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M R Scott

Publications and source records attributed to M R Scott.

At least 19 recordsLinked to original sources
PubMed2001

Distribution of 137Cs in the Lena River estuary-Laptev Sea system.

Surface sediment samples in the Laptev Sea have average 137Cs content of 7.1 Bq kg(-1), a value intermediate between that of the western Kara Sea (23 Bq kg(-1) and the East Siberian Sea (4.2 Bq kg-'). Both surface sediment content and sediment inventory of 137Cs in the Laptev Sea sediments show significant variability, and the influence of a variety of environmental factors.137Cs concentrations in the Laptev Sea surface sediments range from 0.8 to 16 Bq kg(-1). There is a marked increase in 137Cs content of surface sediment samples collected near the Lena River delta, and a local enrichment in the 137Cs inventories at these sites is also evident. Fine-grained mixed-layer illite/ smectite rich sediments in the estuary provide effective adsorption sites to fix 137Cs, in spite of desorption processes associated with low salinities in estuarine mixing. The Lena River-Laptev Sea mixing zone is a major site of sea-ice production. River and shelf sediments are incorporated into sea-ice formed in this region (Holmes and Creager, 1974). The irregular 137Cs activity profiles of the Lena River estuary cores indicate disturbance or removal of 137Cs-laden sediments via sea-ice related processes. Lena River and Estuary sediments may have served as a secondary source (i.e. other than direct fallout) of 137Cs in sea-ice. North-east of the Lena River estuary, sediment contains a thin layer of 137Cs-bearing material over an erosion surface. The 137Cs-laden surface layer may be the result of transient deposition of estuarine sediments being delivered by sea-ice or spring floods.

Cesium Radioisotopes↗
PubMed2001

Strain-specified relative conformational stability of the scrapie prion protein.

Studies of prion biology and diseases have elucidated several new concepts, but none was more heretical than the proposal that the biological properties that distinguish different prion strains are enciphered in the disease-causing prion protein (PrP(Sc)). To explore this postulate, we examined the properties of PrP(Sc) from eight prion isolates that propagate in Syrian hamster (SHa). Using resistance to protease digestion as a marker for the undenatured protein, we examined the conformational stabilities of these PrP(Sc) molecules. All eight isolates showed sigmoidal patterns of transition from native to denatured PrP(Sc) as a function of increasing guanidine hydrochloride (GdnHCl) concentration. Half-maximal denaturation occurred at a mean value of 1.48 M GdnHCl for the Sc237, HY, SHa(Me7), and MT-C5 isolates, all of which have approximately 75-d incubation periods; a concentration of 1.08 M was found for the DY strain with a approximately 170-d incubation period and approximately 1.25 M for the SHa(RML) and 139H isolates with approximately 180-d incubation periods. A mean value of 1.39 M GdnHCl for the Me7-H strain with a approximately 320-d incubation period was found. Based on these results, the eight prion strains segregated into four distinct groups. Our results support the unorthodox proposal that distinct PrP(Sc) conformers encipher the biological properties of prion strains.

Animals↗
PubMed2001

Identification of two prion protein regions that modify scrapie incubation time.

A series of prion transmission experiments was performed in transgenic (Tg) mice expressing either wild-type, chimeric, or truncated prion protein (PrP) molecules. Following inoculation with Rocky Mountain Laboratory (RML) murine prions, scrapie incubation times for Tg(MoPrP)4053, Tg(MHM2)294/Prnp(0/0), and Tg(MoPrP, Delta23-88)9949/Prnp(0/0) mice were approximately 50, 120, and 160 days, respectively. Similar scrapie incubation times were obtained after inoculation of these lines of Tg mice with either MHM2(MHM2(RML)) or MoPrP(Delta23-88)(RML) prions, excluding the possibility that sequence-dependent transmission barriers could account for the observed differences. Tg(MHM2)294/Prnp(0/0) mice displayed prolonged scrapie incubation times with four different strains of murine prions. These data provide evidence that the N terminus of MoPrP and the chimeric region of MHM2 PrP (residues 108 through 111) both influence the inherent efficiency of prion propagation.

Animals↗
PubMed2001

Branched polyamines cure prion-infected neuroblastoma cells.

Branched polyamines, including polyamidoamine and polypropyleneimine (PPI) dendrimers, are able to purge PrP(Sc), the disease-causing isoform of the prion protein, from scrapie-infected neuroblastoma (ScN2a) cells in culture (S. Supattapone, H.-O. B. Nguyen, F. E. Cohen, S. B. Prusiner, and M. R. Scott, Proc. Natl. Acad. Sci. USA 96:14529-14534, 1999). We now demonstrate that exposure of ScN2a cells to 3 microg of PPI generation 4.0/ml for 4 weeks not only reduced PrP(Sc) to a level undetectable by Western blot but also eradicated prion infectivity as determined by a bioassay in mice. Exposure of purified RML prions to branched polyamines in vitro disaggregated the prion rods, reduced the beta-sheet content of PrP 27-30, and rendered PrP 27-30 susceptible to proteolysis. The susceptibility of PrP(Sc) to proteolytic digestion induced by branched polyamines in vitro was strain dependent. Notably, PrP(Sc) from bovine spongiform encephalopathy-infected brain was susceptible to PPI-mediated denaturation in vitro, whereas PrP(Sc) from natural sheep scrapie-infected brain was resistant. Fluorescein-labeled PPI accumulated specifically in lysosomes, suggesting that branched polyamines act within this acidic compartment to mediate PrP(Sc) clearance. Branched polyamines are the first class of compounds shown to cure prion infection in living cells and may prove useful as therapeutic, disinfecting, and strain-typing reagents for prion diseases.

Humans↗
PubMed2000

137Cs distribution and geochemistry of Lena River (Siberia) drainage basin lake sediments.

The Lena River is the second largest river that discharges into the Arctic Ocean. It is therefore important to determine not only the direct impact its discharge has on the 137Cs concentration of the Arctic, but also the potential its drainage basin has as a 137Cs source. 137Cs surface sediment concentrations and inventory values, which range from 4.97 to 338 Bq kg(-1) and 357 to 1732 Bq m(-2), respectively, were determined for the Lena River drainage basin lake samples, via gamma analysis. The average geochemical and mineralogical composition of a subset of samples was also determined using neutron activation analysis, X-ray diffraction and X-ray fluorescence spectrometry techniques. Results of these geochemical analyses allowed for the identification of key geochemical factors that influence the distribution of 137Cs in the Lena River drainage basin. 137Cs profiles indicate that Lena River drainage basin lacustrine sediments serve as a record of 137Cs fallout. Based on the downcore 137Cs, %illite, %smectite, %Al and %Mn distribution patterns, it was concluded that a small fraction of non-selectively bound 137Cs was remobilized at depth in some cores. Inconsistencies between the actual 137Cs fallout record and the 137Cs profiles determined for the lake sediments were attributed to 137Cs remobilization in subsurface sediments. In addition to establishing the agreement between the global atmospheric fallout record and the downcore 137Cs distribution patterns determined for these sediments, results indicate that 137Cs deposited during periods of maximum atmospheric release was buried and is not susceptible to surface erosion processes. However, mean 137Cs concentrations of the lacustrine surface sediments (125 Bq kg(-1)) are still significantly higher than those of the nearby Lena River estuary (11.22 Bq kg(-1)) and Laptev Sea (6.00 Bq kg(-1)). Our study suggests that the Lena River drainage basin has the potential to serve as a source of 137Cs to the adjacent Arctic Ocean.

Cesium Radioisotopes↗
PubMed2000

Transgenic models of prion disease.

There is growing concern that bovine spongiform encephalopathy (BSE) may have passed from cattle to humans, resulting in approximately 70 cases of an atypical, variant CJD (vCJD) in teenagers and young adults. We report here that transgenic (Tg) mice expressing full-length bovine (Bo) PrP serially propagate BSE prions and that there is no species barrier for transmission from cattle to Tg(BoPrP) mice. Surprisingly, these same mice were also highly susceptible to vCJD and natural sheep scrapie. The incubation times (approximately 250 d), neuropathology, and PrP(Sc) isoforms in Tg(BoPrP) mice inoculated with vCJD and BSE brain extracts were indistinguishable and differed dramatically from those seen in these mice injected with natural scrapie. In efforts to identify PrP sequences required for prion formation, we found that a redacted prion protein of only 106 amino acids (PrP106) containing two large deletions supported prion propagation. In Tg(PrP106) mice, an artificial transmission barrier for the passage of full-length mouse prions was diminished by the coexpression of full-length wt MoPrP(C), suggesting that wt MoPrP acts in trans to accelerate the replication of "miniprions" containing PrP(Sc)106. Following a single passage (approximately 300 d) in Tg(PrP106) mice, the miniprions efficiently transmitted disease to Tg(PrP106) mice after only approximately 66 days. Our findings with Tg(BoPrP) mice provide compelling evidence that prions from cattle with BSE have infected humans and caused fatal neurodegeneration, the unique features of miniprions offer new insights into the mechanism of prion replication, and the trans-acting effects of full-length PrP coexpression suggest a new approach to the development of even more efficient animal models for prion diseases.

Animals↗
PubMed1999

Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans.

There is growing concern that bovine spongiform encephalopathy (BSE) may have passed from cattle to humans. We report here that transgenic (Tg) mice expressing bovine (Bo) prion protein (PrP) serially propagate BSE prions and that there is no species barrier for transmission from cattle to Tg(BoPrP) mice. These same mice were also highly susceptible to a new variant of Creutzfeldt-Jakob disease (nvCJD) and natural sheep scrapie. The incubation times (approximately 250 days), neuropathology, and disease-causing PrP isoforms in Tg(BoPrP)Prnp(0/0) mice inoculated with nvCJD and BSE brain extracts were indistinguishable and differed dramatically from those seen in these mice injected with natural scrapie prions. Our findings provide the most compelling evidence to date that prions from cattle with BSE have infected humans and caused fatal neurodegeneration.

Animals↗
PubMed1999

Elimination of prions by branched polyamines and implications for therapeutics.

We report that branched polyamines, including polyamidoamide dendimers, polypropyleneimine, and polyethyleneimine, are able to purge PrP(Sc), the protease-resistant isoform of the prion protein, from scrapie-infected neuroblastoma (ScN2a) cells in culture. The removal of PrP(Sc) by these compounds depends on both the concentration of branched polymer and the duration of exposure. Chronic exposure of ScN2a cells to low noncytotoxic concentrations of branched polyamines for 1 wk reduced PrP(Sc) to an undetectable level, a condition that persisted at least 3 wk after removal of the compound. Structure-activity analysis revealed that a high surface density of primary amino groups is required for polyamines to eliminate PrP(Sc) effectively from cells. The removal of PrP(Sc) by branched polyamines is attenuated by chloroquine in living cells, and exposure of scrapie-infected brain extracts with branched polyamines at acidic pH rendered the PrP(Sc) susceptible to protease in vitro, suggesting that endosomes or lysozomes may be the site of action. Our studies suggest that branched polyamines might be useful therapeutic agents for treatment of prion diseases and perhaps a variety of other degenerative disorders.

Animals↗
PubMed1998

A transmembrane form of the prion protein in neurodegenerative disease.

At the endoplasmic reticulum membrane, the prion protein (PrP) can be synthesized in several topological forms. The role of these different forms was explored with transgenic mice expressing PrP mutations that alter the relative ratios of the topological forms. Expression of a particular transmembrane form (termed CtmPrP) produced neurodegenerative changes in mice similar to those of some genetic prion diseases. Brains from these mice contained CtmPrP but not PrPSc, the PrP isoform responsible for transmission of prion diseases. Furthermore, in one heritable prion disease of humans, brain tissue contained CtmPrP but not PrPSc. Thus, aberrant regulation of protein biogenesis and topology at the endoplasmic reticulum can result in neurodegeneration.

Amino Acid Sequence↗
PubMed1997

Identification of a prion protein epitope modulating transmission of bovine spongiform encephalopathy prions to transgenic mice.

There is considerable concern that bovine prions from cattle with bovine spongiform encephalopathy (BSE) may have been passed to humans (Hu), resulting in a new form of Creutzfeldt-Jakob disease (CJD). We report here the transmission of bovine (Bo) prions to transgenic (Tg) mice expressing BoPrP; one Tg line exhibited incubation times of approximately 200 days. Like most cattle with BSE, vacuolation and astrocytic gliosis were confined in the brainstems of these Tg mice. Unexpectedly, mice expressing a chimeric Bo/Mo PrP transgene were resistant to BSE prions whereas mice expressing Hu or Hu/Mo PrP transgenes were susceptible to Hu prions. A comparison of differences in Mo, Bo, and Hu residues within the C terminus of PrP defines an epitope that modulates conversion of PrPC into PrPSc and, as such, controls prion transmission across species. Development of susceptible Tg(BoPrP) mice provides a means of measuring bovine prions that may prove critical in minimizing future human exposure.

Animals↗
PubMed1997

Selective neuronal targeting in prion disease.

The pattern of scrapie prion protein (PrP(Sc)) accumulation in the brain is different for each prion strain. We tested whether the PrP(Sc) deposition pattern is influenced by the Asn-linked oligosaccharides of PrP(C) in transgenic mice. Deletion of the first oligosaccharide altered PrP(C) trafficking and prevented infection with two prion strains. Deletion of the second did not alter PrP(C) trafficking, permitted infection with one prion strain, and had a profound effect on the PrP(Sc) deposition pattern. Our data raise the possibility that glycosylation can modify the conformation of PrP(C). Glycosylation could affect the affinity of PrP(C) for a particular conformer of PrP(Sc), thereby determining the rate of nascent PrP(Sc) formation and the specific patterns of PrP(Sc) deposition.

Animals↗
PubMed1997

Propagation of prion strains through specific conformers of the prion protein.

Two prion strains with identical incubation periods in mice exhibited distinct incubation periods and different neuropathological profiles upon serial transmission to transgenic mice expressing chimeric Syrian hamster/mouse (MH2M) prion protein (PrP) genes [Tg(MH2M) mice] and subsequent transmission to Syrian hamsters. After transmission to Syrian hamsters, the Me7 strain was indistinguishable from the previously established Syrian hamster strain Sc237, despite having been derived from an independent ancestral source. This apparent convergence suggests that prion diversity may be limited. The Me7 mouse strain could also be transmitted directly to Syrian hamsters, but when derived in this way, its properties were distinct from those of Me7 passaged through Tg(MH2M) mice. The Me7 strain did not appear permanently altered in either case, since the original incubation period could be restored by effectively reversing the series of passages. Prion diversity enciphered in the conformation of the scrapie isoform of PrP (PrP(Sc)) (G. C. Telling et al., Science 274:2079-2082, 1996) seems to be limited by the sequence of the PrP substrates serially converted into PrP(Sc), while prions are propagated through interactions between the cellular and scrapie isoforms of PrP.

Animals↗
PubMed1997

Genetics of prions.

Prions are unprecedented infectious pathogens that cause a group of invariably fatal, neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). The human prion disease Creutzfeldt-Jakob disease (CJD) generally presents as a progressive dementia, whereas scrapie of sheep and bovine spongiform encephalopathy (BSE) are manifest as ataxic illnesses. Prions are devoid of nucleic acid and seem to be composed exclusively of a modified isoform of PrP designated PrPSc. The normal, cellular PrP designated PrPC is converted into PrPSc through a process whereby some of its alpha-helical structure is converted into beta-sheet. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens with a nucleic acid genome, prions encipher strain-specific properties in the tertiary structure of PrPSc. Transgenetic studies argue that PrPSc acts as a template upon which PrPC is refolded into a nascent PrPSc molecule through a process facilitated by another protein.

Animals↗
PubMed1996

Psychometrics of neurological soft signs.

OBJECTIVE: To examine the psychometrics of neurological soft signs in young children. METHOD: In a sample of 42 children from the community, two examiners simultaneously rated soft signs using a standardized examination. A subsample (n = 33) was reexamined twice over the next week to estimate test-retest reliability. RESULTS: Total score exhibited acceptable internal consistency as well as interrater and test-retest reliability. Psychometrics for individual items appeared less satisfactory than for the total score. DISCUSSION: Although examiners can reliably rate a variety of soft signs, more research examining test-retest reliability is needed. A reliable examination might be useful in future efforts to document the neuropsychiatric correlates of soft signs.

Child↗