Monday, June 29, 2009

Site for alcohol's action in the brain discovered

http://www.labspaces.net/98322/Site_for_alcohol_s_action_in_the_brain_discovered

Monday, June 29, 2009
  • Alcohol's inebriating effects are familiar to everyone. But the molecular details of alcohol's impact on brain activity remain a mystery. A new study by researchers at the Salk Institute for Biological Studies brings us closer to understanding how alcohol alters the way brain cells work.
  • Their findings, published in the current advance online edition of Nature Neuroscience, reveal an alcohol trigger site located physically within an ion channel protein; their results could lead to the development of novel treatments for alcoholism, drug addiction, and epilepsy.
  • Ethanol, the alcohol in intoxicating beverages, is known to alter the communication between brain cells. "There's been a lot of interest in the field to find out how alcohol acts in the brain," says Paul A. Slesinger, Ph.D., an associate professor in the Peptide Biology Laboratory at the Salk Institute, who led the study. "One of several views held that ethanol works by interacting directly with ion channel proteins, but there were no studies that visualized the site of association."
  • Slesinger and his team now show that alcohols directly interact with a specific nook contained within a channel protein. This ion channel plays a key role in several brain functions associated with drugs of abuse and seizures.
  • Previous research by Slesinger and his group focused on the neural function of these ion channels, called GIRK channels. GIRK channels, short for G-protein-activated inwardly rectifying potassium channels, open up during periods of chemical communication between neurons and dampen the signal, creating the equivalent of a short circuit.
  • "When GIRKs open in response to neurotransmitter activation, potassium ions leak out of the neuron, decreasing neuronal activity," says UCSD Biology graduate student and first author Prafulla Aryal. Alcohols had been previously shown to open up GIRK channels but it was not known whether this was a direct effect or whether this was the by-product of other molecular changes in the cell.
  • Having the location of a physical alcohol-binding site important for GIRK channel activation could point to new strategies for treating related brain diseases. Using this protein structure, it may be possible to develop a drug that antagonizes the actions of alcohol for the treatment of alcohol dependence. Alternatively, "If we could find a novel drug that fits the alcohol-binding site and then activate GIRK channels, this would dampen overall neuronal excitability in the brain and perhaps provide a new tool for treating epilepsy," says Slesinger.
  • Epilepsy is a neurological disease characterized by episodic, abnormal electrical activity that affects more than 3 million Americans. Current medications have serious side effects and the search for new, specific mechanisms of treatment is an area of intense research across the globe.
  • To gain more insight into how alcohols work, Slesinger and Aryal teamed up with Salk colleagues Senyon Choe, Ph.D., a professor in the Structural Biology Laboratory, and Hay Dvir, Ph.D., a postdoctoral researcher in Choe's lab, to determine whether tiny pockets found in a high resolution, three-dimensional structure of a potassium channel were, in fact, the sites of alcohol action in GIRK channels. The Salk researchers noted the similarity of these candidate alcohol-binding sites with alcohol pockets visualized in two other alcohol-binding proteins: alcohol dehydrogenase, the enzyme that breaks down alcohol in the body, and a fruit fly protein, LUSH, that senses alcohol in the environment.
  • When Aryal systematically introduced amino acid substitutions that denied alcohol molecules access to the potential alcohol binding site, alcohol could no longer efficiently activate the channel, confirming that they had hit upon an important regulatory site for alcohol. The team further established that this pocket is a trigger point for channel activation since G protein activation was also altered. "We believe alcohol hijacks the intrinsic activation mechanism of GIRK channels and stabilizes the opening of the channel," says Aryal. "Alcohol may accomplish this by lubricating the activation gears of the channel," adds Slesinger.

How to Save Money on International Student Loan.

http://www.happyschoolsblog.com/save-money-on-student-loan-interest/
  • Did you know, International students can ‘Save BIG’ money by following the tips in this article. There are so many students who are still not sure how much student loan to get approval and how to save money in student loan interest. As far I know, students are paying around 12-13% Interest rate on student loan. But, if you utilize that money in proper way, you could save few thousands on the interest payments.
  • I followed the steps I’m going to outlined here and saved loads of money in interest payments on student loan. Lets assume you have student loan approved for $40,000 for 2 years of education.

First Year Tuition Fee

  • $20,000 ( $6,000 per semester tuition fee ). So for first semester after getting student visa, you can carry
  • $6000 + $4000 = $10,000
  • $3,500 will include cost to buy a laptop( $650 – $900), and living expense for 5-6 months.

Money Saving Part

  • You can save lot of money by following the steps listed below. there is now miracle or hidden tricks to save money on student loan interest. Just follow the steps listed below.
  • 1) For first semester when you come to U.S, don’t carry entire 1 year fees with you. Because, after paying $6000 for first semester, remaining $14,000 will be with you in Checkings Account that will not pay any interest.
  • 2) Carry only $10,000 with you, that will save ~$1,200 in interest.
  • 3) After you reach university, open an bank account and deposit the Demand Draft or Travelers Check. Check here if you want to know how to carry U.S. Dollars.
  • 4) Pay the first semester tuition fee $6000 and you will be left with $4,000.
  • 6) You will be left with $3,100.
  • 7) Open an Online Savings Account with HSBC Direct and deposit $2000
  • 8) HSBC Direct Savings Account will pay about 2.00% to 5.00% in Interest. So, your effective interest rate for the student loan for the time you have in Savings Account will be reduced to 12% – 3.00%= 9.00%. Savings account interest rate varies, so check with the bank for the current rate.
  • 9) When in need transfer to money from Online HSBC Savings account to you personal checking account
  • 10) At the end of the semester, you can ask your family to send the money for next semester tuition fee.
  • Students typically bring money for one full year and after paying first semester tuition fee, some $10,000 or more will be in Checking Account. Usually Checking account will not pay any interest. So, you are paying interest for the student loan in India while your money is at some bank in U.S. without making any interest.
  • Right now interest rate in HSBC savings account in 2.50%. Holding $10,000 for 1 month will earn around $25 per month. Over period of 2 years, you can save lost of money.

How to Access the Money from HSBC

  • Online Savings Account is same as Regular Bank account. You will have access to cash anytime through ATM Withdrawal or you can transfer the money to your existing bank account. Following details are from HSBC Bank Site on How to Transfer, Access the money, …

How do I make a withdrawals?

There are several ways:
  • Withdraw money at any ATM.
  • Electronically transfer funds to any linked account.
  • Request that we mail you a check by sending us a BankMail.

How quickly can I transfer money between linked accounts?

  • You can transfer funds between your HSBC Direct accounts instantly. The time it takes for transfers between other linked accounts may vary, but you can expect it to take up to three business days.
  • You can find more details about money deposit, transfer, account opening and more details from HSBC Direct or Orange Savings Account.

Role of statins in protection against Alzheimer's Disease

http://www.scientistsolutions.com/t11544-role+of+statins+in+protection+against+alzheimer_amp%3bapos%3bs+disease.html

  • High cholesterol levels are considered to be a risk factor not only for cardiovascular disease including stroke, but also for the development of Alzheimer’s disease. Therefore, many cholesterol lowering drugs, including statins, have been developed in recent years.
  • In addition to the cholesterol reducing effect , statins can protect nerve cells against damage which occur in the brain of Alzheimer’s disease patients. Treatment with a statin called Lovastatin could prevent the death of nerve cells in Alzheimer's patients. Earlierstudies show that statins stimulate the protective capacity of tumor necrosis factor, which is a key player in the brain’s immune response.

For further reading refer :

“Pretreatment with Lovastatin Prevents N-Methyl-D-Aspartate-Induced Neurodegeneration in the Magnocellular Nucleus Basalis and Behavioral Dysfunction” Amalia M. Dolga, Ivica Granic, Ingrid M. Nijholt, Csaba Nyakas, Eddy A. van der Zee, Paul G. M. Luiten, and Ulrich L. M. Eisel is published in Volume 17:2 (June 2009) of the Journal of Alzheimer's Disease.
  • Statins have been found to be very useful for human health. The basic definition says the statins (or HMG-CoA reductase inhibitors) are a class of drugs that lower cholesterol levels in people with or at risk of cardiovascular disease.
  • Scientifically, statins are referred to as HMG-CoA reductase inhibitors. Cholesterol is critical to the normal function of every cell in the body. However, it also contributes to the development of atherosclerosis, a condition in which cholesterol-containing plaques form within arteries. These plaques block the arteries and reduce the flow of blood to the tissues that arteries supply. When plaques rupture, a blood clot forms on the plaque, thereby further blocking the artery and reducing the flow of blood.
  • When blood flow is reduced sufficiently in the arteries that supply blood to the heart, the result is angina (chest pain) or a heart attack. If the clot occurs on plaques in the brain, the result is a stroke.
  • If the clots occur on plaques in the leg, they cause intermittent claudication (pain in the legs while walking). By reducing the production of cholesterol, statins are able to slow the formation of new plaques and occasionally can reduce the size of plaques that already exist. In addition, through mechanisms that are not well understood, statins may also stabilize plaques and make them less prone to rupturing and promoting the development of clots.
  • Statins exhibit action beyond lipid-lowering activity in the prevention of atherosclerosis. Researchers hypothesize that statins prevent cardiovascular disease via four proposed mechanisms (all subjects of a large body of biomedical research):
  1. Improve endothelial function
  2. Modulate inflammatory responses
  3. Maintain plaque stability
  4. Prevent thrombus formation

Molecule That Triggers Immune System in Rheumatoid Arthritis Discovered

http://www.elements4health.com/molecule-that-triggers-immune-system-in-rheumatoid-arthritis-discovered.html

  • Researchers have found that a signal molecule made by the human body that triggers the immune system into action could be important in rheumatoid arthritis.
  • Rheumatoid arthritis is the most common autoimmune disease, affecting around 1 in 100 people. It causes painful and persistent swelling in the joints that can result in damage to the bone and cartilage. Around half of all rheumatoid arthritis patients do not respond to one or more of the treatments currently available, and even these can become less successful over time. Stopping rheumatoid arthritis closer to the root of the problem could be the best way to prevent and treat the disease.
  • When a microbe infects the body, the body responds by turning on a molecular switch to set the immune system into action and protect the body from disease. The findings show that a signal molecule called tenascin-C can trigger the same molecular switch and also activate the immune system. High levels of tenascin-C present in joints therefore may cause the activated immune system to attack the joint leading to the persistent inflammation of rheumatoid arthritis.
  • The molecular switch is called TLR4, and is found on the surface of immune cells. Previous research has shown that mice without TLR4 do not show chronic joint inflammation. The researchers hope scientists can develop new treatments that target the interaction between tenascin-C and TLR4, which may help to combat rheumatoid arthritis.
  • Dr Kim Midwood, lead author of the study said: "Rheumatoid arthritis is a debilitating and painful disease and, unfortunately, there is no cure. Furthermore, current rheumatoid arthritis treatments are not effective for many patients."
  • The researchers reached their conclusions by carrying out five studies. One study suggested that tenascin-C was needed to sustain inflammation. The researchers induced joint inflammation in mice with and without the gene for tenascin-C. They found the mice that could produce tenascin-C had severe joint swelling with bone and cartilage destruction, but the mice that could not produce tenascin-C had no swelling or tissue destruction at all.
  • In a subsequent study, the researchers injected the active part of the tenascin-C molecule into mice joints. They found it caused the joints of the mice to become inflamed and that this reaction was more intense with higher doses.
  • Another experiment demonstrated that tenascin-C causes swelling in the joints by increasing levels of molecules that cause inflammation. The researchers took human immune cells called macrophages and cells called fibroblasts from the swollen joint of patients with rheumatoid arthritis and added tenascin-C. After the tenascin-C was added, the cells produced more molecules that cause inflammation.
  • The authors plan to work out the precise mechanism by which tenascin-C increases these levels of inflammatory molecules in the human joint and try to find ways to inhibit this action.
References:
1. Kim Midwood, et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nature Medicine. doi:10.1038/nm.1987.

Sunday, June 28, 2009

Why A Low-Calorie Diet Extends Lifespans: Critical Enzyme Pair Identified

http://www.sciencedaily.com/releases/2009/06/090624152811.htm

ScienceDaily (June 28, 2009)
Experiment after experiment confirms that a diet on the brink of starvation expands lifespan in mice and many other species. But the molecular mechanism that links nutrition and survival is still poorly understood. Now, researchers at the Salk Institute for Biological Studies have identified a pivotal role for two enzymes that work together to determine the health benefits of diet restriction.
  • When lacking one enzyme or the other, roundworms kept on a severely calorie-restricted diet no longer live past their normal lifespan, they report in the June 24, 2009, advance online edition of the journal Nature.
  • "The only other known factor regulating longevity in response to diet restriction operates at the very end of the signaling cascade," said Howard Hughes Medical Investigator and senior author Andrew Dillin, Ph.D., an associate professor in the Molecular and Cell Biology Laboratory. "These two enzymes are further up the ladder, bringing us closer to the receptor that receives the signal for throwing the switch to promote a healthy lifespan."
  • Identifying the receptor may allow researchers to design drugs that mimic the signal and could lead to new treatments for age-related diseases. This could enable us to reap the health benefits of calorie restriction without adhering to extreme diets in which the satisfying feel of a full stomach is strictly off limits.
  • Although lifestyle factors such as obesity clearly influence life expectancy, genetic factors are considered central to the process of aging. To date, there are only three known genetic networks that ensure youthfulness when manipulated. One centers on the insulin/insulin growth factor-1, which regulates metabolism and growth; the second is driven by mitochondria, the cell's power plants; and the third is linked to diet restriction.
  • But first author Andrea C. Carrano, Ph.D., a postdoctoral researcher in American Cancer Society Professor Tony Hunter's laboratory, hadn't set out to unravel the molecular connection between dietary restriction and increased lifespan when she started to investigate the role of the mammalian enzyme WWP-1. "I only knew that WWP-1 was a ubiquitin ligase and that mammalian cells contain three copies, which would make it difficult to study its function."
  • Ubiquitin ligases work in tandem with so called ubiquitin-conjugating enzymes to attach a chain of ubiquitin molecules to other proteins. This process, called ubiquitination, flags protein substrates for destruction but can also serve as a regulatory signal.
  • Since the laboratory roundworm Caenorhabditis elegans only contains one copy, Carrano teamed up with Salk researcher Dillin, who studies aging and longevity in C. elegans. Initial experiments revealed that worms without the WWP-1 gene seemed normal but were more susceptible to various forms of stress. "This finding was the first hint that WWP-1 might play a role in the aging process since mutations that affect stress very often correlate with longevity," she says.
  • Prompted by the findings, Carrano's next set of experiments focused on WWP-1's potential role in the regulation of lifespan. When she genetically engineered worms to overexpress WWP-1, well-fed worms lived on average 20 percent longer. Deleting PHA-4, which was discovered in Dillin's lab and so far is the only gene known to be essential for lifespan extension in response to diet restriction, abolished the life-extending effects of additional WWP-1 placing the ubiquitin ligase as a central rung on the same genetic ladder as PHA-4. Without WWP-1, cutting down on calories no longer staved off death.
  • When a study by others found that UBC-18 interacts with WWP-1, Carrano wondered whether it could play a role in diet-restriction-induced longevity as well. She first confirmed that the UBC-18 functions as an ubiquitin-conjugating enzyme and gives WWP-1 a hand. She then tested whether it played a role in lifespan regulation. "Overexpression of UBC-18 was not enough to extend the lifespan of worms but depleting it negated the effects of caloric restriction," says Carrano, who is busy looking for potential substrates of the UBC-18-WWP-1 ubiquitination complex.
  • "The WWP-1 pathway is highly conserved between worms and mammals and could play a role in the human aging process," says senior author Tony Hunter, Ph.D., a professor in the Molecular and Cell Biology Laboratory. "We didn't expect that this protein would be involved in the regulation of lifespan but it is very exciting when experiments lead you in a surprising direction."

This work was supported by the National Institutes of Health, the Ellison Medical and Glenn Medical Foundations, the American Cancer Society and the Rossi Endowment.

Zheng Liu, Ph.D., a research associate, in the Dillin Laboratory also contributed to the work.

A helping hand for addicts

http://www.nature.com/news/2009/090625/full/news.2009.600.html
  • Vincent Clark, of the University of New Mexico in Albuquerque, thinks he has something like a crystal ball for drug addicts. By applying traditional psychiatric evaluation and modern fMRI brain imaging to people recovering from drug addiction, he claims to be able to spot who is likely to relapse — months before the relapse actually happens.
  • Clark puts people recovering from cocaine and methamphetamine addiction in an fMRI machine, then asks them to play a game called 'oddball task' which is common in addiction research. Participants hit a button when they see an 'X' on a screen, but not when they see a 'T'. Mixed in are a few distracting 'C's: when these appear, they trigger activity in the posterior cingulate region of the brain in some addicts. Clark later meticulously tracks the volunteers, taking hair and urine samples, to see if they have begun using drugs again.
  • With more than 80% accuracy, Clark says, the test predicted who would relapse (those whose posterior cingulate did not light up) and who would stay straight (those whose posterior cingulate did) over the next six months. Combined with a simple test for a history of mania, it was 89% accurate, he says.
  • Clark presented the results during the annual meeting of the Organization for Human Brain Mapping in San Francisco, California, on 19 June. Nature News

talked to him about how he keeps such research going.

Would it be crass to call this measuring willpower?

  • It's kind of the highest level of the same constellation. When people do the task and they see the 'distracter' they tend to get very annoyed — all they are supposed to do is press when they see the 'X', and the 'C' comes up. These brain areas are involved in your emotional response. But in this case there is just a transient kind of … not depression, but more annoyance.
  • The relapsing group really didn't show any response. One hypothesis about addiction relapse is that individuals who don't react strongly to their environment get in situations that are much more disruptive to themselves. They kind of wander into it blindly.

What's the significance of a history of mania?

  • Mania, chemically, is probably very similar to what stimulants do to you. Drugs really just mimic what you already have. So these people who have evidence of a potentially overactive internal stimulant system have this possibility of relapse that's higher later.

But that in itself isn't enough for these people to relapse.

  • No, not at all. But that combined with imaging gives you this close-to-90% [predictive power].

So you envision someone checking into a clinic, playing this game in the scanner and getting tested for mania in their past. If both come out positive, then they would get more intensive care.

  • It would suggest that this person needs more attention. Up to half of our population of addicts is not being that well served by treatments that are available. We've looked at a number of different populations. Individuals in drug court, they do a crime and the judge says, "You go get treatment and if you use again you are going to jail." In that group, at six months, about 50% use [drugs]. They know they are going to get caught and they do it anyway. Residential treatment centres, where they are living in a special environment and getting treated every day – that's [also] about 50% at six months. We recruited for this study at outpatient treatment, where they were living at home and getting some kind of treatment a couple of times a week – that's 50% [too]. It suggests that there is this native property in these people that results in relapse which isn't being touched all that well by treatment.

Getting more than that together would be difficult?

  • But not impossible. What we would like to propose to the National Institute on Drug Abuse — which funded this originally — is to go into local prisons in New Mexico, scan people in prison and then monitor them after they are released. The Mind Research Network [that I work with] has the world's first mobile MRI system that can do functional brain mapping.

Did the patients know what this study was about?

  • Absolutely. We said we were looking for ways to predict who is going to relapse. They do care. These people want to be a part of the solution.

Did you catch those who relapsed through drug testing, or did they confess?

  • Many people came back and said, "Sorry, I relapsed." In the worst cases, we could not find them and we called their families or friends.

Predicting relapse is not the same as targeting the part of the brain that is causing it, though, is it?

It could be. If we find a brain network that is causal, then learn how to affect its behaviour, we can help keep people sober longer. Maybe even cure [the addiction].

Saturday, June 27, 2009

New Drug Kills Cancer with Few Side Effects

http://www.technologyreview.com/biomedicine/22928/?nlid=2130
A personalized therapy targets the molecular mechanism behind a specific kind of tumor.
  • The drug, called olaparib, is the first success story from a new and highly personalized approach to anticancer drug development. This strategy harnesses a concept known as synthetic lethality, in which a drug is designed to work in tandem with the molecular glitch underlying a specific kind of cancer.
  • "It's a whole new way to develop drugs," says J. Dirk Iglehart, a professor of women's cancers and surgery at Brigham and Women's Hospital, in Boston, and coauthor of an editorial accompanying the paper. Iglehart was not involved in the study.
  • While existing chemotherapeutic agents may take advantage of synthetic lethality to some degree, they do so by accident rather than by design, says Daniel P. Silver, an assistant professor of cancer biology at the Dana-Farber Cancer Institute and coauthor of the editorial. "It's a particularly elegant idea," says Silver. "I do think that this will become an important methodology among many for developing cancer drugs."
  • A small percentage of breast, ovarian, and prostate cancers are associated with defects in one copy of the BRCA1 or BRCA2 gene, which encode proteins that help proofread the genome during replication.
  • If a BRCA-mutated cell happens to lose its one functional copy of the gene, proofreading is impaired, and mutations begin to accumulate as the cell divides. These mutations can cause a multitude of other cell processes to go awry, opening the door to tumor development.
  • Because there are several mechanisms for DNA repair, the loss of BRCA function doesn't completely incapacitate a cell.
  • But it does create a weakness not present in normal cells, which still carry a working copy of the BRCA gene. Olaparib targets that weakness by inhibiting an enzyme involved in another DNA proofreading pathway, generating a lethal double whammy to the cancer cell's DNA while sparing healthy cells.
  • Of 19 patients with BRCA-associated cancer treated by olaparib in the trial, 12 experienced substantial and lasting stabilization or shrinkage of their tumors. "[The drug] was given as a single agent to treatment-resistant advanced cancers--these cancers shouldn't respond to a piddly little enzyme inhibitor," says Iglehart. "So the fact that it was so effective was very exciting to people."
  • The drug's specificity means that unlike conventional chemotherapy drugs, which are toxic to normal cells and cancer cells alike, olaparib causes remarkably few side effects. "Compared to chemotherapy, this drug's a breeze," says Johann de Bono, a medical oncologist at the Institute of Cancer Research, in Sutton, England, who is co-leading the trial. "It's like taking Tylenol twice a day."


Being More Infantile May Have Led to Bigger Brains

http://www.scientificamerican.com/article.cfm?id=being-more-infantile&sc=DD_20090625

Genetic evidence suggests that juvenile traits helped separate chimps from us

  • For decades scientists have noted that mature humans physically resemble immature chimps—we, too, have small jaws, flat faces and sparse body hair. The retention of juvenile features, called neoteny in evolutionary biology, is especially apparent in domesticated animals—thanks to human preferences, many dog breeds have puppy features such as floppy ears, short snouts and large eyes. Now genetic evidence suggests that neoteny could help explain why humans are so radically different from chimpanzees, even though both species share most of the same genes and split apart only about six million years ago, a short time in evolutionary terms.
  • In animals, neoteny comes about because of delays in development, points out molecular biologist Philipp Khaitovich of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. For instance, humans sexually mature roughly five years after chimps do, and our teeth erupt later. “Changes in the timing of development are some of the most powerful mechanisms evolution can use to remodel organisms, with very few molecular events required,” he explains.
  • To look for genetic evidence that neoteny played a role in the evolution of Homo sapiens, Khaitovich and his colleagues compared the expression of 7,958 genes in the brains of 39 humans, 14 chimpanzees and nine rhesus monkeys. They collected samples from the dorsolateral prefrontal cortex—a region linked with memory that is relatively easy to identify in the primate brain. These tissues came from deceased individuals at several stages of life, from infancy to middle age, enabling the researchers to see how genetic activity changed over time in each species.
  • In both humans and chimps, about the same percentage of genes changed in activity over time. But roughly half these age-linked genes in humans differed from chimps in terms of when they were active during development. Analysis of the 299 genes whose timings had shifted in all three species revealed that almost 40 percent were expressed later in life in humans, with some genetic activity delayed well into adolescence.
  • Although the specific function of many of these neotenic genes remains uncertain, they are especially active in the gray matter of the human brain, where higher thought occurs, the researchers note in the April 7 Proceedings of the National Academy of Sciences USA. They are now probing other parts of the brain in humans, chimps and macaques to see where neoteny might play a role.
  • Actually proving that neoteny helped to drive human evolution and brain size is difficult. Khaitovich suggests analyzing genetic activity in cases of faster-than-normal development in people, “which past research already shows can lead to a reduction in cognitive abilities,” he says.
  • Other experts certainly think that neoteny’s role is reasonable. The ability of the brain to learn is apparently greatest before full maturity sets in, “and since neoteny means an extended childhood, you have this greater chance for the brain to develop,” says molecular phylogeneticist Morris Goodman of Wayne State University, who did not participate in this study. In other words, human evolution might have been advanced by the possibilities brimming in youth.
  • Note: This story was originally printed with the title, "Juvenile Thoughts."

Bacteria Cells Programmed to Count

http://dsc.discovery.com/news/2009/06/09/cells-count.html
  • June 9, 2009 -- Escherichia coli bacteria may be simple organisms, but scientists have now created ones that can count to three.
  • "We didn't teach the bacteria to count, we programmed them to count," said James Collins, a professor at Boston University and a co-author on the study, which appeared in a recent issue of the journal Science.
  • Scientists programmed the E. coli to count by injecting them with a molecule containing two DNA sequences that behave like switches. One switch turns on a minute-counter. The other switch turns on an hour-counter.
  • The first switch turns on proteins that physically flip a piece of RNA when the E. coli are exposed to sugar over the course of several minutes.
  • The second switch turns on proteins that flip a small section of DNA over the course of 10 to 15 hours in response to alternating periods of light and dark.
  • Both switches can flip only three times -- or count to three. Once they reach that number the DNA switches turn on another engineered protein, called a green fluorescent protein, or GFP, which glows green and lets the scientists know that their bacterial timers worked.
  • This function allows scientists to detect as bacteria count up -- 1, 2, 3, etc. So, the cells could be used to count the number of times it encounters a particular toxin or drug.
  • Right now cells, bacteria and otherwise, act as one-and-done detectors. As soon as they detect a particular chemical, it triggers a reaction. This can be helpful for detecting the presence of a chemical, but not useful for measuring the number of times a chemical occurs.
  • But the timer could also act like a time bomb countdown -- 3, 2, 1. At T-minus-zero, the cell could self-destruct, presumably after it's finished its job. Cells already perform a self-annihilation naturally under other circumstances, such as when they begin to divide too quickly or indefinitely, like they do in cancer. The replications add up and trigger apoptosis, or programmed cell death.
  • Scientists used the tools of synthetic biology to program this new ability into E. coli. The genes that encode for the bacterial counters should be relatively easily transferred to other bacteria.
  • The real trick, according to Stanford University professor Christina Smolke, another scientist using synthetic biology, is to couple the bacterial counters with other systems that make it easier to register the counts.
  • "The field of synthetic biology is still trying to develop a framework that can take all these components and stick them together to build a fully functional circuit," said Smolke.
  • "Overall I'm sure that we would want to count to much higher, but this is a start, it demonstrates a foundation, but there are lots of challenges to come as we start linking these models up."

10 Websites That Every College Student Should Know About

http://www.designyourdormblog.com/?p=96

1. Rate My Professors – this site is a great way for you to find out what you are getting yourself into when signing up for a particular class. Past students can rate the professor on easiness, helpfulness, clarity and rater interest. They can also write comments about the professor so you can decide if this is the right class for you or not.

2. Evernote – Evernote is a very useful site that will help you to keep every aspect of your life organized. For a college student, it is great when you are working on a class project. Instead of keeping a million tabs open on your web browser, you can store all of the information you need on Evernote. The best part about Evernote is that you don’t need to always be on the computer or internet to access your notebooks. Evernote can be used on the web, your desktop, Blackberry, Palm Pre and iPhone/iPod Touch.

3. Half.com
– Half.com makes surfing Ebay even easier. Simply search for the item you are looking for and instantly find the BEST price being offered. They also categorize the items based on the condition of the item. Definitely a great way to save money on textbooks!

4. Craigslist
– you can find anything and everything you need on craigslist. This site allows people to post items that they no longer want and its basically a first-come, first-serve. You can find furniture, DVDs, textbooks, pets and so much more!

5. Twitter
– if you haven’t gotten into twitter yet, I would highly suggest that you do. It is a great way not only to keep in touch with friends and family but also to network with other people and businesses. Depending on where you live, you may find that local businesses have twitters and give away free stuff or special deals to people that follow them. What college student doesn’t like FREE stuff?

6. Student Universe
– find great flight deals just for being a college student.

7. UrbanSpoon
– whether you have an iPhone/iPod Touch or not, UrbanSpoon is a great way to find the best restaraunts in town. You can find restaraunts, where they are located, what other people think about them and more through this site. Great for those late night cravings when you know exactly what you want but have no idea where to go!

8. Quarterlife – interning is a HUGE part of the college experience. Most majors encourage you to get an internship and others force you. Either way, Quarter Life makes it easy to find the internship you are looking for.

9. Internship Ratings
– debating between a few different internships? Not sure which company is right for you? This site may help. People who have interned with the company before can rate and review their experience which may make your decision a lot easier.

10. Unigo – are you about to head off to college for the first time in the fall? Get a feel for what the university is like ahead of time. On this site people can post their experiences and what they love/hate about the campus. It is also a good source on how you can get involved on

Ten Simple Rules for Choosing between Industry and Academia

http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1000388

One of the most significant decisions we face as scientists comes at the end of our formal education. Choosing between industry and academia is easy for some, incredibly fraught for others. The author has made two complete cycles between these career destinations, including on the one hand 16 years in academia, as grad student (twice, in biology and in computer science), post-doc, and faculty, and on the other hand 19 years in two different industries (computer and pharmaceutical). The following rules reflect that experience, and my own opinions.

Rule 1: Assess Your Qualifications

If you are a freshly minted Ph.D., you know that you will need a good post-doc or two before you can be seriously considered for a junior faculty position. If you're impatient, you might be thinking of industry as a way to short-circuit that long haul. You should be aware that companies will strongly consider your post-doctoral experience (or lack thereof) in determining your starting position and salary. While you may not relish extending your indentured servitude in academia, any disadvantage, financial and otherwise, can quickly be made up in the early years of your career in industry. In other words, trying to get off the mark quickly is not necessarily a good reason to choose industry over academia.

On the other hand, you may have completed an undergraduate or Master's program with a view to going to industry all along, with never a thought of an academic career. You should still consider the point of the previous paragraph. While abbreviated “practical” bioinformatics training programs can be excellent, a Ph.D. is a significant advantage in all but the most IT-oriented positions in industry, at least at the outset. This is not to discourage anyone from embarking on a fast-track-to-industry program if their heart is in it, but be aware that the further you climb the educational ladder, the higher and faster you can start when you step across to the business ladder, and the better you will compete for a job in the first place. The days are long past when bioinformaticists were in such short supply that any qualification would do.

If you are an old hand and have already notched up a post-doc or two, take stock of your star power. This unspoken but universally understood metric encompasses such factors as whom you've trained with, where you've published (and how much), and what recent results of yours are on everyone's lips. If you are fortunate enough to have significant capital in this department, then the world may be your oyster, but you still need to consider where you will get the greatest leverage. While your stardom may be less taken for granted in industry, my feeling is that academia is a better near-term choice in such circumstances. Consider that it was in academia that you achieved the success you own thus far, so you obviously “get it.” The simple fact is that academia is rather more of a star system (as in Hollywood) than is industry.

Finally, if you count among your qualifications a stint in industry already, as an intern or perhaps as part of a collaboration, you will not only be in a better position to compete for a permanent job, but you will be much better prepared to make the decision facing you. Stated another way, if you are seriously considering industry as a career path, you should probably have already taken advantage of the many opportunities out there to dip your toes in the water.

Rule 2: Assess Your Needs

In taking stock of your needs, and perhaps those of your family, a decent living is generally at or near the top of the list. Salaries are still higher in industry, though the gap is not nearly so wide as it once was. If you need a quick infusion of cash, companies may offer signing bonuses, though again these were more common when bioinformatics was a rarer commodity.

Industry offers forms of compensation unavailable in academia, and you will need to consider how to value them relative to your present and future needs. Despite recent bad press, bonus systems are often part of the equation, and depending on your entry point they may constitute a significant percentage of total compensation. There is a tendency among academics to discount bonus programs in their comparison shopping, sometimes to zero, and this is a mistake. Bonuses are considered core aspects of compensation in most companies, and though they always have a performance-based multiplier, the base levels have historically been fairly dependable. That said, these are tough times in industry, and there are no guarantees. Your best strategy is to understand the reward system thoroughly, ask for historical data, and avoid comparing only base salaries unless you are extraordinarily risk-averse.

Share options are another matter. While in the past these were very attractive, and fruitful in practice, most industry types will tell you frankly that any options they've received in the past decade are deep underwater and a deep disappointment. Many consider pharma shares (and therefore options) to be a bargain at the moment, but that's between you and your financial adviser to assess. In any case, it is not a short-term consideration, since options typically take several years to vest.

If you are looking at biotech, however, share options and similar ownership schemes need to be a key consideration, since these are a major rationale for assuming risk—more on that below.

Finally, you may have more specific needs to consider, such as a spouse also in need of a job. The two-body problem has always been tougher in academia than in industry, and probably always will be. If you are both academics, note that industry often has good contacts with local universities, and can facilitate interviews. Being a star certainly helps, so don't be afraid to negotiate. In fact, a general rule of thumb is that it never hurts to make your specific needs known, within reason. Academia will try to accommodate them as a community, while on the other hand business (particularly large, diversified companies) may have resources to address them that you wouldn't have expected. Nobody wants to hear a peremptory demand, but if a company wants you, be sure to let them know anything that might offer them a way to attract you.

Rule 3: Assess Your Desires

There are needs, and then there are desires. Do you want riches? Fame? A life at the frontiers of knowledge? The hurly-burly of the business world? How do you really feel about teaching, publishing, managing, interacting, traveling, negotiating, collaborating, presenting, reporting, reviewing, fundraising, deal-making, and on and on? Though it may seem obvious, this is a good time to decide what really drives you.

First, the obvious. Do you want to teach? If lecturing is in your blood, your decision is made, although if a smattering will suffice you may have the option from within industry of an adjunct academic appointment. (By the same token, if you are not so enchanted with lecturing, grading, tutoring, etc., there are often options for research track professorships that minimize teaching duties.) Do you want to publish? While it will always be “publish or perish” in academia, it is certainly possible to grow your CV in industry, and it can even enhance your career, depending on the company. However, it might be largely on your own time, and you will likely encounter restrictions in proprietary matters, though in practice you can generally find ways to work within them. Ask about publication at the interview, both policies and attitudes, and watch out for any defensiveness.

An important question, surprisingly often overlooked, is how you want to actually spend your time, day by day and hour by hour. In academia, you will immediately be plunged into hands-on science, and your drivers will be to start out on your career by getting results, publishing, networking, and building your reputation with a view to impressing your tenure committee. A career in industry may put more of an early emphasis on your organizational aptitude, people skills, powers of persuasion, ability to strategize and execute to plan, etc.; in terms of growing your reputation, your audience will be the rather narrower community of your immediate management. A somewhat more cynical view would be that in business you will spend seemingly endless hours in meetings and writing plans and reports, while in academia you will spend all that time and more in grantsmanship—in this regard, you must pick your poison.

Finally there is the elephant-in-the-room question: Do you want to make money, or to help people? This is, of course, a false dichotomy, but many people consciously or unconsciously frame the decision in just this way, and you had best deal with it. Try thinking of it not so much in terms of the profit motives of the respective institutions, but in terms of the people with whom you would spend your career. You should have encountered a good sampling of scientists from industry during meetings, internships, collaborations, interviews, etc. (or in any case you should certainly try to do so before making judgments). If you are left in any doubt as to their ethics or sincere desire to relieve human suffering as efficiently as possible, or if you feel these are somehow trumped by the corporate milieu, then by all means choose academia—but only after applying analogous tests to the academics you already know well. In my experience, business doesn't have a monopoly on greed, nor are humanitarian impulses restricted to academia. That said, in the final analysis you must be comfortable with your role in the social order and not finesse the question.

Rule 4: Assess Your Personality

Not surprisingly, some personality types are better-suited to one environment or the other. Raw ambition can be viewed as unseemly in either case, but there is more latitude for it in industry, and greater likelihood of being recognized and rewarded sooner if you are “on the go.” In fact, one of the clearest differences between academia and industry are their respective time constants. Although the pace of academia may have quickened of late, it is still stately by comparison with industry, and much more scheduled (so many years to tenure, so many months to a funding decision, etc.). If you are impatient, industry offers relatively fast-paced decision-making and constant change. If you thrive more under structured expectations, academia would be better for you, for although industry has all the trappings of long-range strategies and career planning, the highly reactive environment means these are more honored in the breach. For one thing, reorganizations are common, and in the extreme case mergers (I have experienced two) can reset everything, for good or ill, and devour many months.

This is not to say that all is chaos—industry certainly favors a goal-directed personality, but with plenty of flexibility. On the other hand, flexibility is more the hallmark of academic research, where you will have the opportunity to follow wherever the science leads, once you are running your own shop. In industry, the flexibility is more of the conforming sort, since you won't be able to investigate every promising lead and change your research direction at will. In academia, diverging from the Specific Aims of a grant may be a problem when the time comes to renew, but the risk is yours, as is the reward. In industry, you can make the case for a new program of research, but the decision is management's and will be guided by business considerations. The “lone wolf” or “one-person band” may be increasingly rare in academia in an age of collaboration, but it is unheard of in industry, where being able to work in teams with specialized division of labor is essential. It should be apparent, as well, that mavericks and quirky personalities tend to do better in academia.

The pecking order in industry is deeper and more pyramidal than in academia, and you might end up languishing in a pay grade (or feel like you are), but there are usually plenty of opportunities for lateral moves and a variety of experiences—not to mention that it's easier to switch companies than colleges. In industry, one does need to be able to thrive in a hierarchy; you will always answer to someone, though the degree to which you are monitored will vary. By the same token, if your personality is such that climbing a management ladder and assuming steadily greater responsibility suits you, industry is built for that, and plenty of management training is on offer in larger companies. Learning to manage is much more hit-or-miss in academia; opportunities to lead large organizations are rare (and to manage them actively rather than by consensus, rarer still).

If your personality type is that of a risk-taker, biotechs and/or startups may fit you to a tee. These are the wild and wooly end of the industry spectrum, and the risks and rewards are well-known. You will work longer hours than in large pharma, and maybe even more than in academia. You will most likely share more in ownership, and learn entrepreneurial skills that will serve you well, once the bug has bitten. Bear in mind the very common pattern of faculty spinning off startups or otherwise participating in boards and the like, not to mention staking out intellectual property (shared with their university); thus, you may well be able to scratch this itch from the vantage of academia as well.

A final word about politics. Whether you are an enthusiastically political animal, or abhor this aspect of the human condition, you will encounter plenty of politics in both academia and industry. The flavors differ, to be sure. As a student you doubtless heard the clichĂ©s about tedious academic committees and underhanded deans, but you have probably had more exposure to the realities behind those stories than the corresponding ones about the dog-eat-dog corporate world. Company politics, I would hazard to say, are more transparent—the maneuvering more open and the motives more apparent. The results are often more life-altering, unbuffered by tenure and academic convention. Again, it is a matter of taste, but in my opinion the differences are overblown, for the simple reason that people are the same everywhere, in both environments governed by an underlying sense of fair play, but also occasional opportunism.

Rule 5: Consider the Alternatives

As I've suggested, the choice you face is far more fine-grained than simply that between industry and academia. Industry is a spectrum, from large pharma to mature biotech to startup. By the same token, the academic side has at one extreme the research powerhouses, where you will be judged by volume of grants, and at the other the teaching institutions, which may not even have graduate departments. Unless you are very sure of yourself, you'd be well-advised to consider the full range, given the competition you may face.

Also, don't neglect other careers that may value your training. If you love the language, consider science journalism, either writing or editing—Science and Nature have large staffs, and you will often encounter them and representatives of other journals at the same scientific meetings you attend. The same is true of government agencies such as the NIH, NSA, DOE, and so forth, where grants administration is very actively tied to research trends and can be an entrĂ©e into the world of science policy. There are many more such positions when foundations, interest groups, and other private funding bodies are included. If you have a knack for business, many management consulting firms have scientific and technical consulting arms that value Ph.D.s and offer intensive training opportunities, and, though it may not be attractive at the moment, a career as a financial analyst specializing in biotech is yet another possibility.

Rule 6: Consider the Timing

The current business environment cannot help but be among your considerations. Pharma has certainly been contributing to the unemployment rolls of late. Corporate strategies, which used to be very similar across the sector, have started to diverge, so that some companies are divesting bioinformatics at the same time that others are hiring computational types disproportionately as they place more of an emphasis on mathematical modeling, systems approaches, pharmacogenomics, drug repurposing, and the like. Overall, though, the industry trend has been to shrink R&D, and this may well continue through a round of consolidation, with several mega-mergers now under way. As noted above, mergers are times of upheaval, carrying both risk and opportunity, and usually a period in limbo as well. At the same time, it is worth bearing in mind that a corollary of downsizing is outsourcing, so that there may be new opportunities for startups and even individual consultants.

For much of the last decade, academia has also been in the doldrums, as NIH budgets have effectively contracted. As I write this, things are definitely looking up, with prospects for renewed funding of science and even near-term benefits to the NIH and NSA from the Obama stimulus package. Whether universities will respond proportionately with faculty hiring, given the losses in their endowment funds and cutbacks in salaries and discretionary spending, remains to be seen. There is a lot of slack to be taken up, and in particular a backlog of meritorious grant applications that are now being reconsidered. Nevertheless, on balance, an academic career has to be somewhat more promising today than a year ago, and a career in pharma rather less so, in the opinion of the author.

Rule 7: Plan for the Long Term

Having noted the current situation in Rule 6, it's important also to say that a career decision should be made with the long haul in mind. The business cycle will eventually reverse itself, and while the business model may need to change irrevocably, the aging population alone dictates that healthcare will be an increasing global priority. Likewise, history shows that growth in government funding for science waxes and wanes, with a time constant somewhat longer than a decade. Trying to optimize a career decision based on current conditions is a bit like trying to time the stock market—you are sure to be overtaken by events.

One approach is to choose some reasonably long time frame, perhaps a decade, and ask yourself whether you'd be content to have lived through the average ups and downs you'd experience in a given job over that period. In academia, that would include a tenure decision (rate your chances), a lot of grant applications with mixed success at best, and maybe some great students and really significant scientific contributions. In pharma or large biotech, it would encompass a couple of promotions, your own group and maybe a department, at least one merger or other big disruption, and several rounds of layoffs. In small business, it might include a failed startup (or two, or three), an IPO if you're lucky, and a lucrative exit strategy or long-term growth if you're really lucky.

If you game these scenarios with various probabilities, and use your imagination, it just might become clear which ones you have no stomach for, and which ones really hold your interest.

Rule 8: Keep Your Options Open

Job-hopping is much more prevalent now than in days of yore, and you should consider this in your scenarios. In industry, there is little stigma attached to changing employers, and if you can tolerate the relocation and/or want to see the world, it is a more or less standard way to advance your career by larger-than-usual increments. This stratagem is far from unknown in academia, but perhaps a bit trickier to execute, though of course it is de rigueur if you fail to get tenure.

Of greater interest is the question of moving between academia and industry. From the former to the latter is fairly easy, but the reverse is not as common, for a variety of reasons. Superstar academics in relevant areas are in great demand in industry, to which they are often exposed through consulting or scientific advisory boards. There are multiple examples of senior academics taking over major R&D organizations in industry, sometimes orders of magnitude larger than anything they managed in academia, and you might even consider this well-trod path as a career goal from the outset.

It is not impossible to return to academia from industry, particularly if you were already quite prominent when you left, but if you start your career in industry you may be at a disadvantage unless you go to great lengths to maintain an academic-style publication record and CV. Important exceptions would be if the work that you did in industry was particularly novel and/or high-profile, or if your business experience is valued in the post you seek. Examples of the latter might be faculty positions with a prominent management component (centers, institutes, core facilities, and the like), or an interface role back to industry, or perhaps a joint business school appointment.

Rule 9: Be Analytic

Approach the decision with the analytic skills you've learned to apply to scientific questions. Gather data from all available sources and organize it systematically. When you interview, don't just impress, but get impressions; record everything down to your gut feelings. Do some bibliometric or even social network analyses of your potential colleagues. Check the industry newsletters and blogs, albeit with a grain of salt, to get a sense of the mood around R&D units (not to be confused with manufacturing, sales and marketing, or other divisions, which may have completely different cultures within the same company).

You might even try out some decision theoretic methodologies, such as decision matrices and Bayesian decision trees, or run simulations on the scenarios of Rule 7. I recommend taking a look at expected utility theory and prospect theory, for an interesting quantitative excursion. But honestly, these suggestions are just a more sophisticated informatics version of the classic advice to “make a list of pros and cons,” which always makes one feel a little more in control.

Rule 10: Be Honest with Yourself

Another homily: Now, if ever, is the time to be honest with yourself. Take a hard look at your qualifications, with as much objectivity as you can muster, and use these rules to decide where you would be best-suited and positioned for success. But even more importantly, deal with your emotional responses to industry and academia. If something is nagging at you, tease it out into the open, and try to decide if it is well-founded or not; if you can't decide, then you have to acknowledge it, and realize that it may not go away in the future either.

Finally, try to keep some perspective. Your career choice is important, but not irrevocable, and there are more consequential things in life. Don't let the decision process ruin what should be an exciting time for you.

implicates DICER1 mutations in development of familial pleuropulmonary blastoma (PPB)

http://www.genomeweb.com/blog/week-science-118
  • Washington University Medical Center's D. Ashley Hill published work in this week's advanced online edition of Science that implicates DICER1 mutations in development of familial pleuropulmonary blastoma (PPB), a rare pediatric lung tumor.
  • First using a four-family linkage study, the scientists mapped the PPB locus to chromosome 14q, and from this singled out DICER1. Second, they sequenced the genomic DNA of 11 PPB families to find heterozygous germline mutations in DICER1; in 10 of these families, the mutations resulted in proteins that were truncated proximal to the two carboxy-terminal RNase III functional domains, "and thus likely cause loss of function" and tumorigenesis, says the paper.
  • BenoĂ®t Kornmann at UCSF designed an experiment using a synthetic biology screen to find proteins involved in mitochondria/ER junctions. Screening for mutants that could be "complemented by a synthetic protein designed to artificially tether the two organelles," says the abstract, he and his team discovered that the Mmm1/Mdm10/Mdm12/Mdm34 complex could bind the two together. Genome-wide interaction maps showed that the proteins in the complex were associated with phospholipid synthesis and calcium signaling genes.
  • In the print edition this week, there's a special focus on stem cells, including this review of NIH's draft guidelines on stem cell research by Mary Majumder and Cynthia Cohen. The authors say that while the effort is positive, there are certain omissions and concerns about how the guidelines would affect ongoing research in the field.
  • There's also a paper on the evolution of diatoms, which appear to have recruited genes from both red and green algae "to forge a highly successful, species-rich protist lineage," according to the abstract. Lead authors Ahmed Moustafa and Bánk Beszteri used a genome-wide screen to assess the nuclear gene content that came from green algae. There's a perspective piece on the paper, as well as a news report from our sister publication GenomeWeb Daily News.
  • A paper from senior author Martha Bulyk demonstrates the use of microarrays to study the binding specificities of more than 100 DNA binding proteins in mouse. The result was that "virtually every protein analyzed possessing unique preferences," the authors write, noting that this challenges "our molecular understanding of how proteins interact with their DNA binding sites."

New gene discovery links obesity to the brain

http://www.labspaces.net/98313/New_gene_discovery_links_obesity_to_the_brain

Friday, June 26, 2009

  • A variation in a gene that is active in the central nervous system is associated with increased risk for obesity, according to an international study in which Albert Einstein College of Medicine of Yeshiva University played a major role. The research adds to evidence that genes influence appetite and that the brain plays a key role in obesity.
  • Robert Kaplan, Ph.D., associate professor of epidemiology & population health, helped direct the international study, which involved 34 research institutions and is published online in PLoS Genetics. Dr. Kaplan and his U.S. and European colleagues found that people who have inherited the gene variant NRXN3 have a 10-15 percent increased risk of being obese compared with people who do not have the variant.
  • The researchers examined data from eight studies involving genes and body weight. These studies included more than 31,000 people of European origin, ages 45 to 76, representing a broad range of dietary habits and health behaviors.
  • After analyzing more than two million regions of the human genome, the researchers found that the NRXN3 gene variant ─ previously associated with alcohol dependence, cocaine addiction, and illegal substance abuse ─ also predicts the tendency to become obese. Altogether, researchers found the gene variant in 20 percent of the people studied.
  • "We've known for a long time that obesity is an inherited trait, but specific genes linked to it have been difficult to find," says Dr. Kaplan. "A lot of factors ─ the types and quantity of foods you eat, how much you exercise, and how you metabolize foods, for example ─ affect your body shape and size. So we are looking for genes that may have a small role to play in a complex situation."
  • NRXN3 is the third obesity-associated gene to be identified. The fact that all three genes are highly active in encoding brain proteins is significant, says Dr. Kaplan. "Considering how many factors are involved in obesity, it is interesting that research is increasingly pointing to the brain as being very important in its development," he said.
  • Identifying obesity genes could help in preventing the condition and lead to treatments for it. "Someday we may be able to incorporate several obesity genes into a genetic test to identify people at risk of becoming obese and alert them to the need to watch their diet and to exercise," Dr. Kaplan said. "Also, we may eventually see drugs that target the molecular pathways through which obesity genes exert their influence."
  • Since NRXN3 is active in the brain and also implicated in addiction, these traits may share some neurologic underpinnings. "Although we don't have data to suggest a direct connection between drug abuse and obesity, we can indirectly infer a link because both traits have this gene in common," Dr. Kaplan said.

Trio of signals converge to induce liver and pancreas cell development in the embryo

http://www.labspaces.net/98311/Trio_of_signals_converge_to_induce_liver_and_pancreas_cell_development_in_the_embryo

Friday, June 26, 2009

  • Understanding the molecular signals that guide early cells in the embryo to develop into different organs provides insight into ways that tissues regenerate and how stem cells can be used for new therapies.
  • With regenerated cells, researchers hope to one day fill the acute shortage in pancreatic and liver tissue available for transplantation in cases of type I diabetes and acute liver failure.
  • Previous studies on pancreas and liver development have focused on individual molecular signals that induce these tissues to mature from a common precursor cell population. In a new study, published this week in Science, researchers investigated a trio of cell-signaling pathways that work simultaneously, converging to direct pancreas and liver progenitor cells to mature into their final state.
  • They looked at how BMP, TGF-beta, and FGF signaling pathways turn on genes that guide cells to ultimately become pancreas or liver tissue.
  • The structure of the cell-signaling network provides insight into the basis of tissue development and how it can be manipulated to facilitate pancreas and liver-cell regeneration and development from embryonic stem cells.
  • "For my entire scientific life, I've been intrigued by how cells early in development make 'decisions' to turn on one genetic program and exclude others," says Kenneth S. Zaret, PhD, Professor of Cell and Developmental Biology and Associate Director, Institute for Regenerative Medicine at the University of Pennsylvania School of Medicine.
  • The work was conducted while Zaret and co-author Ewa Wandzioch, PhD, Research Associate in the Department of Cell and Developmental Biology, were at the Fox Chase Cancer Center in Philadelphia.
  • Guidance along the correct path is provided by genetic regulatory proteins that attach to chromosomes, marking part of the genome to be turned on or off. But first the two meters of tightly coiled DNA inside the nucleus of every cell must be loosened a bit. The regulatory proteins help with this, exposing a small domain near the target gene. They then act as a landing pad on which other proteins assemble to continue the gene activation process.
  • The Science paper addresses how chemical signals from neighboring cells in the embryo tell early progenitor cells to activate genes encoding the regulatory proteins. The regulatory proteins, in turn, guide the cells to become a liver cell or a pancreas cell. "In the current study we mapped the signaling pathways being turned on before they connected with the target genes," explains Zaret.
  • "We monitored these cues before the cell displayed any overt signs of differentiation. While my lab and others had previously looked at individual signals that influence development, in this paper we simultaneously mapped three signal paths that converge to induce liver and pancreas cells. We're starting to construct a network of the common signals that govern development of these specific cell types. The complexity of this system is somewhat like our 26-letter alphabet being able to encode Shakespeare or a menu at a restaurant."

Getting earlier warnings before earthquakes strike

http://www.economist.com/sciencetechnology/displaystory.cfm?story_id=13933342&fsrc=twitter

YOU never really get used to earthquakes.
  • You wishes the warning would come minutes, rather than mere seconds, earlier. And nowadays there is no technical reason why it should not. Thanks to low-orbit surveillance and communications satellites, such alarm systems are being used along the eastern edge of the Indian Ocean to warn coastal communities of imminent tsunamis.
  • In Japan, they tell speeding bullet-trains to slow down in time to prevent derailments. One day, such earthquake early-warning systems could be as ubiquitous in the home as smoke detectors—at least, in seismically active areas.
  • Providing five-minute warnings of earthquakes is one thing; predicting them days or weeks ahead is quite another. Detecting the primary waves from an earthquake is like seeing the flash of lightning before hearing the thunder and getting drenched by the rain. It is an integral part of a deterministic process that is already under way.
  • The magnitude and timing of an earthquake depend on the size of the fault being ruptured, the stiffness of the rocks in question and the amount of stress that has accumulated in them. Scientists can make rough guesses of what they may be, but the deterministic devil is in the details. Understanding what is happening—at the level of detail that determines the actual outcome—is impossible.
  • That has not stopped people trying. Pseudo-scientific theories and predictions about earthquakes abound. Over the centuries, people have tried everything from the behaviour of animals and unusual cloud formations to the water level in wells and the phases of the moon to predict earthquakes.
  • More recently, researchers have sought to associate electromagnetic fields, the radon or hydrogen content of the soil and seismicity patterns with impending earthquakes. All to no avail.
  • So far it has proved impossible to predict earthquakes in any meaningful way—that is, of a given magnitude, at a given place, on a given day. That is because of the complexity of the problem and the lack of information about how the stresses around the cat’s cradle of neighbouring faults accumulate in some places and are relieved in others. Anyone who says they can predict such things precisely and repeatedly is a charlatan or a crank.
  • What seismologists can do is identify places where there is a high probability of a strong earthquake happening in the future. On average, there are 18 killer quakes of magnitude 7.0 or greater around the world each year. Most occur along the “Ring of Fire”, a belt of seismic and volcanic activity around the Pacific rim that includes California and Japan.
  • Seismologists know, for instance, that similar magnitude 6.0 earthquakes have occurred at regular intervals along the San Andreas fault in California—probably the most intensely studied fault in the world. What they cannot say is precisely when and where the next one will strike. The last time seismologists were bold enough to attempt a forecast, the earthquake came at the designated place but 12 years after the four-year prediction window had closed.
  • With his own interests at heart, your correspondent has been keen to help researchers gather information about such possible earthquakes. His curiosity was sparked by the Quake-Catcher Network (QCN) when it was launched in early 2008 by seismologists from the University of California, Riverside, and Stanford University.
  • The original aim was to supplement seismic data from 800 permanent monitoring stations around California with information fed back from volunteers with Apple or Lenovo laptops that contained accelerometers to protect their hard-drives if dropped. The researchers imagined the accelerometers would also make handy monitors for detecting ground movement caused by an earthquake, which could then be fed to the network along with the laptop-owner’s location.
  • Unfortunately, put to the test last July, when a shock of magnitude 5.4 rattled a large swath of your correspondent’s neck of the woods, only half a dozen of the 1,500 or so laptops signed up sensed any shaking. No more than three sent back data clean enough to use.
  • Laptops make poor seismographs because, unless they are nailed down, any quake worth its salt—and of interest to the QCN researchers—would move the computer bodily along with its sensitive accelerometer, making nonsense of its seismic reading.
  • The QCN organisers have learned from their mistakes and now offer a separate accelerometer that can be screwed to the floor and attached to any computer with a USB cable. Readers wishing to take part in the quake-catching experiment should visit the organisers’ website for details of the software and sensor.

Friday, June 26, 2009

How Michael Jackson Became a Brand Icon

http://blogs.harvardbusiness.org/quelch/2009/06/how_michael_jackson_became_a_b.html

Countless books advise how to build your personal brand. Michael Jackson was so unique that he cannot realistically serve as anyone's role model in that effort. Yet Jackson was unquestionably a brand icon and there are lessons to be learned. Here are the top ten factors that explain his icon status.

  • Start early. Michael began entertaining at the age of four. His career as the uniquely young lead singer in The Jackson Five began with the Motown label at the age of 10. National recognition came with his appearance on the Ed Sullivan show.
  • Let go. Jackson went solo in 1972 at the age of 13. As with Diana Ross and the Supremes, there came a point where the group constrained rather than aided the further development of his talent.
  • Break out. Jackson was a multidimensional entertainer. His expert dancing could be showcased via the new medium of music videos. MTV and Jackson rose in tandem when MTV premiered the Jackson video "Thriller" in 1982 from the album of the same name. The album went on to sell over 100 million copies.
  • Get help. Jackson benefited from his long-term professional relationship with producer and songwriter Quincy Jones. He often acknowledged the inspiration he received from James Brown, Diana Ross and other artists.
  • Be visible. All memorable brands have their unique visual trademarks. Jackson understood brand image and how to build it with his fans. The moonwalk that we could all try to imitate. The glove. The uniform. Neverland.
  • Go global. Jackson's music and videos easily transcended national boundaries, as well as race, age and gender. "We Are the World", written by Jackson and Lionel Ritchie in 1985, cemented his global appeal. Jackson sold almost half his 750 million titles outside the United States.
  • Crown yourself. Elvis was already "The King", so Jackson christened himself "The King of Pop." The professional contributions--including 13 Grammies--were so substantial that the moniker stuck. The flawed personal life - the lawsuits, the failed marriages, and the Wacko Jacko incidents like dangling his child from a Berlin hotel balcony - chipped away at Jackson's professional brand equity but never eroded it.
  • Be vulnerable. We cannot relate to icons without imperfections. Jackson was quirky, eccentric, mysterious. For all his wealth and professional excellence, he was - perhaps understandably - flawed, misguided, and sad, but none would say unkind.
  • Give back. Denied a normal childhood, Jackson was amazingly generous to disadvantaged children. Some 39 charities benefited significantly from his support. He also collaborated on Live Aid with other entertainers.
  • Die young. The sold-out 50 concert tour of Europe to start next month will never happen. The likelihood of a Jackson comeback will forever be debated. Elvis Presley, Marilyn Monroe James Dean, and now Michael Jackson - all leave to our imagination thoughts of what might have been. When a brand icon is torn from us prematurely, unexpectedly, it figures even larger in our collective memory.

Wednesday, June 24, 2009

Normal Stress Management Genes May Be Cancer Drug Targets

http://focus.hms.harvard.edu/2009/061909/research_briefs.shtml#Elledge
  • A study in the May 29 issue of Cell has found that cancer cells have an increased reliance on many normal proteins to deal with stress and maintain their deviant state.
  • Researchers at HMS and Brigham and Women’s Hospital used a technique called RNA interference (RNAi) to knock down the production of thousands of proteins and determine which were particularly necessary for cancer cell survival. They discovered that their experimental tumor cells had a heightened need for dozens of normal proteins and therefore were more vulnerable than normal cells when the underlying genes were turned down.
  • “Cancer cells actually leverage many genes that don’t harbor mutations to maintain their malignant lifestyles,” said first author and postdoctoral researcher Ji Luo. “These genes probably help them deal with the problems that develop as a result of the continuous presence of growth and survival signaling in tumor cells.”
  • “Researchers often characterize cancer cells as oncogene addicts, but they’re just as reliant on normal genes that alleviate stress,” explained senior author Stephen Elledge, a Howard Hughes investigator and professor of genetics at HMS and of medicine at Brigham and Women’s Hospital. “These stress management genes deserve attention as potential therapeutic targets.”
  • In recent years, the National Cancer Institute has supported an ambitious effort to understand the molecular basis of cancer by sequencing cancer genomes. Elledge and Luo are concerned that this Cancer Genome Atlas project will miss the stress management genes.

Students may contact Stephen Elledge at selledge@genetics.med.harvard.edu for more information.

Water Bottle Chemicals Leach into Human Body

http://focus.hms.harvard.edu/2009/061909/research_briefs.shtml#Elledge
  • After a spate of health concerns in recent years, polycarbonate bottles, the hard-plastic bottles popular among outdoor enthusiasts and parents of newborns, are under scrutiny once again.
  • A study from HSPH has found that participants’ urinary concentrations of the chemical bisphenol A (BPA) increased by a statistically significant amount after drinking from polycarbonate bottles. BPA is known to disrupt bodily responses to endocrine hormones, and exposure to BPA has been linked to altered sexual maturation in mice and chronic heart disease and diabetes in humans.
  • Led by first author Jenny Carwile, a doctoral student in the Department of Epidemiology, the researchers recruited 77 Harvard College students to participate in the study. For a week in April 2008, the subjects were told to drink all cold beverages from a polycarbonate water bottle. At the end of the week, their urine was collected to measure BPA levels. The researchers also measured BPA in a urine sample taken the week before, during which the students were instructed to drink from a stainless steel bottle in order to reduce any existing BPA levels in their bodies.
  • Comparing the two urine samples, the researchers found that participants’ urinary BPA concentrations increased by 69 percent after drinking from the polycarbonate bottles for one week. This difference was even more pronounced (77 percent) when the results were restricted to participants who reported greater than 90 percent compliance, compared to 55 percent for a lower-compliance group. The difference between the two groups, however, was not statistically significant.
  • The authors noted that participants drank only cold beverages from the bottles, to mimic conditions of normal use. “If we had asked them to put hot liquids in there, the effect would have been bigger,” said Michels. “This is, in fact, what happens with baby bottles.”
  • Since its publication online May 21 in the journal Environmental Health Perspectives, the study has touched off a debate about the safety of BPA in places as far away as Denmark and Germany. Some countries, such as Canada, have banned the chemical from baby bottles outright. “This study is coming at an important time because many states are deciding whether to ban the use of BPA in baby bottles and sippy cups,” said Carwile.
  • “I think this has increased awareness that BPA is measurable and can get into your body,” said Michels. “People realize it is real, and more serious.”—Jue Wang

Students may contact Karin Michels at kmichels@rics.bwh.harvard.edu for more information.


Tuesday, June 23, 2009

Mouse Model Of Parkinson's Reproduces Nonmotor Symptoms

http://www.sciencedaily.com/releases/2009/06/090623091123.htm
  • ScienceDaily (June 23, 2009) — The classic symptoms of Parkinson's disease involve tremor, stiffness and slow movements. Over the last decade, neurologists have been paying greater attention to non-motor symptoms, such as digestive and sleep problems, loss of sense of smell and depression.
  • A genetically engineered mouse reproduces many of the non-motor symptoms associated with Parkinson's disease seen in humans and sheds light on their possible causes, Emory scientists report in the June 24 issue of the Journal of Neuroscience.
  • The mice were engineered to be deficient in VMAT2 (vesicular monoamine transporter 2), a protein that helps to store the brain chemicals Parkinson's patients gradually lose the ability to produce.
  • Most non-motor symptoms do not respond to L-dopa, the medication most commonly given to people with Parkinson's.
  • L-dopa can be converted by the body into the neurotransmitter dopamine, the lack of which is responsible for the main motor difficulties in Parkinson's.
  • Within brain cells, VMAT2 packages neurotransmitters such as dopamine, norepinephrine, and serotonin into vesicles, containers that deliver chemical messages to other cells. In the VMAT2-deficient mice, the improperly stored neurotransmitters are thought to damage brain cells.
  • In other mouse models of Parkinson's, scientists use chemicals such as the pesticide rotenone or the neurotoxin MPTP to kill the brain cells analogous to those that patients gradually lose, or they have the mice overproduce proteins that aggregate into toxic clumps.
  • The VMAT2-deficient mice have aggregated proteins in their brains, which appears to be a by-product of improper neurotransmitter storage, Miller says.
  • The Emory scientists showed that the mice have delayed emptying of the stomach, they fall asleep more quickly and they have a loss of the sense of smell.
  • In tests scientists use to model depression, aged VMAT2-deficient mice display signs of depression and respond to classical antidepressants. They also showed greater reluctance to explore elevated, lighted places, a measure of anxiety.

Friday, June 19, 2009

New Strategy Rapidly Reveals Targets for MicroRNA Gene Regulation

http://www.hhmi.org/news/darnell20090617.html
  • A new method promises to cut through the stubborn problem of determining the precise targets of microRNAs – the tiny but powerful bits of nucleic acid that tweak gene expression to influence many aspects of health and human disease, from early development and aging to cancer, heart disease, and diabetes.
  • Researchers using the new technique, called HITS-CLIP, showed that in a single experiment they could map the binding points of scores of different microRNAs throughout a genome in living mouse or human tissue.
  • The research by Howard Hughes Medical Institute investigator Robert Darnell and his colleagues Sung Wook Chi, Julie Zang, and Aldo Mele at The Rockefeller University was reported June 17, 2009, in an advanced online publication of the journal Nature.
  • His team has already used the approach identify the targets and binding sites of nearly 90 percent of the microRNAs that regulate gene expression in the mouse brain. “To a first approximation, we can map every site they bind to on every RNA transcript,” he says. Information gleaned from HITS-CLIP mapping could be helpful in learning how microRNAs influence the progression of diseases, and in identifying targets for new drug therapies, Darnell says.
  • MicroRNAs are short stretches of 20 to 22 nucleotides that do not encode instructions for making a protein. They regulate gene expression by blocking the production of specific proteins. These snippets of RNA do their work in the cell’s cytoplasm, where they intercept messenger RNA that carries a gene’s blueprint to the ribosome factories where proteins are made. MicroRNAs dock onto a binding site on messenger RNA. The interaction shortens the lifetime of the messenger RNA or blocks or weakens its instructions, thus reducing the output of protein.
  • Human genes are subject to the control of more than 500 different microRNAs – collectively thought to regulate more than half of our genes. And hundreds of microRNAs have been identified in other species, as well.
  • “To know what a particular microRNA is doing in a cell you need to know what messenger RNA it is binding to, and exactly where it binds,” says Darnell. But “the field hit a roadblock in finding out what any given microRNA does.
  • That’s because microRNAs latch on to their target transcript with as few as six consecutive nucleotides. That six-nucleotide sequence might occur many times within a single messenger RNA, and finding the actual minuscule “footprint” is a technical challenge. The problem, Darnell explains, is that the messenger RNA “is like a long coastline with a lot of ports, and it’s been very difficult to know where the microRNA docks.” Biochemical and computer prediction methods are imperfect, he says, and so the tedious hunt for binding sites could only be done experimentally, one RNA at a time.
  • HITS-CLIP, which stands for high-throughput sequencing – cross linking immunoprecipitation, was first developed by the Darnell lab in 2008, and is an improvement on their development of CLIP in 2003. CLIP relies on an old laboratory trick that essentially “freezes protein-RNA complexes inside the living cell,” Darnell says.
  • To freeze these complexes, the researchers shine ultraviolet light onto the cells they are studying, which causes all the proteins and RNAs that are very close to each other become cross-linked – they form an unbreakable bond. Applying HITS-CLIP to a protein called Argonaute turned out to be an effective way of revealing microRNA-messenger RNA interactions. Argonaute assists the regulatory activity of microRNAs by latching onto a microRNA and guiding it, like a tugboat, to its dock on the messenger RNA. Ultraviolet crosslinking locks Argonaute into a complex with both the microRNAs and its messenger RNA target.
  • The cells can be broken open with a strong detergent that washes away everything but tightly bound RNAs and proteins. “Then we get rid of the proteins,” says Darnell, “and we’re left with just the microRNA and a tag of the Argonaute protein bound to the messenger RNA.” Sequencing those bits of genetic material reveals where Argonaute was bound to both the microRNA and the messenger RNA.
  • When those data sets are crunched with bioinformatic algorithms, what falls out is the tiny “footprint” on the messenger RNA where the microRNA attaches. “With high-throughput sequencing, we can instantly see all the microRNA binding sites on all the messenger RNAs,” Darnell says.
  • His lab is interested in human brain disorders, and they have been using HITS-CLIP to study how genes are regulated in brain tissue. They first applied HITS-CLIP to the set of microRNAs in the mouse brain and identified binding sites for about 90 percent of those microRNAs with better accuracy and specificity than computer predictions.
  • Darnell is excited about the prospect of using his method to glean a new understanding of how microRNAs tweak genes in defined pathways to shape development and other vital processes. He also plans to compare the role of microRNAs in healthy and diseased brains, and expects other researchers will carry out similar experiments to catalog microRNA interactions in other tissues and under different conditions.

Thursday, June 18, 2009

Powerful Nutrient Cocktail Can Put Kids With Crohn's Into Remission

ScienceDaily (June 17, 2009)
  • Treating children with inflammatory bowel disease (IBD) usually involves the same steroids-based medication prescribed to adults. But such treatments can have negative side effects for kids and teens dealing with IBDDr. Raanan Shamir of Tel Aviv University's Sackler School of Medicine and Schneider Children's Medical Centre shows that there is another path to treating IBD in children: a nutritional formula that was first developed for astronauts.
  • This supplement puts 60-70% of children with Crohn's disease, a common IBD disorder, into remission — a success rate similar to that of traditional steroid-based drugs, but without side effects like malnutrition and growth retardation.
  • Dr. Shamir recently reported his research in the Journal of Pediatric Gastroenterology and Nutrition.

Eating Like an Astronaut

  • Dr. Shamir's research was inspired by the problem of malnutrition and growth retardation in children battling IBD. Steroids and other biological agents, the most common treatment for IBD, were having an adverse affect on the children's growth, despite their effectiveness in adult patients.
  • It was a problem first tackled by NASA: How could astronauts most efficiently get their daily nutrients? The answer was a specially-designed powder that contains all the daily nutrients a person needs. Aboard spacecrafts, astronauts dine on this nutritional powder mixed with water. Since then, these powders have become a common item on the pharmacy shelf.
  • A similar concept works wonders for children suffering from IBD. "Prepared powder, with liquids, gives you all the nutritional requirements you need for the day," Dr. Shamir explains. "We don't know why these formulas work, and nobody has shown that any one formula is preferable to another. People have to be committed and eat nothing else during the period of time they are on nutrition therapy, and it is difficult to do — but if they do it, they go into remission."
  • To induce remission, children need to be on nutrition therapy for 6-8 weeks. And in order to maintain remission, 25-50% of their caloric intake must be supplied by nutrition therapy, sometimes for years. This is why children experiencing the treatment need the support of physicians, dieticians, psychologists, and of course their families.
  • Dr. Shamir's quest to educate the international medical community about the benefits of nutrition therapy has been an uphill battle. "The acceptance of this is difficult," he says. "You have to persuade the family. Not all physicians know it works, and it's much easier to give someone a prescription than try to work with the child."

A Replacement for Steroids

  • "In adults, studies have shown that steroids are more effective in the battle against IBD than nutrition-based therapies. I think it is easier to get compliance from children, especially when it involves their growth. For adults, growth is not a concern — they just want to feel better," explains Dr. Shamir.
  • Dr. Shamir and his team of researchers have worked to show the international medical community that nutrition was equal to steroids in the treatment of children with IBD. "We published the most recent meta-analysis to show that nutrition is as good as steroids as a first-line therapy for Crohn's disease," he says.

The next step in his research, says Dr. Shamir, is to "define exactly the role of nutrition in inducing remission in these patients, and the role of nutrition in maintaining remission.


Adapted from materials provided by Tel Aviv University.

Friday, June 12, 2009

Networking for the College Student

http://www.associatedcontent.com/article/1812108/networking_for_the_college_student_pg2.html

Part 3 - Networking Principles:- The intention to analyse general networking principles of which college students should be aware and the specific ways in which a college student may network.

Networking Principle #1 - Make a Good First Impression
  1. One of the most important things about networking is being on good terms with your contacts. Often, making a good first impression can do a lot more to build a strong relationship than can large amounts of effort later on.
  2. Consider meeting with your advisor for the first time. This may be an informal meeting where you discuss things like your interests and intended major.
  3. However, doing things like wearing a dress shirt, dress pants, and tie, if male, or a nice blouse and skirt, if female, can help to impress an advisor that is used to seeing students in more relaxed attire.
  4. This might let him or her know that you are a dedicated student, and may help you be taken more seriously.
  5. Dressing nicely in your first few meetings with your advisor could help him or her to learn your name and become familiar with you faster, which might allow you to reap benefits of networking, such as earlier scheduling dates and recommendations for on-campus positions later.
  6. Consider each first impression you make as the foundation of a future relationship. Clearly, you will not wish to make every introduction the same, and cannot be expected to act the same way when meeting different people in different settings.
  7. However, remember the basic concepts of courtesy, manners, and generosity, and try to learn names quickly. These things will help you to make good first and second impressions, and will likely allow you to network more easily.

Networking Principle #2 - Communicate Well
  1. One of the easiest ways to make a good impression and build a strong social network is to communicate well with others. This may mean speaking more formally than you do with friends, or may mean being a better listener than a speaker.
  2. When networking, be true to yourself. If you are a talker, talk, but if you are a quieter person, just listen. People will appreciate someone who listens and provides thoughtful insight, as opposed to someone that talks over them. Work with your strengths.

Networking Principle #3 - Stay in Touch
  1. You may be able to establish personal connections easily and quickly, but they will not be helpful to you if you do not work to maintain them. With all of the people in your network, you must work to stay in touch.
  2. Depending on your relationship, this may mean more constant communication, or it may mean getting in touch with people every few months.
  3. Small things like greeting cards on holidays and birthdays or thank you notes can do a lot to show your contacts that you care.


Networking Principle #4 - Give
  1. Giving back to your contacts is one of the most important concepts in networking. If you are ever going to ask a favor of them, you have to be willing to help them in whatever way you can.
  2. I don't mean to say that your contacts should "owe you one," but if they ask for your assistance in something, make the most of the opportunity to make a good impression and lend them a hand. They will be grateful and more willing to help you out in the future. Plus, they may be able to attest to your dedication and work ethic.
Networking Principle #5 - Ask for Help When Needed
  1. For some people, the hardest thing about networking is actually asking for help when it is needed. Whether it is for a written recommendation, a phone call to a professional contact, or sponsorship for a research opportunity, making your needs known to other people can be difficult depending on your personality.
  2. Remember that asking for help is not a sign of weakness. Let's some logic to prove this.
  • Premise #1 - Letters of recommendation are needed for admittance to graduate school.
  • Premise #2 - All M.A.s and Ph. D.s have gone to graduate school.
  • Premise #3 - Your college professor is an M.A. or Ph. D.
Conclusion - Your college professor has asked for a letter of recommendation.
No one's transcript speaks for itself. You will need help eventually. Likewise, no one gets through life without knowing others and being on the receiving end of a few favors. Get used to the idea of being helped, or your existence will be difficult.

Networking Principle #6 - Make the Best of the Opportunities You Are Given
  1. Something to understand about networking is that when someone finally does a favor for you by connecting you to one of their contacts, you have to take the opportunity seriously.
  2. You shouldn't be indifferent about the experience, or it reflects poorly on you and on the person that gave you the recommendation. My biology professor, for example, lamented the fact that some students were given research positions with world-class scientists and stopped showing up because they realized they weren't that interested in the position.
  3. If you're not sure whether you're going to like something or not, ask to shadow before you commit. At least in this situation you are not committing and are capable of backing out if necessary.
  4. If a professor had given the above students a recommendation, the research head would likely value the recommendations of that professor much less than he or she would have had the students taken the opportunity seriously.
  5. As a great courtesy to yourself and everyone with whom you ever work or network, act professionally.
  6. When you are hired, work hard. While you are hired, work hard. When you quit, give two weeks notice and continue to work hard. Let your employers and contacts know that you are dedicated to doing what you are doing well, even if you find that it's not your cup of tea.
  7. Seeing that you are doing your best work will let your boss know that you are a good worker, which might result in a future recommendation, and will let your contact remain in good stead with your boss.
  8. Remember to thank your contacts when they help you. If you do not show your gratitude, people will be much less likely to do favors for you in the future.
Thank you for reading!

Muscle Atrophy: When The Body Cannibalizes Itself

ScienceDaily (June 9, 2009)
  • During desperate times, such as fasting, or muscle wasting that afflicts cancer or AIDS patients, the body cannibalizes itself, atrophying and breaking down skeletal muscle proteins to liberate amino acids. In a new study published online June 8 and in the June 15, 2009 print issue of the Journal of Cell Biology
  • Shenhav Cohen, Alfred Goldberg, and colleagues show that muscle atrophy is a more ordered process than was previously thought. These researchers find evidence that enzyme MuRF1 selectively degrades the thick filaments in muscle, while bypassing the thin filaments.
  • We depend on skeletal muscles because they can produce movement, but they serve another purpose too. "Skeletal muscle is a protein reservoir that can be mobilized in times of need," says Goldberg. The structural core of a muscle cell is the myofibril, composed of myosin-containing thick filaments and actin-containing thin filaments.
  • During atrophy, this structure is disassembled, but exactly how was not known. MuRF1, an atrophy-related gene, is a ubiquitin ligase that "ubiquitylates," or tags a protein, by attaching a ubiquitin molecule, marking it for degradation by the cell. It was unclear when and how ubiquitylation was involved in disassembling skeletal muscles.
  • The researchers triggered atrophy in mice containing defective MuRF1 (lacking its RING-finger domain crucial for ubiquitylation). These mutant mice break down less muscle than wild-type mice, and less ubiquitylation takes place in the mutants.
  • Cohen and colleagues found that MuRF1 targets the thick filament, demolishing various components in a specific order. The researchers hypothesize that removal of certain thick filament components first permits subsequent MuRF1 access to the myosin heavy chain. However, MuRF1 doesn't exert the same power over the thin filament, which began to come apart even when MuRF1 was absent.
  • This mechanism "allows the muscle to still be a muscle and function," Goldberg says. "Atrophy doesn't just destroy muscle cells, like apoptosis."
  • The results indicate that MuRF1 doesn't have to wait for caspases or calpains to "pre-digest" the myofibril components.
  • The work also bears on the practical question of whether atrophy can be halted or reversed with drugs. "It argues against MuRF1 inhibitors" for this purpose, Goldberg says, because the enzyme is responsible for degrading only some muscle components, whereas others fall victim to other ubiquitin ligases and autophagy. Inhibitors that work upstream to block signals that activate ubiquitin ligases and initiate autophagy are a better bet.

Cohen, S., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200901052.

Saturday, June 6, 2009

List of Autoimmune Diseases

http://www.aarda.org/research_display.php?ID=47

A comprehensive list of autoimmune diseases

  • Acute Disseminated Encephalomyelitis (ADEM)
  • Acute necrotizing hemorrhagic leukoencephalitis
  • Addison's disease
  • Agammaglobulinemia
  • Allergic asthma
  • Allergic rhinitis
  • Alopecia areata
  • Amyloidosis
  • Ankylosing spondylitis
  • Anti-GBM/Anti-TBM nephritis
  • Antiphospholipid syndrome (APS)
  • Autoimmune aplastic anemia
  • Autoimmune dysautonomia
  • Autoimmune hepatitis
  • Autoimmune hyperlipidemia
  • Autoimmune immunodeficiency
  • Autoimmune inner ear disease (AIED)
  • Autoimmune myocarditis
  • Autoimmune pancreatitis
  • Autoimmune retinopathy
  • Autoimmune thrombocytopenic purpura (ATP)
  • Autoimmune thyroid disease
  • Axonal & neuronal neuropathies
  • Balo disease
  • Behcet’s disease
  • Bullous pemphigoid
  • Cardiomyopathy
  • Castleman disease
  • Celiac sprue (nontropical)
  • Chagas disease
  • Chronic fatigue syndrome
  • Chronic inflammatory demyelinating polyneuropathy (CIDP)
  • Churg-Strauss syndrome
  • Cicatricial pemphigoid/benign mucosal pemphigoid
  • Crohn’s disease
  • Cogans syndrome
  • Cold agglutinin disease
  • Congenital heart block
  • Coxsackie myocarditis
  • CREST disease
  • Essential mixed cryoglobulinemia
  • Demyelinating neuropathies
  • Dermatomyositis
  • Devic's disease (neuromyelitis optica)
  • Discoid lupus
  • Dressler’s syndrome
  • Endometriosis
  • Eosinophilic fasciitis
  • Erythema nodosum
  • Experimental allergic encephalomyelitis
  • Evans syndrome
  • Fibromyalgia**
  • Fibrosing alveolitis
  • Giant cell arteritis (temporal arteritis)
  • Glomerulonephritis
  • Goodpasture’s syndrome
  • Graves' disease
  • Guillain-Barre syndrome
  • Hashimoto’s disease
  • Hemolytic anemia
  • Henoch-Schonlein purpura
  • Herpes gestationis
  • Hypogammaglobulinemia
  • Idiopathic thrombocytopenic purpura (ITP)
  • IgA nephropathy
  • Immunoregulatory lipoproteins
  • Inclusion body myositis
  • Insulin-dependent diabetes (type1)
  • Interstitial cystitis
  • Juvenile arthritis
  • Juvenile diabetes
  • Kawasaki syndrome
  • Lambert-Eaton syndrome
  • Leukocytoclastic vasculitis
  • Lichen planus
  • Lichen sclerosus
  • Ligneous conjunctivitis
  • Linear IgA disease (LAD)
  • Lupus (SLE)
  • Lyme disease
  • Meniere’s disease
  • Microscopic polyangiitis
  • Mixed connective tissue disease (MCTD)
  • Mooren’s ulcer
  • Mucha-Habermann disease
  • Multiple sclerosis
  • Myasthenia gravis
  • Myositis
  • Narcolepsy
  • Neuromyelitis optica (see Devic's)
  • Neutropenia
  • Ocular cicatricial pemphigoid
  • Palindromic rheumatism
  • PANDAS(Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus)
  • Paraneoplastic cerebellar degeneration
  • Paroxysmal nocturnal hemoglobinuria (PNH)
  • Parry Romberg syndrome
  • Parsonnage-Turner syndrome
  • Pars planitis (peripheral uveitis)
  • Pemphigus
  • Peripheral neuropathy
  • Perivenous encephalomyelitis
  • Pernicious anemia
  • POEMS syndrome
  • Polyarteritis nodosa
  • Type I, II, & III autoimmune polyglandular syndromes
  • Polymyalgia rheumatica
  • Polymyositis
  • Postmyocardial infarction syndrome
  • Postpericardiotomy syndrome
  • Progesterone dermatitis
  • Primary biliary cirrhosis
  • Psoriasis
  • Psoriatic arthritis
  • Idiopathic pulmonary fibrosis
  • Pyoderma gangrenosum
  • Pure red cell aplasia
  • Raynauds phenomenon
  • Reflex sympathetic dystrophy
  • Reiter’s syndrome
  • Relapsing polychondritis
  • Restless legs syndrome
  • Retroperitoneal Fibrosis
  • Rheumatic fever
  • Rheumatoid arthritis
  • Sarcoidosis
  • Schmidt syndrome
  • Scleritis
  • Scleroderma
  • Sjogren's syndrome
  • Sperm & testicular autoimmunity
  • Stiff person syndrome
  • Subacute bacterial endocarditis (SBE)
  • Sympathetic ophthalmia
  • Takayasu’s arteritis
  • Temporal arteritis/Giant cell arteritis
  • Thrombocytopenic purpura (TTP)
  • Tolosa-Hunt syndrome
  • Transverse myelitis
  • Ulcerative colitis
  • Undifferentiated connective tissue disease (UCTD)
  • Uveitis
  • Vasculitis
  • Vesiculobullous dermatosis
  • Vitiligo
  • Wegener’s granulomatosis

**NOTE Fibromyalgia and Chronic Fatigue are listed, not because they are autoimmune, but because many persons who suffer from them have associated autoimmune disease(s)

American Autoimmune Related Diseases Association
22100 Gratiot Avenue, Eastpointe, MI 48021-2227
www.aarda.org
Ph 586-776-3900
Fx 586-776-3903

Huntington’s Disease Protein May Have An Accomplice

http://www.usnews.com/mobile/articles_mobile/huntingtons-disease-protein-may-have-an-accomplice/index.html

Experiments could explain why only some neurons in the brain are vulnerable to the disease By Tina Hesman Saey, Science News

Researchers may have discovered how a neuron-killing protein selects its victims — it has an accomplice.

  • Scientists identified a mutant form of the protein huntingtin as the culprit in Huntington’s disease in 1993. The protein is found in every cell in the body, but it only turns deadly in brain cells — particularly cells in the striatum, a part of the brain that helps control movement. Why mutant huntingtin preferentially kills those cells has been a mystery.
  • Now, researchers at Johns Hopkins University in Baltimore report in the June 5 Science that a protein called Rhes may goad huntingtin into killing brain cells in the striatum, leading to Huntington’s disease. If confirmed, the finding could provide new avenues for developing therapies to treat the fatal neurodegenerative disease, says Nancy Wexler, president of the Hereditary Disease Foundation and a Huntington’s disease researcher at Columbia University.
  • “This study really gave me a peek into what the future of the field might look like,” says William Seeley, a neurologist at the University of California, San Francisco’s Memory and Aging Center. Many researchers study the role of individual proteins in causing or preventing disease, but few studies before this one go beyond the molecular level and explain why neurodegenerative diseases attack only certain parts of the brain. “What makes it so special for me is that it builds a bridge back to the anatomy of the disease,” Seeley says.
  • Solomon Snyder, a neuroscientist at Johns Hopkins University, and his team investigated the protein Rhes (a nickname for Ras homolog enriched in striatum), which is produced mostly in the striatum. The researchers found that Rhes interacts with huntingtin, and the association is even stronger with the disease-causing form of huntingtin. The scientists grew human embryonic cells and mouse brain cells in petri dishes, and produced the two proteins (Rhes and the mutant form of huntingtin) in the cells. Cells making either protein alone stayed healthy, but cells that contained both proteins quickly died.
  • Through a process called sumoylation, Rhes adds another, small protein called SUMO to huntingtin, the team discovered. Usually, the mutant form of huntingtin just forms big clumps in cells, but adding SUMO seemed to partially dissolve the clumps, leading to cell death. The researchers suggest that the clumping renders the mutant form of huntingtin harmless, but that sumoylation makes the protein soluble and thus toxic. Why is unclear.
  • Future drugs that would block the interaction of Rhes with the mutant huntingtin protein or that would stop sumoylation could prevent or delay the development of Huntington’s disease, Snyder says.
  • But some Huntington’s disease researchers are not as enthusiastic about the new study. “It’s of questionable relevance,” says Jang-Ho Cha of Massachusetts General Hospital’s Institute for Neurodegenerative Disease in Charlestown. “You can model things in a dish, but does it have anything to do with the way cells die in a Huntington’s disease brain?
  • Other researchers agree that much more research is needed, particularly experiments in mice that might show whether removing Rhes could prevent the mutant huntingtin protein from becoming toxic. “There’s still a long way to go,” says Carl Johnson, executive director for science for the Hereditary Disease Foundation. But, “there’s no doubt about the correctness of the results that are presented in the paper.”

Meteors may have brought building blocks of life to Earth billions of years ago

http://www.latimes.com/news/custom/scimedemail/la-sci-meteor6-2009jun06,0,2568749.story
By John Johnson Jr. 3:40 PM PDT, June 3, 2009
A British research team suggests that a massive bombardment delivered enough water and carbon dioxide to the planet to create the conditions for life to form.

  • A massive bombardment of meteorites billions of years ago could have brought in enough water and carbon dioxide to jump-start the chemistry that allowed the Earth to develop into the garden spot of our solar system.
  • By studying meteorites and other evidence from this bombardment, a team of researchers at Imperial College, England, has calculated that the meteorites could have carried in as many as 10 billion tons of water vapor and carbon dioxide to the young Earth every year for millions of years.
  • That amount of water, about 10 times the daily outflow of the Mississippi River, and carbon dioxide would have been enough to set off a greenhouse effect that eventually made the Earth warm and wet enough to harbor plants and creatures. Meanwhile, the other planets entered existences of torture by fire and ice.
  • What distinguishes the new research, published this week in the earth and planetary science journal Geochimica et Cosmochimica Acta, is its suggestion of when and how the Earth received its shipment of life-giving material.
  • The incident at the heart of the study is known as the Late Heavy Bombardment, a time about 4 billion years ago, not long after the Earth was formed from the dust and debris swirling around the young sun. According to the scientists, the Late Heavy Bombardment lasted 20 million years and rained millions and millions of space rocks onto the surfaces of the Earth, moon and Mars.
  • Because of the Earth's rapidly changing geology, evidence of this event was mostly lost, except for the leftover meteorites themselves. But the moon, with no atmosphere, has little erosion, allowing closer study of the bombardment period's effects on the lunar surface. Court said that at least 6,000 craters greater than 14 miles across remain from this period. On Earth, the bombardment might have produced 22,000 of these huge craters, he said.
  • According to the scientists' theory, the frictional heat of passing through the thin atmosphere that surrounded the Earth at that time would have been enough to strip the oxygen- and water-rich outer layers from the meteorites as they plunged toward the planet. That process would slowly have caused a buildup of oxygen and water in the atmosphere.
  • To find out how much of those critical compounds could be carried by each meteorite, the team heated samples of the ancient rocks left over from the bombardment in a process known as pyrolysis-FTIR. This method uses electricity to flash heat the rock fragments in the absence of oxygen to prevent combustion. The gases given off during the heating process can then be measured.
  • The team found that, on average, as much as 12% of a meteorite's mass was made up of water. Another 6% was carbon dioxide, a potent greenhouse gas whose further concentration in the atmosphere today is causing temperatures to rise all over the world.
  • The British researchers believe Mars experienced the same unrelenting asteroid bombardment as the Earth. The Martian rovers Spirit and Opportunity have uncovered evidence that the Red Planet once featured standing seas and relatively mild weather. That ended billions of years ago. Today, the water on Mars is locked up underground at the poles.
  • The Imperial College team believes the key difference between the fates of the two planets is the Earth's molten iron core, which allowed our planet to develop a magnetic field. That magnetic field prevents most harmful solar radiation from damaging the atmosphere.
  • Mars lost its magnetic shield long ago, allowing the atmosphere to be gradually worn away by the sun's relentless radiation. Slowing of volcanic activity also cooled the planet, causing the water to retreat underground at the poles.

The consequences of genetic drift for bacterial genome complexity

http://genome.cshlp.org/content/early/2009/06/05/gr.091785.109

Abstract-Genetic drift, which is particularly effective within small populations, can shape the size and complexity of genomes by affecting the fixation of deleterious mutations. In Bacteria, assessing the contribution of genetic drift to genome evolution is problematic because the usual methods, based on intraspecific polymorphisms, can be thwarted by difficulties in delineating species' boundaries. The increased availability of sequenced bacterial genomes allows application of an alternative estimator of drift, the genome-wide ratio of replacement to silent substitutions in protein-coding sequences. This ratio, which reflects the action of purifying selection across the entire genome, shows a strong inverse relationship with genome size, indicating that drift promotes genome reduction in bacteria.

Genetic Drift-
  1. Genetic drift or allelic drift is the change in the relative frequency with which a gene variant (allele) occurs in a population that results from the fact that alleles in offspring are a random sample of those in the parents, and because of the role of chance in determining whether a given individual survives and reproduces. Genetic drift may cause gene variants to disappear completely, and thereby reduce genetic variability.
  2. Genetic drift is one of several evolutionary processes which lead to changes in allele frequencies over time. In contrast to natural selection, which makes gene variants more or less common due to their causal effects on reproductive success,[1] the changes due to genetic drift are not driven by environmental or adaptive pressures, and may be beneficial, neutral, or detrimental to reproductive success.
  3. The effect of genetic drift is larger in small populations, and smaller in large populations. Vigorous debates wage among scientists over the relative importance of genetic drift compared with natural selection.

Geography and History Shape Genetic Differences in Humans

http://www.hhmi.org/news/pritchard20090605.html

  • In recent years, geneticists have identified a handful of genes that have helped human populations adapt to new environments within just a few thousand years—a strikingly short timescale in evolutionary terms. Other factors -- the movements of humans within and among continents, the expansions and contractions of populations, and the vagaries of genetic chance – have heavily influenced the distribution of genetic variations in populations around the world.
  • The research was carried out by Jonathan Pritchard, a Howard Hughes Medical Institute investigator at the University of Chicago, and a team of colleagues including Graham Coop at the University of California, Davis; Joseph Pickrell at the University of Chicago; and Marcus Feldman, Richard Myers, and Luca Cavalli-Sforza at Stanford University. The team found that for most genes, it can take at least 50,000-100,000 years for natural selection to spread favorable traits through a human population.
  • Natural selection occurs when a particular genetic difference – which researchers call a variant -- gives an individual a greater opportunity to have children and pass on his or her genes to future generations. These genetic differences, which arise by mutation and then are inherited from parent to child, might confer a survival advantage in a given environment, such as being able to survive malaria or digest milk from animals. As individuals thrive and pass on their genes to their offspring, the variant can become more common in a population. This natural selection of advantageous genes—the raw material of evolution—leaves signals in our DNA that can be detected when researchers compare human genomes.
  • Pritchard and his colleagues published the results of their analysis on June 5, 2009, in Public Library of Science (PLoS) Genetics.
  • Pritchard says the genetic variants responsible for light skin are good examples of the effects of natural selection. Modern humans evolved in Africa more than 150,000 years ago and then spread throughout Africa and the rest of the world. As these humans moved into northern latitudes, natural selection favored traits that helped them survive in their new environment. Dark skin became a disadvantage, possibly because it blocked too much of the sunlight that humans need to synthesize vitamin D for healthy bones. People with genetic variants that produced lighter skin therefore tended to be healthier and had more children, and today those variants are common in people of European and northern Asian ancestry.
  • Selection may also play a role in determining susceptibility to several common diseases. This is another reason why geneticists would like to identify genes that have undergone selection. For example, the “thrifty gene” hypothesis holds that natural selection favored being able to put weight on quickly when food was abundant to tide humans through periods of scarcity. Now that humans in many areas of the world have access to virtually unlimited amounts of food, genetic variants associated with this trait may be contributing to an epidemic of obesity and diabetes.
  • Pritchard and his colleagues set out to answer a fundamental question facing human geneticists: Is it possible to determine which genetic variants have increased because of selection and which have increased because of population changes or genetic chance? New data that became available last year from the Human Genome Diversity Project at Stanford University provided a much denser sampling of worldwide genetic differences than was previously available. Pritchard and his colleagues used this resource to carry out a new and more rigorous test for selection.
  • To determine whether the frequency of a particular variant resulted from natural selection, Pritchard and his colleagues compared the distribution of variants in parts of the genome that affect the structure and regulation of proteins to the distribution of variants in parts of the genome that do not affect proteins. Since these neutral parts of the genome are less likely to be affected by natural selection, they reasoned that studying variants in these regions should reflect the demographic history of populations. Genetic variants that have been influenced by selection, in contrast, should show different patterns of distribution.

  • Their analysis immediately identified known examples of selection, including those involved in determining skin pigmentation, resistance to pathogens, and the ability to digest milk as an adult, the last is a trait that arose in Europe, the Middle East, and Africa following the domestication of dairy animals. The study also revealed several genes of unknown function that appear to have been under strong selective pressures. “We’re keen to learn what these genes are and how they work,” says Coop, who was the lead author on the PLoS Genetics paper.
  • In the next few years, a wealth of new data will become available to investigate these questions. For example, the 1000 Genomes Project, supported by the Wellcome Trust Sanger Institute and the National Human Genome Research Institute, is seeking to produce the complete DNA sequences of more than a thousand people from around the world.

Friday, June 5, 2009

Allergies May Prevent Some Cancers

http://www.accessibility.com.au/news/allergies-may-prevent-some-cancers
  • There may be a silver -- and healthy -- lining to the miserable cloud of allergy symptoms: Sneezing, coughing, tearing and itching just may help prevent cancer -- particularly colon, skin, bladder, mouth, throat, uterus and cervix, lung and gastrointestinal tract cancer, according to a new Cornell study.
  • These cancers, interestingly, involve organs that "interface directly with the external environment," said Paul Sherman, Cornell professor of neurobiology and behavior, who led the study. He and colleagues analyzed 646 studies on allergies and cancers published over the past 50 years, putting together "the most comprehensive database yet available" on allergies and cancers.


  • The study revealed "a strong relationship" between allergies and cancer in environmentally exposed tissues, Sherman said. This relationship seldom exists, he noted, between allergies and cancers of tissues that are not directly exposed to the environment, such as cancers of the breast and prostate, as well as myelocytic leukemia and myeloma.
  • Moreover, the study found that allergies linked to tissues that are exposed to environmental factors -- eczema, hives, hay fever, and animal and food allergies -- were most strongly associated with lower rates of cancers in exposed tissues.
  • The study, co-authored with Erica Holland '05 (now a medical student at the University of Massachusetts) and Janet Shellman Sherman, a Cornell research scientist and lecturer in neurobiology and behavior, is published in the December issue of The Quarterly Review of Biology (83:4).
  • Sherman believes that allergy symptoms may help protect against cancer by shedding foreign particles from the body. Some of those particles, he said, might be carcinogenic or carry carcinogens.


  • "The idea is that the immunoglobulin E system (which is widespread among mammals) and its associated allergy symptoms serve a common prophylactic function," Sherman said, "namely engulfing in mucous and rapidly expelling pathogens, natural venoms and toxins and other potentially carcinogen-carrying antigens before they can trigger neoplasia [the abnormal proliferation of cells]."
  • Two cancers did not ostensibly fit with the pattern of allergies and lower rates of cancer in environmentally exposed tissues, Sherman noted. However, on closer examination, these "outliers were illuminating." Studies show that allergies are correlated with lower incidences of glioma and pancreatic cancer, which affect internal tissues. However, both glia (which participate in signal transmission in the nervous system, and whose stem cells are exposed to chemicals from the nasal epithelium via the olfactory tract), and pancreatic cells (which can be exposed to intestinal contents if the intervening sphincter malfunctions) "can sometimes come into direct contact with carcinogens from the external environment," Sherman said.
  • Asthma is linked to higher rates of lung cancer. Unlike other allergies, however, asthma reduces the ability to expel mucus, while other allergies facilitate mucous expulsion and are correlated with lower rates of lung cancer.
  • The hypothesis that allergies may protect against certain types of cancer because they promote the expulsion of toxins and carcinogen-carrying antigens is also consistent with studies that find that people who express allergy symptoms are less likely to have toxic chemicals in their bodies, Sherman said.
  • So should people routinely suppress all allergy symptoms with medications? Sherman said the jury is still out. However, allergies are not merely disorders of the immune system, but rather are the evolved front line of defense against certain parasites and cancers. In sum, allergic reactions may be like fevers and morning sickness: uncomfortable responses that survived natural selection because they provided direct benefits.
Author: Blaine Friedlander
Source: Cornell
Country of Origin: US
Date originally Published: 12-Nov-08
Date added to Accessibility: 13-Nov-08

Macrophage Isolation: When things get cloudy

http://www.scientistsolutions.com/
by Heather Buschman
  • Macrophages are dedicated phagocytes that love nothing more than seeking out infection or inflammation and gobbling up bacteria, dead cells, and other debris. Once activated, these innate immune defenders also release chemokines and cytokines that trigger an inflammatory cascade.
  • In the lab, macrophages are used to test all kinds of things, from phagocytosis to trans-endothelial migration. One of the most common ways to obtain macrophages is to elicit them from the mouse peritoneum. First, healthy mice are injected intraperitoneally (i.p.) with 3 mL of 3-4% thioglycollate. This causes inflammation, triggering monocyte differentiation and localization to the body cavity. Thus, this method results in a higher yield of macrophages than techniques that rely on collecting only resident macrophages. However, thioglycollate-derived macrophages are “activated”, and therefore are not appropriate for every experiment. (Alternatively, murine monocytes can be collected from the bone marrow and differentiated into macrophages, with high yields and little activation.)
  • After 3-5 days, the thioglycollate-injected mice are sacrificed, injected i.p. with 5-10 mL of sterile, ice cold phosphate buffered saline (PBS), and gently massaged. Then the skin is carefully snipped and peeled back to reveal the intact peritoneum, distended with fluid. At this point, a large gauge needle and syringe are used to draw back out as much of the injected PBS as possible, without disturbing the membrane or organs. This extraction should be cloudy with white cells, but mostly free of red blood cells. Keeping this solution cold, the cells are gently centrifuged and rinsed with fresh cold PBS several times before resuspending in tissue culture media.
  • As discussed in the mouse peritoneal macrophages isolation forum at Scientist Solutions®, the easiest method for separating the macrophages from the other white blood cells is by simple adherence. When plated in a tissue culture dish, the macrophages will stick overnight and the rest of the cells can be rinsed away the next day. To increase macrophage yields, several posters suggest “aging” the thioglycollate. Nobody seems exactly sure why, but everyone agrees that autoclaved thioglycollate stored for a week to several months just works better. Some forum participants also report better results extracting with 16-30% sucrose rather than PBS.
  • What’s your preferred technique? Do you have experience with bone marrow-derived macrophages? The Scientist Solutions community wants to know.

Thursday, June 4, 2009

Hydrogen Peroxide Marshals Immune System

http://www.newswise.com/articles/view/552963/?sc=swhn

MULTIMEDIA
http://hms.harvard.edu/public/video/tm_060309.mov 

PRINCIPAL INVESTIGATOR
Timothy Mitchison, professor of systems biology, Harvard Medical School, http://mitchison.med.harvard.edu/

  • Using the zebrafish as an animal model, researchers in the lab of Harvard Medical School professor of systems biology Timothy Mitchison and Dana Farber Cancer Institute professor Thomas Look have discovered that when the tail fins of these creatures are injured, a burst of hydrogen peroxide is released from the wound and into the surrounding tissue. Teams of rescue-working white blood cells respond to this chemical herald, crawl to the site of damage, and get to work. 
  • These findings are reported in the June 4 issue of the journal Nature. 
  • Philipp Niethammer, a postdoc in Mitchison’s lab, and Clemmens Grabber, a postdoc in Look’s lab, initiated this research project with no interest in wound healing. Rather, they were studying a groups of molecules called reactive oxygen species, or ROS. These small oxygen-derived molecules, of which hydrogen peroxide is one, have the potential to be both helpful and hurtful. Niethammer and Grabber were simply curious to find ways to detect ROS molecules in an organism. 
  • To do this, they took a gene engineered to change color in the presence of hydrogen peroxide and inserted it into zebrafish embryos. Once the embryos entered the larvae stage after a few days, this synthetic gene spread throughout the entire body, essentially “wiring” the fish so that any discreet location in which hydrogen peroxide appears would glow. 

    But how do you coax the fish to produce a reactive chemical like hydrogen peroxide in the first place? 

    Since white blood cells have long been known to produce hydrogen peroxide, one obvious way to initiate chemical production would be to inflict a small wound onto the fish, and then, using microscopy, observe patterns of this chemical as white blood cells gathered around the wound. But much to the researchers surprise, they found that hydrogen peroxide immediately appeared at the wound site, prior to the arrival of any white blood cell, and quickly disseminated into neighboring tissue. 

    They repeated the experiment, this time in zebrafish where they’d disabled a protein that was previously discovered to produce hydrogen peroxide in the human thyroid gland. Not only did hydrogen peroxide not appear at the wound site, but white blood cells failed to respond to the injury. 

    “This was our real eureka! moment,” says Niethammer. “We weren’t too surprised that we could block hydrogen peroxide production through this technique, but what we didn’t expect at all was that white blood cells wouldn’t respond. This proved that the white blood cells needed hydrogen peroxide to sense the wound, and move towards it.” 

    Of course, zebrafish are not people, and while our genomes share many similarities with these tiny fish, it isn’t yet clear that natural selection has conserved this process throughout the evolutionary family tree. Still, these findings offer something of a conceptual shift in how to view human conditions where hydrogen peroxide plays a role. 

    “When we look at how hydrogen peroxide works in people, this really starts getting intriguing,” says Mitchison. 

    In the human body, hydrogen peroxide is produced primarily in three places: lung, gut, and thyroid gland. Because hydrogen peroxide, and the proteins responsible for producing other ROS molecules, are especially present in lung and gut, the researchers hypothesize that human diseases relevant to these findings would include any in the lung and gut that involve disproportionate levels of white blood cells, like asthma, chronic pulmonary obstruction, and some inflammatory gut diseases. 

    “Our lungs are supposed to be sterile; our guts are anything but,” says Mitchison. “It’s very logical that both those tissues produce hydrogen peroxide all the time. Perhaps in conditions like asthma, the lung epithelia is producing too much hydrogen peroxide because it’s chronically irritated, which, if our findings translate to humans, would explain inappropriate levels of white blood cells. This is certainly a question worth pursuing.”

How Trivial DNA Changes Can Hurt Health

http://www.scientificamerican.com/article.cfm?id=the-price-of-silent-mutations&sc=WR_20090602

  1. Scientists long assumed that any DNA mutation that does not change the final protein encoded by a gene is effectively “silent.”
  2. Mysterious exceptions to the rule, in which silent changes seemed to be exerting a powerful effect on proteins, have revealed that such mutations can affect health through a variety of mechanisms.
  3. Understanding the subtler dynamics of how genes work and evolve may reveal further insights into causes and cures for disease.
  • Alterations in DNA can make people sick. The classic view assumed that what are termed “silent” mutations were inconsequential to health, because such changes in DNA would not alter the composition of the proteins encoded by genes.
  • Single-letter changes to the DNA, known as point mutations, can therefore change a codon to one that specifies the wrong amino acid (known as a missense mutation) or to a stop signal (nonsense mutation), causing the final protein to be truncated. A single-base change can also alter a stop codon so that it then encodes an amino acid (sense mutation), resulting in a lengthened protein. And a final change is possible: a mutation that alters a nucleotide but yields a synonymous codon. These mutations are the ones termed “silent.”
  • Examples certainly abound of the first three types of point mutations having a major impact on human health. Three different point mutations in the genes encoding proteins that make up the hemoglobin molecules in red blood cells are responsible for three separate and grave diseases, for instance. In the case of sickle cell anemia, a missense mutation exchanges a water-loving (hydrophilic) amino acid for a water-avoiding one (hydrophobic), causing the proteins to clump together and produce characteristic sickle-shaped blood cells. In polycythemia disorders, a nonsense mutation truncates one of the hemoglobin proteins, resulting in thickened blood. And in thalassemia, a sense mutation changes a stop codon (TAA) to the codon for glutamine (CAA), creating a much longer and nonfunctional protein.
  • When the bacterium Escherichia coli specifies the amino acid asparagine, for instance, the codon AAC appears in its DNA much more often than AAT. The reason for this biased usage of codons soon became apparent: cells were preferentially employing certain codons because those choices enhanced the rate or accuracy of protein synthesis.

  • It turned out that tRNAs corresponding to those synonymous codons typically are not equally abundant within the cell. Most important, then, a gene that contains more of the codons matching the relatively abundant tRNAs would be translated faster, because the higher concentration of those tRNAs would make them more likely to be present when needed. In other cases, a single tRNA variety matches more than one synonymous codon but binds more readily to one codon in particular, so the use of that codon maximizes the accuracy of translation. Consequently, a cell has good reasons not to use all codons equally. As expected, in bacteria and yeast the genes that encode especially abundant proteins exhibit the greatest codon bias, with the preferred codons matching the most common or better-binding tRNAs.
  •  Analyses of mammalian genes did indeed reveal tendencies toward favoring certain codons. The similarity between simple organisms and mammals, however, proved to be only superficial. For reasons not yet fully understood, mammalian genomes are organized into large blocks, each with a distinctively skewed nucleotide content: some regions are rich in G and C bases, whereas others are enriched for A and T. As a result, genes residing in a GC-rich region of the genome tend to have many codons containing those bases. Our genes, then, do show a bias for using certain codons, but unlike simpler organisms, the mammalian pattern does not obviously suggest that the reason is to optimize protein synthesis.



Small Molecules Mimic Natural Gene Regulators

http://www.newswise.com/articles/view/553034/?sc=swhn

  • Scientists at the University of Michigan and the University of California  at Berkeley have taken a step forward on that route by developing small molecules that mimic the behavior and function of a much larger and more complicated natural regulator of gene expression. The research, by associate professor of chemistry Anna Mapp and coworkers, is described in the current issue of the journal ACS Chemical Biology.

  • Molecules that can prompt genes to be active are called transcriptional activators because they influence transcription---the first step in the process through which instructions coded in genes are used to produce proteins. Transcriptional activators occur naturally in cells, but Mapp and other researchers have been working to develop artificial transcription factors (ATFs)---non-natural molecules programmed to perform the same function as their natural counterparts. These molecules can help scientists probe the transcription process and perhaps eventually be used to correct diseases that result from errors in gene regulation.
  • Both natural transcriptional activators and their artificial counterparts typically have two essential parts: a DNA-binding domain that homes in on the specific gene to be regulated, and an activation domain that attaches itself to the cell's machinery through a key protein-to-protein interaction and spurs the gene into action. The researchers wanted to know whether their ATFs attached to the same sites in the transcriptional machinery that natural activators did.

  • In the current work, the team showed that their ATFs bind to a protein called CBP, which interacts with many natural activators, and that the specific site where their ATFs bind is the same site utilized by the natural activators, even though the natural activators are much larger and more complex. 
  • Then the researchers altered their ATFs in various ways and looked to see how those changes affected both binding and ability to function as transcriptional activators. Any change that prevented an ATF from binding to CBP also prevented it from doing its job. This suggests that, for ATFs as for natural activators, interaction with CBP is key to transcriptional activity.


  • "Taken together, the evidence suggests that the small molecules we have developed mimic both the function and the mechanism of their natural counterparts," said Mapp, who has a joint appointment in the College of Pharmacy's Department of Medicinal Chemistry. Next the researchers want to understand in more detail exactly how the small molecules bind to that site. "Then we'll use that information to design better molecules."

  • Funding was provided by the National Institutes of Health, the National Science Foundation, Novartis, the U-M Chemistry Biology Interface Training Program, Wyeth and the U-M Pharmaceutical Sciences Training Program