Sulfatide activator protein : alternative splicing that generates three mRNAs and a newly found mutation responsible for a clinical disease

The sulfatide activator protein, also known as SAP-1, is derived from a gene that generates an mRNA coding for four homologous proteins. Its physiological function is to stimulate hydrolysis of sulfatide by arylsulfatase A in vivo. A genetic defect in the sulfatide activator results in a metabolic disorder similar to classical metachromatic leukodystrophy, which is itself caused by a genetic defect in arylsulfatase A. In a patient with sulfatide activator deficiency, a nucleotide transversion G722----C (counted from A of the initiation codon ATG) was found in the mRNA of the sulfatide activator precursor, resulting in the substitution of serine for Cys241 in the mature sulfatide activator. The remainder of the coding sequence was completely normal except for a polymorphism C to T in position 1389, which does not change the amino acid sequence. The patient produces at least three different forms of mRNA for the precursor. Two of them include a stretch of an additional 9 and 6 bases, respectively, within the sulfatide activator coding region. In normal individuals this stretch of additional bases has also been observed. This could be explained by the presence of a small 9-base pair exon which can be introduced, or not, by alternative splicing as a stretch of 9 or 6 bases into the mature mRNA. The shortest form of the mRNA yields an active sulfatide activator (Fürst, W., Schubert, J., Machleidt, W., Meier, H. E., and Sandhoff, K. (1990) Eur. J. Biochem. 192, 709-714)

Influence of short-term dietary measures on dioxin concentrations in human milk.

Breast-feeding may expose infants to high levels of toxic chlorinated dioxins. To diminish intake of these lipophilic compounds by the baby, two diets were tested for their ability to reduce concentrations of dioxins in human milk. The diets were a low-fat/high- carbohydrate/low-dioxin diet. (about 20% of energy intake derived from fat) and a high fat /low-carbohydrate/low-dioxin diet. These diets were tested in 16 and 18 breast-feeding women, respectively. The test diets were followed for 5 consecutive days in the fourth week after delivery. Milk was sampled before and at the end of the dietary regimen, and dioxin concentrations and fatty acid concentrations were determined. Despite significant influences of these diets on the fatty acid profiles, no significant influence on the dioxin concentrations in breast milk could be found. We conclude that short-term dietary measures will not reduce dioxin concentration in human milk

Absence of stable collinear configurations in Ni(001)ultrathin films: canted domain structure as ground state

Brillouin light scattering (BLS) measurements were performed for (17-120) Angstrom thick Cu/Ni/Cu/Si(001) films. A monotonic dependence of the frequency of the uniform mode on an in-plane magnetic field H was observed both on increasing and on decreasing H in the range (2-14) kOe, suggesting the absence of a metastable collinear perpendicular ground state. Further investigation by magneto-optical vector magnetometry (MOKE-VM) in an unconventional canted-field geometry provided evidence for a domain structure where the magnetization is canted with respect to the perpendicular to the film. Spin wave calculations confirm the absence of stable collinear configurations.Comment: 6 pages, 3 figures (text, appendix and 1 figure added

The Sagnac Phase Shift suggested by the Aharonov-Bohm effect for relativistic matter beams

The phase shift due to the Sagnac Effect, for relativistic matter beams counter-propagating in a rotating interferometer, is deduced on the bases of a a formal analogy with the the Aharonov-Bohm effect. A procedure outlined by Sakurai, in which non relativistic quantum mechanics and newtonian physics appear together with some intrinsically relativistic elements, is generalized to a fully relativistic context, using the Cattaneo's splitting technique. This approach leads to an exact derivation, in a self-consistently relativistic way, of the Sagnac effect. Sakurai's result is recovered in the first order approximation.Comment: 18 pages, LaTeX, 2 EPS figures. To appear in General Relativity and Gravitatio

Influence of uncorrelated overlayers on the magnetism in thin itinerant-electron films

The influence of uncorrelated (nonmagnetic) overlayers on the magnetic properties of thin itinerant-electron films is investigated within the single-band Hubbard model. The Coulomb correlation between the electrons in the ferromagnetic layers is treated by using the spectral density approach (SDA). It is found that the presence of nonmagnetic layers has a strong effect on the magnetic properties of thin films. The Curie temperatures of very thin films are modified by the uncorrelated overlayers. The quasiparticle density of states is used to analyze the results. In addition, the coupling between the ferromagnetic layers and the nonmagnetic layers is discussed in detail. The coupling depends on the band occupation of the nonmagnetic layers, while it is almost independent of the number of the nonmagnetic layers. The induced polarization in the nonmagnetic layers shows a long-range decreasing oscillatory behavior and it depends on the coupling between ferromagnetic and nonmagnetic layers.Comment: 9 pages, RevTex, 6 figures, for related work see: http://orion.physik.hu-berlin.d

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Specific saposin C deficiency: CNS impairment and acid β-glucosidase effects in the mouse

Saposins A, B, C and D are derived from a common precursor, prosaposin (psap). The few patients with saposin C deficiency develop a Gaucher disease-like central nervous system (CNS) phenotype attributed to diminished glucosylceramide (GC) cleavage activity by acid β-glucosidase (GCase). The in vivo effects of saposin C were examined by creating mice with selective absence of saposin C (C−/−) using a knock-in point mutation (cysteine-to-proline) in exon 11 of the psap gene. In C−/− mice, prosaposin and saposins A, B and D proteins were present at near wild-type levels, but the saposin C protein was absent. By 1 year, the C−/− mice exhibited weakness of the hind limbs and progressive ataxia. Decreased neuromotor activity and impaired hippocampal long-term potentiation were evident. Foamy storage cells were observed in dorsal root ganglion and there was progressive loss of cerebellar Purkinje cells and atrophy of cerebellar granule cells. Ultrastructural analyses revealed inclusions in axonal processes in the spinal cord, sciatic nerve and brain, but no excess of multivesicular bodies. Activated microglial cells and astrocytes were present in thalamus, brain stem, cerebellum and spinal cord, indicating regional pro-inflammatory responses. No storage cells were found in visceral organs of these mice. The absence of saposin C led to moderate increases in GC and lactosylceramide (LacCer) and their deacylated analogues. These results support the view that saposin C has multiple roles in glycosphingolipid (GSL) catabolism as well as a prominent function in CNS and axonal integrity independent of its role as an optimizer/stabilizer of GCase

Neurolysosomal pathology in human prosaposin deficiency suggests essential neurotrophic function of prosaposin

A neuropathologic study of three cases of prosaposin (pSap) deficiency (ages at death 27, 89 and 119 days), carried out in the standard autopsy tissues, revealed a neurolysosomal pathology different from that in the non-neuronal cells. Non-neuronal storage is represented by massive lysosomal accumulation of glycosphingolipids (glucosyl-, galactosyl-, lactosyl-, globotriaosylceramides, sulphatide, and ceramide). The lysosomes in the central and peripheral neurons were distended by pleomorphic non-lipid aggregates lacking specific staining and autofluorescence. Lipid storage was borderline in case 1, and at a low level in the other cases. Neurolysosomal storage was associated with massive ubiquitination, which was absent in the non-neuronal cells and which did not display any immunohistochemical aggresomal properties. Confocal microscopy and cross-correlation function analyses revealed a positive correlation between the ubiquitin signal and the late endosomal/lysosomal markers. We suppose that the neuropathology most probably reflects excessive influx of non-lipid material (either in bulk or as individual molecules) into the neurolysosomes. The cortical neurons appeared to be uniquely vulnerable to pSap deficiency. Whereas in case 1 they populated the cortex, in cases 2 and 3 they had been replaced by dense populations of both phagocytic microglia and astrocytes. We suggest that this massive neuronal loss reflects a cortical neuronal survival crisis precipitated by the lack of pSap. The results of our study may extend the knowledge of the neurotrophic function of pSap, which should be considered essential for the survival and maintenance of human cortical neurons