Excitatory and inhibitory pathways involved in lower reflex integration

Zusammenfassung Auf Grund der Frequenzabhängigkeit des respiratorischen Effektes der afferenten Vagusreizung und des lokalisatorischen Nachweises von zwei getrennten zentralen Schaltstellen für den inspiratorischen und den exspiratorischen Effekt läßt sich ein funktionelles Schema der vagalen Atmungsreflexe aufstellen. Die afferenten Lungenfasern des Vagus treten in synaptische Verbindung mit Schaltneuronen im Nucleus tractus solitarii und in der angrenzenden Zone der Formatio reticularis lateralis. Auf einem mehr kaudalen Niveau sind diese Schaltneurone inspiratorisch wirksam; ihre Neuriten bilden erregende Synapsen an den inspiratorischen Motoneuronen. Auf einem etwas mehr kranialen Niveau sind sie exspiratorisch wirksam; es wird angenommen, daß sie über besondere Synapsen eine direkte Hemmung auf die inspiratorischen Motoneurone ausüben. Diese exspiratorischen bzw. inspiratorischhemmenden Schaltneurone haben ein geringeres «Summationsvermögen» als die inspiratorischen und werden daher erst durch höhere afferente Erregungsfrequenzen in Aktion versetzt. Ihr hemmender Einfluß ist aber imstande, die motorische Auswirkung der gleichzeitig immer vorhandenen inspiratorischen Aktivierung gänzlich zu verhindern. Dieses Prinzip des doppelten zentralen Schaltweges für Erregung und Hemmung läßt sich in verallgemeinerter Form auf spinale Reflexe anwenden, wo ein hemmender Einfluß steigender afferenter Erregungsfrequenzen ebenfalls besteht. Ein in ähnlicher Weise antagonistisch wirkendes Schaltneuron-system ist für Reflexe mit tonischem Charakter als grundlegend anzunehmen, während der direkte monosynaptische Schaltweg als sekundär vereinfachter Mechanismus für gewisse phasische Reaktionen zu betrachten ist.     

Adriatic species of Schizomavella (Bryozoa: Cheilostomata)

In this paper, material belonging to the genus Schizomavella, collected along the Croatian coast of the Adriatic Sea, is revised. Nine species were identified, including five species new to science: S. cornuta, S. halimedae, S. linearis, S. mamillata, S. adriatica sp. nov.,S. mystacea sp. nov., S. rosae sp. nov., S. stanislavi sp. nov. and S. tubulata sp. nov. Previous records of Schizomavella from the Adriatic are also discussed. The checklist of Adriatic Schizomavella species is updated to 11 species; a further two species are doubtful owing to wrong previous identifications. The presence of a calcified ‘hood’ covering the opesia of the suboral avicularium is described and its function is discussed. The morphological diversity of ovicells within the genus Schizomavella is compiled and discussed.

http://zoobank.org/urn:lsid:zoobank.org:pub:987D8AE0-1E02-430D-9AB5-50B77BEAF52E     

Functional and pharmacological induced structural changes of the cystic fibrosis transmembrane conductance regulator in the membrane solved using SAXS

The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is a membrane-integral protein that belongs to the ATP-binding cassette superfamily. Mutations in the CFTR gene cause cystic fibrosis in which salt, water, and protein transports are defective in various tissues. To investigate the conformation of the CFTR in the membrane, we applied the small-angle x-ray scattering (SAXS) technique on microsomal membranes extracted from NIH/3T3 cells permanentely transfected with wild-type (WT) CFTR and with CFTR carrying the ΔF508 mutation. The electronic density profile of the membranes was calculated from the SAXS data, assuming the lipid bilayer electronic density to be composed by a series of Gaussian shells. The data indicate that membranes in the microsome vesicles, that contain mostly endoplasmic reticulum membranes, are oriented in the outside-out conformation. Phosphorylation does not change significantly the electronic density profile, while dephosphorylation produces a significant modification in the inner side of the profile. Thus, we conclude that the CFTR and its associated protein complex in microsomes are mostly phosphorylated. The electronic density profile of the ΔF508-CFTR microsomes is completely different from WT, suggesting a different assemblage of the proteins in the membranes. Low-temperature treatment of cells rescues the ΔF508-CFTR protein, resulting in a conformation that resembles the WT. Differently, treatment with the corrector VX-809 modifies the electronic profile of ΔF508-CFTR membrane, but does not recover completely the WT conformation. To our knowledge, this is the first report of a direct physical measurement of the structure of membranes containing CFTR in its native environment and in different functional and pharmacological conditions.     

A SAXS-based ensemble model of the native and phosphorylated regulatory domain of the CFTR

The cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein in cystic fibrosis, is an anion channel activated by protein kinase A phosphorylation. The regulatory domain (RD) of CFTR has multiple phosphorylation sites, and is responsible for channel activation. This domain is intrinsically disordered, rendering the structural analysis a difficult task, as high-resolution techniques are barely applicable. In this work, we obtained a biophysical characterization of the native and phosphorylated RD in solution by employing complementary structural methods. The native RD has a gyration radius of 3.25 nm, and a maximum molecular dimension of 11.4 nm, larger than expected for a globular protein of the same molecular mass. Phosphorylation causes compaction of the structure, yielding a significant reduction of the gyration radius, to 2.92 nm, and on the maximum molecular dimension to 10.2 nm. Using an ensemble optimization method, we were able to generate a low-resolution, three-dimensional model of the native and the phosphorylated RD based on small-angle X-ray scattering data. We have obtained the first experiment-based model of the CFTR regulatory domain, which will be useful to understand the molecular mechanisms of normal and pathological CFTR functioning.     

The gating of the CFTR channel

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel expressed in the apical membrane of epithelia. Mutations in the CFTR gene are the cause of cystsic fibrosis. CFTR is the only ABC-protein that constitutes an ion channel pore forming subunit. CFTR gating is regulated in complex manner as phosphorylation is mandatory for channel activity and gating is directly regulated by binding of ATP to specific intracellular sites on the CFTR protein. This review covers our current understanding on the gating mechanism in CFTR and illustrates the relevance of alteration of these mechanisms in the onset of cystic fibrosis.     

Hermeneutical contributions to the history of science: Gadamer on ‘presentism’

This article examines how Hans G. Gadamer’s philosophical hermeneutics can contribute to contemporary debates on the concept of ‘presentism’. In the field of the history of science, this term is usually employed in two ways. First, ‘presentism’ refers to the kind of historiography which judges the past to legitimate the present. Second, this concept designates the inevitable influence of the present in the interpretation of the past. In this paper, I argue that both dimensions of the relationship between the present and the past are explored by Hans G. Gadamer in Truth and Method and other texts. In the first place, Gadamer’s critique of historicism calls into question the anti-presentist ideal of studying the past for ‘its own sake’. In the second place, Gadamer’s thesis that all understanding inevitably involves some prejudice poses the question of the inherent “present-centredness” of historical interpretations. By examining Gadamer’s hermeneutics, I seek to provide historians with new arguments and perspectives on the question of ‘presentism’.     

NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells

NLRs (nucleotide-binding domain leucine-rich-repeat-containing receptors; NOD-like receptors) are a class of pattern recognition receptor (PRR) that respond to host perturbation from either infectious agents or cellular stress. The function of most NLR family members has not been characterized and their role in instructing adaptive immune responses remains unclear. NLRP10 (also known as PYNOD, NALP10, PAN5 and NOD8) is the only NLR lacking the putative ligand-binding leucine-rich-repeat domain, and has been postulated to be a negative regulator of other NLR members, including NLRP3 (refs 4-6). We did not find evidence that NLRP10 functions through an inflammasome to regulate caspase-1 activity nor that it regulates other inflammasomes. Instead, Nlrp10(-/-) mice had a profound defect in helper T-cell-driven immune responses to a diverse array of adjuvants, including lipopolysaccharide, aluminium hydroxide and complete Freund's adjuvant. Adaptive immunity was impaired in the absence of NLRP10 because of a dendritic cell (DC) intrinsic defect in emigration from inflamed tissues, whereas upregulation of DC costimulatory molecules and chemotaxis to CCR7-dependent and -independent ligands remained intact. The loss of antigen transport to the draining lymph nodes by a subset of migratory DCs resulted in an almost absolute loss in naive CD4(+) T-cell priming, highlighting the critical link between diverse innate immune stimulation, NLRP10 activity and the immune function of mature DCs.