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PubMed1998

Sec-independent insertion of thylakoid membrane proteins. Analysis of insertion forces and identification of a loop intermediate involving the signal peptide.

A group of membrane proteins are synthesized with cleavable signal sequences but inserted into the thylakoid membrane by an unusual Sec/SRP-independent mechanism. In this report we describe a key intermediate in the insertion of one such protein, photosystem II subunit W (PSII-W). A single mutation in the terminal cleavage site partially blocks processing and leads to the formation of an intermediate-size protein in the thylakoid membrane during chloroplast import assays. This protein is in the form of a loop structure: the N and C termini are exposed on the stromal face, whereas the cleavage site has been translocated into the lumen. In this respect the insertion of this protein resembles that of M13 procoat, which also adopts a loop structure during insertion, and we present preliminary evidence that a similar mechanism is used by another thylakoid protein, PSII-X. However, whereas the negatively charged region of procoat is translocated by an apparently electrophoretic mechanism using the DeltamuH+, the corresponding region of PSII-W is equally acidic but insertion is DeltamuH+ independent. We furthermore show that neutralization of this region has no apparent effect on the insertion process. We propose that a central element in this insertion mechanism is a loop structure whose formation is driven by hydrophobic interactions.

Amino Acid Sequence↗

PubMed1991

Insertion element IS987 from Mycobacterium bovis BCG is located in a hot-spot integration region for insertion elements in Mycobacterium tuberculosis complex strains.

Most strains of the Mycobacterium tuberculosis complex carry multiple copies of an IS3-like element, and these strains are highly polymorphic with regard to the site of integration in the chromosome. In contrast, Mycobacterium bovis BCG contains a single copy of the insertion element, and in all strains this copy is integrated at the same site in the chromosome. In this study, we determined the sequence of the single-copy insertion element from M. bovis BCG, IS987, and its flanking regions. The analysis of IS987 revealed that this element was virtually identical to the sequence of IS986 from M. tuberculosis. IS987 is located in a region containing direct repeats (DRs). The cloned flanking regions contained 20 virtually identical DRs of 36 bp, each separated by 35 to 41 bp of spacer DNA. Analysis of chromosomal DNA by the polymerase chain reaction revealed the presence of a cluster of 49 DRs, and IS987 is inserted in the 30th DR. Furthermore, the DR sequences were found to occur only in species of the M. tuberculosis complex and not in nine other mycobacterial species tested. Analysis of 14 M. tuberculosis strains revealed the presence of one insertion sequence element in the DR-containing region of eight strains, two insertion sequence elements were located in the DR region of five strains, and one strain did not contain an insertion sequence element in this region. Additionally, the DR-containing regions of these 14 M. tuberculosis strains were polymorphic in length and composition. We conclude that the DR cluster is a specific, hot-spot region for integration of insertion elements in the chromosome of M. tuberculosis complex strains.

Amino Acid Sequence↗

PubMed2001

Reverse dot blot assay (insertion site typing) for precise detection of sites of IS6110 insertion in the Mycobacterium tuberculosis genome.

We have developed an amplification-based reverse dot blot assay for the detection of specific sites of insertion of the Mycobacterium tuberculosis insertion sequence IS6110. In this assay, a set of biotin-labeled amplicons representing the various copies of IS6110 and their flanking sequences is generated by linker-mediated PCR. The amplicons are then hybridized to immobilized oligonucleotide probes that are specific for known IS6110 insertion sites. The method was evaluated using an array of oligonucleotide probes corresponding to IS6110 insertion sites from M. tuberculosis strains CDC1551, Erdman, and H37Rv, and multidrug-resistant strain W. A set of 72 DNA samples from 60 M. tuberculosis clinical isolates was analyzed for the presence or absence of these insertion sites, and the assay was found to be highly reproducible. This method of identifying insertion sites has been named "insite" and can be used for the genotyping of M. tuberculosis complex strains based on IS6110 insertion site profiles.

Bacterial Typing Techniques↗

PubMed2006

Confirmed: there is no correlation between the insertional distance between the nasal limbus and the insertion of the medial rectus muscle--and the size of the strabismus angle in infantile esotropia.

INTRODUCTION: Historical systems of measuring the amount of surgical recession of the medial rectus muscles appropriate to be performed for a given size of angle of infantile esotropia, based upon relative recession measurement from the limbus might have proven to be better than relative recession measurement from the insertion--if a positive correlation were found between the size of the angle of the esodeviation and the distance between the insertion of the medial rectus and the nasal limbus. A search of the scientific literature since 1966 as listed in PubMed (National Library of Medicine, formerly Index Medicus) did not reveal any additional confirmatory study of this type in PubMed. We therefore undertook to perform such a study. METHODS: Using standard strabismus calipers, at surgery for esotropia, intraoperative measurements were made of the insertional distance (in mm between the most nasal point of the clear cornea and, following standard surgical excision of the muscle from the globe, the anterior insertional ridge of the medial rectus muscle of the eye) in a series of 104 consecutive infantile esotropes operated by the author between 1987 and 1991. These data were then graphically plotted as the ordinate with the abscissa defined as the size of the angle of the esotropia measured with the prism alternate cover test the day prior to surgery. RESULTS: No correlation was found between the medial rectus muscle insertional distance and the size of the preoperative esodeviation in prism diopters, correlation coefficient r=0.14, p=0.078. DISCUSSION OF RESULTS: In this large series, the lack of a correlation has credibility as it fails to achieve conventional limits of a "statistical significance" of the difference. CONCLUSION: The lack of correlation between the size of the deviation and the insertional distance offers support for the widespread acceptance and use of the alternative, the dose-response curves based on the mm of recession measured from the anterior ridge of the medial rectus muscle insertion.

Esotropia↗

PubMed1994

Construction of a single-transposon-insertion mutant in Rhizobium sp. strain TAL1145 from a double-insertion mutant.

A method for developing a single-transposon-insertion mutant from a double-insertion mutant in Rhizobium is described. An exopolysaccharide (EPS)-defective mutant containing two Tn5-lacZ insertions was complemented with cloned wild-type DNA for EPS synthesis. One of the Tn5-lacZ insertions from the mutant was transferred to the complementing plasmid by homologous recombination. The plasmid containing the Tn5-lacZ insertion in the gene involved in EPS synthesis was transferred into the wild-type strain and the Tn5-lacZ was homogenized to obtain an EPS-defective mutant with a single Tn5-lacZ insertion.

Blotting, Southern↗

PubMed1999

Characterization of insertions of IS476 and two newly identified insertion sequences, IS1478 and IS1479, in Xanthomonas campestris pv. campestris.

Thirty-two plasmid insertion mutants were independently isolated from two strains of Xanthomonas campestris pv. campestris in Taiwan. Of the 32 mutants, 14 (44%), 8 (25%), and 4 (12%) mutants resulted from separate insertions of an IS3 family member, IS476, and two new insertion sequences (IS), IS1478 and IS1479. While IS1478 does not have significant sequence homology with any IS elements in the EMBL/GenBank/DDBJ database, IS1479 demonstrated 73% sequence homology with IS1051 in X. campestris pv. dieffenbachiae, 62% homology with IS52 in Pseudomonas syringae pv. glycinea, and 60% homology with IS5 in Escherichia coli. Based on the predicted transposase sequences as well as the terminal nucleotide sequences, IS1478 by itself constitutes a new subfamily of the widespread IS5 family, whereas IS1479, along with IS1051, IS52, and IS5, belongs to the IS5 subfamily of the IS5 family. All but one of the IS476 insertions had duplications of 4 bp at the target sites without sequence preference and were randomly distributed. An IS476 insertion carried a duplication of 952 bp at the target site. A model for generating these long direct repeats is proposed. Insertions of IS1478 and IS1479, on the other hand, were not random, and IS1478 and IS1479 each showed conservation of PyPuNTTA and PyTAPu sequences (Py is a pyrimidine, Pu is a purine, and N is any nucleotide) for duplications at the target sites. The results of Southern blot hybridization analysis indicated that multiple copies of IS476, IS1478, and IS1479 are present in the genomes of all seven X. campestris pv. campestris strains tested and several X. campestris pathovars.

Amino Acid Sequence↗

PubMed2002

Insertions in the reverse transcriptase increase both drug resistance and viral fitness in a human immunodeficiency virus type 1 isolate harboring the multi-nucleoside reverse transcriptase inhibitor resistance 69 insertion complex mutation.

Recent studies have shown that the accumulation of multiple mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance may be grouped as multi-NRTI resistance (MNR) complexes. In this study, we have examined the viral fitness of recombinant viruses carrying the reverse transcriptase (RT) of a human immunodeficiency virus type 1 (HIV-1) primary isolate harboring mutations comprising the MNR 69 insertion complex. Different RT mutants were prepared in the sequence context of either the wild-type RT sequence of the HIV-1(BH10) isolate or the sequence found in a clinical HIV-1 isolate with the MNR 69 insertion mutation. As expected, in the presence of zidovudine, recombinant viruses harboring the MNR RT from the patient were more fit than wild-type viruses. However, in the absence of drug, the virus with the RT from the original clinical isolate (SS) was more fit than (i) the wild-type virus with an engineered serine insertion between residues 69 and 70 (T69SSS) and (ii) the recombinant virus with the MNR RT where the insertion was removed (2S0S). These results suggest that RT insertions, in the right sequence context (i.e., additional mutations contained in the MNR 69 insertion complex), enhance NRTI resistance and may improve viral fitness. Thus, comparing complex mutation patterns with viral fitness may help to elucidate the role of uncharacterized drug resistance mutations in antiretroviral treatment failure.

Adult↗

PubMed1990

The developmental morphology of a "periosteal" ligament insertion: growth and maturation of the tibial insertion of the rabbit medial collateral ligament.

The structural properties of ligament insertions change dramatically during growth and maturation, but little is known about their developmental anatomy. This study describes and quantifies changes in the gross and microscopic anatomy of the tibial insertion of the rabbit medial collateral ligament (MCL) during development and at skeletal maturity. Eighty animals were used for growth and descriptive studies. From this group, 27 animals, ranging in age from 1 to 24 months, were injected with fluorescent bone markers and their tibial insertions were processed undecalcified for histology. Sections were examined by polarized light and fluorescence microscopy to identify matrix and cells and to quantify mineral formation. Results showed that animals achieved histological skeletal maturity between 9 and 12 months of age. Body weights were a poor index of skeletal maturity. The tibial insertion was composed of five tissue layers, which changed proportions during growth and maturation. In immature animals, MCL fibers entered the periosteum; in older animals, MCL fibers were cemented to the tibia by advancing mineral. The tibial attachment of the MCL was thus transferred from the periosteum to the cortex during growth, suggesting that the term "periosteal insertion" is imprecise in adults. The hypothesis is put forward that these structural changes account for the reported increase in tensile failure of this insertion near skeletal maturity.

Aging↗

PubMed2003

Evolutionary dynamics of large numts in the human genome: rarity of independent insertions and abundance of post-insertion duplications.

We determined the phylogenetic positions of 82 large nuclear pseudogenes of mitochondrial origin (numts) within the human genome. For each numt, two possibilities pertaining to its origin were considered: (1) independent insertion from the mitochondria into the nucleus, or (2) genomic duplication subsequent to the insertion. A significant increase in the rate of numt accumulation is seen after the divergence of Platyrrhini (New World monkeys) from the Catarrhini (Old World monkeys, apes and humans). By using pairwise phylogenetic analyses, we were able to demonstrate that this peak in numt accumulation is mostly the result of duplication of preexisting nuclear numts rather than the result of an increase in mitochondrial-sequence insertion. In fact, only about a third of all the numt repertoire in the human nuclear genome is due to insertions of mitochondrial sequences, the rest originated as duplications of preexisting numts. Hence, we conclude that numt insertion occurs at a much lower rate than previously reported. As expected under the assumption that genomic duplications occur at rates that are uninfluenced by content, older numts were found to be duplicated more times than recently inserted ones.

DNA Transposable Elements↗

PubMed1983

Comparison of wire-guided percutaneous insertion and conventional surgical insertion of intra-aortic balloon pumps in 151 patients.

Over a 25-month period, percutaneous wire-guided balloon catheter insertion was attempted in 51 patients, and intra-aortic balloon pump insertion was attempted by conventional surgical method in 100 patients. The success rate in the group undergoing percutaneous insertion was 90.2 percent (46 of 51) and 90 percent in the group undergoing surgical insertion (90 of 100). The indications for intra-aortic balloon counterpulsation were diverse in both groups. The major complication rate in the patient population undergoing percutaneous intra-aortic balloon pump insertion was 15.2 versus 15.6 percent for the surgical group, and there were no cases of leg amputation or aortic dissection in the percutaneous group; however, two cases of leg amputation and one case of aortic dissection resulting in death occurred in the surgical group. The percutaneous intra-aortic balloon pump insertion technique was successfully employed in conjunction with percutaneous transluminal coronary angioplasty in six cases. It is concluded that the wire-guided percutaneous balloon catheter method is a highly successful and rapid means of instituting intra-aortic balloon counterpulsation in a wide variety of clinical situations. However, because of the significant associated complication rate, the decision to institute balloon counterpulsation must weigh the benefit-to-risk ratio, and this procedure must still be evaluated on a case-by-case basis.

Adult↗

PubMed1988

Comparisons of host cell DNA insertions and altered transcription at the site of insertions in few polyhedra bacilovirus mutants.

Few polyhedgra (FP) mutants of Autographa californica nuclear polyhedrosis virus (AcNPV) and the closely related strain Galleria mellonella (Gm)NPV have been reported which contain Trichoplusia ni host cell DNA sequences inserted into the viral genome between map units 35.0 and 37.7. New FP mutants are described with alterations of the HindIII-I restriction enzyme fragment (33.8 to 37.7 map units) of AcNPV, either deletions of viral DNA sequences or insertions of spodoptera frugiperda host cell DNA sequences. S. frugiperda DNA insertions from FP mutants were compared to T. ni host DNA insertions from FP mutants previously isolated (M.J. Fraser, G.E. Smith, and M.D. Summers (1983) J. Virol. 47, 287-300). Two host cell DNA sequences isolated from FP mutants, one of T. ni origin and one from S. frugiperda DNA, were transcribed in infected cells. Deletions of viral DNA sequences and insertions of host DNA sequences produce altered transcripts at the site of mutation as determined by both Northern and S1 nuclease analysis. Cell-free translation of cRNAs transcribed from wild-type viral DNA revealed an open reading frame coding for a 25-kDa protein at the site where host cell DNA insertions have been mapped. This was the same size as an infected-cell protein missing from most FP mutants examined.

DNA Transposable Elements↗

PubMed2002

A Monte Carlo study of peptide insertion into lipid bilayers: equilibrium conformations and insertion mechanisms.

The membrane insertion behavior of two peptides, Magainin2 and M2 delta, was investigated by applying the Monte Carlo simulation technique to a theoretical model. The model included many novel aspects, such as a new semi-empirical lipid bilayer model and a new set of semi-empirical transfer energies, which reproduced the experimental insertion behavior of Magainin2 and M2 delta without parameter fitting. Additionally, we have taken into account diminished internal (intramolecular) hydrogen bonding at the N- and C-termini of helical peptides. All simulations were carried out at 305 K, above the membrane thermal phase transition temperature, and at pH 7.0. The peptide equilibrium conformations are discussed for a range of bilayers with tail polarities varying from octanol-like to alkane-like. Probability distributions of the individual amino-acid-residue positions show the dynamic nature of these equilibrium conformations. Two different insertion mechanisms for M2 delta, and a translocation mechanism for Magainin2, are described. A study of the effect of bilayer thickness on M2 delta insertion suggests a critical thickness above which insertion is unfavorable. Additionally, we did not need to use an orientational potential or array of hard cylinders to persuade M2 delta to insert perpendicular to the membrane surface. Instead, we found that diminished internal hydrogen bonding in the helical conformation anchored the termini in the headgroups and resulted in a nearly perpendicular orientation.

Amino Acid Sequence↗

PubMed2004

Analyzing topography of membrane-inserted diphtheria toxin T domain using BODIPY-streptavidin: at low pH, helices 8 and 9 form a transmembrane hairpin but helices 5-7 form stable nonclassical inserted segments on the cis side of the bilayer.

Low pH-induced membrane insertion by diphtheria toxin T domain is crucial for A chain translocation into the cytoplasm. To define the membrane topography of the T domain, the exposure of biotinylated Cys residues to the cis and trans bilayer surfaces was examined using model membrane vesicles containing a deeply inserted T domain. To do this, the reactivity of biotin with external and vesicle-entrapped BODIPY-labeled streptavidin was measured. The T domain was found to insert with roughly 70-80% of the molecules in the physiologically relevant orientation. In this orientation, residue 349, located in the loop between hydrophobic helices 8 and 9, was exposed to the trans side of the bilayer, while other solution-exposed residues along the hydrophobic helices 5-9 region of the T domain located near the cis surface. A protocol developed to detect the movement of residues back and forth across the membranes demonstrated that T domain sequences did not rapidly equilibrate between the cis and the trans sides of the bilayer. Binding streptavidin to biotinylated residues prior to membrane insertion only inhibited T domain pore formation for residues in the loop between helices 8 and 9. Pore formation experiments used an approach avoiding interference from transient membrane defects/leakage that may occur upon the initial insertion of protein. Combined, these results indicate that at low pH hydrophobic helices 8 and 9 form a transmembrane hairpin, while hydrophobic helices 5-7 form a nonclassical deeply inserted nontransmembraneous state. We propose that this represents a novel pre-translocation state that is distinct from a previously defined post-translocation state.

Amino Acid Sequence↗

PubMed1999

The Sinorhizobium meliloti insertion sequence (IS) elements ISRm102F34-1/ISRm7 and ISRm220-13-5 belong to a new family of insertion sequence elements.

The Sinorhizobium meliloti insertion sequence (IS) elements ISRm102F34-1 and ISRm220-13-5 are 1481 and 1550 base pairs (bp) in size, respectively. ISRm102F34-1 is bordered by 15 bp imperfect terminal inverted repeat sequences (two mismatches), whereas the terminal inverted repeat of ISRm220-13-5 has a length of 16 bp (two mismatches). Both insertion sequence elements generate a 6-bp target duplication upon transposition. The putative transposase enzymes of ISRm102F34-1 and ISRm220-13-5 consist of 449 or 448 amino acid residues with predicted molecular weights of 50.7 or 51.3 kDa and theoretical isoelectric points of 10.8 or 11.1, respectively. ISRm102F34-1 is identical in 98.9% of its nucleotide sequence to an apparently inactive copy of an insertion sequence element, designated ISRm7, which flanks the left-end of the nodule formation efficiency (nfe) region of plasmid pRmeGR4b of S. meliloti strain GR4. ISRm102F34-1 and ISRm220-13-5 are closely related since they show an overall identity of 57.0% at the nucleotide sequence level and of 47.3% at the deduced amino acid level of their putative transposases. Both insertion sequence elements displayed significant similarity to the Xanthomonas campestris ISXc6 and its homolog IS1478a. Since none of these insertion sequence elements could be allocated to existing families of insertion sequence elements, a new family is proposed. Analysis of the distribution of ISRm102F34-1/ISRm7 in various local S. meliloti populations sampled from Medicago sativa, Medicago sphaerocarpa and Melilotus alba host plants at different locations in Spain revealed its presence in 35% of the isolates with a copy number ranging from 1 to 5. Furthermore, ISRm102F34-1/ISRm7 homologs were identified in other rhizobial species.

Amino Acid Sequence↗

PubMed2006

Detecting statistically significant common insertion sites in retroviral insertional mutagenesis screens.

Retroviral insertional mutagenesis screens, which identify genes involved in tumor development in mice, have yielded a substantial number of retroviral integration sites, and this number is expected to grow substantially due to the introduction of high-throughput screening techniques. The data of various retroviral insertional mutagenesis screens are compiled in the publicly available Retroviral Tagged Cancer Gene Database (RTCGD). Integrally analyzing these screens for the presence of common insertion sites (CISs, i.e., regions in the genome that have been hit by viral insertions in multiple independent tumors significantly more than expected by chance) requires an approach that corrects for the increased probability of finding false CISs as the amount of available data increases. Moreover, significance estimates of CISs should be established taking into account both the noise, arising from the random nature of the insertion process, as well as the bias, stemming from preferential insertion sites present in the genome and the data retrieval methodology. We introduce a framework, the kernel convolution (KC) framework, to find CISs in a noisy and biased environment using a predefined significance level while controlling the family-wise error (FWE) (the probability of detecting false CISs). Where previous methods use one, two, or three predetermined fixed scales, our method is capable of operating at any biologically relevant scale. This creates the possibility to analyze the CISs in a scale space by varying the width of the CISs, providing new insights in the behavior of CISs across multiple scales. Our method also features the possibility of including models for background bias. Using simulated data, we evaluate the KC framework using three kernel functions, the Gaussian, triangular, and rectangular kernel function. We applied the Gaussian KC to the data from the combined set of screens in the RTCGD and found that 53% of the CISs do not reach the significance threshold in this combined setting. Still, with the FWE under control, application of our method resulted in the discovery of eight novel CISs, which each have a probability less than 5% of being false detections.

Chromosome Mapping↗

PubMed2006

Retrospective study of the total insertion period of peripherally inserted central catheter: discussion of anti-thrombogenic surface and other biomaterial requirements.

A retrospective study of patients' records on reviewing the purpose of venous catheter insertion (chemotherapy, blood transfusion, antibiotics or parenteral nutrition); total period of insertion; reason for catheter removal. 120 admitted patients who received fluoroscopic guide PICC (4-French single lumen silicone rubber catheter) insertions into distal SVC via antecubital region of forearm. We retrospectively review human factors including the patients' laboratory data of pre- and post-insertion, total insertion period and reasons for withdrawal. The important human factors that affect the clinical outcome of PICC were also evaluated. The results indicated that the most common complications were wound oozing, phlebitis, occlusion, infection and leaking. Persistent wound oozing for over 3-day-period is the higher incidence of complication. It also demonstrated a surprisingly high ratio (> 77%) in those patients with thrombocytopenia and leukemia. In this group, persistent low platelet counts could be noted, the ratio of failure (remove PICC within 3 days) is 10% and there is 40% decrease insertion period (< 30 days). Prospectively, it is worthwhile to choose new material or new technology of surface coating of PICC, to decrease consumption of platelet thrombogenic proteins and to maintain normal coagulate function of human bodies.

Catheterization, Central Venous↗

PubMed1993

The Drosophila forked gene encodes two major RNAs, which, in gypsy or springer insertion mutants, are partially or completely truncated within the 5'-LTR of the inserted retrotransposon.

Mutations in the forked (f) gene of Drosophila cause deformation of bristles and hairs. Our molecular analysis showed the f gene to span more than 30 kb, and to encode two major RNAs, 6.0 and 2.5 kb long, both of which are prematurely terminated in gypsy and springer insertion mutants. These truncated RNAs were polyadenylated using putative polyadenylation signals within the 5'-LTR of the inserted retrotransposon. No evidence was found for effects of the retrotransposon insertions on the promoters for transcription of the 6.0 and 2.5 kb RNAs. In f1 and fx, a single gypsy element was found to be inserted at identical sites in the second intron of region encoding the 2.5 kb f RNA and both truncated and wild-type sized RNAs were detected. Recessive mutations at suppressor of forked (su(f)) increased the fraction of wild-type sized RNAs considerably, suggesting that the wild-type su(f) product either stimulates premature termination at the gypsy LTR or inhibits normal splicing. In f36a, a springer element inserted in the third exon of the region encoding the 2.5 kb f RNA completely suppressed the formation of apparently wild-type transcripts.

Amino Acid Sequence↗

PubMed2007

Aggregation of prion protein with insertion mutations is proportional to the number of inserts.

Mutation in the prion gene, PRNP, accounts for approx. 10-15% of human prion diseases. However, little is known about the mechanisms by which a mutant prion protein (PrP) causes disease. We compared the biochemical properties of a wild-type human prion protein, rPrP(C) (recombinant wild-type PrP), which has five octapeptide-repeats, with two recombinant human prion proteins with insertion mutations, one with three more octapeptide repeats, rPrP(8OR), and the other with five more octapeptide repeats, rPrP(10OR). We found that the insertion mutant proteins are more prone to aggregate, and the degree and kinetics of aggregation are proportional to the number of inserts. The octapeptide-repeat and alpha-helix 1 regions are important in aggregate formation, because aggregation is inhibited with monoclonal antibodies that are specific for epitopes in these regions. We also showed that a small amount of mutant protein could enhance the formation of mixed aggregates that are composed of mutant protein and wild-type rPrP(C). Accordingly, rPrP(10OR) is also more efficient in promoting the aggregation of rPrP(C) than rPrP(8OR). These findings provide a biochemical explanation for the clinical observations that the severity of the disease in patients with insertion mutations is proportional to the number of inserts, and thus have implications for the pathogenesis of inherited human prion disease.

Antibodies, Monoclonal↗