Wednesday, January 25, 2012
Ship : Costa Concordia
On
the night of Friday, January 13 2012, the luxury cruise ship Costa
Concordia ran aground off Isola del Giglio, Italy. Of the more than
4,200 aboard, 13 have been confirmed dead, 64 injured, 20 remain
missing, and hopes of finding any more survivors are fading quickly.
Untargeted metabolic profiling implicates a new suite of metabolites that may be involved in nerve damage-induced pain.
By Jeffrey M. Perkel |
A rendition of the bioinformatics analysis
superimposed between two neurons. Combined with the METLIN metabolite database,
the analysis ultimately revealed DMS as a naturally occurring metabolite and as
an active molecule in chronic pain.Gary Siuzdak and Gary
Patti
An analysis of the metabolic profile of a rat model of chronic pain has
identified novel dysregulated metabolites that may underlie the condition,
according to a study published today (January 22) in Nature Chemical
Biology. If the results hold up in humans, one of these metabolites, which
has not previously been associated with neuropathic pain, could potentially
serve as both a molecular indicator of and therapeutic target for the condition,
for which few treatment options exist.
The findings are “a great example of how metabolomics is leading to novel
insights into, in this case pain, and how that’s mediated,” said Lloyd Sumner, a
metabolomics researcher at the Samuel Roberts Noble Foundation who was not
involved in the research.
In the United States, more than 30 percent of adults suffer from chronic pain
of one form or another. Neuropathic pain is a form of chronic pain induced by
previous nerve damage, like the phantom pain felt by those who have lost limbs.
“Neuropathic pain is the worst,” because it’s the hardest to treat, said Gary
Patti, an assistant professor at Washington University in St. Louis and lead
author of the study. “It is a disease with an unmet medical need.”
While a research associate at the Scripps Research Institute in La Jolla,
California, Patti and his then-research advisor, Gary Siuzdak, senior director
of the Center for Metabolomics and Mass Spectrometry and professor of Chemistry
and Molecular Biology at Scripps, used an animal model of the condition, in
which rats are subjected to tibial nerve transection (TNT)—that is, the tibial
nerve in one leg is severed and allowed to heal. Three weeks later, these
animals apparently continue to experience pain, though the wound itself has
healed.
Rather than studying the genes involved, or the proteins they encode, the
researchers identified instead potential metabolic players in this response.
Metabolites, after all, are the ultimate molecular arbiters of biological
function, the molecules upon which proteins often act.
The team used an approach called untargeted metabolomics to profile the
metabolites at the site of injury, the neural cell body of the damaged nerve,
the dorsal horn (where the damaged nerve connects to the spinal cord), , and in
the blood. It was essentially a molecular fishing expedition—collecting
boatloads of data that can point to molecules that may be involved.
“We are seeing many more metabolites than can be accounted for by the
canonical pathways in biochemistry textbooks,” Patti said. “The untargeted
approach allows us to explore that space.”
In total, the team observed some 733 mass spectrometric peaks whose levels
varied at least 2-fold between control and TNT animals. The vast majority of
them were localized not at the site of injury, but at the dorsal horn of the
spinal cord. In particular, the researchers noticed differential expression of
several members of the sphingomyelin-ceramide pathway, a lipid metabolic pathway
linked to, among other things, myelin formation and programmed cell death. “That
screamed at us that this pathway was important,” Siuzdak said.
The team then tested these different molecules directly to see whether they
could induce a pain response on their own. Indeed, one such metabolite, called
N,N-dimethylsphingosine (DMS), induced symptoms akin to
neuropathic pain when injected directly into the animals at comparable
concentrations to those found in TNT rats a few weeks after injury. The authors
also determined that DMS may function by activating astrocytes, inducing them to
release cytokines such as IL-1beta and MCP-1, both of which are associated with
inflammation and pain.
If validated in humans, DMS could potentially serve as a biomarker of for
neuropathic pain, Sumner said. Furthermore, “by defining specific molecules
involved in the pain response, [the finding] also provides a pathway for
mediating the pain management,” he added. “If they can mediate how those
molecules are made and modify that with inhibitors or other medications, then
the opportunity for pain management is substantial.”
Indeed, Siuzdak calls his approach “therapeutic metabolomics.” “You survey
the pathways, find molecules that are dysregulated, and then find enzymes that
produce those molecules. We are currently trying to figure out explicitly what
enzyme produces DMS, because that’s a much more specific target.”
(See this
month’s feature article on other efforts to manage chronic pain.)
G.J. Patti et al., “Metabolomics implicates altered sphingolipids in
chronic pain of neuropathic origin,” Nature Chemical Biology, DOI:
10.1038/nchembio, 2012.
Source: TheScientist
Posted by
Robert Karl Stonjek
Scanning the Psychedelic Brain
Brain scans reveal the surprising secret of magic mushrooms’ hallucinogenic effect.
Psilocybin cubensis mushroomFlickr,
Kristie
Gianopulos
The geometric visuals and vivid imaginings experienced by those tripping on
mushrooms are not, as scientists had suspected, the result of increased brain
activity, according to a report out today (23 January) in Proceedings of the
National Academy of Sciences. Instead, under the influence of
psilocybin—the psychedelic component of magic mushrooms—brain activity and
connectivity decrease. The reduced connectivity might be what frees people’s
minds from normal constraints, the researchers propose.
“It was often thought to be the case that these classic hallucinogens must
increase brain function—you know, they expand awareness, expand
consciousness—but in fact what we see is decreased activity,” said Roland
Griffiths of Johns Hopkins Bayview Medical Center, who was not involved in the
study.
“I have to say this was totally unexpected,” said David Nutt of Imperial
College London, who led the study. But, he added, “when you get exactly
the opposite result to what you predict, you know it is right, because there is
no bias.”
Although humans have used magic mushrooms for centuries if not millennia,
very little is known about how they work. Soon after psychedelics gained
widespread popularity in the 1950s and 60s, “the drugs were criminalized and the
research into their beneficial uses was suppressed,” explained Rick Doblin of
the Multidisciplinary Association for Psychedelic Studies, which partly funded
the study.
Because of psilocybin’s illegality, organizing and performing the new study
was a regulatory ordeal, said Nutt. “You have to go through lots of hoops and
get special licenses. You’ve got to have special cupboards and fridges to hold
it… it’s a real rigmarole.”
There was also the ethical concern that the volunteers might experience a
so-called bad trip. Although psilocybin is generally associated with feelings of
euphoria and human connectedness, it can sometimes cause anxiety. Should this
have happened, Nutt explained, the person would have been kept safe, calmed
down, and if necessary, given Valium. To lessen the chance of a bad experience,
all 30 volunteers were chosen on the basis that they had taken hallucinogens at
least once before and so would know what to expect.
It was worth all the effort, said Nutt. Psychedelics offer not only insight
into the biology of human perception and cognition, but may also be of
therapeutic use. And, as it happened, he added, “they all had a good
experience—some had very good experiences, some had experiences they said were
very meaningful and altered the way they thought about life.”
Nutt and his team administered psilocybin to the volunteers by a slow—one
minute long—injection while their brains were scanned by functional magnetic
resonance imaging (fMRI). “We wanted to know exactly what happens when you make
that transition from the normal state to the psychedelic state,” he
explained.
The first 15 volunteers had their brains scanned by arterial spin labeling
(ASL), an fMRI technique that examines blood flow. After seeing widespread
decreases in flow, the researchers were so surprised they scanned a further 15
volunteers by blood-oxygen level dependent (BOLD) fMRI, which more directly
measures metabolism. Both gave strikingly similar results.
Brain blood flow and activity were particularly decreased in the medial
prefrontal cortex—a region involved in emotions, learning, memory, and executive
function—and the posterior cingulate cortex, the function of which is less
clear.
The team also used the fMRI data to look at functional connectivity between
these two regions over time, and found that their deactivation was linked.
“Assessing circuitry in terms of connectivity is a more sophisticated and
informative approach to understanding function, so I think that is the real
strength of their work,” said Mark Geyer of the University of San Diego,
California, who did not participate in the study.
The two regions are connected by the default mode network (DMN), which
integrates brain functions including sensations, memories, and ambitions. “It’s
kind of who you are and how you see the world,” said Nutt. The DMN might also
act as a cognitive constraining mechanism—to filter and make sense of
information. Reduced DMN activity, therefore, might enable an unconstrained mode
of cognition, such as that experienced on a magic mushroom trip.
Interestingly, DMN activity is hyperactive in people with depression,
suggesting that psilocybin may be effective as a depression treatment.
Taking a hallucinogen to deal with depression might not appeal to everyone.
But for those willing to give it a try, the hope is that the need for all
medication might be reduced or even eradicated. “Psilocybin would only be given
a few times under supervision of a therapist…with the hope that at the end of
the process you are no longer dependent on a daily medication,” explained
Doblin. “It would be like opening a door and showing them that there is another
way of being,” said Nutt.
R.L. Carhart-Harris et al., “Neural correlates of the psychedelic
state as determined by fMRI studies with psilocybin,” Proceedings of the
National Academy of Sciences, doi/10.1073/pnas.1119598109,
2012.
Source: TheScientist
Posted by
Robert Karl Stonjek
Password Change
“To
surpass the influence of the illusory energy is very difficult, but
those who are determined to catch hold of the lotus feet of the Lord are
freed from the clutches of maya.” (Shrila Prabhupada, Chaitanya
Charitamrita, Adi 3.89 Purport)As if we are Pavlov’s dog requiring specific training to follow certain actions, repeatedly taking the wrong tact and seeing the negative response is required before we can actually change our behavior. If it weren’t for the negative reactions and our dislike for them, the pattern of behavior would never change. And the change is necessary in order for a higher purpose to be fulfilled. In the absence of the change we’re just wasting time torturing ourselves. The repetitive pattern actually can teach us a lot about the makeup of the world, how the Supreme Controller has perfectly arranged everything for our benefit and how we can use objects around us to further the highest end.
While it’s nice to ponder these concepts theoretically, a practical example is more helpful. Staying in tune with the modern times, the password change suffices, especially that instituted by the managers of an IT infrastructure. If you work in an office these days, you are likely using a computer. A computer uses a system that requires authentication; otherwise any person could sit at your desk and pretend to be you. With authentication comes the ability to track performance and progress, to see if the person sitting at the desk is actually doing the work assigned to them.
In
a computing environment, it is common to have sensitive data,
information that not just anyone should have access to. Hence to
facilitate the authentication and data protection requirements, each
end-user is assigned a login and password combination. The password is
where things get tricky. It is specific to each person and it is so
sensitive that under an ideal setup, the system itself won’t know what
your password is. Should you happen to forget it, the system will allow
you to create a new one, which is stored internally with some sort of
hash applied to the original characters. If your password is say
“Krishna”, the system will perform a hash function to the characters in
the word and maybe store the password as a bunch of unrelated
characters.There is no explicit way to retrieve the crypted password, for the hash function operates only on input. Therefore the only way to get the password is to repeatedly make attempts into the hash function to see if what you entered matches what is stored in the system. Bearing this in mind, a properly implemented system will place a limit on the number of login attempts that you can make. Otherwise one could easily perform what is known as a “dictionary” attack, wherein an automated system tries many combinations of letters and numbers until a correct login is made.
In addition to the limit on the number of failed login attempts, there are specific requirements for what a password can be. In ideal setups, this policy is implemented across the system, which means that even the highest person managing the company has to follow the rules and regulations. Your password likely has to have characters, both upper and lower case, and numbers. The password must also be a minimum length, for the longer the password, the more difficult it is to break or guess.
Here comes the kicker. This last requirement is probably the most annoying for the user. In addition to the length and character requirements, the password must be changed periodically, perhaps every month. This shouldn’t be too difficult, right? Have two passwords that you normally use and just rotate them every month? Ah, but the system is one step ahead of you. You cannot reuse any password that you have used recently. Therefore you really have to come up with a unique password each month, something which you may not even remember so quickly.
This rule is helpful for obvious reasons. Say that you decide to give your login credentials to a friend one time because you’re not at your computer, or perhaps you wrote down your password somewhere on a note placed on your desk. The biggest issue with having secrets is keeping them secret. This especially applies to the password, which is the secret of secrets. Should someone get ahold of your password and have nefarious motives, they could do a lot of damage to the system. The longer that secret stays valid, the greater the chances of a security breach. With the requirement for periodic change, if someone should happen to find your password, they only have a short time to use it, which greatly limits the chances of a violation occurring.
For the end user sitting at the computer regularly, authenticating all the time, the password change every month is beyond annoying. Why is this? If you can touch type - that is type without looking at the keys on the keyboard - the entering in of the password essentially turns into a muscle memory operation. You can likely type your password faster than you can verbalize it. If you had to write down your password, you might have difficulty, for it is your fingers that have memorized it more than your mind. Now that you have a changed password, the next time you go to authenticate, you will surely first enter the most recent password that just expired.
The immediate reaction to this behavior will be an invalid password warning flashing up on the screen. Since the password is so long and the characters masked on the screen, you try to enter it again really quickly, only to have the same message come up. Now the pressure is on. You have one more attempt to log into your account before you are locked out for having reached the failed account login threshold. This time you carefully type the letters, remaining conscious of the keys you are pressing. Whew! You made it. You can now use your computer with your login. You weren’t doing anything wrong before, but somehow the machine treated you like a criminal.
What’s probably more annoying is that you have to follow the same tact repeatedly, at least for a day or two, before your muscles get used to the new password. If not for the stern warnings and the fear of having your account locked out, you would never change your behavior to account for the new password. In this sense the warnings train you, sort of like shock treatments. As if you were a dog that was learning how to relieve himself at the proper time, the machine, for your own safety, to protect your data and identity, trains you every month to use a new password.
“Unseen and indefinite are the good and bad reactions of fruitive work. And without taking action, the desired fruits of such work cannot manifest.” (Lakshmana speaking to Lord Rama, Valmiki Ramayana, Aranya Kand, 66.17)
What
does this mean in the grand scheme of things? The entire world is
filled with smaller and larger versions of the interaction with the
authentication system on the computer. For every action there is a
reaction. This is how karma, or fruitive activity, works. As Shri Lakshmana
so nicely states in the Ramayana, there are both good and bad reactions
to work, pious and sinful activity, and the results are not always
immediately seen. They may not remain manifest for long either.
Nevertheless, for every reaction seen, there is an initial cause, some
work which was applied.Knowing this information is only helpful if we can use it to change our behavior. We should follow actions that will effect changes that are worthwhile. At the same time, we should avoid behaviors that produce negative reactions. Ah, but here is where things get interesting. How will we know which reactions are bad? How will we know which consequences are worth avoiding?
The easiest way is to accept the information from authority figures, those who learned the relevant truths through either their own experience or through the words of wisdom passed down from previous authority figures. Our parents can tell us during childhood to not place our hand in a fire. At such a young age, we have no clue what fire is or that it will burn our hand, so if we follow the advice of our parents, we acquire perfect knowledge of something to avoid. The other option is to try it out ourselves, to feel the sting and then hopefully have it register that the same reaction will occur again and again, each and every single time the same action is repeated.
The latter option is the more painful one, as there is no guarantee of how quickly the proper knowledge will be acquired. For the larger picture, the entire duration of existence within a human body, the Vedas, the scriptural tradition of India, provide information about which activities to avoid and how they relate to the ultimate mission in life. Of the harmful activities, the most sinful, or detrimental towards the achievement of the end goal, are meat eating, gambling, intoxication and illicit sex.
Not to be misunderstood as restrictions meant to punish us or keep us from having fun, the negative reactions from these behaviors are visible even if we should ignore the warnings of the Vedas and the people who teach Vedic wisdom to others. Meat eating is harmful not only because of the detrimental health effects, but also because of the violence that goes into it. In a system of fairness, with no partiality applied by any governing agent, if one side is killed unnecessarily just for the satisfaction of taste buds which can be pleased through so many other areas, the same reaction must be imposed on the killer at some point in the future. In addition, through unnecessary violence, mankind loses his merciful attitude, his ability to harbor compassion. Killing innocent cows without discrimination makes it easy for man to kill innocent babies, confiscate wealth, and have an overall vindictive attitude towards their fellow brothers and sisters. This last attitude is the root cause of all strife in the world, and since it is a byproduct of a contaminated consciousness, we see that meat eating becomes one of the causes for wars and conflict.
The
harmful effects of gambling are quite obvious. The mind feverishly
engages in games and wagers for hopefully winning sums of money that
don’t provide any happiness at all. People’s lives can get ruined by
gambling, as there are support groups to help those with gambling
addictions. The same defect is present in intoxication, as the false
escape from the senses brings tremendous negative effects on one’s
health. Drunk driving is eliminated through abstention from consuming
alcohol, as are so many other negative consequences.Illicit sex brings the most lasting and visible negative effects. If sex urges driven by lust are not controlled, you can get attachments and burdens that you don’t expect. You also remain beholden to an urge that is easily satisfied in the lower species. The monkeys and dogs have sex life without discrimination, so how can imitating their behavior be worthwhile for a human being with advanced intelligence?
The negative reactions resulting from these sinful behaviors are actually a great blessing. Just as the warnings from the invalid entry of the password helped to change our behavior for the better, the harmful sequence of negative effects arriving from impious acts are meant to change the way that we act, to keep us on the straightened path. The Vedas reveal that the precious human form of body is meant for realizing God, the ultimate reservoir of pleasure. Every ritual, regulation, restriction, and recommendation is intended to further that highest aim.
The knowledge coming from Vedic teachings is necessary; otherwise man remains lost like the animals. Thankfully for us, there is one tool that is so powerful that it automatically carries with it sublime wisdom. It brings peace of mind at the same time, which helps steer us clear of the dangerous path of impiety. That tool is the chanting of the holy names, “Hare Krishna Hare Krishna, Krishna Krishna, Hare Hare, Hare Rama Hare Rama, Rama Rama, Hare Hare”. In this age where sin is taken to be piety, where the end-goal of life remains unknown, a positive action is required to teach the highest truths. Repeated negative consequences resulting from sinful behavior can help us gain knowledge of what to avoid, but even with that, the soul needs a constitutional engagement, an area to go where pleasure is found.
The
holy name is that area, as it carries the forms, pastimes and qualities
of the Supreme Personality, who is known as Krishna because of His
sweetness. Krishna’s words spoken in the Bhagavad-gita are sweet, as are His dealings with the cowherd women of Vrindavana.
Krishna’s portrait is sweet, with its peacock feather, beautiful smile,
and flower garland. Krishna’s material energy can also be viewed as
sweet, for she purposefully makes life here difficult so that the wise
will find the loving embrace of Shri Krishna awaiting them in the next
life, in the spiritual sky where no one requires training in their
actions, as they are all driven by the most beneficial attachment to
Shri Krishna’s service.Every month or so password must change,
Has to be new, not within recent range.
Old password entered through memory of muscle,
But with change system gives user much trouble.
The fear of losing access a good thing,
Reason to change behavior it does bring.
In same way forces of nature teach,
That for higher purpose man should reach.
Don’t follow animals who satisfy with ease,
Opportunity for loving God fully seize.
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