Brain Res Mol Brain Res. 2002 Nov 15;107(2):190-4. Decreased hyperlocomotion induced by MK-801, but not amphetamine and caffeine in mice lacking cellular prion protein (PrP(C)).
Coitinho AS, Dietrich MO, Hoffmann A, Dall'Igna OP, Souza DO, Martins VR, Brentani RR, Izquierdo I, Lara DR.
Departamento de Bioquimica, ICBS, UFRGS, Porto Alegre, Brazil. acoitinhahoo.com
The cellular prion protein (PrP(C)) has been involved in several neurodegenerative disorders however it has been proposed that it is also be implicated in psychotic disorders. We investigated the effect of three psychotropic drugs in locomotor activity of PrP(C) knockout (Prnp(O/O)) and wild-type mice. The NMDA receptor channel blocker MK-801 (0.25 mg/kg), the indirect dopamine agonist amphetamine (1 mg/kg) and the adenosine receptor antagonist caffeine (10 mg/kg) were administered i.p. after 60 min of habituation and locomotion was monitored for 3 h. Prnp(O/O) mice presented a diminished hyperlocomotor response to MK-801 treatment but normal response to amphetamine and caffeine compared to wild type mice. These results suggest that lack of PrP(C) leads to a functional alteration in the glutamatergic system, whereas the regulation of both dopaminergic and adenosinergic systems are preserved. Finally, lack of PrP(C) seems not to exacerbate the response to these psychotropic drugs, which modulate neurotransmitter systems possibly involved in schizophrenia and psychotic disorders.
PMID:_12425947
Biochem J. 2003 Feb 15;370(Pt 1):81-90. Detection of bovine spongiform encephalopathy, ovine scrapie prion-related protein (PrPSc) and normal PrPc by monoclonal antibodies raised to copper-refolded prion protein.
Thackray AM, Madec JY, Wong E, Morgan-Warren R, Brown DR, Baron T, Bujdoso R.
Centre for Veterinary Science, Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
Prion-related protein (PrP) is a glycosylphosphatidylinositol-linked cell-surface protein expressed by a wide variety of cells, including those of the nervous system and the immune system. Several functions of normal cellular PrP (PrPc) have been proposed that may be associated with the capacity of this protein to bind copper. In the present study, we describe the generation of a panel of monoclonal antibodies raised to copper-refolded PrP, which may be used to analyse the normal and disease-associated forms of this protein. The anti-PrP monoclonal antibodies were reactive by Western blot and ELISA with recombinant murine PrPc refolded in the presence or absence of either copper or manganese, and with the disease-susceptible allelic form V136R154Q171 ('VRQ'; where single-letter amino-acid notation has been used) and disease-resistant allelic form A136R154R171 ('ARR') of recombinant ovine PrPc. FACS analysis of lymphoid cells using these monoclonal antibodies showed that wild-type non-activated mouse lymphocytes expressed little, if any, PrPc. These monoclonal antibodies were shown to react with the unglycosylated and monoglycosylated forms of PrPSc (abnormal disease-specific conformation of PrP) in prion-infected tissue samples from all of the different species tested by Western blot. In addition, this analysis allowed one to make a distinction between bovine spongiform encephalopathy ('BSE') and scrapie PrPSc) isolates from experimentally infected sheep on the basis of their different electrophoretic mobilities.
PMID:_12429022
Mol Biol Cell. 2002 Nov;13(11):3775-86. Cotranslational partitioning of nascent prion protein into multiple populations at the translocation channel.
Kim SJ, Hegde RS.
Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
The decisive events that direct a single polypeptide such as the prion protein (PrP) to be synthesized at the endoplasmic reticulum in both fully translocated and transmembrane forms are poorly understood. In this study, we demonstrate that the topological heterogeneity of PrP is determined cotranslationally, while at the translocation channel. By evaluating sequential intermediates during PrP topogenesis, we find that signal sequence-mediated initiation of translocation results in an interaction between nascent PrP and endoplasmic reticulum chaperones, committing the N terminus to the lumen. Synthesis of the transmembrane domain before completion of this step allows it to direct the generation of (Ctm)PrP, a transmembrane form with its N terminus in the cytosol. Thus, segregation of nascent PrP into different topological configurations is critically dependent on the precise timing of signal-mediated initiation of N-terminus translocation. Consequently, this step could be experimentally tuned to modify PrP topogenesis, including complete reversal of the elevated (Ctm)PrP caused by disease-associated mutations in the transmembrane domain. These results delineate the sequence of events involved in PrP biogenesis, explain the mechanism of action of (Ctm)PrP-favoring mutations associated with neurodegenerative disease, and more generally, reveal that translocation substrates can be cotranslationally partitioned into multiple populations at the translocon.
PMID:_12429823
Med Hypotheses. 2003 May;60(5):654-9. Overlapping translation of nucleic acid sequences for bioinformatics applications.
Charles Biro J.
Karolinska Institute and Homulus Informatics, Stockholm, Sweden
SUMMARY: An alternative method to TblastX has been developed. Nucleic acids in database and query sequences were translated into overlapping protein-like sequences (overlappingly translated sequences or OTSs) before searching with BlastP. Thus, each nucleic acid sequences is represented by a single 'protein like' sequence instead of three 'proteins' in different reading frames. The 3x3 comparison of TblastX is represented by a single comparison, giving faster results. Additional advantages are: (1) it can be more sensitive to detect weak sequence similarities than either blastN or TblastX; (2) codon redundancy is eliminated; (3) the sensitivity to single nucleotide polymorphism, mutation and sequencing errors is reduced; (4) it is insensitive to frame shifts.RESULTS: BlastP using OTS detected about two thirds of blastN and TblastX matches but discovered additional similarities. When blastN and TblastX against nucleic acids were compared to blastP against OTS, identical matches discovered by blastP were generally longer (602, respectively. 213 letters, p<0.01), had higher scores (748 respectively 460 bits, p<0.05) and lower E values (3.16E-20 vs. 1.17E+03, p<0.01) but the percentage identity was lower (25% respectively 61%, p<0.001). A qualitative evaluation with LALIGN showed an improvement of the visualization when OTS-s were used instead of nucleic acids. Many extensive sequence similarities became better visible, for example the repeating similarity between prion protein and human insulin gene micro-satellite, and the surprising similarity between the first part of prion protein coding region and the human pro-insulin (34.4% identity and additional 17.2% similarity through 238 residues, score >295 which is expected 4.6e-18 times by chance).
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