Monday, May 6, 2013

Infectious particles, stress, and induced prion amyloids: A unifying perspective

Review



Infectious particles, stress, and induced prion amyloids: A unifying perspective


Volume 4, Issue 5 July 1, 2013


Keywords: Alzheimer disease, Parkinson disease, aging, biofilms, environmental pathogens, latency, metagenome, nucleic acids, transmissible encephalopathies, yeast prions


Authors: Laura Manuelidis


View affiliations Hide affiliations Laura Manuelidis Corresponding author:


laura.manuelidis@yale.edu




Yale University Medical School; New Haven, CT USA





 Abstract: Transmissible encephalopathies (TSEs) are believed by many to arise by spontaneous conversion of host prion protein (PrP) into an infectious amyloid (PrP-res, PrPSc) without nucleic acid. Many TSE agents reside in the environment with infection controlled by public health measures. These include the disappearance of kuru with the cessation of ritual cannibalism, the dramatic reduction of epidemic bovine encephalopathy (BSE) by removal of contaminated feed, and the lack of endemic scrapie in geographically isolated Australian sheep with susceptible PrP genotypes. While prion protein modeling has engendered an intense focus on common types of protein misfolding and amyloid formation in diverse organisms and diseases, the biological characteristics of infectious TSE agents, and their recognition by the host as foreign entities, raises several fundamental new directions for fruitful investigation such as: (1) unrecognized microbial agents in the environmental metagenome that may cause latent neurodegenerative disease, (2) the evolutionary social and protective functions of different amyloid proteins in diverse organisms from bacteria to mammals, and (3) amyloid formation as a beneficial innate immune response to stress (infectious and non-infectious). This innate process however, once initiated, can become unstoppable in accelerated neuronal aging.





Received: March 12, 2013; Accepted: April 26, 2013; Published Online: April 30, 2013




snip...




Summary





The structure and strain-determining molecular components of infectious TSE particles remains unknown. An enormous variety of evidence contradicts the conclusion that TSE infectious agents are made of host PrP without nucleic acid or an environmental component. First, different agent strains give the same PrP-res pattern, and conversely, samples with very different PrP-res patterns can propagate the identical infectious agent. Thus observed PrP conformers do not encode or predict strains. Second, all forms of detectable PrP can be destroyed with no loss of infectivity. PrP has also been undetectable in cells with high infectious titers. Third, the host recognizes and mounts early innate immune defenses against individual TSE agents and this determines latency and incubation time. Fourth, PrP-res amyloid appears as part of a late defense mechanism against a foreign agent, and TSE agent replication demonstrates a vastly different trajectory than the conversion kinetics of PrP-res (the “infectious” form). Fifth, PrP acts as a required host receptor for agent survival. In this capacity it can protect the agent while allowing the host to survive for years. Sixth, as other GPI proteins, PrP facilitates cell-to-cell transfer, and can be used by several infectious agents, not just TSEs. Seventh, as in TSE infections, other viruses can induce misfolded protein “prion” aggregates as part of an antiviral innate immune response. Eighth, the ability to fold into an amyloid state is a property shared by many proteins and peptides.





Amyloid aggregation is a process that is highly conserved in evolution and it does not require infection. In yeast, such conversions are involved in a wide range of functions, including transcriptional and translational regulation.38 Dense resistant bacterial biofilms function in socialization and protection69 and can be considered together with mammalian amyloids, including PrP and AD plaques that contain many other elements.23 Infection poses additional unexplored opportunities. The discovery of bacterial plasmid-like elements associated with TSE infectious particles raises the issue of unsuspected exchanges between mammals and bacterial viral elements in disease. Some of these viral elements may be the root cause of TSEs as well as a diversity of chronic conditions. Alternatively, such elements may promote the aggregation of fibrillar proteins in neurodegenerations of unknown etiology. Metagenomic elements, along with environmental toxins, surely deserve broader attention as causal factors in AD and other late-onset diseases.






http://www.landesbioscience.com/journals/virulence/article/24838/?show_full_text=true


Monday, January 9, 2012

Long double stranded RNA is present in scrapie infected cells and tissues

Long double stranded RNA is present in scrapie infected cells and tissues

Yervand Karapetyan


The Scripps Research Institute, Scripps Florida


Current address: Yale University School of Medicine


The nature of the infectious agent causing scrapie and other Transmissible Spongiform Encephalopathies remains an enigma despite decades of research efforts. The protein-only prion hypothesis posits that abnormal conformer of a host protein is the infectious agent. Virus and virino theories include host- independent nucleic acid as the genome of the infectious agent in addition to protein component (in case of virino a host protein and in case of virus a viral protein). Viral or sub-viral nucleic acids have long been sought in scrapie to explain the existence of multiple agent strains.


Many different approaches were undertaken to find such nucleic acid. Despite that no scrapie specific nucleic acid sequences have been found in infected cells or tissues.


Most viruses induce synthesis of long double stranded RNA (dsRNA) during their replication in cells. Therefore the presence of long dsRNA would be an indication of viral infection in cells. J2 monoclonal antibody against long dsRNA is a great tool for easy screening of cells and tissues for the presence of suspected unknown viral infection.


This antibody has not been used for testing of scrapie infected tissues.


Evidence is presented here for long dsRNA in scrapie infected cells and tissues. Such dsRNA is also found in scrapie free tissue culture cells.






TSS

Saturday, September 10, 2011

Strange Statements Regarding Mad Cow In Canada From Patricia Doyle, PhD 3-6-11 via RENSE.com

re-Strange Statements Regarding Mad Cow In Canada From Patricia Doyle, PhD 3-6-11 via RENSE.com


RENSE.com


Strange Statements Regarding Mad Cow In Canada From Patricia Doyle, PhD 3-6-11


Hello, Jeff - What kind of ProMed comment is this?? The moderator estimates the mad cow's age at 6 and a half years and ponders if 'feed contamination' caused the disease.

My math tells me the ruminants in feed ban took place in 1997 or there about. 1997 is far more than 6 and a half years ago.

Promed's best and brightest then goes on to ponder that maybe it is not a prion but a "virus". Huh?

Also note 'Manitoba' in the title. It is not Manitoba but Alberta. This is all very strange for Promed.

Patty

"A 77-month-old cow is a about 6.5 years old. So a couple of questions come to mind: Is this from a feed contamination issue? Or is this agent really a prion? Could it be a virus?

These are intended as thought provoking questions. These questions are not tossed out to receive answers as there are a host of research papers, as well as opinions, but rather they are tossed out as rhetorical questions. - Moderator TG"

BSE, BOVINE - CANADA: (MANITOBA)


********************************


Date: 4 Mar 2011 Source: Reuters (edited) Alberta Dairy Cow Found To Have Mad Cow Disease

Canadian government officials have found a dairy cow in Alberta with mad cow disease, but the finding is not surprising and shouldn't affect beef exports, a spokesman for the Canadian Food Inspection Agency (CFIA) said on Friday [4 Mar 2011]. The agency confirmed the case of bovine spongiform encephalopathy, or BSE as the disease is also known, on 18 Feb 2011 in a 77-month-old dairy cow, spokesman Guy Gravelle said.

In 2003, the 1st discovery of a cow in Canada with the disease led to closures of numerous export markets to Canadian beef. Most have reopened, other than South Korea and China, and importers are no longer as sensitive to new cases as countries such as Canada now have monitoring systems in place.

Canada continues to be rated a "controlled risk" for the disease by the World Organization for Animal Health, Gravelle said. The newest case may delay any upgrade to Canada's international risk status as a country cannot apply for negligible status sooner than 11 years after the latest-born case.

The cow has been destroyed and no part of its carcass entered the human food or animal feed systems, Gravelle said.

The case, which is believed to be Canada's 18th, should not affect exports of Canadian cattle or beef, he said, as a small number of BSE cases are expected as Canada monitors for the disease.

Byline: Rod Nickel, reporter; Walter Bagley, editor


http://ca.reuters.com/article/domesticNews/idCATRE7233JT20110304



-- Communicated by: Terry S. Singeltary Sr. flounder9@VERIZON.NET


Patricia A. Doyle DVM, PhD Bus Admin, Tropical Agricultural Economics Univ of West Indies Please visit my "Emerging Diseases" message board at:http://www.emergingdisease.org/phpbb/index.php Also my new website: http://drpdoyle.tripod.com/ Zhan le Devlesa tai sastimasa Go with God and in Good Health

Benjamin Franklin said, "They that can give up essential liberty to obtain a little temporary safety deserve neither liberty nor safety."



http://www.rense.com/general93/df.htm




========================================



Hello Patricia Doyle, PhD, and Jeff Rinse et al ;



Patricia Doyle, PhD 3-6-11 said ;


Hello, Jeff - What kind of ProMed comment is this?? The moderator estimates the mad cow's age at 6 and a half years and ponders if 'feed contamination' caused the disease.

My math tells me the ruminants in feed ban took place in 1997 or there about. 1997 is far more than 6 and a half years ago.

Promed's best and brightest then goes on to ponder that maybe it is not a prion but a "virus". Huh?

Also note 'Manitoba' in the title. It is not Manitoba but Alberta. This is all very strange for Promed.


======================================================================



I find your attack on ProMed et al strange, if not rude. this is my personal opinion.

for one thing, regardless whether or not you believe in the prion or the virus theory, or both, MY MATH shows me that the _partial_ and _voluntary_ August 4, 1997 mad cow feed ban by the FDA here in the USA you commented on, you and i both know that this was nothing but ink on paper, that in fact, as late as 2007 (one decade post partial and voluntary mad cow feed ban), in one week, via just two recalls, there was 10,000,000 million pounds of banned mad cow feed still going into commerce. and that was just the tip of the ice berg. prion, virus, whatever, you cannot dispute the fact that feed was the cause of over 300,000 bse dead cattle in the UK, due to the feed. the drastic reductions in numbers of BSE there after the feed ban proved this, as well with transmission studies there after. further more, you know, as well as i do, that the virus vs prion debate is still ongoing. AS ProMed et al so kindly stated ;


"These are intended as thought provoking questions. These questions are not tossed out to receive answers as there are a host of research papers, as well as opinions, but rather they are tossed out as rhetorical questions. - Moderator TG"



SO again, in my opinion, besides your comments being rude, they did not make much sense to me, rather confusing, other than an unwarranted attack. or i missed something?


again, this just is my opinion, ProMed et al did not have in any way nothing to do with this. i just saw it today, and wanted to just give my 2 cents...


terry



let's review, shall we ;



Patricia Doyle, PhD 3-6-11 said ;


"Promed's best and brightest then goes on to ponder that maybe it is not a prion but a "virus". Huh?"


================================


Virus-Like Structure Calls Into Question Origin of Diseases Such as “Mad Cow”

Published: December 10, 2010

http://opac.yale.edu/news/article.aspx?id=8094



Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD

Laura Manuelidis1

(1) Yale University Medical School, 333 Cedar Street, New Haven, CT 06510, USA

http://www.springerlink.com/content/k201658k278254q6/fulltext.html



Endogenous Viral Etiology of Prion Diseases

Claudiu I. Bandea

National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333

cbandea@cdc.gov / October 20, 2009


http://precedings.nature.com/documents/3887/version/1/html



http://precedings.nature.com/documents/3887/version/1



==============================


Patricia Doyle, PhD 3-6-11 said ;


"Promed's best and brightest then goes on to ponder that maybe it is not a prion but a "virus". Huh?"



seems others are still pondering the same thing doesn't it. not just the best and brightest at ProMed, Huh ??? ...tss





=============================



let's review further, shall we ;



Patricia Doyle, PhD 3-6-11 said ;


"Also note 'Manitoba' in the title. It is not Manitoba but Alberta. This is all very strange for Promed."



=============================



IF Patricia Doyle, PhD would have bothered looking, that post was corrected ;


Archive Number 20110305.0720 Published Date 05-MAR-2011 Subject PRO/AH/EDR> BSE, bovine - Canada: (AB)


BSE, BOVINE - CANADA: (ALBERTA)


********************************


A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases


[In the original email version of this post, the province was erroneously identified as Manitoba. The correct province involved was Alberta. ProMED-mail apologizes for this error.]


snip...please see ;


http://www.promedmail.org/pls/apex/f?p=2400:1202:317901045730711::NO::F2400_P1202_CHECK_DISPLAY,F2400_P1202_PUB_MAIL_ID:X,87404




maybe everyone just is not as perfect as Patricia Doyle, PhD et al, or not ???




Patricia Doyle, PhD 3-6-11 said ;


"My math tells me the ruminants in feed ban took place in 1997 or there about. 1997 is far more than 6 and a half years ago."


really ?


SO, let's take a look at the banned mad cow feed in commerce as late as 2007, 1 decade post August 4, 1997 partial and voluntary mad cow feed ban, shall we ;


HOW ABOUT THAT MAD COW FIRE WALL TOO ;


*** BANNED MAD COW FEED IN THE USA IN COMMERCE TONS AND TONS

THIS is just ONE month report, of TWO recalls of prohibited banned MBM, which is illegal, mixed with 85% blood meal, which is still legal, but yet we know the TSE/BSE agent will transmit blood. we have this l-BSE in North America that is much more virulent and there is much concern with blood issue and l-BSE as there is with nvCJD in humans. some are even starting to be concerned with sporadic CJD and blood, and there are studies showing transmission there as well. ... this is one month recall page, where 10 MILLION POUNDS OF BANNED MAD COW FEED WENT OUT INTO COMMERCE, TO BE FED OUT. very little of the product that reaches commerce is ever returned via recall, very, very little. this was 2007, TEN YEARS AFTER THE AUGUST 4, 1997, PARTIAL AND VOLUNTARY MAD COW FEED BAN IN THE USA, that was nothing but ink on paper. i have listed the tonnage of mad cow feed that was in ALABAMA in one of the links too, this is where the infamous g-h-BSEalabama case was, a genetic relation matching the new sporadic CJD in the USA. seems this saga just keeps getting better and better.......$$$


10,000,000+ LBS. of PROHIBITED BANNED MAD COW FEED I.E. BLOOD LACED MBM IN COMMERCE USA 2007

Date: March 21, 2007 at 2:27 pm PST

RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINES -- CLASS II


___________________________________


PRODUCT

Bulk cattle feed made with recalled Darling's 85% Blood Meal, Flash Dried, Recall # V-024-2007

CODE

Cattle feed delivered between 01/12/2007 and 01/26/2007

RECALLING FIRM/MANUFACTURER

Pfeiffer, Arno, Inc, Greenbush, WI. by conversation on February 5, 2007.

Firm initiated recall is ongoing.

REASON

Blood meal used to make cattle feed was recalled because it was cross- contaminated with prohibited bovine meat and bone meal that had been manufactured on common equipment and labeling did not bear cautionary BSE statement.

VOLUME OF PRODUCT IN COMMERCE

42,090 lbs.

DISTRIBUTION

WI

___________________________________

PRODUCT

Custom dairy premix products: MNM ALL PURPOSE Pellet, HILLSIDE/CDL Prot- Buffer Meal, LEE, M.-CLOSE UP PX Pellet, HIGH DESERT/ GHC LACT Meal, TATARKA, M CUST PROT Meal, SUNRIDGE/CDL PROTEIN Blend, LOURENZO, K PVM DAIRY Meal, DOUBLE B DAIRY/GHC LAC Mineral, WEST PIONT/GHC CLOSEUP Mineral, WEST POINT/GHC LACT Meal, JENKS, J/COMPASS PROTEIN Meal, COPPINI - 8# SPECIAL DAIRY Mix, GULICK, L-LACT Meal (Bulk), TRIPLE J - PROTEIN/LACTATION, ROCK CREEK/GHC MILK Mineral, BETTENCOURT/GHC S.SIDE MK-MN, BETTENCOURT #1/GHC MILK MINR, V&C DAIRY/GHC LACT Meal, VEENSTRA, F/GHC LACT Meal, SMUTNY, A- BYPASS ML W/SMARTA, Recall # V-025-2007

CODE

The firm does not utilize a code - only shipping documentation with commodity and weights identified.

RECALLING FIRM/MANUFACTURER

Rangen, Inc, Buhl, ID, by letters on February 13 and 14, 2007. Firm initiated recall is complete.

REASON

Products manufactured from bulk feed containing blood meal that was cross contaminated with prohibited meat and bone meal and the labeling did not bear cautionary BSE statement.

VOLUME OF PRODUCT IN COMMERCE

9,997,976 lbs.

DISTRIBUTION

ID and NV

END OF ENFORCEMENT REPORT FOR MARCH 21, 2007

http://www.fda.gov/Safety/Recalls/EnforcementReports/2007/ucm120446.htm



Saturday, August 14, 2010

BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY

*** (see mad cow feed in COMMERCE IN ALABAMA...TSS)

BANNED MAD COW FEED IN COMMERCE IN ALABAMA

Date: September 6, 2006 at 7:58 am PST PRODUCT

snip...see full text on mad cow feed in commerce through 2007 ;


Saturday, July 23, 2011

CATTLE HEADS WITH TONSILS, BEEF TONGUES, SPINAL CORD, SPECIFIED RISK MATERIALS (SRM's) AND PRIONS, AKA MAD COW DISEASE

http://transmissiblespongiformencephalopathy.blogspot.com/2011/07/cattle-heads-with-tonsils-beef-tongues.html




Saturday, November 6, 2010

TAFS1 Position Paper on Position Paper on Relaxation of the Feed Ban in the EU Berne, 2010 TAFS

INTERNATIONAL FORUM FOR TRANSMISSIBLE ANIMAL DISEASES AND FOOD SAFETY a non-profit Swiss Foundation

http://madcowfeed.blogspot.com/2010/11/tafs1-position-paper-on-position-paper.html




Archive Number 20101206.4364 Published Date 06-DEC-2010 Subject PRO/AH/EDR> Prion disease update 2010 (11)

PRION DISEASE UPDATE 2010 (11)

http://www.promedmail.org/pls/apex/f?p=2400:1001:5492868805159684::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,86129



http://www.isid.org/about/about.shtml




P.9.21

Molecular characterization of BSE in Canada

Jianmin Yang1, Sandor Dudas2, Catherine Graham2, Markus Czub3, Tim McAllister1, Stefanie Czub1 1Agriculture and Agri-Food Canada Research Centre, Canada; 2National and OIE BSE Reference Laboratory, Canada; 3University of Calgary, Canada

Background: Three BSE types (classical and two atypical) have been identified on the basis of molecular characteristics of the misfolded protein associated with the disease. To date, each of these three types have been detected in Canadian cattle.

Objectives: This study was conducted to further characterize the 16 Canadian BSE cases based on the biochemical properties of there associated PrPres. Methods: Immuno-reactivity, molecular weight, glycoform profiles and relative proteinase K sensitivity of the PrPres from each of the 16 confirmed Canadian BSE cases was determined using modified Western blot analysis.

Results: Fourteen of the 16 Canadian BSE cases were C type, 1 was H type and 1 was L type. The Canadian H and L-type BSE cases exhibited size shifts and changes in glycosylation similar to other atypical BSE cases. PK digestion under mild and stringent conditions revealed a reduced protease resistance of the atypical cases compared to the C-type cases. N terminal- specific antibodies bound to PrPres from H type but not from C or L type. The C-terminal-specific antibodies resulted in a shift in the glycoform profile and detected a fourth band in the Canadian H-type BSE.

Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan. This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada.

*** It also suggests a similar cause or source for atypical BSE in these countries.

http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf



PLEASE SEE ;

Unacceptable risk: When the potential harm either to animal or humans from a feed product attains a level not acceptable to decision-makers. The level may vary depending on the type of harm.

http://www.fda.gov/cvm/AFSS3rdDraftFramework.html



Friday, September 4, 2009

FOIA REQUEST ON FEED RECALL PRODUCT 429,128 lbs. feed for ruminant animals may have been contaminated with prohibited material Recall # V-258-2009

http://madcowfeed.blogspot.com/2009/09/foia-request-on-feed-recall-product.html



Saturday, August 29, 2009

FOIA REQUEST FEED RECALL 2009 Product may have contained prohibited materials Bulk Whole Barley, Recall # V-256-2009

http://madcowfeed.blogspot.com/2009/08/foia-request-feed-recall-2009-product.html



C O N F I R M E D


----- Original Message -----

From: "Terry S. Singeltary Sr."

To:

Sent: Thursday, November 05, 2009 9:25 PM

Subject: [BSE-L] re-FOIA REQUEST ON FEED RECALL PRODUCT contaminated with prohibited material Recall # V-258-2009 and Recall # V-256-2009

http://madcowfeed.blogspot.com/2009/11/re-foia-request-on-feed-recall-product.html



PLEASE UNDERSTAND, with a Transmissible Spongiform Encephalopathy, once clinical, the disease is 100% fatal. There should be NO debate of the 'unacceptable risk factor', with any TSE. ...TSS

Sunday, June 26, 2011

Risk Analysis of Low-Dose Prion Exposures in Cynomolgus Macaque


http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/risk-analysis-of-low-dose-prion.html




Friday, March 4, 2011

Alberta dairy cow found with mad cow disease

http://transmissiblespongiformencephalopathy.blogspot.com/2011/03/alberta-dairy-cow-found-with-mad-cow.html



Wednesday, August 11, 2010

REPORT ON THE INVESTIGATION OF THE SIXTEENTH CASE OF BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) IN CANADA

http://bse-atypical.blogspot.com/2010/08/report-on-investigation-of-sixteenth.html




Thursday, August 19, 2010

REPORT ON THE INVESTIGATION OF THE SEVENTEENTH CASE OF BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) IN CANADA

http://bseusa.blogspot.com/2010/08/report-on-investigation-of-seventeenth.html



Thursday, February 10, 2011

TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY REPORT UPDATE CANADA FEBRUARY 2011 and how to hide mad cow disease in Canada Current as of: 2011-01-31

http://madcowtesting.blogspot.com/2011/02/transmissible-spongiform-encephalopathy.html



Wednesday, December 22, 2010

Manitoba veterinarian has been fined $10,000 for falsifying certification documents for U.S. bound cattle and what about mad cow disease ?

http://usdameatexport.blogspot.com/2010/12/manitoba-veterinarian-has-been-fined.html



i wonder if CFIA Canada uses the same OBEX ONLY diagnostic criteria as the USDA ?




Tuesday, November 02, 2010

BSE - ATYPICAL LESION DISTRIBUTION (RBSE 92-21367) statutory (obex only) diagnostic criteria CVL 1992

http://bse-atypical.blogspot.com/2010/11/bse-atypical-lesion-distribution-rbse.html



Sunday, August 21, 2011

The British disease, or a disease gone global, The TSE Prion Disease

http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/british-disease-or-disease-gone-global.html



Saturday, June 25, 2011

Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque



"BSE-L in North America may have existed for decades"


http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/transmissibility-of-bse-l-and-cattle.html




RE - "BSE-L in North America may have existed for decades" YA THINK ???


Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME.

snip...

The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle...


http://web.archive.org/web/20030516051623/http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf




Friday, February 18, 2011

UNITED STATES OF AMERICA VS GALEN J. NIEHUES FAKED MAD COW FEED TEST ON 92 BSE INSPECTION REPORTS FOR APPROXIMATELY 100 CATTLE OPERATIONS ''PLEADS GUILTY"

http://bse-atypical.blogspot.com/2011/02/united-states-of-america-vs-galen-j.html




see also ;



Thursday, August 4, 2011

Terry Singeltary Sr. on the Creutzfeldt-Jakob Disease Public Health Crisis, Date aired: 27 Jun 2011

(see video here) ;


http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/terry-singeltary-sr-on-creutzfeldt.html




Sunday, August 21, 2011

The British disease, or a disease gone global, The TSE Prion Disease

(see video here)


http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/british-disease-or-disease-gone-global.html




http://www.organicconsumers.org/articles/article_23850.cfm




http://www.cjdblogger.com/journal-old/2011/8/25/clarifications.html#comment14995903



Patricia Doyle, PhD, and Jeff Rinse et al ;


it is, what it is, prion vs virus vs whatever ? that is exactly how ProMed et al stated it, and again, the mad cow feed ban, was what it was, non existent through 2007.

what i find really strange and sad here is, Patricia A. Doyle DVM, PhD rude comments, via Jeff Rense, about ProMed et al endless efforts to track down these deadly pathogens around the globe.
I applaud ProMed et al for their efforts.

This is all very strange for Patricia Doyle, PhD, and Jeff Rense et al. ...


kindest regards, terry

Monday, December 13, 2010

Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD

FOUND IN: Health & Medicine

Virus-Like Structure Calls Into Question Origin of Diseases Such as “Mad Cow”

Published: December 10, 2010

New Haven, Conn. — A Yale University researcher has found virus-like genetic material within samples of Creutzfeldt-Jakob disease (CJD) and scrapie, a finding that challenges scientific consensus on the nature of these deadly brain-wasting diseases.

Many scientists say that transmissible spongiform encephalopathies (TSEs) — including CJD, scrapie and epidemic “mad cow” disease — are caused by a misfolded normal protein that spontaneously becomes infectious. This infectious prion form is transmitted without nucleic acid used by infectious agents such as viruses, they say.

But other scientists, such as Laura Manuelidis, professor of surgery at Yale School of Medicine, say a slow-acting virus may be the cause of TSEs.

In the study, published this week in the online edition of the Journal of Neurovirology, Manuelidis reports extracting new circular virus-like DNA sequences from infectious particles of three samples of CJD and scrapie. These viral signatures would not be expected to be found in CJD or scrapie samples if infected prions were the sole culprits in the disease, she said.

“These findings won’t end the TSE debate, but hopefully it will open the door to more discussions about the nature of the causal infectious agent in TSEs and other late onset neurological diseases” Manuelidis said.

While these sequences, called Sphinx elements, were only visible in preparations of the infectious particles, ultimately they were found at very low amounts in uninfected cells, the study reports. Manuelidis believes that more of these sequences may be discovered in preparations of other infectious particles.

“They are intriguing, not only for their function in TSEs, but also because they may have once been incorporated from distant bacterial viruses,” Manuelidis says.

PRESS CONTACT: Bill Hathaway 203-432-1322

http://opac.yale.edu/news/article.aspx?id=8094


Research Author: Yale University Last Updated: Dec 10, 2010 - 9:30:26 AM

--------------------------------------------------------------------------------

Virus-Like Structure Calls Into Question Origin of Diseases Such as “Mad Cow”

By Yale University Dec 10, 2010 - 9:27:45 AM

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(HealthNewsDigest.com) - New Haven, Conn. - A Yale University researcher has found virus-like genetic material within samples of Creutzfeldt-Jakob disease (CJD) and scrapie, a finding that challenges scientific consensus on the nature of these deadly brain-wasting diseases.

Many scientists say that transmissible spongiform encephalopathies (TSEs) — including CJD, scrapie and epidemic “mad cow” disease — are caused by a misfolded normal protein that spontaneously becomes infectious. This infectious prion form is transmitted without nucleic acid used by infectious agents such as viruses, they say.

But other scientists, such as Laura Manuelidis, professor of surgery at Yale School of Medicine, say a slow-acting virus may be the cause of TSEs.

In the study, published this week in the online edition of the Journal of Neurovirology, Manuelidis reports extracting new circular virus-like DNA sequences from infectious particles of three samples of CJD and scrapie. These viral signatures would not be expected to be found in CJD or scrapie samples if infected prions were the sole culprits in the disease, she said.

“These findings won’t end the TSE debate, but hopefully it will open the door to more discussions about the nature of the causal infectious agent in

TSEs and other late onset neurological diseases” Manuelidis said.

While these sequences, called Sphinx elements, were only visible in preparations of the infectious particles, ultimately they were found at very low amounts in uninfected cells, the study reports. Manuelidis believes that more of these sequences may be discovered in preparations of other infectious particles.

“They are intriguing, not only for their function in TSEs, but also because they may have once been incorporated from distant bacterial viruses,” Manuelidis says.

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http://www.healthnewsdigest.com/news/Research_270/Virus-Like_Structure_Calls_Into_Question_Origin_of_Diseases_Such_as_Mad_Cow.shtml


Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD

Laura Manuelidis1

(1) Yale University Medical School, 333 Cedar Street, New Haven, CT 06510, USA

Laura Manuelidis Email: laura.manuelidis@yale.edu

Received: 14 September 2010 Revised: 19 October 2010 Accepted: 22 October 2010 Published online: 7 December 2010

Abstract

In transmissible encephalopathies (TSEs), it is commonly believed that the host prion protein transforms itself into an infectious form that encodes the many distinct TSE agent strains without any nucleic acid. Using a ?29 polymerase and chromatography strategy, highly infectious culture and brain preparations of three different geographic TSE agents all contained novel circular DNAs. Two circular “Sphinx” sequences, of 1.8 and 2.4 kb, copurified with infectious particles in sucrose gradients and, as many protected viruses, resisted nuclease digestion. Each contained a replicase ORF related to microviridae that infect commensal Acinetobacter. Infectious gradient fractions also contained nuclease-resistant 16 kb mitochondrial DNAs and analysis of >4,000 nt demonstrated a 100% identity with their species-specific sequences. This confirmed the fidelity of the newly identified sequences detailed here. Conserved replicase regions within the two Sphinx DNAs were ultimately detected by PCR in cytoplasmic preparations from normal cells and brain but were 2,500-fold less than in parallel-infected samples. No trace of the two Sphinx replicases was found in enzymes, detergents, or other preparative materials using exhaustive PCR cycles. The Sphinx sequences uncovered here could have a role in TSE infections despite their apparently symbiotic, low-level persistence in normal cells and tissues. These, as well as other cryptic circular DNAs, may cause or contribute to neurodegeneration and infection-associated tumor transformation. The current results also raise the intriguing possibility that mammals may incorporate more of the prokaryotic world in their cytoplasm than previously recognized.

Keywords Prion - Phi 29 polymerase - Acinetobacter plamids - Neurodegeneration - Cancer - Circovirus

http://www.springerlink.com/content/k201658k278254q6/fulltext.html


SEE FULL TEXT ;

Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD

Laura Manuelidis

Online First™, 7 December 2010

Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD

Laura Manuelidis Received: 14 September 2010 / Revised: 19 October 2010 / Accepted: 22 October 2010 # Journal of NeuroVirology, Inc. 2010

http://www.springerlink.com/content/k201658k278254q6/fulltext.pdf


http://www.springerlink.com/content/k201658k278254q6/fulltext.html


http://info.med.yale.edu/neurosci/faculty/manuelidis_main.html


http://www.yalesurgery.org/neuropathology/research/index.aspx


http://www.yalesurgery.org/neuropathology/research/prion.aspx


TSS

Friday, September 3, 2010

Endogenous Viral Etiology of Prion Diseases

Endogenous Viral Etiology of Prion Diseases

Eradicating transmissible spongiform encephalopathies (TSEs) in farm animals by deleting the endogenous viral gene PRNP is technologically feasible, ethically acceptable, makes sense commercially and, by eliminating the risk for TSE transmission to humans and to domestic and wild animals, it is a sensible public health preventive measure.

Unlike the prion hypothesis, the endogenous TSE virus model is consistent with all current data, it makes evolutionary sense, and it provides solutions to many TSE enigmatic features ([1]; see comment above). Moreover, by explaining the TSE phenomenon, this model opens the door to new therapeutic approaches and it offers a new strategy for eradicating TSEs, such as "mad cow disease" [bovine spongiform encephalopathy (BSE)] in cattle, and scrapie in sheep and goats (see comments above). This strategy consists of deleting the endogenous viral gene PRNP from reproductive stocks. As discussed next, using this approach to eradicate TSEs is technologically feasible, ethically acceptable, and makes sense commercially. More importantly, though, by eradicating the TSEs in farm animals, this program would abolish the transmission of these fatal diseases to humans and to other domesticated and wild animals, which would be an extraordinary public health accomplishment.

The devastating BSE epidemic in the United Kingdom (UK), and the strong evidence that BSE was transmitted to humans causing the variant Creutzfeldt-Jacob disease (vCJD) [2;3] have profoundly changed the guidelines for animal farming and associated industries, as well as for public health [4;5]. One of the major long-term measures to prevent future TSE epidemics was the implementation of large-scale selective breeding programmes that would reduce the risk for developing TSE (reviewed in [6-9]). This approach was based on the findings that certain alleles (i.e. "mutations") of a gene called PRNP, which was first identified as a TSE-associated genetic locus in mice and sheep [10] and later as a TSE specific gene in mice [11] and other vertebrates (reviewed in [12]), are associated with a reduced risk for developing TSE (reviewed in [6-9]).

The rationale, the strategies, and the early results of these selective breeding programmes, particularly as applied to sheep, have been discussed at length in numerous publications (reviewed in [6-9]). These programmes are remarkable examples of successfully integrating diverse scientific, political, social, and economical interests into an impressive effort to control one of the most frightening diseases of our time. However, as discussed next, when the scientific foundation and the understanding of a disease is inadequate, or even misleading, the effort is undermined.

The prion concept, which has been the working hypothesis in the TSE field for more than two decades [13], was developed under the umbrella of the misleading dogma of viruses as virus particles, and it was founded on a poor understanding of the biochemistry and dynamics of protein folding and the relationship between genotype and phenotype ([1;14]; see comments above). As discussed in the paper and in the comments above, by defining the 'prion protein' (i.e. PrP-Sc) as a novel type of self-replicating pathogen independent of its gene PRNP, the prion concept has not only tarnished our scientific intellect and academic integrity but has negatively affected the progress in TSE and related fields, including finding a cure or developing strategies for eradicating this group of fatal diseases and, possibly, for understanding other related human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington 's disease (HD).

A case in point is the role this flawed concept has played in the implementation of the selective breeding programmes for reducing the risk for TSE, instead of, or in parallel with, a superior alternative approach consisting of inactivating or deleting the PRNP gene. This alternative approach is superior because unlike the selective breeding programmes, which only reduce the risk to some, but not necessarily to all forms of TSEs, deleting or inactivating the PRNP gene would completely eradicate all forms of TSEs, and more importantly would eliminate TSE transmission to humans and other animals. There is, however, a big problem with deleting or inactivating this gene, a problem associated with the misleading prion hypothesis. In order to promote and sustain its novelty that the TSEs do not have a viral etiology, the prion hypothesis has trumpeted for decades the false statement that PRNP is a normal cellular gene [11;13]. And, as it is well known, experimentally tampering with or modifying the genes of livestock is not ethically acceptable [15].

However, as first hypothesized twenty five years ago [16], and since then proven correct beyond any reasonable doubt (see paper and comments above), the PRNP is an endogenous viral gene and, therefore, it would make sense to inactivate or delete it from breeding livestock, such as cows, sheep and goats, which are susceptible to developing TSE. Paradoxically, even within the current scientific establishment, it is fully accepted that some members of the PRNP gene family (e.g. PRNT) have a viral nature [12;17]. However, accepting that TSEs have a viral etiology would invalidate the prion hypothesis, which has directed the thinking and the research in the TSE and related fields for more than two decades, and that might be a sensitive issue. Clearly, however, TSEs have endogenous viral etiology, and it would make sense to abandon the misleading prion hypothesis and liberate the TSE and associated fields from its obvious limitations.

The selective breeding approach has been challenging from the beginning because after more than two decades of very intense research involving dozens of laboratories and hundreds of researchers, the primary function of PRNP is still not known (note: although the PRNP gene causes TSE, it is assumed that the primary phenotype conferred by this gene is a non-pathogenic phenotype, and that TSE is just a secondary, 'accidental' phenotype). As discussed in the paper and in the comments above, this lack of progress in figuring out the primary function of PRNP is another pragmatic and costly example of the limitations imposed by the misleading prion hypothesis on the TSE research. On top of not knowing the function of PRNP, and therefore not knowing what phenotype(s) it might control the researchers and breeders were faced with two additional issues, which are inherent to most strong selective breeding programmes, namely: the potential for co-selection of genetically-linked undesirable traits, and a reduction in the genetic diversity of the breeding population. (Note: to address these major concerns, reproductive cells from unselected breeding stock have been stored as an emergency safety measure in case of a need to re-introduce the 'natural' genetic variation). If conducted on a large scale, generating livestock of cows, sheep, and goats with their endogenous viral PRNP inactivated or deleted, which is technologically and commercially feasible, would minimize these legitimate concerns and problems.

Fortunately, it appears that the main biological and performance traits, such as fertility, health and survival, growth rate, carcass composition, or milk production in the selected breeding stock are not negatively affected, at least not in the short term and not to an extent that overrides the potential benefits from reducing the risk for TSE. However, it is important to realize that these results were expected because we have known for two decades that mice and more recently cows and goats that have had their PRNPs deleted or inactivated (commonly referred to as PRNP 'null' animals) are relatively normal [18-20]. The rationale behind this expectation is that, if inactivating or deleting the PRNP gene does not seem to affect whatever 'hidden' phenotype (s) this gene controls, neither would the mutations. Nonetheless, monitoring the biological and performance traits of the animals carrying selected PRNP alleles, or for that matter monitoring PRNP 'null' animals, is necessary because all experimental laboratory findings need to be validated in the field.

Although, unlike the "PRNP null approach", the "PRNP selection approach" reduces the genetic variation in the breeding stocks (again, this is a intrinsic feature of all selective breeding approaches), when it comes to preserving the main biological and performance (i.e. commercial) traits, both approaches appear to work well. However, when it comes to TSE, the two approaches are no longer equivalent. What is important to realize is that the "PRNP selection approach" does not eradicate TSE. It only reduces the risk for developing TSE. And, it might do that only for the "classical forms" of TSEs, not other forms of TSE such as the "atypical forms" that were recently discovered [21-33] In fact, it is possible that this approach might increase the risk for the development and transmission of some of the new forms of TSE. In contrast, the "PRPN null approach" leads to the eradication of all forms of TSEs, and completely abolishes transmission to humans and other domestic or wild animals.

Before concluding this comment, it is relevant to discuss a very important issue that concerning the primary, or "natural," function of the endogenous TSE virus gene PRNP. As discussed at length in the paper and the comments above, the endogenous PRNP viral gene has evolved and has been maintained in vertebrate lineage because it provides a symbiotic, beneficial function to the host and to itself of course, specifically a protective function against other viruses. This is a relatively common phenomenon in virus/host relationships; indeed, many if not most viruses have evolved various mechanisms for protecting the infected cells, and themselves, from other viruses. Apparently, the endogenous PRNP viral gene uses two protective mechanisms, one is protein-based and the other RNA-based (in addition to the genetic, biochemical, structural, and evolutionary evidence, the discovery of the RNA-elements produced by the PRNP gene also points to its viral nature, and once more invalidates the prion hypothesis). The concern here, particularly as it relates to the "PRPN null approach," is that inactivating or deleting this gene might increase susceptibility to some viral infections (note: selection of certain PRNP alleles might have a similar effect, although possibly less severe). Definitely, this is a legitimate concern, but it might be of less relevance for livestock for multiple reasons. First of all, the antiviral protective functions provided by the endogenous TSE virus gene PRNP is only one of the many innate and adaptive immune antiviral mechanisms in these animals. Therefore, the contribution of the PRNP in the survival of these animals might only be relevant for long term evolutionary success in a natural environment and under the laws of natural selection, not under farming conditions. Second, we have developed numerous vaccines and other antiviral preventive measures and therapies, and continue to do so; therefore, the threat for many viral infections has already been reduced to a great extent. Third, in "PRPN null approach," the PRNP does not need to be completely deleted or inactivated. In fact, the RNA-based protective mechanism might be left intact, or even enhanced [if necessary, I can provide a very specific, nucleotide-by-nucleotide (so-to-speak) procedure of how to accomplish this task experimentally]. Also, it might be possible that protein-based protective mechanisms don't need to be completely abolished, but rather modified to such an extent that they will be incompatible with the TSE phenomenon.

In conclusion, the selective breeding programmes currently implemented in UK and many other countries might lead to an increase in resistance to some forms of TSEs, but possibly not all. Moreover, this approach leaves the door open for future TSE epidemics in farm animals and for TSEs transmission to humans and other domestic and wild animals. On the other hand, the "PRPN null approach" eradicates TSE and completely eliminates the risk for transmission. Based alone on the huge commercial losses associated with a TSE epidemic in livestock, as was the case with the BSE epidemic in UK where the losses were in the billions of pounds, it would make more sense to inactivate or delete the pathogenic endogenous viral gene PRNP. Even more, considering the horrendous morbidity and mortality caused by TSE epidemics in both farm animals and humans, implementing the "PRPN null approach" would not only make scientific sense but from a humanitarian, medical and public health perspective it could be regarded as a responsibility.

[I have already made the disclaimer in the paper that "the findings and conclusions in this report are those of the author and do not necessarily represent the views or the opinions of the U.S. Department of Health and Human Services or Centers for Disease Control and Prevention" (see paper); however, it might be appropriate to refresh it in context of this comment].

Endogenous Viral Etiology of Prion Diseases

Claudiu I. Bandea

National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA

October 20, 2009

Claudiu I. Bandea

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of incurable neurodegenerative disorders, including Kuru and Creutzfeldt-Jakob disease in humans, "mad cow"disease in cattle, and scrapie in sheep. This paper presents structural, genetic, and evolutionary evidence supporting an endogenous TSE virus model that integrates the three major traditional views on the nature of TSE pathogens, the conventional virus view, the prion hypothesis, and the virino concept, into a novel conceptual and evolutionary framework. According to this model, the TSE pathogens are symbiotic endogenous viruses that inadvertently produce transmissible viral particles that lack the viral genome and are composed primarily of the viral prion protein (PrP). Production of defective viral particles that contain a partial genome or lack the viral genome entirely is a relatively common event in the life cycle of many viruses. Similar to the normal viral particles, which contain a genome, these defective viral particles can be transmitted to new host cells. Obviously, in the absence of viral genome, these protein-only viral particles cannot establish a productive infection. However, if these viral particles enter a host cell that carries the parental or arelated virus and induce the production of similar protein-only particles, then they would appear as self-replicating, protein-only infectious pathogens if mistakenly taken out from the context of the viral life cycle. This misconception, which is rooted into the current dogma of viruses as viral particles, led to the development of the prion theory. The endogenous TSE virus model is consistent with the TSE data and offers solutions to many enigmatic features associated with TSE, including the function of PrP that, despite more than two decades of TSE research conducted primarily within the framework of the prion hypothesis, is still not known. According to the TSE endogenous virus model,PrP is the protein of an endogenous virus that has co-evolved with their vertebrate hosts by providing a protective function against pathogenic viruses. The evidence for the endogenous TSE virus model and for the antiviral protective function of PrP is strong, and they are fully open to additional experimental testing. The endogenous virus model opens the TSE research field to new interpretations and directions, both in basic research and in associated biomedical and public health fields, and could lead to development of new diagnostic and therapeutic approaches.


http://precedings.nature.com/documents/3887/version/1/files/npre20093887-1.pdf


http://precedings.nature.com/documents/3887/version/1/html



Endogenous Viral Etiology of Prion Diseases Claudiu I. Bandea1

Correspondence: cbandea [at] cdc.gov

1.Centers for Disease Control and Prevention, Atlanta, GA 30333 PDF (144.7 KB) .Document Type:Manuscript Date:Received 21 October 2009 18:35 UTC; Posted 23 October 2009

Subjects: Microbiology, Neuroscience, Evolutionary Biology

Tags:TSE Transmissible Spongiform Encephalopathies prions endogenous viruses viral evolution Scrapie

Abstract:

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of incurable neurodegenerative disorders, including Kuru and Creutzfeldt-Jakob disease in humans, “mad cow” disease in cattle, and scrapie in sheep. This paper presents structural, genetic, and evolutionary evidence supporting an endogenous TSE virus model that integrates the three major traditional views on the nature of TSE pathogens, the conventional virus view, the prion hypothesis, and the virino concept, into a novel conceptual and evolutionary framework. According to this model, the TSE pathogens are symbiotic endogenous viruses that inadvertently produce transmissible viral particles that lack the viral genome and are composed primarily of the viral prion protein (PrP). Production of defective viral particles that contain a partial genome or lack the viral genome entirely is a relatively common event in the life cycle of many viruses. Similar to the normal viral particles, which contain a genome, these defective viral particles can be transmitted to new host cells. Obviously, in the absence of viral genome, these protein-only viral particles cannot establish a productive infection. However, if these viral particles enter a host cell that carries the parental or a related virus and induce the production of similar protein-only particles, then they would appear as self-replicating, protein-only infectious pathogens if mistakenly taken out from the context of the viral life cycle. This misconception, which is rooted into the current dogma of viruses as viral particles, led to the development of the prion theory. The endogenous TSE virus model is consistent with the TSE data and offers solutions to many enigmatic features associated with TSE, including the function of PrP that, despite more than two decades of TSE research conducted primarily within the framework of the prion hypothesis, is still not known. According to the TSE endogenous virus model, PrP is the protein of an endogenous virus that has co-evolved with their vertebrate hosts by providing a protective function against pathogenic viruses. The evidence for the endogenous TSE virus model and for the antiviral protective function of PrP is strong, and they are fully open to additional experimental testing. The endogenous virus model opens the TSE research field to new interpretations and directions, both in basic research and in associated biomedical and public health fields, and could lead to development of new diagnostic and therapeutic approaches.


http://precedings.nature.com/documents/3887/version/1


Yervand Karapetyan on 30 December 2009 17:53 UTC

While I agree with some of the points made by the author in this paper – e.g. PrP being a capsid protein of a virus – I do not see any evidence of PrP alone being infectious without specific RNA coming form infected brain. None of the papers cited in this manuscript with this regard show that an infectious viral particle of any virus can be assembled from proteins alone without specific viral RNA. One can even substitute viral RNA with synthetic polyA in order to assemble TMV virion like particles (1) , but the infectivity of these complexes has never been demonstrated. While RNA alone, if delivered in enough quantity and protected properly, can be infectious.

The fact that TSE agent does not have coding nucleic acid doesn’t mean it does not have any nucleic acid genome! It can have non coding nucleic acid which will still carry infectivity and strain specific properties just like in the case of viroids and virusoids.

A virusoid (satellite RNA) in order to replicate would need a helper virus to be in every species and cell that is susceptible to infection. Hence the need for latent RNA virus in all TSE susceptible species (you may consider this kind of a virus an ””endogenous”” if you wish).

Interestingly enough Gajdusek proposed such scenario almost four decades ago (2): “These viruses could be associated or satellite viruses which serve to activate or are themselves activated by some helper virus latent in the susceptible host (Gajdusek, 1972).” [Gajdusek, D. C. (1972). Slow virus infections and activation of latent virus infections in aging. Advanc. geront. Res., 4, 201-218.]

References:

1. Schön A, Mundry KW. Coordinated two-disk nucleation, growth and properties, of virus-like particles assembled from tobacco-mosaic-virus capsid protein with poly(A) or oligo(A) of different length. Eur J Biochem. 1984 Apr 2;140(1):119-27.

2. D. Carleton Gajdusek. Spongiform virus encephalopathies doi:10.1136/jcp.s3-6.1.78 1972;s3-6;78-83 J. Clin. Pathol.


see discussions and more comments ;

http://precedings.nature.com/documents/3887/version/1



Originally published in Science Express on 31 December 2009

Science 12 February 2010: Vol. 327. no. 5967, pp. 869 - 872 DOI: 10.1126/science.1183218


Reports



Darwinian Evolution of Prions in Cell Culture


Jiali Li,* Shawn Browning,* Sukhvir P. Mahal, Anja M. Oelschlegel, Charles Weissmann


http://www.sciencemag.org/cgi/content/abstract/327/5967/869



E-Letters: Submit a response to this article

Published E-Letter responses:

Could Prion Protein Assumptions Engender Misleading Sensational Conclusions?

Igor V. Zaitsev (19 March 2010) The Backwards Evolution of Prions Laura Manuelidis (19 March 2010)


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Could Prion Protein Assumptions Engender Misleading Sensational Conclusions?

19 March 2010

Igor V. Zaitsev Science Department, Borough of Manhattan Community College, The City University of New York, USA

Respond to this E-Letter: Re: Could Prion Protein Assumptions Engender Misleading Sensational Conclusions?

The Report "Darwinian evolution of prions in cell culture" (J. Li et al., 12 February 2010, p. 869, published online 31 December 2009) has caused a sensation on the Web. A group of Florida-based scientists headed by Charles Weissmann have claimed that prion proteins develop drug resistance—that is to say, they are capable of adaptive change, mutation, and evolution. However, in 1997, Laura Manuelidis of the Yale School of Medicine published a Report on the evolution of a strain of Creutzfeldt-Jakob diseases, with a careful analysis of the infection (1), contradicting the conclusion of Weissmann's team.

It is important to ascertain whether Weissmann's team was dealing exclusively with prion proteins, given that it is very difficult to isolate them from nucleic acid contamination. Many scientists, including protein-only hypothesis adherents, identified RNA in similar transplanted inoculants. Stanley Prusiner, the leading advocate for the protein-only hypothesis, confirmed during a 2004 interview with The New York Times that protein-only infection would be conclusively evident if experimental scientists inoculate a synthetic protein to produce transmissible spongiform encephalopathy in animals—in that case, there would be no possibility of inoculum contamination (2).

Prusiner and his research team tried to initiate the disease by inoculating laboratory mice with what he claimed was a synthetic protein. However, Prusiner's team observed only some questionable signs of infection at about 600 or more days after inoculation (3), approximately the life expectancy of laboratory mice. Inoculation with an infected brain homogenate normally leads to an indication of brain pathology in mice brains in about 70 days (4).

The adaptation that Weissmann's team observed is a perfect example of a conventional RNA virus behavior, not of a protein. Therefore, what this group has discovered might be evidence of a virus hypothesis, not a protein-only hypothesis.

Igor V. Zaitsev

Science Department, Borough of Manhattan Community College, The City University of New York, New York, NY 10007-1097, USA.

References

1. L. Manuelidis et al., Science 277, 94 (1997).

2. S. Blakeslee, The New York Times, 30 July 2004.

3. G. Legname et al., Science 305, 673 (2004).

4. C. A. Baker et al., J. Virol. 73, 6 (1999).

The Backwards Evolution of Prions 19 March 2010

Laura Manuelidis, Professor and Head of Neuropathology Yale Medical School, New Haven, CT 06510, USA Respond to this E-Letter: Re: The Backwards Evolution of Prions

J. Li et al. report swainsonine-induced mutation in a single cell type infected with one scrapie strain ("Darwinian evolution of prions in cell culture," Reports, 12 February 2010, p. 869, published online 31 December 2009). They claim that host prion protein encodes the infectious mutant by misfolding (PrPSc). However, they found no evidence of either a new PrPSc or a new mouse strain. Nevertheless, they conclude: "You have exactly the same process of mutation and adaptive change in prions as you see in viruses; adaptability has moved one level down—to prions and protein folding—and it's clear that you do not need nucleic acid (DNA or RNA) for the process of evolution" (1). Many very distinct scrapie and Creutzfelt-Jacob disease (CJD) strains also show the same PrPSc in standard mice (2). Moreover, one can stably change the PrPSc conformation in murine cell cultures for more than 1 year, and only the original strain, not the PrPSc, breeds true (Ref. 15 in the Report). Two CJD strains, as easy to recognize as night and day, retained their unique properties as shown by re-inoculation in mice. The same is true for infected tissues such as spleen. Yet the authors propose that mutant PrPSc strains form outside the brain, regardless of overwhelming evidence to the contrary.

As shown in our Report in Science titled "Evolution of a strain of CJD that induces BSE-like plaques," I certainly agree that transmissible spongiform encephalopathy (TSE) agents can evolve and adapt, or be selected from a quasi-species (3). Moreover, two distinct strains can infect the same cell by superinfection (4). Agent mutation also implicates an intrinsic nucleic acid. The protein of tobacco mosaic virus was similarly declared infectious by ignoring its nucleic acid component. Accumulating evidence has falsified the major claims of infectious PrP [reviewed in (5)]. Yet the authors do not question their prion premise, even though there are substantial data that do not fit, including virus-like structural features and associated nucleic acids that appear to be necessary for infection (6). Moreover, different TSE strains have specific geographic and environmental origins that are inconsistent with spontaneous generation of host-encoded infectivity (2, 7). Clearly, in epidemic bovine spongiform encephalopathy, as in kuru, when you remove the environmental pathogen, the infection (and disease) dramatically falls. Recognition of these facts is critical for public health.

Swainsonine affects many glycosylated cell proteins and it has induced increased PrPSc elsewhere (8), a change opposite to the reduction reported here. Thus, its effects on PrPSc and scrapie strains are variable. The inherent genetic instability of the tumor cells used is also problematic. The extraordinary stability of TSE agents contrasts with a proposed very high mutation rate that appears to be based on cell doublings rather than agent titers. More critically, agent virulence is defined by many factors and realities that underscore host responses to an evasive, exogenous pathogen (9). Widely accepted paradigm-shifting features of the prion concept have now spread to a whole class of neurodegenerative proteins (10).

Laura Manuelidis

Yale Medical School, New Haven, CT 06510, USA.

References

1. C. Weissmann, at http://news.bbc.co.uk/2/hi/health/8435320.stm.

2. L. Manuelidis, T. Chakrabarty, K. Miyazawa, N.-A. Nduom, K. Emerling, Proc. Natl. Acad. Sci. U.S.A. 106, 13529 (2009).

3. L. Manuelidis, W. Fritch, Y.-G. Xi, Science 277, 94 (1997).

4. N. Nishida, S. Katamine, L. Manuelidis, Science 310, 493 (2005).

5. L. Manuelidis, J. Cell Biochem. 100, 897 (2007).

6. S. Simoneau, et al., Natureprecedings (2009); http://precedings.nature.com/documents/3344/version/1.

7. N. Hunter, D. Cairns, J. Gen. Virol. 79, 2079 (1998).

8. K. F. Winklhofer, U. Heller, A. Reintjes, J. Tatzelt, Traffic 4, 313 (2003).

9. L. Manuelidis, Virulence (2009); www.landesbioscience.com/journals/virulence/article/10822.

10. G. Miller, Science 326, 1337 (2009).

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Science. ISSN 0036-8075 (print), 1095-9203 (online)


http://www.sciencemag.org/cgi/eletters/327/5967/869



Science 4 July 1997: Vol. 277. no. 5322, pp. 94 - 98 DOI: 10.1126/science.277.5322.94 Prev Table of Contents Next

Reports

Evolution of a Strain of CJD That Induces BSE-Like Plaques

Laura Manuelidis, * William Fritch, You-Gen Xi

Bovine spongiform encephalopathy (BSE) has become a public health issue because a recently evolved BSE agent has infected people, yielding an unusual form of Creutzfeld-Jakob disease (CJD). A new CJD agent that provokes similar amyloid plaques and cerebellar pathology was serially propagated. First-passage rats showed obvious clinical signs and activated microglia but had negligible PrP-res (the more protease-resistant form of host PrP) or cerebellar lesions. Microglia and astrocytes may participate in strain selection because the agent evolved, stabilized, and reproducibly provoked BSE-like disease in subsequent passages. Early vacuolar change involving activated microglia and astrocytes preceded significant PrP-res accumulation by more than 50 days. These studies reveal several inflammatory host reactions to an exogenous agent.

Section of Neuropathology, Yale Medical School, 310 Cedar Street, New Haven, CT 06510, USA. * To whom correspondence should be addressed. E-mail: laura.manuelidis@yale.edu

http://www.sciencemag.org/cgi/content/abstract/277/5322/94


http://www.sciencemag.org/cgi/content/full/277/5322/94



Prospect A 25 nm virion is the likely cause of transmissible spongiform encephalopathies


Laura ManuelidisArticle first published online: 16 OCT 2006

DOI: 10.1002/jcb.21090


http://onlinelibrary.wiley.com/doi/10.1002/jcb.21090/abstract;jsessionid=4C517EA57A70B99693DBC6DD1A71BD8E.d02t02


Laura Manuelidis

Professor & Head of Neuropathology Department of Surgery and Faculty of Neurosciences & Virology B.A. Sarah Lawrence College M.D. Yale Medical School

Contact: Tel: 203-785-4442 Email: laura.manuelidis@yale.edu

current research


http://info.med.yale.edu/neurosci/faculty/manuelidis_main.html


http://www.yalesurgery.org/neuropathology/research/index.aspx


The backwards evolution of the prion concept

http://www.yalesurgery.org/neuropathology/research/prion.aspx


Pub-Med

http://www.ncbi.nlm.nih.gov/pubmed?term=Manuelidis+L.%5Bau%5D


Prion Diseases: No Accomplice Needed

by Jennifer Couzin-Frankel on January 28, 2010 12:00 AM

http://news.sciencemag.org/sciencenow/2010/01/28-03.html



Monday, August 9, 2010

Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more Prionbaloney ?

http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html


Saturday, August 14, 2010

BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY

http://prionpathy.blogspot.com/2010/08/bse-case-associated-with-prion-protein.html


Wednesday, July 28, 2010

re-Freedom of Information Act Project Number 3625-32000-086-05, Study of Atypical BSE UPDATE July 28, 2010

http://bse-atypical.blogspot.com/2010/07/re-freedom-of-information-act-project.html


Tuesday, July 27, 2010

Spontaneous generation of mammalian prions

http://madcowspontaneousnot.blogspot.com/2010/07/spontaneous-generation-of-mammalian.html


P.9.21

Molecular characterization of BSE in Canada

Jianmin Yang1, Sandor Dudas2, Catherine Graham2, Markus Czub3, Tim McAllister1, Stefanie Czub1 1Agriculture and Agri-Food Canada Research Centre, Canada; 2National and OIE BSE Reference Laboratory, Canada; 3University of Calgary, Canada

Background: Three BSE types (classical and two atypical) have been identified on the basis of molecular characteristics of the misfolded protein associated with the disease. To date, each of these three types have been detected in Canadian cattle.

Objectives: This study was conducted to further characterize the 16 Canadian BSE cases based on the biochemical properties of there associated PrPres. Methods: Immuno-reactivity, molecular weight, glycoform profiles and relative proteinase K sensitivity of the PrPres from each of the 16 confirmed Canadian BSE cases was determined using modified Western blot analysis.

Results: Fourteen of the 16 Canadian BSE cases were C type, 1 was H type and 1 was L type. The Canadian H and L-type BSE cases exhibited size shifts and changes in glycosylation similar to other atypical BSE cases. PK digestion under mild and stringent conditions revealed a reduced protease resistance of the atypical cases compared to the C-type cases. N terminal- specific antibodies bound to PrPres from H type but not from C or L type. The C-terminal-specific antibodies resulted in a shift in the glycoform profile and detected a fourth band in the Canadian H-type BSE.

Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan. This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada. It also suggests a similar cause or source for atypical BSE in these countries.

http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf


Wednesday, August 11, 2010

REPORT ON THE INVESTIGATION OF THE SIXTEENTH CASE OF BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) IN CANADA

http://bse-atypical.blogspot.com/2010/08/report-on-investigation-of-sixteenth.html


Thursday, August 19, 2010

REPORT ON THE INVESTIGATION OF THE SEVENTEENTH CASE OF BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) IN CANADA

http://bseusa.blogspot.com/2010/08/report-on-investigation-of-seventeenth.html


Thursday, August 19, 2010

SCRAPIE CANADA UPDATE Current as of 2010-07-31 The following table lists sheep flocks and/or goat herds confirmed to be infected with scrapie in Canada in 2010.

Current as of: 2010-07-31

http://nor-98.blogspot.com/2010/08/scrapie-canada-update-current-as-of.html


14th ICID International Scientific Exchange Brochure -

Final Abstract Number: ISE.114

Session: International Scientific Exchange

Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America

update October 2009

T. Singeltary

Bacliff, TX, USA

Background:

An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.

Methods:

12 years independent research of available data

Results:

I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.

Conclusion:

I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.

http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdf


Wednesday, March 31, 2010

Atypical BSE in Cattle

http://bse-atypical.blogspot.com/2010/03/atypical-bse-in-cattle-position-post.html



let's take a closer look at this new prionpathy or prionopathy, and then let's look at the g-h-BSEalabama mad cow.

This new prionopathy in humans? the genetic makeup is IDENTICAL to the g-h-BSEalabama mad cow, the only _documented_ mad cow in the world to date like this, ......wait, it get's better. this new prionpathy is killing young and old humans, with LONG DURATION from onset of symptoms to death, and the symptoms are very similar to nvCJD victims, OH, and the plaques are very similar in some cases too, bbbut, it's not related to the g-h-BSEalabama cow, WAIT NOW, it gets even better, the new human prionpathy that they claim is a genetic TSE, has no relation to any gene mutation in that family. daaa, ya think it could be related to that mad cow with the same genetic make-up ??? there were literally tons and tons of banned mad cow protein in Alabama in commerce, and none of it transmitted to cows, and the cows to humans there from ??? r i g h t $$$



ALABAMA MAD COW g-h-BSEalabama

In this study, we identified a novel mutation in the bovine prion protein gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United States of America. This mutation is identical to the E200K pathogenic mutation found in humans with a genetic form of CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most likely has caused BSE in "the approximately 10-year-old cow" carrying the E221K mutation.

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000156


http://www.plospathogens.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.ppat.1000156&representation=PDF


Saturday, August 14, 2010

BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY


(see mad cow feed in COMMERCE IN ALABAMA...TSS)


http://prionpathy.blogspot.com/2010/08/bse-case-associated-with-prion-protein.html



FRIENDLY FIRE FROM ALL OF THE ABOVE ;



Wednesday, August 18, 2010

Incidence of CJD Deaths Reported by CJD-SS in Canada as of July 31, 2010

http://creutzfeldt-jakob-disease.blogspot.com/2010/08/incidence-of-cjd-deaths-reported-by-cjd.html


Sunday, April 18, 2010

SCRAPIE AND ATYPICAL SCRAPIE TRANSMISSION STUDIES A REVIEW 2010

http://scrapie-usa.blogspot.com/2010/04/scrapie-and-atypical-scrapie.html


TSS

Thursday, August 19, 2010

SCRAPIE CANADA UPDATE Current as of 2010-07-31 The following table lists sheep flocks and/or goat herds confirmed to be infected with scrapie in Canada in 2010.

Current as of: 2010-07-31

http://nor-98.blogspot.com/2010/08/scrapie-canada-update-current-as-of.html


Monday, August 9, 2010

National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)

(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)

http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html


Thursday, August 12, 2010

USA Blood products, collected from a donor who was at risk for vCJD, were distributed July-August 2010

http://creutzfeldt-jakob-disease.blogspot.com/2010/08/usa-blood-products-collected-from-donor.html



TSS