Homodimerization as a molecular switch between low and high efficiency PrPC cell surface delivery and neuroprotective activity

PrP^C is associated with a variety of functions, and its ability to interact with a multitude of partners, including itself, may largely explain PrP multifunctionality and the lack of consensus on the genuine physiological function of the protein in vivo. In contrast, there is a consensus in the literature that alterations in PrP^C trafficking and intracellular retention result in neuronal degeneration. In addition, a proteolytic modification in the late secretory pathway termed the α-cleavage induces the secretion of PrPN1, a PrP^C-derived metabolite with fascinating neuroprotective activity against toxic oligomeric Aβ molecules implicated in Alzheimer disease. Thus, studies focusing on understanding the regulation of PrP^C trafficking to the cell surface and the modulation of α-cleavage are essential. The objective of this commentary is to highlight recent evidences that PrP^C homodimerization stimulates trafficking of the protein to the cell surface and results in high levels of PrPN1 secretion. We also discuss a hypothetical model for these results and comment on future challenges and opportunities.     

Effects of direct transfer from freshwater to seawater on respiratory and circulatory variables and acid-base status in rainbow trout

Summary The effects of increased ambient salinity (35 mg · ml^-1) were studied at 1, 6, and 24 h after direct transfer of rainbow trout from freshwater to seawater. Two series of experiments were carried out successively. The first series was designed to simultaneously study all the respiratory (except Hb affinity for O₂), circulatory, and acid-base variables in each fish. In this series, fish were fitted with catheters chronically inserted into the cardiac bulbus, the dorsal aorta, and the opercular and buccal cavities. In the second series, designed to study haemoglobin O₂ affinity, fish were fitted with only a dorsal aorta catheter. The ventilatory flow ( ) was markedly increased just after transfer (by 55% at 1 h), then more moderately (by 20% at 6 h and 32% at 24 h). The initial hyperventilation peak was associated with frequent couphing motions. These ventilatory changes resulted essentially from increase in ventilatory amplitude. Initially, standard oxygen consumption (MM}O₂) decreased slightly, the moderately increased (by 12% at 24 h), so that the oxygen convection requirement ( ) increased substantially. In spite of an increased ventilation, the partial pressure of oxygen in arterial blood (P _aO₂) decreased slightly at 1 h, prior to returning to control levels, while partial pressure of carbon dioxide in arterial blood (P _aCO₂) was not significantly decreased. Gill oxygen transfer factor decreased substantially at 1 h (by 35%) then more moderately (by 7% at 1 h and 12% at 24 h). These results suggest a decrease in gas diffusing capacity of the gills. As P _aCO₂ remained approximatively unchanged, the gradual decrease in arterial pH (pH_a) from 7.94 to 7.67 at 24 h must therefore be regarded as a metabolic acidosis. The strong ion difference decreased markedly because the concentration of plasma chloride increased more than that of sodium. Arterial O₂ content (C _aO₂) gradually decreased (by 38% at 24 h) simultaneously with the decrease in pH_a, while the ratio P _aO₂/C _aO₂ increased. In parallel, seawater exposure induced a marked decrease in affinity of haemoglobin for O₂, so that at 24 h, P₅₀ was increased by 26% above the value obtained in freshwater-adapted trout. The increase in could be ascribed initially (at 1 h) to the decrease of P _aO₂ and later to a stimulation of respiratory neurons resulting from the lowered medullary interstitial pH. The decrease in C _aO₂ could be interpreted mainly as a consequence of a decreased affinity of haemoglobin for O₂, likely to be due to the blood acidosis and a predictable increase in chloride concentration within erythrocytes. Cardiac output ( ) slightly decreased at 1 h, then progressively increased by 30% at 24 h. Branchial vascular resistance increased at 1 h by 28%, then decreased by 18% of the control value at 24 h. Systemic vascular resistance decreased markedly by 40% at 24 h. As heart rate (HR) remained significantly unchanged, the cardiac stroke volume initially decreased then increased in relation to the changes in . The increase of , allowing compensation for the effect of decreased C _aO₂ in tissue O₂ supply, was interpreted as a passive consequence of the decrease in total vascular resistance occurring during seawater exposure.Abbreviations a.u. arbitrary units - C _aO₂ arterial oxygen content - pH₅₀ arterial pH at P₅₀ - C _vO₂ venous oxygen content - Hb haemoglobin - HR heart rate - Hct hematocrit - n_Hill Hill coefficient - O₂ standard oxygen consumption - P _aCO₂ arterial partial pressure of carbon dioxide - P _aO₂ arterial partial pressure of oxygen - P _vO₂ oxygen partial pressure in mixed venous blood - P₅₀ oxygen tension at half saturation of haemoglobin - P _VA, P _DA blood pressure in ventral and dorsal aorta - pH_a arterial pH - PIO₂, PEO₂ oxygen partial pressure of inspired and expired water - PO₂ oxygen partial pressure - cardiac output - SEM standard error of mean - S.I.D. strong ion difference - SV cardiac stroke volume - TO₂ gill oxygen transfer factor - U oxygen extraction coefficient - VA ventilatory amplitude - VF ventilatory frequency - VR_G, VR_S branchial and systemic vascular resistances - ventilatory flow - ventilatory oxygen convection requirement     

CFC syndrome: a syndrome distinct from Noonan syndrome

We report two children with a common pattern of birth defects. Both have very sparse, curly hair, nystagmus and mental retardation. The first one has Noonan syndrome habitus associated with keratosis plantaris and nystagmus; the second one has a slightly Noonan-like face, macrocephaly, keratosis pilaris, and hypertrophic cardiomyopathy. They represent the extreme of a spectrum of congenital defects recently reported independently as CFC syndrome by Reynolds and as "Noonan-like short stature syndrome with sparse hair" by Baraitser and Patton. The clinical features are reviewed and the autonomy of the syndrome with regards to Noonan syndrome, is disputed, since every sign seems to occur independently in Noonan syndrome. The father of the second case probably has a minor syndrome expression, pointing to probable autosomal dominant inheritance.     

Dielectric properties and oxygenation of hemoglobin

Dielectric properties of human and horse hemoglobin were studied at frequencies ranging from 20 kc./sec. to 7 Mc./sec. The relative errors in the measurements were usually less than 10^?3 even for mildly conducting solutions (10^?3M KCl). The experimental setup allowed us variation and measurement of the degree of oxygenation of the protein and to determine its dielectric parameters. Our main conclusion is that it was not possible to find any variation of the dielectric increment for hemoglobin oxygenation levels of 25, 50, 75, and 100%, approximately. This result is at variance with some previous reports. We cannot give the reason for this discrepancy but discuss some possible explanations. The specific dielectric increment, Δε_s/c, of human hemoglobin was shown to be significantly smaller than that of horse hemoglobin (0.28 against 0.32). This physical property is lowered with increasing ionic strength I: Δε_s/c = 0.28 and 0.20 for I = 10^?4 and 10^?3, respectively (human protein).     

Widespread formation of intracellular calcium carbonates by the bloom-forming cyanobacterium Microcystis

The formation of intracellular amorphous calcium carbonates (iACC) has been recently observed in a few cultured strains of Microcystis, a potentially toxic bloom-forming cyanobacterium found worldwide in freshwater ecosystems. If iACC-forming Microcystis are abundant within blooms, they may represent a significant amount of particulate Ca. Here, we investigate the significance of iACC biomineralization by Microcystis. First, the presence of iACC-forming Microcystis cells has been detected in several eutrophic lakes, indicating that this phenomenon occurs under environmental conditions. Second, some genotypic (presence/absence of ccyA, a marker gene of iACC biomineralization) and phenotypic (presence/absence of iACC) diversity have been detected within a collection of strains isolated from one single lake. This illustrates that this trait is frequent but also variable within Microcystis even at a single locality. Finally, one-third of publicly available genomes of Microcystis were shown to contain the ccyA gene, revealing a wide geographic and phylogenetic distribution within the genus. Overall, the present work shows that the formation of iACC by Microcystis is common under environmental conditions. While its biological function remains undetermined, this process should be further considered regarding the biology of Microcystis and implications on the Ca geochemical cycle in freshwater environments.     

Bioguided Fractionation and Isolation of an Antiplasmodial Saponin from the Roots of Nauclea xanthoxylon (A.Chev.) Aubrév. (Rubiaceae)

The root extract of Nauclea xanthoxylon (A.Chev.) Aubrév. displayed significant 50 % inhibition concentration (IC₅₀s) of 0.57 and 1.26 μg/mL against chloroquine resistant and sensitive Plasmodium falciparum (Pf) Dd2 and 3D7 strains, respectively. Bio-guided fractionation led to an ethyl acetate fraction with IC₅₀s of 2.68 and 1.85 μg/mL and subsequently, to the new quinovic acid saponin named xanthoxyloside ( 1 ) with IC₅₀s of 0.33 and 1.30 μM, respectively against the tested strains. Further compounds obtained from ethyl acetate and hexane fractions were the known clethric acid ( 2 ), ursolic acid ( 3 ), quafrinoic acid ( 4 ), quinovic acid ( 5 ), quinovic acid 3-O-β-D-fucopyranoside ( 6 ), oleanolic acid ( 7 ), oleanolic acid 3-acetate ( 8 ), friedelin ( 9 ), β-sitosterol ( 10a ), stigmasterol ( 10b ) and stigmasterol 3-O-β-D-glucopyranoside ( 11 ). Their structures were characterised with the aid of comprehensive spectroscopic methods (1 and 2D NMR, Mass). Bio-assays were performed using nucleic acid gel stain (SYBR green I)-based fluorescence assay with chloroquine as reference. Extracts and compounds exhibited good selectivity indices (SIs) of >10. Significant antiplasmodial activities measured for the crude extract, the ethyl acetate fraction and xanthoxyloside ( 1 ) from that fraction can justify the use of the root of N. xanthoxylon in ethnomedicine to treat malaria.     

Evidence for two possible glnB-type genes in Herbaspirillum seropedicae.

Two glnB-like genes have been isolated from Herbaspirillum seropedicae by complementation of the Klebsiella pneumoniae glnB502 mutant for growth on nitrate. One of these glnB-like genes has been sequenced and shows strong identity with GlnB proteins derived from other organisms. A Tn5-20 mutation of this glnB was Nif negative.     

Highly concentrated urine-purified Tac peptide fails to inhibit IL-2-dependent cell proliferation in vitro.

Tac peptide, i.e., the p55 chain of the human interleukin-2 receptor (IL-2R) complex, is detectable as a soluble from (sIL-2R) in normal sera and, at increased levels, in patients with different diseases. Since several immunological abnormalities are observed in most conditions associated with an increase in sIL-2R levels, a down-regulatory effect on IL-2-dependent functions has been postulated as a consequence of binding and functional block of IL-2 by the excess of sIL-2R. To test this hypothesis, we purified sIL-2R from the urine of a patient with hairy cell leukemia and investigated the possible inhibitory effect of this peptide on the in vitro IL-2-induced cell proliferation. The urine-purified molecule was detectable by the specific immunoassay utilized to measure the serum Tac peptide and was constructed by a single polypeptide of about 50 kDa which was able to bind IL-2. Experiments performed with the IL-2-dependent murine CTLL-2 cell line and with PHA-stimulated human peripheral blood mononuclear cells showed that the purified sIL-2R at concentrations up to about 300 nM was unable to block IL-2-dependent cell proliferation. According to these data, which can be explained by the low affinity for IL-2 of the p55 IL-2R chain, it seems unlikely that in vivo the soluble Tac peptide can exert a down regulatory effect on IL-2-induced phenomena through a functional block of IL-2.