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Tampilkan postingan dengan label medicine. Tampilkan semua postingan
Tampilkan postingan dengan label medicine. Tampilkan semua postingan

Rabu, 10 Juni 2009

How Proteins Find The Right DNA Sequences

Illustration of how proteins find the right DNA sequences. (Credit: Image courtesy of Uppsala University)


Researchers at Uppsala University and Harvard University have collaboratively developed a new theoretical model to explain how proteins can rapidly find specific DNA sequences, even though there are many obstacles in the way on the chromosomes.





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In living cells, DNA-binding proteins regulate the activity of various genes so that different cells carry out the right tasks at the right time. For this to work, the DNA-binding proteins need to find the right DNA site sufficiently quickly. The research team behind the new study has previously succeeded in determining that it takes only a few minutes for an individual protein molecule to look through the millions of nearly identical binding alternatives and find the right place to bind. This is nevertheless slower than what is predicted by the established theoretical model for how DNA-binding proteins find their way to the proper place by alternating between diffusing in the cell cytoplasm and along DNA strands.
"By also taking into consideration the fact that there are many obstacles in the way when proteins are to diffuse along DNA strands, we can now calculate more exactly how long it takes them to find their way," says Johan Elf, associate professor of molecular biotechnology at the Center for Bioinformatics.
Besides offering a more precise prediction regarding the time needed to find the right site on DNA, the new theoretical model explains why there is an optimal total concentration of DNA-binding proteins. If there were more, it would simply be impossible for them to find a binding place in a reasonable time, since the proteins would be in each other's way. If there were fewer it would go slower as well, since not enough proteins would be searching. Finally, the new model provides an explanation why so many DNA-binding proteins also bind auxiliary binding sites close to the regulatory site, thus forming DNA loops. It turns out that this can shorten the time to find the right sites.
"This more detailed understanding of gene regulation is important, since it can ultimately provide a better understanding of diseases that occur as a result of problems in the control functions of cells, such as in cancer" says Johan Elf.
The researchers behind the study are Gene-Wei Li, Otto G. Berg, and Johan Elf. The findings are being published March 16 in the scientific journal Nature Physics.
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New Antibiotics Could Come From A DNA Binding Compound That Kills Bacteria In 2 Minutes

A synthetic DNA binding compound has proved surprisingly effective at binding to the DNA of bacteria and killing all the bacteria it touched within two minutes. The DNA binding properties of the compound were first discovered in the Department of Chemistry at the University of Warwick by Professor Mike Hannon and Professor Alison Rodger (Professor Mike Hannon is now at the University of Birmingham). However the strength of its antibiotic powers have now made it a compound of high interest for University of Warwick researchers working on the development of novel antibiotics.

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Dr Adair Richards from the University of Warwick said: "This research will assist the design of new compounds that can attack bacteria in a highly effective way which gets around the methods bacteria have developed to resist our current antibacterial drugs. As this antibiotic compound operates by targeting DNA, it should avoid all current resistance mechanisms of multi-resistant bacteria such as MRSA."
The compound [Fe2L3]4+ is an iron triple helicate with three organic strands wrapped around two iron centres to give a helix which looks cylindrical in shape and neatly fits within the major groove of a DNA helix. It is about the same size as the parts of a protein that recognise and bind with particular sequences of DNA. The high positive charge of the compound enhances its ability to bind to DNA which is negatively charged.
When the iron-helicate binds to the major groove of DNA it coils the DNA so that it is no longer available to bind to anything else and is not able to drive biological or chemical processes. Initially the researchers focused on the application of this useful property for targeting the DNA of cancer cells as it could bind to, coil up and shut down the cancer cell's DNA either killing the cell or stopping it replicate. However the team quickly realised that it might also be a very clever way of targeting drug-resistant bacteria.
New research at the University of Warwick, led by Dr Adair Richards and Dr Albert Bolhuis, has now found that the [Fe2L3]4+ does indeed have a powerful effect on bacteria. When introduced to two test bacteria Bacillus subtilis and E. coli they found that it quickly bound to the bacteria's DNA and killed virtually every cell within two minutes of being introduced - though the concentration required for this is high.
Professor Alison Rodger, Professor of Biophysical Chemistry at the University of Warwick, said: "We were surprised at how quickly this compound killed bacteria and these results make this compound a key lead compound for researchers working on the development of novel antibiotics to target drug resistant bacteria."
The researchers will next try and understand how and why the compound can cross the bacteria cell wall and membranes. They plan to test a wide range of compounds to look for relatives of the iron helicate that have the same mechanism for action in collaboration with researchers around the world.


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Rabu, 22 April 2009

Minimizing The Spread Of Deadly Hendra Virus

This artificially coloured electron micrograph of Hendra virus is from the first identified case in Brisbane in 1994. (Credit: CSIRO)
CSIRO Livestock Industries' scientists working at the Australian Animal Health Laboratory (AAHL), in Geelong Victoria, have made a major breakthrough in better understanding how Hendra spreads from infected horses to other horses and humans.


Funded by the Australian Biosecurity CRC for Emerging Infectious Diseases, Dr Deb Middleton and her team at AAHL have defined the period following the first signs of disease when horses are most likely to shed Hendra virus and therefore infect other horses and people.
First identified in Brisbane in 1994, Hendra virus, which spreads from flying foxes, has regularly infected horses in Australia. Of the 11 equine outbreaks, four have led to human infection, with three of the six known human cases being fatal, the most recent of these in August 2008.
Dr Deb Middleton and her team at AAHL have defined the period following the first signs of disease when horses are most likely to shed Hendra virus and therefore infect other horses and people.





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Dr Middleton says limited information in the past, on when the disease can transmit, has made it difficult to manage infected horses to stop Hendra spreading further to people and other susceptible horses.
"Our research has also determined the best biological samples required for rapid diagnosis of the virus in horses and identified the important relationship between the period of highest transmission risk and the time with which the disease can easily be detected," Dr Middleton says.
As a result of these findings, veterinarians and horse owners are likely to consider the possibility of Hendra virus infection sooner when dealing with sick horses. This will mean appropriate management strategies can be put in place immediately, reducing the risk of spread while testing is being carried out.
"Unlike in horse flu, where apparently healthy horses can transmit the virus, horses in the early stages of Hendra infection generally appear to be at lower risk compared to animals with more advanced signs of illness."
These research findings will be used to update the guidelines that horse owners and vets use to handle potential Hendra virus infections.
Dr Middleton says her research also indicates there is an opportunity to diagnose Hendra virus in horses early, prior to advanced clinical signs and the highest risk of transmission.
"Developing a sensitive and specific stall-side test, which vets could use out in the field to diagnose the disease, has become even more important. However there are still key challenges to developing this type of advanced technology."
Although it is still not known how Hendra spreads from flying foxes to horses, Dr Middleton says the key to preventing human exposure and the exposure of additional horses is first understanding the disease in horses and secondly controlling the viral spread from diseased horses.
All research for the project was undertaken within AAHL's high-biocontainment facility.
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Selasa, 14 April 2009

Medicine From Milk: Gene Therapy Could Transform Goats Into Pharmaceutical Factories

Researchers have used gene therapy to reduce the time it takes to breed goats capable of producing therapeutic proteins in their milk, such as insulin or those that fight cancer. (Credit: iStockphoto)

University of Pennsylvania researchers have used gene therapy to reduce the time it takes to breed large animals capable of producing therapeutic proteins in their milk, such as insulin or those that fight cancer. This represents a significant milestone in drug development, as current methods involve cloning, which takes more time and generally costs more.



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"Having an easier way to harness nature's power to produce large quantities of specific proteins in milk could increase the availability of drugs for people who could otherwise not afford these treatments," said Ina Dobrinski, one of the researchers on the study.
The study also is significant because it may also be a new way to eliminate diseases in future generations of animals, such as those used for livestock. Here's why: To get the goats to produce specific proteins, the researchers used radiation to kill a portion of a male goat's germ cells (the cells that produce sperm). Then they used a modified adeno-associated virus (a well studied and tolerated gene therapy vector) to insert a gene in the remaining cells. Once the new gene took hold in the germ cells, a predictable number of offspring carried the gene necessary to produce the desired protein in their milk.
The advance is immediately valuable for pharmaceutical development and biology research, but a similar approach could be used to bolster the food supply by eliminating genetic disorders in animals over several generations. It is also possible that once perfected, this technique could eliminate disease genes in humans over several generations, assuming ethical concerns can be resolved adequately.
This study is published in the February 2008 print edition of The FASEB Journal.
"For thousands of years, people have domesticated cows and goats to make milk, butter and cheese. And for thousands of years dairy products have been used as folk remedies for practically every human illness. Most have been completely ineffective." said Gerald Weissmann, MD, editor-in-chief of The FASEB Journal. "So it is reassuring that modern science would find a way to use the milk we drink to yield of drugs that actually work."
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Selasa, 27 Januari 2009

How Safe is the Air Indoors?

What is in the air in your home, where you work, or in public buildings? There may be bioaerosols — airborne biological contaminants. Aerobiological health hazards affect everyone on a daily basis and include allergens, mold spores, bacteria, and viruses that cause infectious diseases. How can these hazards be controlled indoors?

Aspergillus fumigatus is a fungus whose spores are common inhalation pollutants that pose a health hazard. Photo: Centers for Disease Control and Prevention.

Aerobiological engineering is a field of study that combines elements of engineering and microbiology that focus on reducing the risk of airborne disease by controlling the aerobiology of our indoor environments. It offers some solutions to the hazards of bioaerosols:

  • Existing technologies can collectively control these bioaerosols if we retrofit old buildings or specifically design new buildings to control airborne microbes.
  • By re-engineering our buildings on city-wide scales, the population can be broadly protected and potentially immunized against epidemics.
  • Developing standards for indoor environments and educating the public are critical steps to transforming our disease-prone society.



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Aerobiological health threats

Contagious diseases are the most dangerous and costly threats posed to building occupants today, including influenza, SARS, tuberculosis, pneumonia, and meningitis. Emerging pathogens such as avian flu and the resurgence of old diseases like plague, scarlet fever, whooping cough, and measles highlight the increasing vulnerability of populations to epidemic disease.
Evolving drug resistance, especially among hospital-acquired infections, complicates treatment of microbial agents, and physicians see their once abundant arsenal of antibiotics shrinking faster than new miracle drugs can be developed. Vaccines, once thought to be magic bullets, seem insufficient by themselves to combat airborne pathogens that can be transmitted freely in our unprotected buildings and have the potential to spread globally and cause pandemics.
Relatively mundane health threats like mold, dander, and allergens burden homes, schools, and offices, while the threat of bioterrorism leaves our buildings vulnerable to manmade epidemics that could decimate cities. Such formidable challenges can be placed into a manageable context if we recognize that protecting our buildings against the most common microbes simultaneously protects against the most dangerous threats as well.
Air- and surface-cleaning technologies

The technologies needed to create healthy buildings already exist, but they are not implemented widely enough to interdict epidemics. Optimized combinations of filtration and ultraviolet germicidal irradiation (UVGI) can be used to remove airborne microbes with high efficiencies. Combining and optimizing these technologies is the most cost effective means of disinfecting indoor air.
  • Filtration removes airborne particles including mold spores, many bacteria, and allergens.
  • UVGI eliminates many harmful bacteria and viruses.

Existing buildings can be retrofitted with air disinfection systems, but the most economic long-term solution is to construct new buildings that maintain aerobiological cleanliness by design. Air circulation is often poor in older buildings, and there are limits to what retrofitted air-cleaning systems can do for them. New buildings can be built in which the airflow is more evenly distributed and in which effectiveness of air cleaning can be maximized.2 A variety of other technologies, including photocatalytic oxidation (PCO), ozone, pulsed light, and antimicrobial materials, are also available options for air and surface biocontamination problems.

Criteria for rating healthy buildings

Modern air disinfection systems can achieve high levels of air cleaning, but limited budgets often require us to ask exactly how much air cleaning is needed to protect health. This question ultimately hinges on how buildings rate:

  • aerobiologically — the indoor levels of airborne microbes
  • epidemiologically — the infection risk of the building

Airborne levels of microbes

Indoor air contains a great variety of bioaerosols, most of which are relatively harmless to healthy humans. The concentration of airborne microbes in indoor environments, treated collectively without regard to species, provides a reasonable indication of overall aerobiological air quality. Levels of bacteria and fungi vary by season, with lows in winter, and increase with occupancy, as people are the primary source of contagious pathogens. Airborne levels are measured in terms of colony-forming units (cfu) of bacteria or fungi per cubic meter. Some hospital operating rooms are designed to maintain levels as low as 10 cfu/m3, although this level often proves difficult to achieve. Levels in homes and offices need not be this low, making solutions there less cost-prohibitive.

Infection risk

The infection risk (IR) of any building might be estimated by collecting data on infection rates and symptoms or through methods of risk analysis.3 Another approach is to estimate the risk using computer models of building airflow to calculate daily doses of inhaled contaminants. Airborne levels can be easily, if not always accurately, assessed with air samplers. The IR to an occupant in a particular building can be evaluated from epidemiological data. The IR can also be inversely viewed as the percentage of occupants protected from infection, a parameter called the building protection factor (BPF).

The BPF is the complement of the IR— a low IR implies a high BPF— and it can be used to rate and compare buildings under a common design basis. The BPF is primarily a function of the volume, airflow, outside air fraction, and removal efficiency of the air disinfection system. Being an intrinsic property of the building, it applies generically to all microbial species.4
Buildings differ according to their operating parameters. A completely unprotected building may have a BPF of 0% to 1%, whereas a building that maximizes protection of occupants may have a BPF of up to 99%. BPF can be considerably improved in existing buildings through the addition of air cleaning or other ventilation system improvements.

At least four general categories of buildings have been suggested:

  1. Problem buildings foster aerobiological problems or act as amplifiers. Their airborne levels may exceed 10,000 cfu/m3. IR can approach 99% or more and BPF 1% or less.
  2. Normal buildings have average airborne levels, about 500 to 5000 cfu/m3. Typically, IR is about 50% to 75% and BPF about 25% to 50%.
  3. Healthy buildings promote good air quality and health or are above average. Airborne levels are 100 to 1000 cfu/m3. Typically, IR is less than 50% and BPF 50% or higher.
  4. Immune buildings are designed to actively prevent airborne disease transmission. Airborne levels are as low as 10 cfu/m3. IR is less than 10% and BPF 90% or higher.

Disease-free buildings

Buildings concentrate allergens due mainly to the protective effects of shade, warmth, substrate materials, and moisture. For the same basic reasons, they act as vectors (carriers) for contagious airborne diseases. Humans have been building enclosed habitats for perhaps half a million years, and in this course of time airborne pathogens evolved the ability to survive indoors just long enough to transmit to new hosts. They have adapted to our enclosed habitats so completely that they cannot survive outdoors. This evolutionary process accelerated when man began husbanding animals, from which almost all human pathogens seem to have jumped species. The evolutionary process continues today as emerging pathogens adapt to indoor transmission, and the number of new disease species has increased exponentially over time, in concert with the size and density of the human population.

By designing our habitats strictly for human comfort, we have unwittingly fostered the adaptation and proliferation of dangerous pathogens. It is only by re-engineering our buildings to eliminate, rather than foster, airborne disease transmission that we can reverse this evolutionary trend. By immunizing enough buildings against disease, it is theoretically possible to develop herd immunity in a community or city. The percentage of buildings that would need to be immunized to block an airborne epidemic is similar to the percentage of a population vaccinated to achieve herd immunity, and depending on the contagiousness of the species, this may be as low as 30%.

In addition to air disinfection and improved delivery of clean air, there are other factors that can aid in the development of healthy buildings. Rugs, carpets, furniture, draperies, and the like can absorb mold spores and regenerate new ones if they become wet. Material selectivity can be one beneficial approach, and other alternatives include the use of self-disinfecting materials, pressurization, and isolation of zones within buildings, including the provision of buffer zones between the inside and outdoor air and the creation of clean inner zones safe from airborne health threats.

Regulating healthy buildings

Implementing changes to building construction on a vast enough scale to control epidemics would require governmental programs. As yet there are virtually no existing standards or laws regarding the aerobiological healthiness of buildings. It is curious to note that airborne chemical contaminants are regulated in many states while airborne pathogens, which cause far more fatalities, are not.

The key to regulation is the development of aerobiological air quality standards. Several organizations and government agencies are involved in the control of disease epidemics, including the Centers for Disease Control and Prevention (CDC), National Institute of Occupational Safety and Health (NIOSH), and World Health Organization (WHO), but none of them is responsible for regulating the living environments in which these diseases are transmitted.

The task of improving air quality in homes, schools, and offices has mostly fallen to independent professional societies. The American Society of Heating, Refrigerating, and Air-Conditioning Engineers (ASHRAE) has had a long and active interest in air quality, healthy buildings, and green buildings, and it is currently developing new programs in these directions. The International Ultraviolet Association (IUVA) is currently drafting a set of guidelines to assist in the design, development, implementation, and testing of UVGI and other air- and surface-cleaning systems.

Aerobiologically green buildings

Green building design is a field geared toward constructing sustainable indoor environments without damaging the environment. Green is clean, as they say, and healthy. The concept of human health is intrinsic to both this field and to aerobiological engineering, and common ground can be found through the exploration of aerobiologically green buildings that implement sustainable technologies for air and surface cleaning.

An example of where these fields overlap is the selection of building materials and furnishings that are both ecofriendly and less likely to contribute to health problems. Solar exposure can provide benefits, since sunlight can destroy mold spores, bacteria, and viruses. Radiant floor heating is an energy-efficient alternative to covering floors with carpets, as are dedicated outside air systems that efficiently control humidity. Although forced air is generally considered a necessity for air cleaning, buildings can also be naturally ventilated using wind energy.

Hygienic protocols

Engineering may go a long way toward the control of airborne diseases, but it may not be sufficient to eradicate them if other transmission routes remain unattenuated. Direct contact may be the dominant route of infection for many pathogens considered airborne, and engineering alone cannot control unhygienic human behavior. People must be educated to protect themselves, and for this purpose we need to define a set of protocols for human hygiene. These might include hand-washing procedures, quarantining contagious individuals, and other commonsense practices that can be taught in elementary school.

Many office workers today are so motivated they come to work during the contagious phase of their infection, placing other workers at risk. Economic losses from lost work and diminished productivity can be staggering. Working at home and in-office quarantine are two options for employers.

What can the individual do?

The most important thing individuals can do to protect themselves against airborne disease is to become educated about sources and transmission routes of airborne pathogens. Proximity to a contagious individual for as little as one hour can cause a secondary infection. Families with children must be especially careful since the youngest children tend to bring home diseases from schools, which are then transmitted to the rest of the family. Frequent hand washing and isolating sick children in bedrooms is one approach to protecting the rest of the family.

In regard to allergens, the home environment can be improved in some simple ways even without air cleaning. Old rugs and carpets that absorb spores can be cleaned, removed, or replaced with alternatives such as linoleum or other growth-resistant materials, and the amount of sunlight entering a home can be increased in various ways.

Misconceptions about disease must be dispelled. For example:

  • The myth that colds and flus come from outdoor air has persisted since the ancient world and is kept alive every time children are told to “bundle up or you’ll catch a cold.”
  • Another popular misconception is that some disease is beneficial, or that disease makes you stronger, but such fuzzy ideas are not grounded in science. Acquired immunity from pathogenic disease is always specific, never providing any general protection, and is often temporary at best. It is true our bodies are filled with friendly bacteria that were once parasites, but if selection for antibiotic resistance is allowed to continue, millions could become victims of unnecessary plagues.

Conclusion

Humanity stepped beyond the hardships of living in the elements by building habitats, but modern human culture and technology have created new contingencies and unexpected problems. It is well within human capabilities to redesign buildings and cities to be resistant to epidemic airborne disease, which is arguably the most serious threat we face today. Human health is a global concern, and achieving it begins with education, redesign of living environments, and large-scale implementation of aerobiological standards. The ultimate goal of these efforts must be disease eradication; all other remedies are merely triage and half-measures that fail to deal directly with the environments that are the root of the airborne disease problem today.

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Senin, 26 Januari 2009

New Family Of Antibacterial Agents Uncovered

As bacteria resistant to commonly used antibiotics continue to increase in number, scientists keep searching for new sources of drugs. One potential new bactericide has now been found in the tiny freshwater animal Hydra.
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The protein identified by Joachim Grötzinger, Thomas Bosch and colleagues at the University of Kiel, hydramacin-1, is unusual (and also clinically valuable) as it shares virtually no similarity with any other known antibacterial proteins except for two antimicrobials found in another ancient animal, the leech.
Hydramacin proved to be extremely effective though; in a series of laboratory experiments, this protein could kill a wide range of both Gram-positive and Gram-negative bacteria, including clinically-isolated drug-resistant strains like Klebsiella oxytoca (a common cause of nosocomial infections). Hydramacin works by sticking to the bacterial surface, promoting the clumping of nearby bacteria, then disrupting the bacterial membrane.
Grötzinger and his team also determined the 3-D shape of hydramacin-1, which revealed that it most closely resembled a superfamily of proteins found in scorpion venom; within this large group, they propose that hydramacin and the two leech proteins are members of a newly designated family called the macins.

Journal reference:
Jung et al. Hydramacin-1, Structure and Antibacterial Activity of a Protein from the Basal Metazoan Hydra. Journal of Biological Chemistry, 2008; 284 (3): 1896 DOI: 10.1074/jbc.M804713200



Hydra. (Credit: Wikimedia commons, public domain image.)




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