phosphorylation and second messenger-dependent membrane binding (1, 2). First, newly synthesized enzymes undergo a series of ordered phosphorylations that lock the enzyme into a stable, catalytically competent, and autoinhibited species (3, 4). This species is maintained in an autoinhibited conformation by a pseudosubstrate segment that blocks the substrate-binding cavity, a conformation that also protects the priming sites of PKC from dephosphorylation. The inactive species are localized throughout the cell, often tethered to scaffold proteins (5). This processing by phosphorylation is constitutive and required to protect PKC from degradation; unphosphorylated protein is rapidly degraded (1). Second, binding to lipid second messengers allosterically controls the enzyme by facilitating the release of the autoinhibitory pseudosubstrate segment from the substrate-binding cavity (6). Thus, this conformational transition is acutely controlled by activation of receptors that signal using diacylglycerol as the second messenger. The membranebound conformation has an increased sensitivity to phosphatases by 2 orders of magnitude The PKC family is composed of nine genes (9, 10), of which the conventional (␣, the alternatively spliced ␤I and ␤II, and brain-enriched ␥) and novel (␦, ⑀, , and hematopoietic-enriched ) isozymes are matured by phosphorylation on three conserved sites originally identified in PKC ␤II: the activation loop at the entrance to the active site and two C-terminal sites, the turn motif and hydrophobic motif (3). Atypical PKC isozymes ( and ) are also phosphorylated at the activation loop and turn motif, but a phosphomimetic is present at the hydrophobic motif. The upstream kinase PDK-1 4 catalyzes the phosphorylation of the activation loop of all PKC isozymes, an event that correctly aligns residues in the active site for catalysi

Mother-to-infant and father-to-infant initial emotional involvement

While infant attachment has been largely studied, parental attachment is still relatively unknown, especially when referred to fathers. However, it is mainly recognised that parents’ emotional involvement with the newborn contributes to the quality of the interaction and the care they provide. The aim of this study was to study mother-to-infant and father-to-infant initial emotional involvement; namely, differences between mothers and fathers and changes in mother’s emotions toward the neonate within the first days after delivery. The Bonding Scale, an extended Portuguese version of the ‘New Mother-to-Infant Bonding Scale’, was administered during the first two days after childbirth to a sample of 315 mothers and 141 fathers (n = 456), at the Júlio Dinis Maternity Hospital (Portugal). Most mothers and fathers show positive emotions and only a few of them showed negative emotions toward the infant. Maternal and paternal emotional involvement toward the newborn tend to be similar; nevertheless, fathers show less fear and better emotional involvement with the neonate, while mothers are sadder and show more emotions not related to bonding. During the first days following delivery, emotions not related to bonding, such as fear, seem to decrease in mothers.Bial Foundation - Grant 58/02.Human Development and Health Service of the Calouste Gulbenkian Foundation - Grant 48914

More Than Fish - Framing Aquatic Animals within Sustainable Food Systems

Aquatic animals are diverse in terms of species, but also in terms of production systems, the people involved, and the benefits achieved. In this concept piece, we draw on literature to outline how the diversity of aquatic animals, their production, and their consumption all influence their impact within the food system. Built on evidence from an array of reductionist and non-reductionist literature, we suggest that food systems researchers and policymakers adapt current methods and theoretical frameworks to appropriately contextualise aquatic animals in broader food systems. We do this through combining current understandings of food systems theory, value chain, livelihoods, nutritional outcomes, and planetary boundaries thinking. We make several claims around understanding the role of aquatic animals in terms of nutritional output and environmental impacts. We suggest a need to consider: (1) the diversity of species and production methods; (2) variable definitions of an “edible yield”; (3) circular economy principles and the impacts of co-products, and effects beyond nutrient provision; (4) role of aquatic animals in the overall diet; (5) contextual effects of preservation, preparation, cooking, and consumer choices; (6) globalised nature of aquatic animal trade across the value chain; and (7) that aquatic animals are produced from a continuum, rather than a dichotomy, of aquaculture or fisheries. We conclude by proposing a new framework that involves cohesive interdisciplinary discussions around aquatic animal foods and their role in the broader food system