Cerebral sensory development: Genetic programming versus environmental stimuli

Dec. 22, 2013 — Hiroshi Kawasaki and colleagues at Kanazawa University, Tokyo University, Tokyo Institute of Technology and Kumamoto University in Japan have identified how sensory map development is regulated in mice pups at birth, and the molecular signalling responsible.

The part of the brain associated with the sense of touch -- the somatosensory cerebral cortex -- has attracted numerous studies aimed at determining the influence of extrinsic environmental and intrinsic genetic factors in sensory development. Understanding the role of these factors in sensory map formation and development may provide insights into the mechanisms behind other circuits in the central nervous system.

Now Hiroshi Kawasaki and colleagues at Kanazawa University, Tokyo University, Tokyo Institute of Technology and Kumamoto University in Japan have identified how sensory map development is regulated in mice pups at birth, and the molecular signalling responsible.

Rodents have a sensory map in the primary somatosensory cerebral cortex, characterized by cell clusters called barrels filled with patches of nerve fibre. Inputs from the part of the brain that link to the rodent's whiskers terminate at these barrels. The barrel distribution pattern is the same as the distribution of the whiskers on the snout and forms soon after birth.

The researchers induced preterm birth in mice and quantitatively compared the degree of development of whisker-related barrel pattern formation with mice born after the full term of pregnancy. At set periods after conception, barrel formation was significantly more advanced in the mice born preterm. Further experiments ruled out the role of maternal hormones prior to birth and identified the critical effect of serotonin reductions during the days after birth.

"Interestingly, the regulatory mechanisms described here were also found to regulate eye-specific segregation in the visual system, raising the possibility that they are utilized in various brain regions," the researchers suggest. They add that further investigation of the range of roles of serotonin and the underlying mechanisms will be interesting for future research.

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Story Source:

The above story is based on materials provided by Organization of Frontier Science and Innovation, Kanazawa University.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. Tomohisa Toda, Daigo Homma, Hirofumi Tokuoka, Itaru Hayakawa, Yukihiko Sugimoto, Hiroshi Ichinose, Hiroshi Kawasaki. Birth Regulates the Initiation of Sensory Map Formation through Serotonin Signaling. Developmental Cell, 2013; 27 (1): 32 DOI: 10.1016/j.devcel.2013.09.002

Note: If no author is given, the source is cited instead.

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Quantitative approaches provide new perspective on development of antibiotic resistance

Nov. 28, 2013 — Using quantitative models of bacterial growth, a team of UC San Diego biophysicists has discovered the bizarre way by which antibiotic resistance allows bacteria to multiply in the presence of antibiotics, a growing health problem in hospitals and nursing homes across the United States.

Two months ago, the Centers for Disease Control and Prevention issued a sobering report estimating that antibiotic-resistant bacteria last year caused more than two million illnesses and approximately 23,000 deaths in the United States. Treating these infections, the report said, added $20 billion last year to our already overburdened health care system.

Many approaches are now being employed by public health officials to limit the spread of antibiotic resistance in bacteria -- such as limiting the use of antibiotics in livestock, controlling prescriptions of antibiotics and developing new drugs against bacteria already resistant to conventional drug treatments. But understanding how bacteria grow and evolve drug resistance could also help stop its spread by allowing scientists to target the process of evolution itself.

"Understanding how bacteria harboring antibiotic resistance grow in the presence of antibiotics is critical for predicting the spread and evolution of drug resistance," the UC San Diego scientists say in an article published in the November 29 issue of the journal Science.

In their study, the researchers found that the expression of antibiotic resistance genes in strains of the model bacterium E. coli depends on a complex relationship between the bacterial colony's growth status and the effectiveness of the resistance mechanism.

"In the course of developing complete resistance to a drug, a strain of bacteria often first acquires a mechanism with very limited efficacy," says Terry Hwa, a professor of physics and biology who headed the research effort. "While much effort has been spent elucidating individually how a drug inhibits bacterial growth and how a resistance mechanism neutralizes the action of a drug, little is known previously about how the two play off of each other during the critical phase where drug resistance evolves towards full strength."

According to Hwa, the interaction between drug and drug-resistance is complex because the degree of drug resistance expressed in a bacterium depends on its state of growth, which in turn depends on the efficacy of drug, with the latter depending on the expression of drug resistance itself. For a class of common drugs, the researchers realized that this chain of circular relations acted effectively to promote the efficacy of drug resistance for an intermediate range of drug doses.

The use of predictive quantitative models was instrumental in guiding the researchers to formulate critical experiments to dissect this complexity. In their experiments, E. coli cells possessing varying degrees of resistance to an antibiotic were grown in carefully controlled environments kept at different drug doses in "microfluidic" devices -- which permitted the researchers to manipulate tiny amounts of fluid and allowed them to continuously observe the individual cells. Hwa and his team found a range of drug doses for which genetically identical bacterial cells exhibited drastically different behaviors: while a substantial fraction of cells stopped growing despite carrying the resistance gene, other cells continued to grow at a high rate. This phenomenon, called "growth bistability," occurred as quantitatively predicted by the researchers' mathematical models, in terms of both the dependence on the drug dose, which is set by the environment, and on the degree of drug resistance a strain possesses, which is set by the genetic makeup of the strain and is subject to change during evolution.

"Exposing this behavior generates insight into the evolution of drug resistance," says Hwa. "With this model we can chart how resistance is picked up and evaluate quantitatively the efficacy of a drug." However, this model has only been established for one class of drugs and one class of drug-resistance mechanisms. Hwa believes it is important to establish such predictive models for all the common drugs in pathogenic bacterial species.

"My hope," he adds, "is to get the message out to drug companies and hospitals that there is an informative, quantitative way to look at the action of a drug on bacteria and at the consequences of using a drug on bacteria as they try to pick up resistance, and that this approach can be incorporated in both the design and evaluation of drug efficacy in clinically relevant settings."

Hwa says the principle of interaction between drug and drug-resistance is important to understand not only for the evolution of antibiotics, but also for the emergence of drug resistance in other diseases. A prominent example is the rapid emergence of cancer lines resistant to drug treatment, which underlies most failures in cancer drug therapies. While there are obviously numerous differences between the evolution of drug resistance in bacteria and in cancer, Hwa noted that the connection between the two was sufficient to motivate the Physical Science-Oncology program of the National Cancer Institute to co-sponsor this study.

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New discovery on early immune system development

Nov. 12, 2013 — Researchers at Lund University have shed light on how and when the immune system is formed, raising hope of better understanding various diseases in children, such as leukemia.

The immune system is complex and a number of genetic diseases are attributed to defects in the cells that form its origins. The study from Lund and Oxford University presents unique findings on the formation of these cells.

We know that the first blood stem cells are formed in the aorta region and then travel to the liver, which is the body's major blood-forming organ during the fetal stage. In the liver, the blood stem cells produce the more mature blood cells that form our blood system. At the same time, T- and B-cells are formed, which comprise the basis of our advanced immune system. From birth, this process takes place in the bone marrow and the liver ceases to form blood cells.

Researchers have long believed that the first cells that lead to the development of our immune system, the immune-competent cells, are formed from blood stem cells in the liver while the fetus is developing. Blood stem cells can be found in the liver from day 11-12 in a mouse fetus, which is the equivalent of around 6-7 weeks' gestation in humans.

In the current study, which was performed on mice, researchers showed that these cells linked to our immune system are formed even earlier than this, in the embryo's yolk sac, i.e. before the first blood stem cells are formed. In the human embryo, the yolk sac is one of the three fetal sacs and appears in around the fifth week of pregnancy.

"The question we have posed is whether the immune system is formed in a different way in the fetus than in an adult and how early in the development of the fetus the cells that form our early immune system can be found. Knowledge of this is important because it helps us to understand how and when our immune system begins to form and what can go wrong in that process," explained Charlotta Boiers, a postdoctoral fellow at Lund University.

Childhood leukemia is one example of how important it is to understand how the immune system is formed. The first mutation on the path to childhood leukemia has been shown to take place while the child is still in the womb.

"It is still not known in which cell or cells this first step takes place and it is therefore important for us to continue our research on how the immune system starts in humans. The aim is now to continue our investigations in humans," said Charlotta Boiers.

If it is possible to prove that the cells mutate at this very early stage of development, then this would increase our understanding of how childhood leukemia occurs.

"These first cells seem to disappear in the late stages of development of the fetus. This may not happen when there is a mutation. Perhaps the defective cells instead remain alive, and further mutations occur that in turn could lead a child to develop cancer."

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Propofol discovery may aid development of new anesthetics

Sep. 22, 2013 — Researchers at Washington University School of Medicine in St. Louis and Imperial College London have identified the site where the widely used anesthetic drug propofol binds to receptors in the brain to sedate patients during surgery.

Until now, it hasn't been clear how propofol connects with brain cells to induce anesthesia. The researchers believe the findings, reported online in the journal Nature Chemical Biology, eventually will lead to the development of more effective anesthetics with fewer side effects.

"For many years, the mechanisms by which anesthetics act have remained elusive," explained co-principal investigator Alex S. Evers, MD, the Henry E. Mallinckrodt Professor and head of the Department of Anesthesiology at Washington University. "We knew that intravenous anesthetics, like propofol, act on an important receptor on brain cells called the GABA-A receptor, but we didn't really know exactly where they bound to that receptor."

Propofol is a short-acting anesthetic often used in patients having surgery. It wears off quickly and is less likely to cause nausea than many other anesthetics. But the drug isn't risk-free. Its potentially dangerous side effects include lowering blood pressure and interfering with breathing.

In an attempt to understand how propofol induces anesthesia during surgery, scientists have tried to identify its binding site within the gamma-aminobutyric acid type A (GABA-A) receptor on brain cells. Activating these receptors -- with propofol, for example -- depresses a cell's activity.

Researchers have altered the amino acids that make up the GABA-A receptor in attempts to find propofol's binding site, but Evers said those methods couldn't identify the precise site with certainty.

"In previous work to directly identify anesthetic binding sites, GABA-A receptors had to be extracted from membranes and purified prior to performing the binding studies," he said. "Our method allowed us to study propofol binding to the intact receptor in its native membrane environment."

Having developed the techniques to analyze the interactions between anesthetics and GABA-A receptors in their native environment, Evers' laboratory teamed up with a group at Imperial College that had been taking the same approach. Led by Nicholas P. Franks, PhD, professor of biophysics and anaesthetics, the group has spent years creating a photoanalogue of propofol that both behaves in precisely the same way as propofol and contains a labeling group that permanently attaches to its binding site on the GABA-A receptor when exposed to a specific wavelength of light.

In creating the analogue of propofol, it's as if the researchers put a tiny hook onto the molecule so that when it binds to the GABA-A receptor, it grabs onto the receptor and won't let go.

"Normally, an anesthetic drug binds to the GABA-A receptor transiently," Franks explained. "But for the purposes of this research, we wanted to create an analogue that behaved exactly like propofol except that we could activate this chemical hook to permanently bind the drug to the receptor. The next step was then to extract the receptor, cut it into pieces and identify the precise piece of the protein where the propofol analogue had attached to the receptor. This was the tricky step that the Evers group at Washington University had perfected."

Evers and Franks believe this technique has implications beyond propofol and other anesthetics.

"Anesthetics have desirable effects -- they induce anesthesia, for example -- but they also have undesirable effects," Evers said. "Propofol can lower blood pressure or interfere with breathing, for example. By understanding precisely what the binding sites look like on the proteins that induce those potential problems, we eventually hope to design and select for drugs that have the benefits we want without dangerous side effects."

Using the techniques they have developed, Evers and Franks now plan to identify binding sites of other anesthetic agents. They believe their approach also can be used to study other types of drugs, such as psychiatric agents and anti-seizure drugs.

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Governments to agree increased focus on people with disabilities in development strategies

20 September 2013 | Geneva - WHO welcomes the forthcoming agreement at a High-Level Meeting at the United Nations General Assembly which will further improve access to health care and related services for people with disabilities and ensure that they are able to contribute to the sustainable development of their communities.

On 23 September, Heads of State – in their first-ever global meeting on this topic – are scheduled to recommend:

• including people with disabilities in the setting and implementation of development agendas post-2015;
• addressing the many barriers people with disabilities face in daily life – such as difficulties in accessing health-care services, including rehabilitation and assistive devices;
• taking urgent action by all stakeholders, including the health sector, to ensure that all development policies benefit people with disabilities;
• improving collection and analysis of data on disability and devising ways to use it more effectively to guide development policies and programmes.

Improving access to health care

The more than 1 billion people living worldwide with disabilities all have the same general health needs as non-disabled people – such as immunization, cancer screening and reproductive health services. They may also have specific disability-related health conditions, such as ulcers, urinary tract infections, paralysis and depression associated with spinal cord injury. Many people with disabilities require rehabilitation, such as support to regain strength following hospitalization for diabetic coma or provision of a prosthesis after a limb amputation.

“Too often, people with disabilities face barriers in accessing health and rehabilitation services,” says Dr Margaret Chan, Director-General of WHO. “These include stigma and discrimination, lack of accessibility, and the inability to pay. The new UN agreement can help bring down such barriers.”

Today, people with disabilities are twice as likely to report that health care providers’ skills and facilities do not meet their needs. They are three times more likely to be denied health care and four times more likely to be treated badly in the health care system than people without disabilities.

Half the people living with disabilities worldwide are unable to afford the health care they need. They are 50% more likely than persons without disability to suffer catastrophic health expenditure, which pushes them into poverty.

Many people with disabilities are unable to access the assistive devices and related rehabilitation services they need. For example, 360 million people have moderate to profound hearing loss, but production of hearing aids meets only 10% of global need and 3% of developing country need; 200 million people need spectacles or low vision devices, but have no access to them. Some 70 million people need a wheelchair, yet only 5-15% have access to one.

The High-Level Meeting outcome document highlights the importance of:

• making quality health services available and affordable to people with disabilities, whoever they are and wherever they live;
• developing national disability policies and programmes that address the health and rehabilitation needs of people with disabilities, and allocating appropriate resources;
• improving data to better understand these health and rehabilitation needs and monitor and evaluate the impact of policies and programmes.

WHO is already scaling up efforts in line with the outcome document by preparing a seven-year global action plan "Better health for persons with disabilities". The action plan is based on approaches that have proved effective in improving the health and well-being of people with disability.

The draft plan also builds on the Convention on the Rights of Persons with Disabilities and the recommendations of the "World report on disability" (2011). It is currently being reviewed through a series of regional and targeted consultations and on an online consultation process which ends on 11 October 2013. It will be presented to the WHO Executive Board meeting in January 2014 in preparation for consideration at the Sixty-seventh World Health Assembly in May 2014.

For more information please contact:

Gregory Hartl
Coordinator
News, Social Media and Monitoring, WHO
Telephone: +41 22 7914458
Mobile: +41 79203 6715
E-mail: hartlg@who.int

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Worm research: Right combination of sugars regulates brain development

Sep. 19, 2013 — If the development of our nervous system is disturbed, we risk developing serious neurological diseases, impairing our sensory systems, movement control or cognitive functions. This is true for all organisms with a well-developed nervous system, from man to worm. New research from BRIC, University of Copenhagen reveals how a tiny molecule called mir-79 regulates neural development in roundworms. The molecule is required for correct migration of specific nerve cells during development and malfunction causes defects in the nervous system of the worm. The research has just been published in the journal Science.

Hundreds of worms lie in a small plastic plate under the laboratory microscope. Over the last three years, the group of Associate Professor Roger Pocock has used the roundworm C. elegans to study the development of the nervous system. They have just made an important discovery.

"Our new results show that a small molecule called mir-79 is indispensable for development of the worm's nervous system. mir-79 acts by equipping special signal molecules with a transmitter, which tells the nerve cells how they should migrate during development of the worm. If we remove mir-79 with gene technology, development of the worm nervous system goes awry," says postdoc Mikael Egebjerg Pedersen, who is responsible for the experimental studies.

Mir-79 adds just the right combination of sugar

The research shows that mir-79 acts by controlling the addition of certain groups of sugars to selected signaling molecules. In the world of cells, sugar molecules act as transmitters.

When the nerve cells come into contact with the sugar-transmitters, they are informed where to locate themselves during neural development. If the researchers remove mir-79, the migration of the nerve cells is misguided causing neuronal defects in the worms.

"It has earlier been shown that signaling molecules guide nerve migration, but our research shows that mir-79 regulates nerve cell migration by controlling the correct balance of sugar-transmitters on signaling molecules. If mir-79 does not function, the worm nervous system is malformed. In the wild, such defects would be harmful for worm survival," says Roger Pocock who leads the research group behind the finding.

Worm studies reveal important clues for neuronal repair

A version of mir-79 called mir-9 is found in humans. Therefore, these results are important for understanding how our nervous system develops during fetal development. In addition, the results add to the understanding of how nerve cells may be stimulated to repair damage in our brain or spinal cord.

"Our nervous system is a tissue which is not easily repaired after damage. So, how certain molecular cues can stimulate nerve cells to migrate is an important brick in the puzzle. This will enable us to understand how nerve tissue can be regenerated after, for example, a stroke or an accident. If we can use such knowledge to mimic the signals, we may be able to stimulate nerve cells to migrate into a damaged area," says Roger Pocock.

Worms are a fantastic model to study how the nervous system develops and how nerve cells form neuronal circuits. Most of the genes that control nervous system development in the worm are also found in humans. At the same time, the reduced complexity of the worm nervous system allows researchers to investigate central biological mechanisms. With new technologies they can mark single cells or molecules, and as worms are transparent, the researchers can track the marked molecules or cells live during worm development.

The next step for the researchers is to investigate how the regulatory pathway they have revealed is regulated in cultures of human cells.

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Identifies the mechanisms to supervise development professional Oncology network of researchers.

Roswell Park cancer researchers of the Institute (RPCI) will stimulate interfere with antitumor response discovered a new pathway in breast cancer how cancer cells, bone marrow-derived suppressor cells (MDSCs) expansion of known blood cell population. Survey results will be published online today in the journal of clinical investigation may shed new light on that fuel tumor growth of pathological events, it will lead to development of new distractions.

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