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effects of chronic wasting disease on reproduction and fawn harvest vulnerability in wisconsin white-tailed deer.chronic wasting disease (cwd) is a fatal, transmissible spongiform encephalopathy that affects free-ranging and captive north american cervids. although the impacts of cwd on cervid survival have been documented, little is known about the disease impacts on reproduction and recruitment. we used genetic methods and harvest data (2002-04) to reconstruct parentage for a cohort of white-tailed deer (odocoileus virginianus) fawns born in spring 2002 and evaluate the effects of cwd infection on reprod ...201222493111
the role of genetics in chronic wasting disease of north american cervids.chronic wasting disease (cwd) is a major concern for the management of north american cervid populations. this fatal prion disease has led to declines in populations which have high cwd prevalence and areas with both high and low infection rates have experienced economic losses in wildlife recreation and fears of potential spill-over into livestock or humans. research from human and veterinary medicine has established that the prion protein gene (prnp) encodes the protein responsible for transmi ...201222460693
capillary electromigration based techniques in diagnostics of prion protein caused diseases.transmissible spongiform encephalopathies are a group of fatal neurodegenerative diseases with long incubation time. this group includes creutzfeld-jakob disease, kuru, scrapie, chronic wasting disease, and bovine spongiform encephalopathy. sensitive and specific detection of abnormal prion protein as "a source agent" of the above-mentioned diseases in blood could provide a diagnostic test or a screening assay for animal and human prion protein diseases diagnostics. therefore, diagnostic tests f ...201223161211
resistance of soil-bound prions to rumen digestion.before prion uptake and infection can occur in the lower gastrointestinal system, ingested prions are subjected to anaerobic digestion in the rumen of cervids and bovids. the susceptibility of soil-bound prions to rumen digestion has not been evaluated previously. in this study, prions from infectious brain homogenates as well as prions bound to a range of soils and soil minerals were subjected to in vitro rumen digestion, and changes in prp levels were measured via western blot. binding to clay ...201222937149
prion disease: chemotherapeutic strategies.prion diseases, also known as transmissible spongiform encephalopathies, are invariably fatal neurodegenerative diseases for which there are no efficacious treatments. thousands of compounds have been screened for anti-prion effect, and yet of those that have effect in vitro, very few show effect in vivo, especially if administered in the later stages of disease. however, with new techniques for early diagnosis being developed, and with further insight into the pathogenesis of early disease, inc ...201222420513
could immunomodulation be used to prevent prion diseases?all prion diseases are currently without effective treatment and are universally fatal. the underlying pathogenesis of prion diseases (prionoses) is related to an autocatalytic conformational conversion of prp(c) (c for cellular) to a pathological and infectious conformer known as prp(sc) (sc for scrapie) or prp(res) (res for proteinase k resistant). the past experience with variant creutzfeldt-jakob disease, which originated from bovine spongiform encephalopathy, as well as the ongoing epidemic ...201222397565
occurrence, transmission, and zoonotic potential of chronic wasting disease.chronic wasting disease (cwd) is a fatal, transmissible prion disease that affects captive and free-ranging deer, elk, and moose. although the zoonotic potential of cwd is considered low, identification of multiple cwd strains and the potential for agent evolution upon serial passage hinders a definitive conclusion. surveillance for cwd in free-ranging populations has documented a continual geographic spread of the disease throughout north america. cwd prions are shed from clinically and preclin ...201222377159
facilitated cross-species transmission of prions in extraneural tissue.prions are infectious pathogens essentially composed of prp(sc), an abnormally folded form of the host-encoded prion protein prp(c). constrained steric interactions between prp(sc) and prp(c) are thought to provide prions with species specificity and to control cross-species transmission into other host populations, including humans. we compared the ability of brain and lymphoid tissues from ovine and human prp transgenic mice to replicate foreign, inefficiently transmitted prions. lymphoid tiss ...201222282814
sensitivity of protein misfolding cyclic amplification versus immunohistochemistry in ante-mortem detection of chronic wasting disease.as the only prion disease affecting free-ranging animals, ante-mortem identification of affected cervids has become paramount in understanding chronic wasting disease (cwd) pathogenesis, prevalence and control of horizontal or vertical transmission. to seek maximal sensitivity in ante-mortem detection of cwd infection, this study used paired tonsil biopsy samples collected at various time points from 48 cwd-exposed cervids to compare blinded serial protein misfolding cyclic amplification (spmca) ...201222278825
detection and control of prion diseases in food animals.transmissible spongiform encephalopathies (tses), or prion diseases, represent a unique form of infectious disease based on misfolding of a self-protein (prp(c)) into a pathological, infectious conformation (prp(sc)). prion diseases of food animals gained notoriety during the bovine spongiform encephalopathy (bse) outbreak of the 1980s. in particular, disease transmission to humans, to the generation of a fatal, untreatable disease, elevated the perspective on livestock prion diseases from food ...201223738120
genetic predictions of prion disease susceptibility in carnivore species based on variability of the prion gene coding region.mammalian species vary widely in their apparent susceptibility to prion diseases. for example, several felid species developed prion disease (feline spongiform encephalopathy or fse) during the bovine spongiform encephalopathy (bse) epidemic in the united kingdom, whereas no canine bse cases were detected. whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or cwd) remains an open question. variation in the host-encoded pri ...201223236380
prion remains infectious after passage through digestive system of american crows (corvus brachyrhynchos).avian scavengers, such as american crows (corvus brachyrhynchos), have potential to translocate infectious agents (prions) of transmissible spongiform encephalopathy (tse) diseases including chronic wasting disease, scrapie, and bovine spongiform encephalopathy. we inoculated mice with fecal extracts obtained from 20 american crows that were force-fed material infected with rml-strain scrapie prions. these mice all evinced severe neurological dysfunction 196-231 d postinoculation (x =198; 95% ci ...201223082115
genetic depletion of complement receptors cd21/35 prevents terminal prion disease in a mouse model of chronic wasting disease.the complement system has been shown to facilitate peripheral prion pathogenesis. mice lacking complement receptors cd21/35 partially resist terminal prion disease when infected i.p. with mouse-adapted scrapie prions. chronic wasting disease (cwd) is an emerging prion disease of captive and free-ranging cervid populations that, similar to scrapie, has been shown to involve the immune system, which probably contributes to their relatively facile horizontal and environmental transmission. in this ...201223002439
susceptibility of cattle to the agent of chronic wasting disease from elk after intracranial inoculation.cattle could be exposed to the agent of chronic wasting disease (cwd) through contact with infected farmed or free-ranging cervids or exposure to contaminated premises. the purpose of the current study was to assess the potential for cwd derived from elk to transmit to cattle after intracranial inoculation. calves (n = 14) were inoculated with brain homogenate derived from elk with cwd to determine the potential for transmission and to define the clinicopathologic features of disease. cattle wer ...201222991389
diagnostic accuracy of rectal mucosa biopsy testing for chronic wasting disease within white-tailed deer (odocoileus virginianus) herds in north america: effects of age, sex, polymorphism at prnp codon 96, and disease progression.an effective live animal diagnostic test is needed to assist in the control of chronic wasting disease (cwd), which has spread through captive and wild herds of white-tailed deer (odocoileus virginianus) in canada and the united states. in the present study, the diagnostic accuracy of rectal mucosa biopsy sample testing was determined in white-tailed deer from 4 cwd-infected captive herds. specifically, the current study compared the immunohistochemical detection of disease-associated prion prot ...201222914819
the walk is never random: subtle landscape effects shape gene flow in a continuous white-tailed deer population in the midwestern united states.one of the pervasive challenges in landscape genetics is detecting gene flow patterns within continuous populations of highly mobile wildlife. understanding population genetic structure within a continuous population can give insights into social structure, movement across the landscape and contact between populations, which influence ecological interactions, reproductive dynamics or pathogen transmission. we investigated the genetic structure of a large population of deer spanning the area of w ...201222882236
evidence for distinct chronic wasting disease (cwd) strains in experimental cwd in ferrets.chronic wasting disease (cwd) is an evolving prion disease of cervids (deer, elk and moose) that has been recognized in north america and korea. infection of non-cervid reservoir or transport species in nature is not reported. however, the ferret (mustela putorius furo) is susceptible to cwd after experimental inoculation. here, we report that infection of ferrets with either of two ferret cwd isolates by various routes of exposure has revealed biologically distinct strain-like properties distin ...201221918005
functional genomics approach for identification of molecular processes underlying neurodegenerative disorders in prion diseases.prion diseases or transmissible spongiform encephalopathies (tses) are infectious neurodegenerative disorders leading to death. these include cresutzfeldt-jakob disease (cjd), familial, sporadic and variant cjd and kuru in humans; and animal tses include scrapie in sheep, bovine spongiform encephalopathy (bse) in cattle, chronic wasting disease (cwd) of mule deer and elk, and transmissible mink encephalopathy. all these tses share common pathological features such as accumulation of mis-folded p ...201223372423
association mapping of genetic risk factors for chronic wasting disease in wild deer.chronic wasting disease (cwd) is a fatal transmissible spongiform encephalopathy affecting north american cervids. we assessed the feasibility of association mapping cwd genetic risk factors in wild white-tailed deer (odocoileus virginianus) and mule deer (odocoileus hemionus) using a panel of bovine microsatellite markers from three homologous deer linkage groups predicted to contain candidate genes. these markers had a low cross-species amplification rate (27.9%) and showed weak linkage disequ ...201223467626
gene expression alterations in rocky mountain elk infected with chronic wasting disease.chronic wasting disease (cwd) is an invariably fatal neurologic disease that naturally infects mule deer, white tailed deer and elk. the understanding of cwd neurodegeneration at a molecular level is very limited. in this study, microarray analysis was performed to determine changes in the gene expression profiles in six different tissues including brain, midbrain, thalamus, spleen, rpln and tonsil of cwd-infected elk in comparison to non-infected healthy elk, using 24,000 bovine specific oligo ...201222561165
relationships between prpsc stability and incubation time for united states scrapie isolates in a natural host system.transmissible spongiform encephalopathies (tses), including scrapie in sheep (ovis aries), are fatal neurodegenerative diseases caused by the misfolding of the cellular prion protein (prp(c)) into a â-rich conformer (prp(sc)) that accumulates into higher-order structures in the brain and other tissues. distinct strains of tses exist, characterized by different pathologic profiles upon passage into rodents and representing distinct conformations of prp(sc). one biochemical method of distinguishin ...201222916207
soil-mediated prion transmission: is local soil-type a key determinant of prion disease incidence?prion diseases, including chronic wasting disease (cwd) and scrapie, can be transmitted via indirect environmental routes. animals habitually ingest soil, and results from laboratory experiments demonstrate prions can bind to a wide range of soils and soil minerals, retain the ability to replicate, and remain infectious, indicating soil could serve as a reservoir for natural prion transmission and a potential prion exposure route for humans. preliminary epidemiological modeling suggests soil tex ...201222265680
development of monoclonal antibodies against the abnormal prion protein isoform (prp(res)) associated with chronic wasting disease (cwd).monoclonal antibodies (mabs) specific for the abnormal prion protein isoform (prp(res)) are indispensable for diagnosing chronic wasting disease (cwd). in this study, eight mabs were developed by immunizing prp knockout mice with recombinant elk prp and an immunogenic prp peptide. the reactivity of the mabs to recombinant prp and the prp peptide was measured, and their isotypes were subsequently determined. among them, four mabs (b85-05, b85-08, b85-12, and b77-75) were shown by western blotting ...201223271186
could avian scavengers translocate infectious prions to disease-free areas initiating new foci of chronic wasting disease?mechanisms for the spread of transmissible spongiform encephalopathy diseases, including chronic wasting disease (cwd) in north american cervids, are incompletely understood, but primary routes include horizontal and environmental transmission. birds have been identified as potential vectors for a number of diseases, where they ingest or are exposed to infected material and later shed the disease agent in new areas after flying substantial distances. we recently identified american crows (corvus ...201323822910
targeting hunter distribution based on host resource selection and kill sites to manage disease risk.endemic and emerging diseases are rarely uniform in their spatial distribution or prevalence among cohorts of wildlife. spatial models that quantify risk-driven differences in resource selection and hunter mortality of animals at fine spatial scales can assist disease management by identifying high-risk areas and individuals. we used resource selection functions (rsfs) and selection ratios (srs) to quantify sex- and age-specific resource selection patterns of collared (n = 67) and hunter-killed ...201324324876
small-molecule theranostic probes: a promising future in neurodegenerative diseases.prion diseases are fatal neurodegenerative illnesses, which include creutzfeldt-jakob disease in humans and scrapie, chronic wasting disease, and bovine spongiform encephalopathy in animals. they are caused by unconventional infectious agents consisting primarily of misfolded, aggregated, β -sheet-rich isoforms, denoted prions, of the physiological cellular prion protein (prp(c)). many lines of evidence suggest that prions (prp(sc)) act both as a template for this conversion and as a neurotoxic ...201324324497
influence of landscape factors and management decisions on spatial and temporal patterns of the transmission of chronic wasting disease transmission in white-tailed deer.chronic wasting disease (cwd) has been reported in white-tailed deer at the border of the us states of illinois and wisconsin since 2002. transmission of infectious prions between animals and from the environment has resulted in spatial and temporal structure observable in the spatio-temporal patterns of reported cases. case locations of 382 positive cases from 28,954 deer tested between 2002 and 2009 provided insight into the potential risk factors and landscape features associated with transmi ...201324258897
procedures for identifying infectious prions after passage through the digestive system of an avian species.infectious prion (prp(res)) material is likely the cause of fatal, neurodegenerative transmissible spongiform encephalopathy (tse) diseases(1). transmission of tse diseases, such as chronic wasting disease (cwd), is presumed to be from animal to animal(2,3) as well as from environmental sources(4-6). scavengers and carnivores have potential to translocate prp(res) material through consumption and excretion of cwd-contaminated carrion. recent work has documented passage of prp(res) material throu ...201324300668
prion-seeding activity in cerebrospinal fluid of deer with chronic wasting disease.transmissible spongiform encephalopathies (tses), or prion diseases, are a uniformly fatal family of neurodegenerative diseases in mammals that includes chronic wasting disease (cwd) of cervids. the early and ante-mortem identification of tse-infected individuals using conventional western blotting or immunohistochemistry (ihc) has proven difficult, as the levels of infectious prions in readily obtainable samples, including blood and bodily fluids, are typically beyond the limits of detection. t ...201324282599
drug resistance confounding prion therapeutics.there is not a single pharmaceutical that halts or even slows any neurodegenerative disease. mounting evidence shows that prions cause many neurodegenerative diseases, and arguably, scrapie and creutzfeldt-jakob disease prions represent the best therapeutic targets. we report here that the previously identified 2-aminothiazoles ind24 and ind81 doubled the survival times of scrapie-infected, wild-type mice. however, mice infected with rocky mountain laboratory (rml) prions, a scrapie-derived stra ...201324128760
complement protein c3 exacerbates prion disease in a mouse model of chronic wasting disease.accumulating evidence shows a critical role of the complement system in facilitating attachment of prions to both b cells and follicular dendritic cells and assisting in prion replication. complement activation intensifies disease in prion-infected animals, and elimination of complement components inhibits prion accumulation, replication and pathogenesis. chronic wasting disease (cwd) is a highly infectious prion disease of captive and free-ranging cervid populations that utilizes the complement ...201324038599
introducing a rigid loop structure from deer into mouse prion protein increases its propensity for misfolding in vitro.prion diseases are fatal neurodegenerative disorders characterized by misfolding of the cellular prion protein (prp(c)) into the disease-associated isoform (prp(sc)) that has increased β-sheet content and partial resistance to proteolytic digestion. prion diseases from different mammalian species have varying propensities for transmission upon exposure of an uninfected host to the infectious agent. chronic wasting disease (cwd) is a highly transmissible prion disease that affects free ranging an ...201323825561
estimating prion adsorption capacity of soil by bioassay of subtracted infectivity from complex solutions (basics).prions, the infectious agent of scrapie, chronic wasting disease and other transmissible spongiform encephalopathies, are misfolded proteins that are highly stable and resistant to degradation. prions are known to associate with clay and other soil components, enhancing their persistence and surprisingly, transmissibility. currently, few detection and quantification methods exist for prions in soil, hindering an understanding of prion persistence and infectivity in the environment. variability i ...201323484043
oxidation of methionine 216 in sheep and elk prion protein is highly dependent upon the amino acid at position 218 but is not important for prion propagation.we employed a sensitive mass spectrometry-based method to deconstruct, confirm, and quantitate the prions present in elk naturally infected with chronic wasting disease and sheep naturally infected with scrapie. we used this approach to study the oxidation of a methionine at position 216 (met216), because this oxidation (metso216) has been implicated in prion formation. three polymorphisms (ile218, val218, and thr218) of sheep recombinant prion protein were prepared. our analysis showed the nove ...201323458153
bovine spongiform encephalopathy: a tipping point in one health and food safety.bovine spongiform encephalopathy (bse) is a protein misfolding disease of cattle which belongs to the group of transmissible spongiform encephalopathies (tses) or prion diseases. this group also includes scrapie in sheep and goats, chronic wasting disease (cwd) of cervids and creutzfeldt-jakob disease (cjd) humans. the first case of bse was recognised in england in 1986 as a progressive, neurological condition where affected animals behaved abnormally, exhibited anxiety, ataxia, hypersensitivity ...201322976349
strain characterization of the korean cwd cases in 2001 and 2004.chronic wasting disease (cwd) has been recognized as a naturally occurring prion disease in north american deer (odocoileus species), rocky mountain elk (cervus elaphus nelsoni) and moose (alces alces). the disease was confirmed only in elk in the republic of korea in 2001, 2004 and 2005. epidemiological investigations showed that cwd was introduced via importation of infected elk from canada between 1994 and 1997. in spite of the increasing geographic distribution and host range of cwd, little ...201322972463
susceptibility of domestic cats to chronic wasting disease.domestic and nondomestic cats have been shown to be susceptible to feline spongiform encephalopathy (fse), almost certainly caused by consumption of bovine spongiform encephalopathy (bse)-contaminated meat. because domestic and free-ranging nondomestic felids scavenge cervid carcasses, including those in areas affected by chronic wasting disease (cwd), we evaluated the susceptibility of the domestic cat (felis catus) to cwd infection experimentally. cohorts of 5 cats each were inoculated intrace ...201323236066
aerosol transmission of chronic wasting disease in white-tailed deer.while the facile transmission of chronic wasting disease (cwd) remains incompletely elucidated, studies in rodents suggest that exposure of the respiratory mucosa may be an efficient pathway. the present study was designed to address this question in the native cervid host. here, we demonstrate aerosol transmission of cwd to deer with a prion dose >20-fold lower than that used in previous oral inoculations. inhalation of prions may facilitate transmission of cwd and, perhaps, other prion infecti ...201323175370
evaluating spatial overlap and relatedness of white-tailed deer in a chronic wasting disease management zone.wildlife disease transmission, at a local scale, can occur from interactions between infected and susceptible conspecifics or from a contaminated environment. thus, the degree of spatial overlap and rate of contact among deer is likely to impact both direct and indirect transmission of infectious diseases such chronic wasting disease (cwd) or bovine tuberculosis. we identified a strong relationship between degree of spatial overlap (volume of intersection) and genetic relatedness for female whit ...201323437171
pathological characterization of tgelk mice injected with brain homogenate from elk with chronic wasting disease.chronic wasting disease (cwd) is classified as a transmissible spongiform encephalopathy or prion disease that affects cervids. cwd has been reported in 15 us states, two canadian provinces, and in imported elk on several farms in korea. this study was conducted to examine the molecular biological and pathogenic characteristics of a cwd-associated prion isolated in korea. the epidemiological origin of this pathogen was also determined. homozygous tgelk mice were infected with a cwd-affected elk ...201323388435
distinguishing between indirect and direct modes of transmission using epidemiological time series.pathogen transmission can involve direct and/or indirect pathways. using theoretical models, in this study we ask, "do directly and indirectly transmitted pathogens yield different population-level epidemiological dynamics?" and "can the transmission pathway be inferred from population-level epidemiological data?" our approach involves comparing the continuous-time dynamics of a class of compartmental epidemiological models with direct versus environmentally mediated indirect transmission pathwa ...201323348785
insufficient autoantigen presentation and failure of tolerance in a mouse model of rheumatoid arthritis.in the k/bxn mouse model of rheumatoid arthritis, t cells reactive for the self antigen glucose-6-phosphate isomerase (gpi) escape negative selection even though gpi expression is ubiquitous. we sought to determine whether insufficient gpi presentation could account for the failure of negative selection and for the development of arthritis.201323840022
immunization with a synthetic peptide vaccine fails to protect mule deer (odocoileus hemionus) from chronic wasting disease.chronic wasting disease (cwd) adversely affects both wild and captive cervid populations. a vaccine to prevent cwd would be a highly desirable tool to aid in disease management. to this end, we tested in mule deer a combination of cwd vaccines consisting of cervid prion peptide sequences 168-vdqynnqntfvhdc-182 and 145-ndyedryyrenmyrypnq-164 that had previously been shown to delay onset of clinical disease and increase survival in a mouse-adapted scrapie model. thirteen captive mule deer (odocoil ...201323778624
experimental chronic wasting disease in wild type vm mice.chronic wasting disease (cwd) is a naturally occurring prion disease in north american deer (odocoileus species), rocky mountain elk (cervus elaphus nelsoni) and moose (alces alces). the disease was first confirmed in the republic of korea in 2001, and subsequent cases were diagnosed in 2004, 2005 and 2010. the experimental host range of cwd includes ferrets, several species of voles, white-footed mice, deer mice and syrian golden hamsters. in addition, cwd was transmitted to the transgenic mous ...201323708962
intranasal inoculation of white-tailed deer (odocoileus virginianus) with lyophilized chronic wasting disease prion particulate complexed to montmorillonite clay.chronic wasting disease (cwd), the only known prion disease endemic in wildlife, is a persistent problem in both wild and captive north american cervid populations. this disease continues to spread and cases are found in new areas each year. indirect transmission can occur via the environment and is thought to occur by the oral and/or intranasal route. oral transmission has been experimentally demonstrated and although intranasal transmission has been postulated, it has not been tested in a natu ...201323671598
efficacy of antemortem rectal biopsies to diagnose and estimate prevalence of chronic wasting disease in free-ranging cow elk (cervus elaphus nelsoni).a reliable antemortem test is needed to understand the ecology of chronic wasting disease (cwd) in elk (cervus elaphus nelsoni). we measured the ability of antemortem biopsy samples from the rectal mucosa to detect the abnormal prion protein associated with cwd (prp(cwd)), the relationship between test results from the obex and rectal biopsies at varying stages of cwd progression, and the prevalence of cwd in free-ranging elk from rocky mountain national park, colorado, usa. we sampled and place ...201323568902
evaluation of a wild white-tailed deer population management program for controlling chronic wasting disease in illinois, 2003-2008.we evaluated population management programs for controlling chronic wasting disease (cwd) in wild white-tailed deer in illinois between november 2002 and march 2008. the intervention consisted of measures of deer removal from three deer population control programs: illinois department of natural resources culling, deer population control permits and nuisance deer removal permits. we included in the analysis a total of 14,650 white-tailed deer cwd test results. these data also included location a ...201323558033
chronic wasting disease in bank voles: characterisation of the shortest incubation time model for prion diseases.in order to assess the susceptibility of bank voles to chronic wasting disease (cwd), we inoculated voles carrying isoleucine or methionine at codon 109 (bv109i and bv109m, respectively) with cwd isolates from elk, mule deer and white-tailed deer. efficient transmission rate (100%) was observed with mean survival times ranging from 156 to 281 days post inoculation. subsequent passages in bv109i allowed us to isolate from all cwd sources the same vole-adapted cwd strain (bv(109i)cwd), typified by ...201323505374
in vitro detection of prionemia in tse-infected cervids and hamsters.blood-borne transmission of infectious prions during the symptomatic and asymptomatic stages of disease occurs for both human and animal transmissible spongiform encephalopathies (tses). the geographical distribution of the cervid tse, chronic wasting disease (cwd), continues to spread across north america and the prospective number of individuals harboring an asymptomatic infection of human variant creutzfeldt-jakob disease (vcjd) in the united kingdom has been projected to be ~1 in 3000 reside ...201324224043
from prion diseases to prion-like propagation mechanisms of neurodegenerative diseases.prion diseases are fatal neurodegenerative sporadic, inherited, or acquired disorders. in humans, creutzfeldt-jakob disease is the most studied prion disease. in animals, the most frequent prion diseases are scrapie in sheep and goat, bovine spongiform encephalopathy in cattle, and the emerging chronic wasting disease in wild and captive deer in north america. the hallmark of prion diseases is the deposition in the brain of prp(sc), an abnormal β -sheet-rich form of the cellular prion protein (p ...201324222767
thienyl pyrimidine derivatives with prp(sc) oligomer-inducing activity are a promising tool to study prions.transmissible spongiform encephalopathies (tses), also called prion diseases, are fatal, infectious, genetic or sporadic neurodegenerative disorders of humans and animals. in humans, tses are represented by creutzfeldt-jakob disease (cjd), gerstmann-sträussler-scheinker syndrome, fatal familial insomnia and kuru. in animals, the most prominent prion diseases are scrapie of sheep and goats, bovine spongiform encephalopathy (bse) of cattle and chronic wasting disease (cwd) of deer and elk. a criti ...201324059332
rapid antemortem detection of cwd prions in deer saliva.chronic wasting disease (cwd) is an efficiently transmitted prion disease of cervids, now identified in 22 united states, 2 canadian provinces and korea. one hallmark of cwd is the shedding of infectious prions in saliva, as demonstrated by bioassay in deer. it is also clear that the concentration of prions in saliva, blood, urine and feces is much lower than in the nervous system or lymphoid tissues. rapid in vitro detection of cwd (and other) prions in body fluids and excreta has been problema ...201324040235
seeded fibrillation as molecular basis of the species barrier in human prion diseases.prion diseases are transmissible spongiform encephalopathies in humans and animals, including scrapie in sheep, bovine spongiform encephalopathy (bse) in cattle, chronic wasting disease (cwd) in deer, and creutzfeldt-jakob disease (cjd) in humans. the hallmark of prion diseases is the conversion of the host-encoded prion protein (prp(c)) to its pathological isoform prp(sc), which is accompanied by prp fibrillation. transmission is not restricted within one species, but can also occur between spe ...201323977331
mother to offspring transmission of chronic wasting disease in reeves' muntjac deer.the horizontal transmission of prion diseases has been well characterized in bovine spongiform encephalopathy (bse), chronic wasting disease (cwd) of deer and elk and scrapie of sheep, and has been regarded as the primary mode of transmission. few studies have monitored the possibility of vertical transmission occurring within an infected mother during pregnancy. to study the potential for and pathway of vertical transmission of cwd in the native cervid species, we used a small cervid model-the ...201323977159
molecular cloning and sequence analysis of prion protein gene in xiji donkey in china.prion diseases are a group of human and animal neurodegenerative disorders caused by the deposition of an abnormal isoform prion protein (prp(sc)) encoded by a single copy prion protein gene (prnp). prion disease has been reported in many herbivores but not in equus and the species barrier might be playing a role in resistance of these species to the disease. therefore, analysis of genotype of prion protein (prp) in these species may help understand the transmission of the disease. xiji donkey i ...201323954254
a case of chronic wasting disease in a captive red deer (cervus elaphus).a 22-month-old, female red deer (cervus elaphus) was submitted to the university of minnesota veterinary diagnostic laboratory for necropsy and chronic wasting disease (cwd) testing. the deer was found positive for the abnormal prion protein in the obex and the retropharyngeal lymph node by immunohistochemical staining. microscopic lesions of spongiform encephalopathy and immunohistochemical staining patterns and intensity were similar to those in cwd-positive elk and experimentally infected red ...201323950558
stability properties of prp(sc) from cattle with experimental transmissible spongiform encephalopathies: use of a rapid whole homogenate, protease-free assay.transmissible spongiform encephalopathies (tses), including scrapie in sheep, chronic wasting disease (cwd) in cervids, transmissible mink encephalopathy (tme), and bovine spongiform encephalopathy (bse), are fatal diseases of the nervous system associated with accumulation of misfolded prion protein (prp(sc)). different strains of tses exist, associated with different prp(sc) conformations that can be probed by the stability assay, in which prp(sc) is treated with increasing concentrations of t ...201323945217
in vitro prion protein conversion suggests risk of bighorn sheep (ovis canadensis) to transmissible spongiform encephalopathies.transmissible spongiform encephalopathies (tses) affect both domestic sheep (scrapie) and captive and free-ranging cervids (chronic wasting disease; cwd). the geographical range of bighorn sheep (ovis canadensis; bhs) overlaps with states or provinces that have contained scrapie-positive sheep or goats and areas with present epizootics of cwd in cervids. no tses have been documented in bhs, but the susceptibility of this species to tses remains unknown.201323938169
ethics in prion disease.this paper is intended to discuss some of the scientific and ethical issues that are created by increased research efforts towards earlier diagnosis, as well as to treatment of, human prion diseases (and related dementias), including the resulting consequences for individuals, their families, and society. most patients with prion disease currently are diagnosed when they are about 2/3 of the way through their disease course (geschwind et al., 2010a; paterson et al., 2012b), when the disease has ...201323906487
chimeric elk/mouse prion proteins in transgenic mice.chronic wasting disease (cwd) of deer and elk is a highly communicable neurodegenerative disorder caused by prions. investigations of cwd are hampered by slow bioassays in transgenic (tg) mice. towards the development of tg mice that will be more susceptible to cwd prions, we created a series of chimeric elk/mouse transgenes that encode the n terminus of elk prp (elkprp) up to residue y168 and the c terminus of mouse prp (moprp) beyond residue 169 (mouse numbering), designated elk3m(snivvk). bet ...201323100369
mucosal transmission and pathogenesis of chronic wasting disease in ferrets.chronic wasting disease (cwd) of cervids is almost certainly transmitted by mucosal contact with the causative prion, whether by direct (animal-to-animal) or indirect (environmental) means. yet the sites and mechanisms of prion entry remain to be further understood. this study sought to extend this understanding by demonstrating that ferrets exposed to cwd via several mucosal routes developed infection, cwd prion protein (prp(cwd)) amplification in lymphoid tissues, neural invasion and florid tr ...201323100363
in vitro amplification of scrapie and chronic wasting disease prp(res) using baculovirus-expressed recombinant prp as substrate.protein misfolding cyclic amplification (pmca) is an in vitro simulation of prion replication, which relies on the use of normal brain homogenate derived from host species as substrate for the specific amplification of abnormal prion protein, prp(sc). studies showed that recombinant cellular prp, prp(c), expressed in escherichia coli lacks n-glycosylation and an glycophosphatidyl inositol anchor (gpi) and therefore may not be the most suitable substrate in seeded pmca reactions to recapitulate p ...201425495764
multimodal fluorescence microscopy of prion strain specific prp deposits stained by thiophene-based amyloid ligands.the disease-associated prion protein (prp) forms aggregates which vary in structural conformation yet share an identical primary sequence. these variations in prp conformation are believed to manifest in prion strains exhibiting distinctly different periods of disease incubation as well as regionally specific aggregate deposition within the brain. the anionic luminescent conjugated polythiophene (lcp), polythiophene acetic acid (ptaa) has previously been used to distinguish prp deposits associat ...201425495506
prion protein interaction with soil humic substances: environmental implications.transmissible spongiform encephalopathies (tse) are fatal neurodegenerative disorders caused by prions. animal tse include scrapie in sheep and goats, and chronic wasting disease (cwd) in cervids. effective management of scrapie in many parts of the world, and of cwd in north american deer population is complicated by the persistence of prions in the environment. after shedding from diseased animals, prions persist in soil, withstanding biotic and abiotic degradation. as soil is a complex, multi ...201424937266
homogenization, sex, and differential motility predict spread of chronic wasting disease in mule deer in southern utah.chronic wasting disease (cwd) is an infectious prion disease that affects mule deer, along with other cervids. it is a slow-developing, fatal disease which is rare in the free-ranging deer population of utah. we present a sex-structured, spatial model for the spread of cwd over heterogeneous landscapes, incorporating both horizontal and environmental transmission pathways. to connect the local movement of deer to the regional spread of cwd, we use ecological diffusion with motility coefficients ...201423846241
molecular dynamics studies on the nmr and x-ray structures of rabbit prion proteins.prion diseases, traditionally referred to as transmissible spongiform encephalopathies (tses), are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of mammalian species, manifesting as scrapie in sheep and goats, bovine spongiform encephalopathy (bse or mad-cow disease) in cattle, chronic wasting disease in deer and elk, and creutzfeldt-jakob diseases, gerstmann-sträussler-scheinker syndrome, fatal familial insomnia, and kulu in humans, etc. these neur ...201424184221
modeling seasonal behavior changes and disease transmission with application to chronic wasting disease.behavior and habitat of wildlife animals change seasonally according to environmental conditions. mathematical models need to represent this seasonality to be able to make realistic predictions about the future of a population and the effectiveness of human interventions. managing and modeling disease in wild animal populations requires particular care in that disease transmission dynamics is a critical consideration in the etiology of both human and animal diseases, with different transmission ...201424035840
the importance of localized culling in stabilizing chronic wasting disease prevalence in white-tailed deer populations.strategies to contain the spread of disease often are developed with incomplete knowledge of the possible outcomes but are intended to minimize the risks associated with delaying control. culling of game species by government agencies is one approach to control disease in wild populations but is unpopular with hunters and wildlife enthusiasts, politically unpalatable, and erodes public support for agencies responsible for wildlife management. we addressed the functional differences between hunti ...201424128754
assessing the susceptibility of transgenic mice overexpressing deer prion protein to bovine spongiform encephalopathy.several transgenic mouse models have been developed which facilitate the transmission of chronic wasting disease (cwd) of cervids and allow prion strain discrimination. the present study was designed to assess the susceptibility of the prototypic mouse line, tg(cerprp)1536(+/-), to bovine spongiform encephalopathy (bse) prions, which have the ability to overcome species barriers. tg(cerprp)1536(+/-) mice challenged with red deer-adapted bse resulted in 90% to 100% attack rates, and bse from catt ...201424257620
sero-diagnosis of surra exploiting recombinant vsg antigen based elisa for surveillance.trypanosoma evansi, a haemoflagellate, causes "surra" an important chronic wasting disease of a wide range of wild and domestic herbivorous and carnivorous animals including cattle, buffaloes, camels, horses, etc. the untreated recovered animal can act as a carrier without exhibiting the disease symptoms and can be a source of infection to healthy animals. the diagnosis and subsequent treatment of the carrier animals is helpful to curb the disease. as the parasitaemia in carrier animals is very ...201425269987
six-year follow-up of a point-source exposure to cwd contaminated venison in an upstate new york community: risk behaviours and health outcomes 2005-2011.it is currently unknown whether chronic wasting disease (cwd), a transmissible spongiform encephalopathy of cervids, is transmissible to humans. reported on here are the behavioural risk factors and health conditions associated with a six-year follow-up of a known point-source exposure to a cwd infected deer in an upstate new york community.201425225155
structural effects of prp polymorphisms on intra- and interspecies prion transmission.understanding the molecular parameters governing prion propagation is crucial for controlling these lethal, proteinaceous, and infectious neurodegenerative diseases. to explore the effects of prion protein (prp) sequence and structural variations on intra- and interspecies transmission, we integrated studies in deer, a species naturally susceptible to chronic wasting disease (cwd), a burgeoning, contagious epidemic of uncertain origin and zoonotic potential, with structural and transgenic (tg) m ...201425034251
detection of chronic wasting disease in the lymph nodes of free-ranging cervids by real-time quaking-induced conversion.chronic wasting disease (cwd), a transmissible spongiform encephalopathy of deer, elk, and moose, is the only prion disease affecting free-ranging animals. since the disease was first identified in northern colorado and southern wyoming in 1967, new epidemic foci of the disease have been identified in 20 additional states, as well as two canadian provinces and the republic of south korea. identification of cwd-affected animals currently requires postmortem analysis of brain or lymphoid tissues u ...201424958799
can plants serve as a vector for prions causing chronic wasting disease?prions, the causative agent of chronic wasting disease (cwd) enter the environment through shedding of bodily fluids and carcass decay, posing a disease risk as a result of their environmental persistence. plants have the ability to take up large organic particles, including whole proteins, and microbes. this study used wheat (triticum aestivum l.) to investigate the uptake of infectious cwd prions into roots and their transport into aerial tissues. the roots of intact wheat plants were exposed ...201424509640
safety, specificity and immunogenicity of a prp(sc)-specific prion vaccine based on the yyr disease specific epitope.prions are a novel form of infectivity based on the misfolding of a self-protein (prp(c)) into a pathological, infectious isomer (prp(sc)). the current uncontrolled spread of chronic wasting disease in cervids, coupled with the demonstrated zoonotic nature of select livestock prion diseases, highlights the urgent need for disease management tools. while there is proof-of-principle evidence for a prion vaccine, these efforts are complicated by the challenges and risks associated with induction of ...201424509522
prion transmission prevented by modifying the β2-α2 loop structure of host prpc.zoonotic prion transmission was reported after the bovine spongiform encephalopathy (bse) epidemic, when >200 cases of prion disease in humans were diagnosed as variant creutzfeldt-jakob disease. assessing the risk of cross-species prion transmission remains challenging. we and others have studied how specific amino acid residue differences between species impact prion conversion and have found that the β2-α2 loop region of the mouse prion protein (residues 165-175) markedly influences infection ...201424431459
prion disease tempo determined by host-dependent substrate reduction.the symptoms of prion infection can take years or decades to manifest following the initial exposure. molecular markers of prion disease include accumulation of the misfolded prion protein (prpsc), which is derived from its cellular precursor (prpc), as well as downregulation of the prp-like shadoo (sho) glycoprotein. given the overlapping cellular environments for prpc and sho, we inferred that prpc levels might also be altered as part of a host response during prion infection. using rodent mod ...201424430187
the case for involvement of spiroplasma in the pathogenesis of transmissible spongiform encephalopathies.spiroplasma biofilm formation explains the role of these wall-less bacteria in the pathogenesis of transmissible spongiform encephalopathies (tses). spiroplasma embedded in the biofilm polysaccharide matrix are markedly resistant to physical and chemical treatment, simulating the biologic properties of the tse agent. microcolonies of spiroplasma embedded in biofilm bound to clay are the likely mechanism of lateral transmission of scrapie in sheep and chronic wasting disease in deer via soil inge ...201424423635
molecular barriers to zoonotic transmission of prions.the risks posed to human health by individual animal prion diseases cannot be determined a priori and are difficult to address empirically. the fundamental event in prion disease pathogenesis is thought to be the seeded conversion of normal prion protein to its pathologic isoform. we used a rapid molecular conversion assay (protein misfolding cyclic amplification) to test whether brain homogenates from specimens of classical bovine spongiform encephalopathy (bse), atypical bse (h-type bse and l- ...201424377702
impacts of wildlife baiting and supplemental feeding on infectious disease transmission risk: a synthesis of knowledge.baiting and supplemental feeding of wildlife are widespread, yet highly controversial management practices, with important implications for ecosystems, livestock production, and potentially human health. an often underappreciated threat of such feeding practices is the potential to facilitate intra- and inter-specific disease transmission. we provide a comprehensive review of the scientific evidence of baiting and supplemental feeding on disease transmission risk in wildlife, with an emphasis on ...201424365654
variant cjd. 18 years of research and surveillance.it is now 18 years since the first identification of a case of vcjd in the uk. since that time, there has been much speculation over how vcjd might impact human health. to date there have been 177 case reports in the uk and a further 51 cases worldwide in 11 different countries. since establishing that bse and vcjd are of the same strain of agent, we have also shown that there is broad similarity between uk and non-uk vcjd cases on first passage to mice. transgenic mouse studies have indicated t ...201425495404
a survey and a molecular dynamics study on the (central) hydrophobic region of prion proteins.prion diseases which are serious neurodegenerative diseases that affect humans and animals occur in various of species. unlike many other neurodegenerative diseases affected by amyloid, prion diseases can be highly infectious. prion diseases occur in many species. in humans, prion diseases include the fatal human neurodegenerative diseases such as creutzfeldt-jakob disease (cjd), fatal familial insomnia (ffi), gerstmann-strussler-scheinker syndrome (gss) and kuru etc. in animals, prion diseases ...201425373387
distribution of peripheral prp(sc) in sheep with naturally acquired scrapie.accumulation of prion protein (prpsc) in the central nervous system is the hallmark of transmissible spongiform encephalopathies. however, in some of these diseases such as scrapie or chronic wasting disease, the prpsc can also accumulate in other tissues, particularly in the lymphoreticular system. in recent years, prpsc in organs other than nervous and lymphoid have been described, suggesting that distribution of this protein in affected individuals may be much larger than previously thought. ...201424828439
"atypical" chronic wasting disease in prnp genotype 225ff mule deer.we compared mule deer (odocoileus hemionus) of two different prnp genotypes (225ss, 225ff) for susceptibility to chronic wasting disease (cwd) in the face of environmental exposure to infectivity. all three 225ss deer had immunohistochemistry (ihc)-positive tonsil biopsies by 710 days postexposure (dpe), developed classic clinical signs by 723-1,200 dpe, and showed gross and microscopic pathology, enzyme-linked immunosorbent assay (elisa) results, and ihc staining typical of prion disease in mul ...201424807352
swainsonine-containing plants and their relationship to endophytic fungi.swainsonine, an indolizidine alkaloid with significant physiological activity, is an α-mannosidase and mannosidase ii inhibitor that alters glycoprotein processing and causes lysosomal storage disease. swainsonine is present in a number of plant species worldwide and causes severe toxicosis in livestock grazing these plants. consumption of these plants by grazing animals leads to a chronic wasting disease characterized by weight loss, depression, altered behavior, decreased libido, infertility, ...201424758700
chronic wasting disease agents in nonhuman primates.chronic wasting disease is a prion disease of cervids. assessment of its zoonotic potential is critical. to evaluate primate susceptibility, we tested monkeys from 2 genera. we found that 100% of intracerebrally inoculated and 92% of orally inoculated squirrel monkeys were susceptible, but cynomolgus macaques were not, suggesting possible low risk for humans.201424751215
quinacrine promotes replication and conformational mutation of chronic wasting disease prions.quinacrine's ability to reduce levels of pathogenic prion protein (prp(sc)) in mouse cells infected with experimentally adapted prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. we show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk prp(sc) accumulation and promotes propagation ...201424711410
mineral licks: motivational factors for visitation and accompanying disease risk at communal use sites of elk and deer.free-ranging cervids acquire most of their essential minerals through forage consumption, though occasionally seek other sources to account for seasonal mineral deficiencies. mineral sources occur as natural geological deposits (i.e., licks) or as anthropogenic mineral supplements. in both scenarios, these sources commonly serve as focal sites for visitation. we monitored 11 licks in rocky mountain national park, north-central colorado, using trail cameras to quantify daily visitation indices (d ...201424711146
evidence that bank vole prp is a universal acceptor for prions.bank voles are uniquely susceptible to a wide range of prion strains isolated from many different species. to determine if this enhanced susceptibility to interspecies prion transmission is encoded within the sequence of the bank vole prion protein (bvprp), we inoculated tg(m109) and tg(i109) mice, which express bvprp containing either methionine or isoleucine at polymorphic codon 109, with 16 prion isolates from 8 different species: humans, cattle, elk, sheep, guinea pigs, hamsters, mice, and m ...201424699458
using auxiliary information to improve wildlife disease surveillance when infected animals are not detected: a bayesian approach.there are numerous situations in which it is important to determine whether a particular disease of interest is present in a free-ranging wildlife population. however adequate disease surveillance can be labor-intensive and expensive and thus there is substantial motivation to conduct it as efficiently as possible. surveillance is often based on the assumption of a simple random sample, but this can almost always be improved upon if there is auxiliary information available about disease risk fac ...201424676479
transmission of chronic wasting disease in wisconsin white-tailed deer: implications for disease spread and management.few studies have evaluated the rate of infection or mode of transmission for wildlife diseases, and the implications of alternative management strategies. we used hunter harvest data from 2002 to 2013 to investigate chronic wasting disease (cwd) infection rate and transmission modes, and address how alternative management approaches affect disease dynamics in a wisconsin white-tailed deer population. uncertainty regarding demographic impacts of cwd on cervid populations, human and domestic anima ...201424658535
current perspectives in transfusion-transmitted infectious diseases: emerging and re-emerging infections.in august 2009, a group from the aabb (stramer et al., transfusion 2009;99:1s-29s, emerging infectious disease agents and their potential threat to transfusion safety; http://www.aabb.org/resources/bct/eid/pages/default.aspx) published a supplement to transfusion that reviewed emerging infectious disease (eid) agents that pose a real or theoretical threat to transfusion safety, but for which an existing effective intervention is lacking. the necessary attributes for transfusion transmission were ...201425210533
persistence of ovine scrapie infectivity in a farm environment following cleaning and decontamination.scrapie of sheep/goats and chronic wasting disease of deer/elk are contagious prion diseases where environmental reservoirs are directly implicated in the transmission of disease. in this study, the effectiveness of recommended scrapie farm decontamination regimens was evaluated by a sheep bioassay using buildings naturally contaminated with scrapie. pens within a farm building were treated with either 20,000 parts per million free chorine solution for one hour or were treated with the same but ...201525362003
quantitative assessment of prion infectivity in tissues and body fluids by real-time quaking-induced conversion.prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving the templated conversion of the normal cellular prion protein (prp(c)) to a pathogenic misfolded conformation. templated conversion has been modelled in several in vitro assays, including serial protein misfolding amplification, amyloid seeding and real-time quaking-induced conversion (rt-quic). as rt-quic measures formation of amyloid fibrils in real-time, it can be used to estim ...201525304654
chronic wasting disease of cervids: current knowledge and future perspectives.a naturally occurring transmissible spongiform encephalopathy (tse) of mule deer was first reported in colorado and wyoming in 1967 and has since spread to other members of the cervid family in 22 states, 2 canadian provinces, and the republic of korea. chronic wasting disease (cwd), caused by exposure to an abnormally folded isoform of the cellular prion protein, is characterized by progressive neurological disease in susceptible natural and experimental hosts and is ultimately fatal. cwd is th ...201525387112
lesion profiling and subcellular prion localization of cervid chronic wasting disease in domestic cats.chronic wasting disease (cwd) is an efficiently transmitted, fatal, and progressive prion disease of cervids with an as yet to be fully clarified host range. while outbred domestic cats (felis catus) have recently been shown to be susceptible to experimental cwd infection, the neuropathologic features of the infection are lacking. such information is vital to provide diagnostic power in the event of natural interspecies transmission and insights into host and strain interactions in interspecies ...201524577721
peliosis hepatis presenting with massive hepatomegaly in a patient with idiopathic thrombocytopenic purpura.peliosis hepatis is a rare condition that can cause hepatic hemorrhage, rupture, and ultimately liver failure. several authors have reported that peliosis hepatis develops in association with chronic wasting disease or prolonged use of anabolic steroids or oral contraceptives. in this report we describe a case in which discontinuation of steroid therapy improved the condition of a patient with peliosis hepatis. our patient was a 64-year-old woman with a history of long-term steroid treatment for ...201526770928
methods for differentiating prion types in food-producing animals.prions are an enigma amongst infectious disease agents as they lack a genome yet confer specific pathologies thought to be dictated mainly, if not solely, by the conformation of the disease form of the prion protein (prp(sc)). prion diseases affect humans and animals, the latter including the food-producing ruminant species cattle, sheep, goats and deer. importantly, it has been shown that the disease agent of bovine spongiform encephalopathy (bse) is zoonotic, causing variant creutzfeldt jakob ...201526580664
bayesian modeling of prion disease dynamics in mule deer using population monitoring and capture-recapture data.epidemics of chronic wasting disease (cwd) of north american cervidae have potential to harm ecosystems and economies. we studied a migratory population of mule deer (odocoileus hemionus) affected by cwd for at least three decades using a bayesian framework to integrate matrix population and disease models with long-term monitoring data and detailed process-level studies. we hypothesized cwd prevalence would be stable or increase between two observation periods during the late 1990s and after 20 ...201526509806
empirical estimation of r0 for unknown transmission functions: the case of chronic wasting disease in alberta.we consider the problem of estimating the basic reproduction number r0 from data on prevalence dynamics at the beginning of a disease outbreak. we derive discrete and continuous time models, some coefficients of which are to be fitted from data. we show that prevalence of the disease is sufficient to determine r0. we apply this method to chronic wasting disease spread in alberta determining a range of possible r0 and their sensitivity to the probability of deer annual survival.201526452231
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