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HIV Patients Have Increased Risk Of Pneumonia, Death Following Surgery

Posted by tumicrobiology on December 20, 2006

Science Daily HIV-infected patients undergoing surgical procedures may be more likely to develop pneumonia after surgery and to die within 12 months than those without HIV, according to a report in the December issue of Archives of Surgery, one of the JAMA/Archives journals. In addition, HIV patients with a preoperative viral load (number of copies of the virus in the blood) greater than 30,000 per milliliter appear to have increased risk of surgical complications.

Since the development of medication regimens known as highly active antiretroviral therapy (HAART), HIV has become a chronic, manageable condition, according to background information in the article. “Consequently, many HIV-infected patients elect to undergo surgical procedures to correct physical ailments that would not have been treated previously, and undergo operative interventions in lieu of medical therapies for certain conditions,” the authors write.

Michael A. Horberg, M.D., M.A.S., and colleagues at Kaiser Permanente Medical Care Program–Northern California, Oakland, studied surgical outcomes in 332 HIV-infected patients who underwent a variety of procedures (including abdominal, orthopedic and heart surgeries) between 1997 and 2002. For comparison, the researchers selected a group of 332 patients who did not have HIV but were the same age and sex and had a similar procedure at around the same time and at the same location as one of the HIV-infected patients. The investigators then used health plan databases to obtain clinical information about the HIV patients’ disease and to track whether any of the patients had complications after surgery or died within 12 months.

The surgical procedures analyzed included abdominal or pelvic procedures (80.8 percent), cardiac or breast procedures (8.4 percent) and orthopedic procedures (10.8 percent). Most complications–including infections and delayed wound healing–occurred equally frequently in patients with and without HIV. No difference between the two groups was found in the length of hospital stay, number of complications or need for additional procedures to treat complications. However, more HIV patients developed pneumonia (eight or 2.4 percent vs. one or .3 percent) and more died within 12 months (10 or 3 percent vs. two or .6 percent). “The causes of death varied” in HIV patients, the authors write. “While none of the causes appeared to be a direct consequence of the operation, two deaths were within 30 days of the operation.”

The researchers also examined risk factors for complications and death among HIV patients, including CD4 cell count response, a measure of the state of the immune system. The lower the CD4 count, the more likely a patient with HIV/AIDS is to develop secondary infections or illnesses. Those with a CD4 count of less than 50 cells per cubic millimeter of blood had more complications than those with higher CD4 counts. In addition, viral loads–measured as the number of copies of the virus in a milliliter of blood–of more than 30,000 were associated with a higher complication rate. Whether the patients were taking antiretroviral therapy did not appear to be related to their risk of developing complications. “Our results indicate that a higher HIV viral load seems to be a greater predictor of surgically related complications than either the CD4 cell count or the presence or absence of HAART use,” the authors write.

“Patients with HIV are living longer and regaining a substantial amount of immune function,” they conclude. “Many HIV-infected patients will require surgical attention because of a variety of disorders. In many cases, HIV serostatus [whether a person is infected with HIV or not] should not be a criterion when determining the need for surgery if patients have adequate viral control.”

Note: This story has been adapted from a news release issued by JAMA and Archives Journals.

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Bacterial infection ID method created

Posted by tumicrobiology on December 20, 2006

UPI— US scientists say they’ve developed a method of identifying specific sites of localized bacterial infections in living animals.
Bradley Smith of the University of Notre Dame and colleagues previously developed fluorescent molecular probes containing zinc that could be used to discriminate between common pathogenic bacteria, such as E. coli and Staphylococcus aureus, and mammalian cells.
In the new study, the scientists used the probes to pinpoint the sites of staph infections in laboratory mice. The scientists say physicians might have difficulty distinguishing localized bacterial infections from sites of sterile inflammation.
“Bacterial imaging is an emerging technology that has many health and environmental applications,” the researchers said. “For example, there is an obvious need to develop highly sensitive assays that can detect very small numbers of pathogenic bacterial cells in food, drinking water or biomedical samples. In other situations, the goal is to study, in vivo, the temporal and spatial distribution of bacteria in live animals.”
The study is described in a report scheduled for the Jan. 10 issue of the Journal of the American Chemical Society.
Copyright 2006 by United Press International. All Rights Reserved.

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Scientists Find Potential Weapon Against Tuberculosis Infection

Posted by tumicrobiology on December 14, 2006

The discovery of a unique copper-repressing protein in the bacterium that causes tuberculosis in humans may pave the way toward new strategies for halting tuberculosis infection.

Scientists have known that when macrophages – the host’s immune cells – swallow an invading bacterium, they dump excessive amounts of copper onto the invader in an effort to kill it. While all cells need copper to function, too much of the metal ion causes cell death.

“But the invaders fight back with their own defense,” says Adel Talaat, a microbiologist at the University of Wisconsin-Madison School of Veterinary Medicine. “They block the excess copper.”

In a paper published in the January 2007 issue of Nature Chemical Biology, Talaat and colleagues from Texas A&M University and University of Saskatchewan in Saskatoon, Canada describe a unique protein repressor that they have identified as the mechanism used by invading bacterium cells to fight off the host’s copper attack.

Prior to the discovery of this repressor protein, scientists did not know exactly how invading bacterium protected themselves from copper ions used by the body as a defense against infection.

“With this discovery, we can now pursue ways to deactivate the repressor protein,” says Talaat. “Our goal is to disable the tuberculosis bacterium from fighting back against the host body’s defense mechanisms, so that we can stop tuberculosis.”
Source: University Of Wisconsin-Madison

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Study: How shigella causes dysentery

Posted by tumicrobiology on December 14, 2006

French scientists say they believe they’ve discovered how shigella bacteria survive in the gut to be able to cause dysentery.

Laurence Arbibe and colleagues at the Pasteur Institute in Paris found a protein produced by shigella is injected into host cells and blocks production of immune signals required for preventing the infection.

Shigella affects millions of people worldwide, killing hundreds of thousands annually.

The researchers studied Shigella flexneri infection of human colon cells to understand the bacterial factors required to initiate disease. Shigella bacteria are known to inject up to 20 proteins into intestinal cells for the purpose of promoting infection and for dampening immune responses.

They found one of the injected proteins, OpsF, could prevent gut cells from switching on genes involved in immune responses. As a consequence, Shigella flexneri avoids being killed by their host’s immune cells and is able to spread throughout the gut.

The scientists say their study highlights the precision with which pathogens such as shigella can dramatically alter host cells. It also suggests blocking OspF may provide a target for treating bacterial dysentery.

The study is reported in the January issue of the journal Nature Immunology.

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Three studies focus on malaria parasite

Posted by tumicrobiology on December 14, 2006

The US and British scientists have produced three studies that independently characterize the genetic diversity of the parasite that causes malaria.

Two studies focused on Plasmodium falciparum, the most deadly of the Plasmodium species known to cause human malaria, while the other study compares it with the related Plasmodium reichenowi, which infects chimpanzees.

Overall, the scientists say the data constitute a valuable resource that should improve understanding of drug resistance in malaria and identify candidate targets for vaccines.

Dyann Wirth and colleagues at the Harvard School of Public Health produced a genome-wide map of diversity in P. falciparum, including full sequencing of 16 new and geographically diverse strains and targeted sequencing of 54 other worldwide isolates.

Xin-zhuan Su, Philip Awadalla and colleagues at the U.S. National Institutes of Health focus on sequencing genomic regions coding for proteins within 4 P. falciparum isolates.

In the third study, Manolis Dermitzakis, Matthew Berriman and colleagues at the Wellcome Trust Sanger Institute in Hinxton, England, provide the first sequence of the P. reichenowi strain, as well as the sequence of two P. falciparum strains.

All three papers appear in the January issue of Nature Genetics.

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Flu Shot Effective Against Drifted Influenza, Nasal Spray Vaccine Less So

Posted by tumicrobiology on December 14, 2006

During a year in which the circulating strains of influenza showed genetic differences from the strains in vaccines, the traditional killed-virus flu shot was found to be effective in preventing influenza in healthy adults. The live attenuated-virus nasal spray vaccine also prevented illnesses but was less effective.

Both outcomes were determined by laboratory confirmation of flu infection, a University of Michigan study found.

Earlier studies had suggested that the nasal spray, sold by MedImmune as FluMist, might offer better protection against drifted viruses that had genetically changed between vaccine formulation and annual influenza activity. The nasal spray, which is based on a live but weakened virus, was 86 percent protective in one study conducted in children during a major drift year. However, FluMist had not previously been studied head-to-head against the shot in adults with laboratory confirmation.

The killed-virus flu shot is usually billed as 70 to 90 percent effective against circulating strains that are well matched to vaccine strains. During the 2004-2005 flu season, a University of Michigan team found that the killed-virus flu shot was 75 percent effective against a moderately-drifted type A virus and two types of B virus. The standard formulation of both the flu shot and the nasal spray vaccine includes two types of A influenza and one B, but in the 2004-05 season, there were two B strains circulating and one type A.

“On the other hand, FluMist was 48 percent effective. These results may only apply to the 2004-05 flu season,” said Dr. Arnold S. Monto, professor of epidemiology. “In other years the results may be different. We need a more specific understanding of which viral changes matter and which don’t. There are many things about vaccine protectiveness that we still don’t completely understand.”

“It may be that the difference in effectiveness between the shot and the spray can be attributed to poorer protection against type B infections in participants given FluMist,” Monto said, but that’s not clear from this study.

The live attenuated vaccine marketed as FluMist was developed at the University of Michigan by Hunein “John” Massaab, professor emeritus of epidemiology. MedImmune produces it under a license with the University.

Monto’s research team is conducting a randomized, double-blind, placebo-controlled three-year trial with National Institutes of Health funding in which the two vaccines are being compared head-to-head and against a placebo. Prior to the 2004-05 flu season, they vaccinated 1,247 people aged 18 to 46 in four Michigan communities.

A source of confusion about vaccine effectiveness against drifted viruses may stem from study design. Many vaccine evaluation studies rely on a clinical diagnosis of “influenza-like illness,” or measures of the immune response to infection in the blood. For the present study, Monto and lead author Suzanne Ohmit, assistant research scientist in epidemiology, took throat swab specimens from participants experiencing flu symptoms and analyzed them, using virus isolation and PCR techniques, to determine if influenza virus was causing the illness.

Monto and Ohmit suspect that the adult participants in their study in 2004-05 had enough prior experience with influenza that the live attenuated virus may have failed to infect their nasal passages and initiate an immune response as it is intended to do. However, both still believe that the nasal spray is very effective in children and may be more effective than the killed vaccine in the young.

“FluMist works very well in children with naive immune systems,” Ohmit said. The FDA approval of FluMist limits its use to people between age 5 and 49 years.

In another paper in the same edition of the New England Journal of Medicine, FluMist was administered to school children and the children were followed to see if they and their families had been protected against flu. The study’s authors conclude that vaccinating children had some protective effect on the children and their families, confirming a notion of “herd immunity” first tested by Arnold Monto in a 1970 influenza vaccine study.

Without having children in their study, Monto and Ohmit can’t tell whether the two vaccines would have conferred different protection in 2004-05 in that age group. However, data from a study conducted in 2004-05 in children aged 6 to 59 months by MedImmune, suggested that FluMist offered significantly greater protection than the flu shot. A MedImmune study discussed in October at a Toronto conference also found that FluMist was more successful at initiating antibody response than the traditional shot in young children.

Monto and Ohmit will continue to follow study participants vaccinated in Fall 2005 , without vaccinating them this year, to see whether the shot or the spray offer long-term protection.

The paper “Prevention of Antigenically Drifted Influenza by Inactivated and Live Attenuated Vaccines,” appears in the Dec. 14 issue of the New England Journal of Medicine.
Source: University of Michigan

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Snottites, Other Biofilms Hasten Cave Formation

Posted by tumicrobiology on December 14, 2006

Biofilms, which are complex layered communities of sulfur-consuming microbes, increase the rate of cave formation, but may also shed light on other biofilms, including those that grow on teeth and those that corrode steel ships hulls, according to a team of geologists
Cave biofilms are simpler than the microbes that occur in soils where there can be hundreds of thousands of species,” says Dr. Jennifer L. Macalady, assistant professor of geosciences, Penn State. “Some cave biofilms have very few species, 10 to 20. The more complex ones have 100s or 1,000s.”

The researchers investigated the Frasassi cave system located north of Rome and south of Venice in Italy. These limestone caves are like New Mexico’s Carlsbad Caverns and Lechuguilla

Cave, but in those caves, sulfur entered the caves from oil and gas reserves, while in Italy, the sulfur source is a thick gypsum layer below. Having sulfur in the environment allows these biofilms to grow.

Most limestone caves form when rainwater and runoff permeate the caves from above. Water and carbon dioxide mix to form carbonic acid, a very weak acid, that erodes the limestone cave walls. In sulfidic caves, water enters the caves from below, carrying hydrogen sulfide. Microbes in the biofilms use the sulfur for energy and produce sulfuric acid, a very strong acid.

“One type of biofilm, called a snottite because of its appearance, has a pH of zero or one,” says Daniel S. Jones, graduate student in geosciences. “This is very, very acidic.”

Carbonic acid cave systems lose about a third of an inch of wall every thousand years, while sulfuric acid cave systems lose about two and a third inches or six times as much in the same time. The researchers are interested in the make-up of the biofilms and how they cycle sulfur.

Biofilms are made up of thin layers of microbe species that can be very different. All require water, but some biofilms live in the pools, lakes and streams in caves and others live on the damp walls. The layers against the rock surface use oxygen and hydrogen sulfide for energy and produce sulfuric acid. The layer on the outside does as well, but, because middle layers exist, there is an opportunity for microbes that find oxygen poisonous to thrive. These middle layers may convert the sulfuric acid to hydrogen sulfide, creating a complete sulfur cycle in a few microns.

In dental biofilms, the microbes on the teeth are the ones that produce the acids that cause cavities, while the ones on the top create the right conditions for the acid-producing microbes to survive. Cave biofilm layers also fulfill different niches in their very tiny environment.

“Stream biofilms are responsible for the majority of sulfide disappearance in streams,” Jones told attendees today (Dec. 11) at the fall meeting of the American Geophysical Meeting in San Francisco.

Because the cave biofilms are relatively simple, it will be easier to connect the various microbe species to the geochemistry involved. While this work is not yet complete, the researchers are working on the problem. Dr. Greg K. Druschel, assistant professor of geology, University of Vermont, used microelectrode voltammetry to try to determine exactly which biofilm layers produce acids. The levels of hydrogen sulfide and sulfuric acid change, depending on which layer is tested.

“There is also a question about where these microbes originate,” says Macalady. “We do not know if they are always in rocks or if they are transported from somewhere else to establish themselves.”

No matter the answer, the biofilms probably begin growing in tiny cracks in the rock and eventually create some of the largest cave systems in the world. Cave biofilms are also the bottom of the food chain for cave ecosystems. They provide food for a variety of spiders, flat worms, pill bugs and amphipods — shrimp like crustaceans — that form a blind and pigmentless community.

“The only other place we find sulfur-based ecosystems is near the deep sea vents on the ocean floor,” says Jones.

Understanding how cave biofilms dissolve calcium carbonate may help us to understand the communities around ocean floor vents, but it may also, eventually, lead to understanding how biofilms dissolve calcium phosphate on teeth and the steel hulls of ships.

Macalady, Jones and Druschel worked with two undergraduate students: Daniel Eastman, University of Vermont, and Lindsey Albertson, Brown University. The National Science Foundation and NASA Astrobiology institute supported this research.

Source: Penn State

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Male Circumcision Reduces HIV Risk, Study Stopped Early

Posted by tumicrobiology on December 14, 2006

A University of Illinois at Chicago study has been stopped early due to preliminary results indicating that medical circumcision of men reduces their risk of acquiring HIV during heterosexual intercourse by 53 percent.

The study’s independent Data Safety and Monitoring Board met Dec. 12 to review the interim data. Based on the board’s review, the National Institutes of Health halted the trial and recommended that all men enrolled in the study who remain uncircumcised be offered circumcision.

“Circumcision is now a proven, effective prevention strategy to reduce HIV infections in men,” said Robert Bailey, professor of epidemiology in the UIC School of Public Health and principal investigator of the study.

The clinical trial, funded by the National Institute of Allergy and Infectious Diseases and the Canadian Institute of Health Research, enrolled 2,784 HIV negative, uncircumcised men between 18 and 24 years old in Kisumu, Kenya.

Half the men were randomly assigned to circumcision, half remained uncircumcised. All men enrolled in the study received free HIV testing and counseling, medical care, tests and treatment for sexually transmitted infections, condoms and behavioral risk counseling for 24 months.

Study results show that 22 of the 1,393 circumcised men in the study contracted HIV, compared to 47 of the 1,391 uncircumcised men. In other words, circumcised men had 53 percent fewer HIV infections than uncircumcised men.

Until now, public health organizations have not supported circumcision as a method of HIV prevention due to a lack of randomized controlled trials.

“With these findings, the evidence is now available for donor and normative agencies, like WHO and UNAIDS, to actively promote circumcision in a safe context and along with other HIV prevention strategies,” Bailey said.

“Circumcision cannot be a stand-alone intervention. It has to be integrated with all the other things that we do to prevent new HIV infections, such as treating sexual transmitted diseases and providing condoms and behavioral counseling,” Bailey said. “We can’t expect to just cut off a foreskin and have the guy go on his merry way without additional tools to fight against getting infected.”

Opponents of circumcision have speculated that circumcised men may feel they are not at risk of contracting HIV and may be more likely to engage in risky behavior. The Kenya study suggests that circumcision did not increase risky behavior among circumcised or uncircumcised men, according to Bailey.

“Both uncircumcised and circumcised men are reducing their sexual risk behavior,” he said, “which indicates that our counseling is doing some good.”

The study also evaluated the safety of circumcision in a community health clinic with specially trained practitioners. There were no severe or lasting complications from circumcision. However, 1.7 percent of surgeries resulted in mild complications, such as bleeding or infection.

Bailey said that promoting circumcision in Africa must be done in conjunction with proper technical training and medical tools, equipment and supplies necessary to perform large numbers of circumcisions safely.

“Already, there are large numbers of boys and young men who are seeking circumcision in areas of Africa where men are not traditionally circumcised,” he said. “The danger is that unqualified practitioners will fill a niche by providing circumcision, but with much higher complication rates.”

An estimated 30 million people in Africa are infected with HIV/AIDS and more than 90 percent of HIV infections in adults result from heterosexual intercourse. In Kisumu, the third-largest city in Kenya, an estimated 26 percent of uncircumcised men are HIV infected by age 25.

“This study will likely not have a large impact on the incidence of HIV/AIDS in the United States or Europe where heterosexual transmission of HIV is low compared with areas like sub-Saharan Africa and parts of Asia,” Bailey said. “However, there are other proven health benefits of circumcision, including better hygiene, fewer urinary tract infections, and less risk of cervical cancer in the partners of circumcised men.”

The armamentarium of HIV prevention strategies is very small, according to Bailey. The only other strategy proven effective is the use of antiretroviral drugs to reduce transmission from mother to child.

If a significant proportion of men in a population get circumcised, it will have an enormous impact on preventing HIV infection in men, as well as reducing infections in women, Bailey said.

Co-investigators of the study include Stephen Moses and Ian Maclean at the University of Manitoba, Jekoniah Ndinya-Achola at the University of Nairobi, Corette Parker at Research Triangle International, Kawango Agot at UNIM Project, John Krieger at University of Washington, and Richard Campbell at UIC.

During the past two decades, more than 40 observational epidemiological studies and one previous clinical trial have reported an association between male circumcision and a reduced risk of HIV infection.

On Dec. 12, the NIH stopped another clinical trial of male circumcision undertaken by investigators in Uganda and at Johns Hopkins University, after the study’s Data Safety Monitoring Board reviewed the preliminary results and found a protective effect similar to that found in Bailey’s study.

Source: University of Illinois at Chicago
Date: December 13, 2006

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Natural Radioactivity Could Provide Microbes In The Deep Biosphere With Vitality

Posted by tumicrobiology on December 6, 2006

Source: Max-Planck-Gesellschaft

An international team of researchers from the USA and Germany has published an explanation for life in the deep biosphere in the journal Science. Using the latest technologies from biogeochemistry, molecular biology and microbiology, the scientists collected a wide range of samples from the bottom of the sea. After intensive analysis, Bo B. Jørgensen and Steven D´Hondt have now published a model with which they explain that microorganisms might survive due to the natural radioactivity deep under the sea floor (Science, 10th November 2006).

It is estimated today that between 10 and 50 percent of all the biomass on the Earth is found deep below ground. Researchers working with Steven D´Hondt from the University of Rhode Island, USA, and Bo B. Jørgensen from the Max Planck Institute for Marine Microbiology in Bremen have confirmed this in the course of the Ocean Drilling Program. On a voyage on the research ship “Joides Resolution” they found life up to 400 meters below the sea floor. Tests revealed that the drilled cores contained living microorganisms; contamination was ruled out. In the upper layers of sediment, the researchers counted up to 100 million unicellular organisms per millilitre; deeper, in the 35 million year old sediments on the Earth’s crust, they still found one million microorganisms. This is a puzzle for scientists: only the upper layers of these deposits are in contact with the water – so where does the energy to provide life in the depths of the sediment come from?

Taking as a basis the energy sources in the deposits that are available to the cells in the form of organic carbon compounds, it is possible to calculate that the cells could only divide every thousand years. This extremely long period for reproduction cannot be reconciled with current understanding of living cells.

Jørgensen and D’Hondt are now proposing, on the basis of their data, a process which could represent an alternative source of energy for life deep under large sections of the Pacific – natural radioactivity. Water is broken down by radioactive radiation, which arises during the decomposition of naturally occurring potassium, thorium and uranium isotopes. This process (radiolysis) creates hydrogen and oxygen. Estimates of the energy balance show that this process can supply sufficient energy for the microorganisms. This would make life forms in the Deep Biosphere independent of the processes on the Earth’s surface. The authors point out that an exotic habitat like this could also have developed on other planets, far away from any suns.

In December 2006 the researchers will be taking the drilling ship “RV Roger Revelle” to the South Pacific. There, far away from the continental shelves, the quantity of carbon compounds which could serve the microorganisms as a basis for life is very low. This makes the researchers all the more curious about the sediment samples from the bottom of the sea.

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Scientists spot unknown gene interaction

Posted by tumicrobiology on December 6, 2006

Italian genetic researchers say they’ve made a discovery that might provide an important tool for controlling and treating breast cancer.

Scientists at Milan’s National Tumor Institute discovered proteins produced by the genes HER-2 and FHIT interact in a way that encourages tumor growth, the Italian news agency ANSA reported Wednesday. The researchers determined HER-2 prevents FHIT from blocking cell proliferation. Without FHIT’s action, cells can multiply quickly and end up producing a tumor.

“The analysis carried out for our research shows how the activity of HER-2 leads to the degradation of FHIT,” Sylvie Menard, head of experimental oncology at INT, told ANSA.

Medical researchers previously determined breast tumor development was often accompanied by an overproduction of proteins by the HER-2 gene. It is also known that in 70 percent of breast cancer cases, FHIT has stopped working for some reason.

Menard told ANSA it should be possible to find pharmaceuticals to prevent FHIT degradation, thereby slowing the development of tumors.

The research appears in the current issue of the journal of the American Academy of the Sciences.

Copyright 2006 by United Press International. All Rights Reserved.

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Scientists Explore Function Of ‘Junk DNA’

Posted by tumicrobiology on November 22, 2006

University of Iowa scientists have made a discovery that broadens understanding of a rapidly developing area of biology known as functional genomics and sheds more light on the mysterious, so-called “junk DNA” that makes up the majority of the human genome.

The team, led by Beverly Davidson, Ph.D., a Roy J. Carver Biomedical Research Chair in Internal Medicine and UI professor of internal medicine, physiology and biophysics, and neurology, have discovered a new mechanism for the expression of microRNAs — short segments of RNA that do not give rise to a protein, but do play a role in regulating protein production. In their study, Davidson and colleagues not only discovered that microRNAs could be expressed in a different way than previously known, they also found that some of the junk DNA is not junk at all, but instead consists of sequences that can generate microRNAs.

Davidson and her colleagues, including Glen Borchert, a graduate student in her lab, investigated how a set of microRNAs in the human genome is turned on, or expressed. In contrast to original assertions, they discovered that the molecular machinery used to express these microRNAs is different than that used to express RNA that encodes proteins. Expression of the microRNAs required an enzyme called RNA Polymerase III (Pol III) rather than the RNA Polymerase II (Pol II), which mediates expression of RNA that encode proteins. The study is published in Nature Structural and Molecular Biology Advance Online Publication (AOP) on Nov. 12.

“MicroRNAs are being shown to play roles in cancer and in normal development, so learning how these microRNAs are expressed may give us insight into these critical biological processes,” said Borchert, who is lead author of the study. “Up to now it’s been understood that one enzyme controls their expression, and we now show that in some cases it’s a completely different one.”

Genes that code for proteins make up only a tiny fraction of the human genome. The function of the remaining non-coding sequence is just beginning to be unraveled. In fact, until very recently, much of the non-coding sequence was dismissed as junk DNA. In 1998, scientists discovered that some DNA produced small pieces of non-coding RNA that could turn off, or silence, genes. This discovery won Andrew Fire and Craig Mello the 2006 Nobel Prize for medicine or physiology. Since their discovery, the field has exploded and small, non-coding RNAs have been shown to play an important role in development and disease in ways that scientists are only just beginning to understand.

“Not so many years ago our understanding was that DNA was transcribed to RNA, which was then translated to protein. Now we know that the levels of control are much more varied and that many RNAs don’t make protein, but instead regulate the expression of proteins,” Davidson explained. “Non-coding RNA like microRNAs represent a set of refined control switches, and understanding how microRNAs work and how they are themselves controlled is likely to be very important in many areas of biology and medicine.”

Over 450 microRNAs have been identified in the human genome. Learning how they are turned on and in what cells and what they do, may allow scientists to turn that knowledge to their advantage as a medical tool.

In addition to Davidson and Borchert, William Lanier, a graduate student in the UI Department of Biological Sciences, was also part of the research team. The study was funded in part by the National Institutes of Health.

Source: University of Iowa
Date: November 21, 2006

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New Protective Action For Powerful Anti-HIV Factor Identified

Posted by tumicrobiology on October 30, 2006

Scientists at the Gladstone Institute of Virology and Immunology (GIVI) have identified a previously unknown function of APOBEC3G (A3G), a protein that acts against HIV, a finding that may lead to new approaches for controlling HIV infection.

The work is published today, Oct. 2, 2006, in Proceedings of the National Academy of Sciences, USA.

The research, conducted by scientists in the laboratory of GIVI Director Warner C. Greene, MD, PhD, explains why CD4 T cells — the immune system cells targeted by HIV — are sometimes so susceptible to HIV infection and at other times are highly resistant.

Scientists have known that resistant CD4 T cells, called “resting cells,” are made up predominantly of CD4+ T cells that are in an inactive state, awaiting a stimulus to move into action. In these cells, A3G blocks HIV at an early step in its life cycle. However, when resting CD4 T cells are stimulated by a foreign protein or other signal, A3G is rapidly recruited into large RNA protein complexes within the cells. This change neutralizes the anti-HIV properties of A3G, opening the door to HIV infection.

In the current study, the researchers set out to decipher the protein and RNA components of the A3G RNA protein complexes. In so doing, Ya-Lin Chiu, PhD, a postdoctoral fellow in Greene’s laboratory, determined that the complexes help to prevent a threat within cells posed by a class of “jumping genes,” or retro-elements, which are sequences of DNA that change position within the genome, causing mutations, activating or inactivating other genes, or duplicating themselves, thereby increasing the quantity of DNA in each cell.

As with HIV, the replication and movement of these retro-elements to new chromosomal sites with potentially damaging effect involves copying DNA into RNA and then back into DNA again. The A3G RNA protein complex, Chiu determined, interrupts this retro-element replication cycle by binding the retro-element RNAs and sequestering them in the cytoplasm away from the nuclear machinery required for copying the RNA back into DNA and inserting the retro-element at a new chromosomal site.

Understanding A3G’s role in activated CD4 T cells could lead to a new strategy against HIV.

“If we can find a way to partially block A3G assembly into the large complexes during CD4 T cell activation, we could both preserve the potent anti-HIV effect of the small form of A3G and the protective function of the large A3G complex against select mobile genetic elements,” Greene said. Gladstone scientists are now exploring various ways to achieve this desired balance.

Other authors on the study were Gladstone postdoctoral fellows Mario Santiago PhD, and Vanessa B. Soros, PhD, and H. Ewa Witkowska and Steven C. Hall of the University of California, San Francisco, and Cécile Esnault and Thierry Heidmann from the Institut Gustave Roussy in Villejuif, France. Funding for the study came from the National Institutes of Health, San Francisco Women’s HIV Interdisciplinary Network, the American Foundation for AIDS Research, UCSF-GIVI Center for AIDS Research, Ligue Nationale Contre le Cancer, Sandler Family Foundation and the J. David Gladstone Institutes. The Gladstone Institute of Virology and Immunology is one of three research institutes of The J. David Gladstone Institutes, a private, nonprofit biomedical research institution. It is affiliated with UCSF, a leading university that consistently defines health care worldwide by conducting advanced biomedical research, educating graduate students in the health professions and life sciences, and providing complex patient care.

Source: University of California – San Francisco
Date: October 30, 2006

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Headway Against Hepatitis C: Study Shows Liver Damage Can Be Reversed

Posted by tumicrobiology on October 30, 2006

Saint Louis University Liver Center scientists are presenting research today on a more effective way to treat hepatitis C patients who have been unresponsive to current drug therapies.

They have shown that a cocktail of ribavirin and Infergen, a highly potent Interferon, is nearly twice as effective at controlling hepatitis C than standard treatments.

They are sharing their findings at the annual American Association for the Study of Liver Diseases meeting in Boston.

“The results are promising,” says Bruce R. Bacon, M.D., principal investigator and director of the division of gastroenterology and hepatology at Saint Louis University School of Medicine. “This group of non-responders is a very challenging population to treat, and we found that patients who followed through with the therapy had a response nearly twice that of previous trials looking at this population.”

Saint Louis University Liver Center researchers led a study of more than 500 patients with hepatitis C at 40 sites, 77 percent of whom had advanced fibrosis. Fourteen percent of patients taking 9mcg of Infergen daily and 20 percent taking 15 mcg were virus negative after six months.

A quarter of the non-cirrhotic patients receiving Infergen were also virus negative after 24 weeks. The optimal response to antiviral therapy is for the hepatitis C viral RNA to become undetectable on treatment and to remain undetectable for at least another six months off therapy; this is referred to as a sustained virologic response, essentially a cure of the disease. Rates of sustained virologic response are still to be determined in this ongoing study.

Infergen is a highly potent type of interferon currently used for adult patients with chronic hepatitis C three times a week, Bacon says. This trial is expected to be completed in 2007.

An estimated 3.9 million Americans have hepatitis C. About 250,000 who have been offered therapy are unresponsive to current drug therapies, and the number is growing by 50,000 annually, according to the CDC.

Second Study Shows Liver Damage Can Be Reversed

In another study being presented at the AASLD conference, SLU researchers found that liver damage may be able to be reversed in patients with chronic hepatitis C who have undergone successful therapy.

“They are not only at a very low risk for relapse but may also see improvements to their liver,” says lead author Adrian Di Bisceglie, M.D., professor in the division of gastroenterology and hepatology at Saint Louis University School of Medicine.

Researchers studied the long-term effects in 150 patients with chronic hepatitis C following therapy. The level of liver damage in 79 percent of patients with stage 2 or worse fibrosis greatly improved and was unchanged in the rest of the patients.

“Little is known about how these patients fare after their treatment,” says Di Bisceglie, M.D., also acting chair of the department of internal medicine at SLU. “This is the largest study of its kind to examine just how much improvement patients with hepatitis C have five years after a sustained virologic response, and the results are very encouraging.”

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Oldest Complex Organic Molecules Found In Ancient Fossils

Posted by tumicrobiology on October 30, 2006

Ohio State University geologists have isolated complex organic molecules from 350-million-year-old fossil sea creatures — the oldest such molecules yet found.

The molecules may have functioned as pigments, but the study offers a much bigger finding: an entirely new way to track how species evolved.

Christina O’Malley, a doctoral student in earth sciences at Ohio State, found orange and yellow organic molecules inside the fossilized remains of several species of sea creatures known as crinoids. The oldest fossils in the study date back to the Mississippian period.

She reported the find Wednesday at the meeting of the Geological Society of America in Philadelphia.

Crinoids still exist today. Though they resemble plants, they are marine animals. They cling to the seafloor and feast on plankton that float by.

The crinoids in this study had flower-like fronds capping skinny stalks about six inches high — a look resembling “starfish on a stick,” said William Ausich, professor of earth sciences and O’Malley’s co-advisor with Yu-Ping Chin, also a professor of earth sciences.

Today’s crinoids display a range of colors, some variegated shades of red, orange, and yellow, so the geologists weren’t surprised that some of those colors turned up in the 350-million-year-old crinoids, Ausich said.

“People have suspected for a long time that organic molecules could be found inside fossils,” he added. “This is just the first time that scientists have succeeded in finding them.”

Though the organic molecules could be classified as pigments, nobody can be sure that they functioned as pigments inside these ancient animals, the geologists emphasized. They may have served some other purpose besides coloration — perhaps to defend the animal from predators by making it less palatable.

Because the molecules appear to be a little different for each species of crinoid, scientists can now use the pigments as biomarkers to map relationships on the creatures’ family tree. Until now, they could only infer crinoid lineage based on the size and shape of key features on the animals’ skeletons.

“This could be a new tool for figuring out how long-dead creatures became so prolific and successful. We can’t travel back in time, but now we can look for clues about these creature’s lives in a way that hasn’t been attempted or taken advantage of before,” O’Malley said.

Scientists can only view fossilized plants and animals in the grays and tans of sedimentary rock, such as the limestone fossils in this study. Rock is inorganic, and replaces organic molecules such as pigments during fossilization. What O’Malley and her colleagues discovered is that some organic molecules occasionally survive the process.

“Crinoid skeleton is very porous, and we think that when inorganic molecules filled in the spaces of the skeleton during preservation, some of the organic molecules were trapped inside the fossil,” she said.

O’Malley found pigments in every crinoid specimen that she sampled from three fossil sites, one in Switzerland and two in Indiana.

The Indiana samples date back to 350 million years ago, during the Mississippian period, when much of North America was covered by a shallow inland sea. The Switzerland fossils date back to 60 million years ago, during the Jurassic period. The sites preserved the crinoids exceptionally well, probably because a sudden storm buried them in sediment.

Should pigments be found in other fossils, the technique could prove to be a reliable way to trace species’ evolution. So far, the crinoid biomarkers mesh well with scientists’ concepts of how those species are related.

O’Malley isolated the pigments by grinding up small bits of fossil and dissolving the organic molecules into a solution. Then she injected a tiny sample of the solution into a machine called a gas chromatograph mass spectrometer. The machine vaporized the solution so that a magnet could separate individual molecules based on electric charge and mass. Computer software then identified the molecules.

Orange and yellow organic molecules emerged, along with several other molecules that the geologists have yet to identify. The off-the-shelf software was only designed to identify common laboratory compounds, O’Malley explained. She would like to generate her own database of fossil organic molecules, and also extract pigments from other marine fossils, including some from sites in Iowa.

Source: Ohio State University

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Social Amoebas’ Family Tree Reveals Evolutionary Clues

Posted by tumicrobiology on October 30, 2006

The full family tree of the species known as social amoebas has been plotted for the first time – a breakthrough which will provide important clues to the evolution of life on earth.

Researchers, headed by evolutionary biologist Professor Sandie Baldauf, of the University of York, and biochemist Professor Pauline Schaap, of the University of Dundee, have produced the first molecular ‘dictionary’ of the 100 or so known species of social amoeba.

Using this family tree, they have devised a model system to establish how single cell organisms communicate and interact to create multi-cellular structures in response to changing environmental conditions. Previously, there was almost no molecular data for social amoeba – Dictyostelia – which are a hugely diverse and ancient group.

Social amoebas are a group of organisms with a genetic diversity that is greater than that of fungi and similar to that of all animals. They offer an excellent experimental system for studying aspects of evolution and communication that are not easy to study in more complex multi-cellular organisms.

The York and Dundee teams have worked with field biologists in Germany, the US and Japan, and their research is published today (Friday 27 October 2006) in the prestigious international journal Science.

The published paper shows for the first time the family tree of all known social amoeba species and the evolution of their multicellular life style.

“This provides a starting point in allowing us to examine what happens at the molecular level as species evolve and mutate,” said Professor Schaap, of the Division of Cell and Developmental Biology in the College of Life Sciences at Dundee.

“The availability of a family tree allows us to reconstruct the evolution of the signalling mechanisms that generate multicellularity. It also provides a powerful tool to identify core ancestral processes that regulate the most basic aspects of development.”

Professor Baldauf, of the Department of Biology at York, said: “We have investigated the evolution of plants and animals for a very long time but our whole eco-system depends on single cell organisms. If we want to look at the fundamentals of life we have to look at single cell organisms.

“Amoebas are some of the closest single cell relatives of animals so understanding how they work and evolve is important because it helps us to understand how animals evolve. We have developed a new model system for the study of the evolution of forms.

“We have written the dictionary. Now we know what the words are – but we still have to construct the sentences.”

The research teams were able to build the family tree by amplifying and comparing highly conserved genes from all known species of social amoeba.

The existing family tree of the social amoeba was based on how the multicellular structures of each species look on the outside. However, this tree was completely uprooted by the molecular data gathered by the researchers in Dundee and York.

By plotting all existing information of the amoebas’ cellular and multi-cellular shapes and behaviour to the molecular tree, it appeared that increased cell specialization and organism size is a major trend in the evolution of social amoeba.

Professor Schaap and her team are now working to establish how the regulation and function of genes with important roles in development was altered and elaborated during the course of evolution to generate novel cell-types and morphological features.

The next step for Professor Baldauf and her team will be to investigate the origin of these amoebas, and also to search for new species and to establish their position on the family tree. Meanwhile, a number of research projects, including teams in the USA and Germany, have won sponsorship to sequence the genomes of social amoeba species identified by the work in York and Dundee.

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Enzyme involved in allergic diseases found

Posted by tumicrobiology on October 30, 2006

A U.S. research team says it has identified an enzyme involved in allergic reactions, possibly providing a new target for the treatment of such maladies.

The scientists from Virginia Commonwealth University, the Hospital for Special Surgery and Weill Cornell Medical College in New York note allergic diseases such as asthma and hay fever afflict about 30 percent of people in the developed world — and allergic reactions are the sixth leading cause of chronic disease in the United States.

The team has demonstrated, for the first time, the role of a proteolytic enzyme called ADAM10 that releases a major allergy regulatory protein from the surface of cells and, thereby, promotes a stronger allergic response.

“Our research, for the first time, may represent a treatment strategy to prevent, rather than simply control, IgE-mediated allergy,” said VCU Professor Daniel Conrad. IgE is an antibody known to trigger Type I allergic disease. “Understanding ADAM10’s role in allergic disease makes it a potential target for the design of drugs to treat asthma and allergic disease.”

The research appears online in the journal Nature Immunology.

Copyright 2006 by United Press International. All Rights Reserved.

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Study: Biofuel cells without the bio cells

Posted by tumicrobiology on October 30, 2006

U.S. scientists say proteins rendered portable from the organisms that spawned them might make miniature bioreactor cells feasible.

Researchers at the U.S. Department of Energy’s Pacific Northwest National Laboratory say they have become the first to measure electrical charges shuttled by proteins removed from living cells.

The scientists say some proteins are enzymes that taxi electrons to chemicals outside the cell, to discharge excess energy generated during metabolism. That maintains energy flow in the cell and, in turn, keeps the cell alive.

Now, the scientists say for the first time they have observed that electricity-shuttling process taking place sans cells, in purified proteins removed from the outer membrane of the versatile, metal-altering soil bacterium Shewanella oneidensis.

“We show that you can directly transfer electrons to a mineral using a purified protein and I don’t think anyone had shown that before,” said Thomas Squier, senior author of the study.

The research appears in the current issue of the Journal of the American Chemical Society.

Copyright 2006 by United Press International. All Rights Reserved.

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New microscope used for nano research

Posted by tumicrobiology on October 30, 2006

U.S. scientists are using a new form of scanning microscopy to simultaneously study physical and electronic profiles of metal nanostructures.

Researchers at the National Institute of Standards and Technology and University of Colorado-Boulder say the new instrument — the scanning photoionization microscope — is expected to be particularly useful for analyzing the make-up and properties of nanoscale electronics and nanoparticles.

The scientists said the instrument combines the high spatial resolution of optical microscopy with the high sensitivity to subtle electrical activity made possible by detecting the low-energy electrons emitted by a material as it is illuminated with laser pulses.

The technique potentially could be used to make pictures of both electronic and physical patterns in devices such as nanostructured transistors or electrode sensors, or to identify chemicals or even elements in such structures.

“You make images by virtue of how readily electrons are photoejected from a material,” said NIST fellow David Nesbitt, leader of the research group. “The method is in its infancy, but nevertheless it really does have the power to provide a new set of eyes for looking at nanostructured metals and semiconductors.”

The instrument is described in the journal Chemical Physics.

Copyright 2006 by United Press International. All Rights Reserved.

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New Pathways For Autoimmune Treatment Identified

Posted by tumicrobiology on May 30, 2006

A rare genetic defect that can trigger a host of diseases from type 1 diabetes to alopecia has helped explain the imbalance of immune regulator and killer cells in autoimmune disease.

Mutation in the Aire gene causes APS1, a disease causing two out of three problems – an underactive parathyroid, yeast infection of the skin and/or mucous membrane and adrenal gland insufficiency – by age 5 and up to 16 autoimmune diseases over a lifetime.

The same mutation causes a defect in iNKT cells, a type of regulatory cell that helps the immune system fight infections while suppressing errant T cells bent on attacking the body, Medical College of Georgia researchers say.

This finding opens new pathways for treating or preventing APS1, or autoimmune polyglandular syndrome type 1, and potentially other autoimmune diseases as well, researchers report in the June issue of Nature Medicine.

“The body should maintain a balance between killing and suppression,” says Dr. Qing-Sheng Mi, immunologist and lead and co-senior author. “If you are killing too hard, it can induce autoimmune disease. If you regulate suppression too hard, you can get cancer. iNKT cells help maintain a healthy balance. But patients with autoimmune disease may not have enough functional iNKT cells.”

“Aire controls the development and function of iNKT cells,” says Drs. Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine and co-senior author. “This relationship means that iNKT cells are critical to most autoimmune diseases and manipulating the iNKT cell population is one possible way to cure autoimmune disease.”

A lipid purified from sea plants, called alpha-GalCer, is already under study as a way to boost iNKT cell numbers and fight autoimmune disease as well as cancer. iNKT cells’ reactivity to alpha-GalCer, prompted the scientists to use it as a marker to examine the status of these cells in a mouse missing the Aire gene. That Aire knockout is a good model for humans with APS1.

They found significantly fewer iNKT cells in the thymus, spleen, liver and bone marrow and severely impaired maturation of those cells in mice missing the Aire gene. And the mice given alpha-GalCer had significantly reduced autoantibody production.

In 2001, Dr. Terry L. Delovitch and his colleagues at Canada’s Robarts Research Institute, including Dr. Mi, reported in Nature Medicine that using alpha-GalCer to boost iNKT cells and re-establish a healthy balance of good and bad immune cells prevented development of type 1 diabetes in an animal model for the disease.

But Drs. Mi and She say new iNKT boosters likely are needed because the action of alpha-GalCer somehow depends on individual genetic architecture as well as other factors. Under certain conditions, the drug can help or worsen an autoimmune disease by producing good or bad cytokines. That’s why it also has worked for some cancers and why a modified version of the glycolipid or totally different drugs may work better, Dr. She says. “By understanding more, we are better able to come up with better targets,” he says.

“iNKT development is still the big question,” says Dr. Mi. “Not only how they develop, but how they develop properly.”

The researchers watched the key regulatory cells come out of the bone marrow and go to the thymus where all T cells go for a process of positive and negative selection and maturation. Positive selection eliminates cells that are dysfunctional. Negative selection is eliminating T-cells that recognize the body’s own proteins, Dr. She says.

Other researchers recently confirmed that the Aire gene is involved in negative selection by controlling some protein expression in the thymus, Dr. Mi says. The thymus is supposed to express most body proteins so any T cells that would react to them can be eliminated through negative selection, he says. “But Aire’s role in protein expression is not sufficient to explain all the clinical symptoms of patients with APS1,” Dr. Mi says. “The Aire gene must have other immune functions.”

iNKT cells also go through a development process but via a somewhat different path than that of other T cells. MCG researchers have learned medullary epithelial cells in the thymus are critical to proper iNKT cell development. A defective Aire gene disrupts this natural nurturing relationship by disrupting medullary epithelial cell function, leading to insufficient numbers of iNKT cells.

“Whether or not you develop autoimmune disease to a large degree depends on the balance of these bad T cells that recognize the body’s own protein and regulatory T cells,” Dr. She says. “It’s all about balance.”
Source: Medical College of Georgia

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We are back again

Posted by tumicrobiology on May 6, 2006

Dear all,
Because of the political instability and the consequences that affected all of us in Nepal and abroad, we could not update our site for a month. Now, were are back.
Let’s be together again.
Cheers
Gaffer, TUMDF

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Scientists Elucidate The Kinome Of Key Model Organism

Posted by tumicrobiology on April 3, 2006

The journal PLoS Genetics has published the findings of a team of scientists at the nonprofit Boston Biomedical Research Institute that provides a whole genome analysis of the protein kinases from a scientifically valuable model organism known as Dictyostelium.Led by Dr. Janet Smith, this study offers important insights into the evolution of kinases, which are enzymes involved in cell communication pathways. Approximately 2.5% of human genes code for protein kinases, and mutations in many of these genes are at the root of a range of human diseases. Dictyostelium is a widely used model organism for scientific study, as it is remarkably similar to mammalian cells, and it is amenable to a range of laboratory techniques.
To solve the kinome of Dictyostelium, Dr. Smith and her colleagues at Boston Biomedical utilized the power of bioinformatics, a cutting edge scientific technique which employs databases and computer algorithms to allow researchers to gain information and compile data about genes and kinases in a fast and efficient way, which can be very useful for drug discovery and development.

According to Dr. Smith, Dictyostelium provides a simple model in which to study conserved cellular processes, and illuminates a period in the evolutionary history of the metazoa after the divergence of the plants but before that of the fungi. "Our findings document the impressive evolutionary creativity of the Dictyostelium kinome- a large portion of the kinases are unique to Dictyostelium, and are probably involved in unique aspects of this organism's biology," said Dr. Smith.

But conservation is also a major theme. By comparing the Dictyostelium kinome with those of other organisms, the authors find 46 types of kinases that appear to be conserved in all organisms, and are likely to be involved in fundamental cellular processes. "We believe this study will be very useful to researchers who are studying cell communication pathways in other organisms, including vertebrates, by demonstrating what aspects of signaling are conserved, and revealing opportunities to use Dictyostelium to understand important human proteins."

Boston Biomedical Research Institute is a not-for-profit institution dedicated to the understanding, treatment and prevention of specific human diseases including cancer, Alzheimer's disease, muscular dystrophy, diabetes and conditions such as obesity and reproductive health problems. For more information visit www.bbri.org.

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Posted by tumicrobiology on April 3, 2006

Scientists Elucidate The Kinome Of Key Model Organism

The journal PLoS Genetics has published the findings of a team of scientists at the nonprofit Boston Biomedical Research Institute that provides a whole genome analysis of the protein kinases from a scientifically valuable model organism known as Dictyostelium.

Led by Dr. Janet Smith, this study offers important insights into the evolution of kinases, which are enzymes involved in cell communication pathways. Approximately 2.5% of human genes code for protein kinases, and mutations in many of these genes are at the root of a range of human diseases. Dictyostelium is a widely used model organism for scientific study, as it is remarkably similar to mammalian cells, and it is amenable to a range of laboratory techniques.

To solve the kinome of Dictyostelium, Dr. Smith and her colleagues at Boston Biomedical utilized the power of bioinformatics, a cutting edge scientific technique which employs databases and computer algorithms to allow researchers to gain information and compile data about genes and kinases in a fast and efficient way, which can be very useful for drug discovery and development.

According to Dr. Smith, Dictyostelium provides a simple model in which to study conserved cellular processes, and illuminates a period in the evolutionary history of the metazoa after the divergence of the plants but before that of the fungi. "Our findings document the impressive evolutionary creativity of the Dictyostelium kinome- a large portion of the kinases are unique to Dictyostelium, and are probably involved in unique aspects of this organism's biology," said Dr. Smith.

But conservation is also a major theme. By comparing the Dictyostelium kinome with those of other organisms, the authors find 46 types of kinases that appear to be conserved in all organisms, and are likely to be involved in fundamental cellular processes. "We believe this study will be very useful to researchers who are studying cell communication pathways in other organisms, including vertebrates, by demonstrating what aspects of signaling are conserved, and revealing opportunities to use Dictyostelium to understand important human proteins."

Boston Biomedical Research Institute is a not-for-profit institution dedicated to the understanding, treatment and prevention of specific human diseases including cancer, Alzheimer's disease, muscular dystrophy, diabetes and conditions such as obesity and reproductive health problems. For more information visit www.bbri.org.

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DNA Gene Vaccine Protects Against Harmful Protein Of Alzheimer’s Disease

Posted by tumicrobiology on April 3, 2006

Doses of DNA-gene-coated gold particles protect mice against a protein implicated in Alzheimer's disease, researchers at UT Southwestern Medical Center have found
By pressure-injecting the gene responsible for producing the specific protein — called amyloid-beta 42 — the researchers caused the mice to make antibodies and greatly reduce the protein's build-up in the brain. Accumulation of amyloid-beta 42 in humans is a hallmark of Alzheimer's disease.

"The whole point of the study is to determine whether the antibody is therapeutically effective as a means to inhibit the formation of amyloid-beta storage in the brain, and it is," said Dr. Roger Rosenberg, the study's senior author and director of the Alzheimer's Disease Center at UT Southwestern.

The gene injection avoids a serious side-effect that caused the cancellation of a previous multi-center human trial with amyloid-beta 42, researchers said. UT Southwestern did not participate in that trial. In that earlier study, people received injections of the protein itself and some developed dangerous brain inflammation.

The new study is available online and appears in an upcoming issue of the Journal of the Neurological Sciences.

The researchers used mutant mice with two defective human genes associated with Alzheimer's, genes that produce amyloid-beta 42. "By seven months, the mice are storing abundant amounts of amyloid-beta 42," said Dr. Rosenberg, who holds the Abe (Brunky), Morris and William Zale Distinguished Chair in Neurology.

While the mice were young, the scientists coated microscopically small gold particles with human amyloid-beta 42 genes attached to other genes that program cells to make the protein. The particles were then injected with a gene gun into the skin cells of the mice's ears using a blast of helium.

After receiving 11 injections over several months, the mice showed a high level of antibodies to amyloid-beta 42, and a 60 percent to 77.5 percent reduction of plaques in their brains.

As controls, the researchers also either injected mutant mice with the gene for a related but harmless protein, amyloid-beta 16, or with a gene vaccine that lacked any amyloid genes. These treatments did not cause antibody production, and the mice showed the large amounts of amyloid-beta 42 brain plaques normally seen in animals with these mutations.

The gene injection showed superior results compared to a previous human study in which amyloid-beta 42 protein itself was injected into muscle, Dr. Rosenberg said. That study was halted when a small percentage of participants developed inflammation of the brain and spinal cord.

Injecting the gene, in contrast, caused no brain inflammation in the mice.

Dr. Rosenberg said the difference was partly because in the human trial, the protein was injected along with a substance called an adjuvant, which increased the immune response to abnormal excessive levels, causing the dangerous brain inflammation. In addition, the immune response in humans may have involved antibodies called Th1, which were probably partly responsible for the inflammation. The gene injection in the mouse study produced Th2 antibodies, which have a low probability of causing brain inflammation. Furthermore, no adjuvant was needed for antibody production.

The gene immunization is now undergoing further animal studies, with the ultimate goal being a clinical trial in humans. The researchers also plan to see if it can reverse the size of established plaques in the brains of mice.

Other UT Southwestern researchers involved in the study were Drs. Bao-Xi Qu, assistant professor of neurology, Philip Boyer, assistant professor of pathology, and Linda Hynan, associate professor of clinical sciences and psychiatry. Dr. Stephen Johnston, formerly with UT Southwestern and now at Arizona State University, also participated.

The work was supported by the National Institute on Aging, the National Alzheimer's Coordinating Center, the Rudman Foundation, the Luttrell Foundation, and UT Southwestern's Winspear Family Special Center for Research on the Neuropathy of Alzheimer's Disease.

Source: UT Southwestern Medical Center

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UW-Madison Engineers Squeeze Secrets From Proteins

Posted by tumicrobiology on March 24, 2006

Proteins, one of the basic components of living things, are among the most studied molecules in biochemistry. Understanding how proteins form or “fold” from sequenced strings of amino acids has long been one of the grand challenges of biology.

 

 

Depictions of proteins used in the study showing the different secondary and tertiary structures investigated: (a) the all-beta, C-terminal domain of protein G (16 residues of 2GB1), (b) an all-alpha fragment of protein A (1BDD), (c) the alpha/beta protein G (2GB1), and (d) the mainly-beta, SH3 domain of the SRC protein kinase (1SRL). (Image courtesy of University of Wisconsin-Madison, College of Engineering) 

 

A common belief holds that the more proteins are confined by their environment, the more stable – or less likely to unfold – they become. Now, as reported on the cover of the March issue of Biophysical Journal, a team of chemical and biological engineers from UW-Madison shows that premise to be untrue. While confinement plays an important role, other factors are also at play.

“Most research in this area looked at proteins in free solution when in fact, most proteins are confined in some way,” says Juan de Pablo, a chemical and biological engineer at the University of Wisconsin-Madison. “What we demonstrate for the first time is that the stability of proteins under severe confinement, which is really the relevant way of looking at them for numerous applications, depends on their shape, their size and their interactions with the environment. It is a delicate balance between the energy available to fold the protein and entropy, or it’s desire to be in the unfolded state.”

De Pablo’s research team developed a method to precisely calculate the entropy and determine how much of a protein’s stability change upon confinement to attribute to energy and how much to entropy. “This is the important part of the calculation,” de Pablo adds.

Protein stability is an incredibly important property in myriad applications, de Pablo says. Consider laundry detergent. A popular ad for detergent once claimed that “protein gets out protein.” The idea behind this is that engineered enzymes are at work in the wash breaking down elements of a stain.

“Once a protein is folded, you can actually unfold it or destabilize it, either by heating it up, or by adding solvents to the system, like urea for example, that just destroy the folded structure of the protein. How resilient the protein is to these assaults is what we often call stability,” de Pablo says. “Detergents like the ones you use to wash your clothes have enzymes that break the fat in stains. When you put you clothes in hot water in your washing machine, you want your detergents to withstand those high temperatures. So what people do is engineer enzymes that do not unfold when you put them in hot water. They design enzymes that are more stable than normal enzymes at high temperatures.”

To better understand protein folding, de Pablo’s team built computer models of proteins under different types of confinement. These models were then simulated to gain a better understand of protein stability. Working with the UW-Madison Nanoscale Science and Engineering Center (NSEC), funded by the National Science Foundation, the researchers will continue to refine their models with the goal of confining, folding and measuring the stability of proteins under more realistic conditions.

Source: University of Wisconsin-Madison

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Mobile animal diagnostic lab developed

Posted by tumicrobiology on March 24, 2006

Texas A&M University scientists say they’ve developed a mobile diagnostic laboratory to test animals in the event of a disease outbreak.

The executive director of the Texas Veterinary Medical Diagnostic Laboratory, Dr. Lelve Gayle, said a rapid, massive response by health officials is critical during a disease outbreak — even if the patients are animals.

The lab — housed in a trailer about the size of a recreational vehicle — will enable the diagnostic laboratory to expand quickly its capability to respond to an animal disease outbreak such as avian flu or livestock diseases not presently in the United States, Gayle said.

The mobile lab can be ready to process blood and tissue samples for animal diseases within 24-48 hours. The samples are then sent to the main laboratory in College Station, Texas, for testing.

The trailer has biosafety level-three rating, which means it had to pass stringent standards to keep disease organisms from escaping into the environment.

If a disease is suspected, laboratory testing is required — and Gayle’s goal is to have the mobile laboratory ready to test samples within two hours, seven days a week.

Copyright 2006 by United Press International. All Rights Reserved.

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