Projo Follies

Here is another letter that I sent to the Journal. Lomborg's "science" required a response, but sadly went unanswered as does most of the junk science that fills the Ptojo's op-ed pages.

The Journal's attack on a much respected scientist with unimpeachable credentials while praising a charlatan continues your paper's long and meritorious tradition of promoting scientific illiteracy. According to your op-ed piece ( " The Zealous Holdren", March 8th, 2009) John Holdren, President Obama's science advisor, participated in the equivalent of an academic lynching by holding Bjorn Lomborg author of "The Skeptical Environmentalist" accountable for a polemic of politicized science that pandered to a niche market of conservatives and business. Lomborg's book, thinly disguised as science, is filled with gross distortions and simplifications of complex issues. Lomborg's sloppy scholarship, disingenuous advocacy, and muddled interpretations and explanations resulted in very negative reviews in Nature, Science ( peer reviewed journals), and Scientific American.

The Danish Commitees on Scientific Dishonesty ultimately found Lomborg's book " to fall within the concept of scientific dishonesty," and "clearly contrary to the standards of good scientific practice". Although, the accusations of "gross negligence" were dismissed, your claim that Lomborg had " achieved vindication" is misleading hyperbole and disingenuous.

We will only solve our many looming environmental problems with an informed public. Providing your readers with authentic information is your duty and responsibility. I fervently hope that your paper will help "restore science to its rightful

Censorship at the Projo

This is one of many letters I have sent to the Providence Journal over the years that have not been published. Generally, I am responding to a point of view that is filled with errors or is simple at odds with the scientific or historical rendering of factual information.I sent a copy of this letter to Rabbi Shafran, a frequent contributor, to the Journal, without reply.


Rabbi Shafran’s editorial (Providence Journal, February 25) demonstrated with “tasty irony” his many misconceptions about Darwinian natural selection. For example, living organisms do not “ forever remain mere works in progress”. Most species disappear over time because they failed nature’s harsh testing regimen. Good ideas as represented by genes increase in frequency because they enhance a species chances of survival. Most random mutations, however, are neutral, or deleterious. Good ideas are replicated while bad ideas end up in the fossil record.

The notion that the good Rabbi and others want to “permit an open discussion of Darwinism” in order to promote critical thinking is disingenuous. Why not use the same arguments to assess the “strengths and weaknesses” of the theory of gravitation, or germ theory, or whether our President committed impeachable offenses and war crimes by subverting the Constitution and launching the illegal war in Iraq. The point is that there are numerous topics which can be used to engage students. However natural selection always seems to be at the top of the list among the Intelligent Design evangelicals. The tactics always evolve some new twist or variation on the theme, but the motivation is always the same; to bring religion into the science classroom.

Rabbi Shafran’s glib assertion that hubris is the cause of what he refers to as “scientific orthodoxy” sadly eludes common sense. On the contrary science is based on evidence and testable hypotheses. It seems far more likely that hubris is an essential ingredient in religions that require no evidence for belief and rely only on faith to inform their reality. As Robert Pirsig, author of Zen and the Art of Motorcycle Maintenance said, “When one person suffers from a delusion it is called insanity. When many people suffer from a delusion it is called Religion.”

Rabbi Shaffran also spoke of the scores of “intrepid biologists” among others as corroboration for his belief that there are “weaknesses in the theory of macro-evolution.” He never cites who these intrepid souls are nor does he bother to provide any examples of the putative weaknesses in the theory, but this is to be expected from those who are uncomfortable in an empirical world. As with the climate denial crowd it would be fairly easy to assemble a list of the “scores” of experts the Rabbi used mount his assault on poor Charles Darwin, hounded and beleaguered, even in death. Michael Behe, of Lehigh University and the Discovery Institute, a creationist, right wing, think tank would be the first on my list. Dare I say irreducible complexity.

Rabbi Shafran betrays his attempts to sound like a proponent of moderation when he writes that the limits of accepted science have been reached when they contradict “what we inherently know to be true”. Who we are remains unclear, but the implications of his absolutism are chilling. The Rabbi requires no evidence to ascertain the truth. We just know what is “inherently” true. Conversely, Rabbi Shafron must inherently know what is not true. Evolution no doubt falls into the latter category.

The faith based critical thinking skills Rabbi Shafron advocates for our students have nothing to do with science. The Rabbi’s ideas easily mesh with the political intrusions during the past eight years that have been nothing short of a war on public education. I would have far more respect for Rabbi Shafron’s inchoate ideas if he had learned a little biology in school and his essay did not “inherently” wreak of politics. Perhaps the disdain that Richard Dawkins expresses for those who do not believe in evolution is the result of too many encounters with those who would replace reason and scientific methodology with intractable superstition. I would also add that the pervasive anti-science bias resonating in Rabbi Shafron’s arguments have become an epidemic in contemporary America’s stampede to the bottom.

Wall Street and its Creepy Denizens

Wall Street and its Creepy Denizens
Naomi Klein writes that the 140 billion dollar stealth give away to the banking industry was done with bipartisan collusion and was an attempt to placate the the toxic little brat known as the stock market or Wall St. The tax package deals with how bank mergers are taxed ( more to be said on that later) and has long been a strenuously lobbied idea by the very industry whose leviathan greed without limits lending practices has brought the American economy to its knees and most surprisingly taken global economies with it in a freefall downward spiral. Apparently greed makes everyone just as stupid as the American corporate oligarchies. The timing of this "crisis" is remarkable in that it has allowed the Bush administration a free wheeling hand in solving the which has made fear the underlying catalyst for every policy it has sought to implement. As for assuaging the nerves of Wall st. criminals, who gives a shit. The stock market has been a roller coaster ride for years . Why? Because it is awash with 401 and pension dollars that are skimmed in regular cyles of "profit taking". It is only a matter of time before the plethora of packages to rescue the free and vibrant market economy includes social security privatization. Americans will buy the plan this time because it will be strenuosly marketed (pun absolutely intended with a pinch of sour irony) as the only thing left to prevent chaos in the golbal markets. In addition to Hank "the Wall Street prankster" Poulsons amazing 2 page analysis of the subprime meltdown in which he called for the original 800 billion dollar "rescue" package, the Federal reserve has doled out 2 trillion dollars in emergency loans to undisclosed entitites. With cavalier disregard for the American taxpayer,transparency has been scrapped for opacity as the people have no right to know how their money is being spent, what kind of criteria went into determining eligibilty for these loans, and what collateral, if any was required to secure the loan.It is always surprising how easily we forget that the government serves the people, actual living beings, instead of multinational corporations that have been granted more legal rights than American citizens. The most recent economic fiasco is strangely reminiscent of the legerdemain and alchemy that took place during the apex housing bubble when loans were made that required little more than a pulse. In Ohio twenty one mortgages were given to deceased home buyers. This does make some sense because afterall what right does the government have to demand anything from the private sector and the invisible hand of the undeniable miracle of free mrket capitalism? That would be socialism. That would be bad. That would be unAmerican. I do hope, at the very least, that all involved in the greatest scam ever told were wearing their American flag pins proudly on the lapels of their plutocrat vestments as the ink was drying and as the mad loot was doled out to the corporate welfare queens of global renegade capitalism and offshore bank accounts continued to swell like bloated blood sucking ticks.

A definition of patriotism should include all that is antithetical to the values of Wall St. and global capitalism.

Brocolli: The New Wonder Drug?

Brocolli: The New Wonder Drug?
Broccoli may undo diabetes damage
Eating broccoli could reverse the damage caused by diabetes to heart blood vessels, research suggests.
A University of Warwick team believe the key is a compound found in the vegetable, called sulforaphane.
It encourages production of enzymes which protect the blood vessels, and a reduction in high levels of molecules which cause significant cell damage.
Brassica vegetables such as broccoli have previously been linked to a lower risk of heart attacks and strokes.
Our study suggests that compounds such as sulforaphane from broccoli may help counter processes linked to the development of vascular disease in diabetes Professor Paul Thornalley University of Warwick
People with diabetes are up to five times more likely to develop cardiovascular diseases such as heart attacks and strokes; both are linked to damaged blood vessels.
The Warwick team, whose work is reported in the journal Diabetes, tested the effects of sulforaphane on blood vessel cells damaged by high glucose levels (hyperglycaemia), which are associated with diabetes.
They recorded a 73% reduction of molecules in the body called Reactive Oxygen Species (ROS).
Hyperglycaemia can cause levels of ROS to increase three-fold and such high levels can damage human cells.
The researchers also found that sulforaphane activated a protein in the body called nrf2, which protects cells and tissues from damage by activating protective antioxidant and detoxifying enzymes.
Countering vascular disease
Lead researcher Professor Paul Thornalley said: "Our study suggests that compounds such as sulforaphane from broccoli may help counter processes linked to the development of vascular disease in diabetes.
"In future, it will be important to test if eating a diet rich in brassica vegetables has health benefits for diabetic patients. We expect that it will."
Dr Iain Frame, director of research at the charity Diabetes UK, stressed that research carried out on cells in the lab was a long way from the real life situation.
However, he said: "It is encouraging to see that Professor Thornalley and his team have identified a potentially important substance that may protect and repair blood vessels from the damaging effects of diabetes.
"It also may help add some scientific weight to the argument that eating broccoli is good for you."
Story from BBC NEWS:http://news.bbc

Through Knowledge is the Power to Act

Caitlin's Page- Current Diabetes Research: Through Knowledge is the Power to act
Diabetes is a peer reviewed journal that publishes research on the cause and treatment of diabetes. This publication avoids the enervating pall of fear propagated by mainstream "advocacy" organizations and offers a focused vision of progress and hope through the empowerment of knowledge based on science.

http://diabetes.diabetesjournals.org/content/vol56/issue1/#ISLET_STUDIES

This article was published on the BBC website this morning. It discusses the results of a new study which found that brocolli can reduce and reverse the adverse effects of hyperglycemia. Brocolli is a good source of anti-oxidants which mitigate free radical damage to cells and tissues. See Tuesday's posting on vitamin C and cancer.
http://news.bbc.co.uk/2/hi/health/7541639.stm


Spleen cells from donor mice were unexpectantly found to transforn into islet cells that produce insulin according to a study from Mass. General Hospital.

http://news.bbc.co.uk/2/hi/health/3266987.stm

Cinnamon and Increased Glucose Metabolism

Cinnamon and Increased Glucose Metabolism
JJ's Abstract:
A study on the effects of of various plant extracts on sugar metabolism published in the ARS showed that cinnamon was the most effective in lowering serum blood sugar levels in type II diabetes.Hopefully, studies to determine if cinnamon will have the same effect in patients with type I diabetes are underway.

scientists and colleagues have isolated and characterized several polyphenolic polymer compounds from cinnamon bark that could one day become natural ingredients in products aimed at lowering blood sugar levels.
The newly identified chemical structures were recently named in a patent application and described in the Journal of Agricultural and Food Chemistry. ARS chemist Richard A. Anderson co-authored the study with colleagues at the Beltsville (Maryland) Human Nutrition Research Center and two universities.
Impaired sugar and fat metabolism is present in millions of people and may lead to type-2 diabetes and cardiovascular diseases. In test tube assays using fat cells, the polyphenolic polymers were found to increase sugar metabolism a whopping 20-fold.
Insulin is a hormone made by the pancreas to regulate sugar metabolism. In people with type-2 diabetes, either the pancreas doesn't make enough insulin or the body is unable to use it correctly. Both conditions lead to unhealthy blood levels of sugar that would otherwise provide energy to muscles.
During a decade of efforts to find natural compounds that could help maintain normal blood sugar levels, the scientists tested several components of cinnamon. The newly characterized chemical structures are closely related to a previously reported chemical derivative of cinnamon, MHCP—methylhydroxychalcone polymer. The researchers also tested scores of other plant extracts, but none displayed insulin-enhancing activity near that of cinnamon.
"These new compounds increase insulin sensitivity by activating key enzymes that stimulate insulin receptors, while inhibiting the enzymes that deactivate them," says Anderson, who is with the Nutrient Requirements and Functions Laboratory.
"Polyphenols are known for their antioxidant, anticancer, and anti-inflammatory functions, but they have not been commonly known to improve insulin function," he says. "The polyphenolic polymers in cinnamon bark have antioxidant effects, which may provide synergistic benefits to persons with various forms of diabetes."
Another recently published human research study from the team showed considerable improvements in glucose and fat metabolism in volunteers who followed a diet that included modest amounts of table cinnamon for 40 days.
Table cinnamon is made from cinnamon bark and contains both water-soluble and fat-soluble compounds. Fat-soluble compounds may accumulate in the body if ingested over a long period. At this time, there is no data on potential effects of long-term ingestion of table cinnamon. But the newly defined chemical structures noted above are isolated from water extracts of cinnamon and appear to be nontoxic in any quantity, according to Anderson.—By Rosalie Marion Bliss, Agricultural Research Service Information Staff.
This research is part of Human Nutrition, an ARS National Program (#107) described on the World Wide Web at www.nps.ars.usda.gov.

Thiamine Supplements and Kidney Disease

Thiamine Supplements and Kidney Disease
As more studies are published demonstrating the efficacy, or lack thereof, of vitamin supplements, it is time for the medical establishment to shed its institutional biases and learn from science. One would like to think that the medical field has state of the art science as its bedrock. Unfortunately, this is all too often not the case. Physicians have become too specialized in fields with narrowing perspectives and tunnel vision. To "practice medicine" is an apt description for practioners who do not stay current, are not required to stay current, and what little post medical school training they receive is often filtered through the myopic and self-serving lens of corporations trying to sell their latest miracle drug or high tech toy. I believe the quality of health care in this country would improve dramatically if physicians listened to their patients and read a lot more than they play golf or worry about their investment portfolio. Many benefits would also flow from a healthcare system that shifted its focus from doctors to patients, that vigorously affirmed the benefits of preventative healthcare, made the dignity and humanity of each patient a prominent clause in the Hippocratic oath, and that provided universal healthcare so that the sick could focus on healing rather than looming bankruptcy. No one who is sick should ever have to be afraid of losing their benefits because insurance companies only want to insure the healthy and not the sick. Profitability is not a bad word except when it deflects the vision of medicine to the bottom line rather than the affirmation of life and human creativity. When America makes healthcare a universal imperative because it is a decent and moral policy then I will begin to audaciously hope that we might one day live up to our professed creed.

Thiamine 'reverses kidney damage'
Doses of vitamin B1 (thiamine) can reverse early kidney disease in people with type 2 diabetes, research shows.
The team from Warwick University tested the effect of vitamin B1, which is found in meat, yeast and grain, on 40 patients from Pakistan.
The treatment stopped the loss of a key protein in the urine, the journal Diabetologia reports.
Charity Diabetes UK called the results "very promising" - but said it was too early for any firm conclusions.
The latest findings build on earlier work by the Warwick University team, showing that many diabetes patients have a deficiency of thiamine.
According to the researchers, this cheap and readily available supplement could benefit most people with diabetes - both type 1 and type 2 - as between 70% and 90% of people with diabetes are thiamine deficient.
In diabetes the small blood vessels in the body can become damaged.
When the blood vessels that supply blood to the kidneys are involved, the kidneys stop working correctly and important proteins, such as albumin, are lost from the blood into the urine.
A third of the patients in the study saw a return to normal urinary albumin excretion after being treated with high dose (300mg) thiamine taken orally each day for three months.
The experts say thiamine works by helping protect cells against the harmful effects of the high blood sugar levels found in diabetes.
Lead researcher Professor Paul Thornalley said: "This is the first study of its kind and suggests that correcting thiamine deficiency in people with diabetes with thiamine supplements may provide improved therapy for early-stage kidney disease."
They plan more work to confirm their findings.
Dr Iain Frame of Diabetes UK said: "Diabetes UK hopes a large clinical trial will be possible as results so far are very promising.
"However, we would like to stress that it's still too early to come to any firm conclusions about the role of vitamin B1 and we would not advise that people look to vitamin supplements to reduce their risk of kidney complications at this stage."
A person should be able to get all the thiamine they need from a normal healthy diet.

Priorities in a Sick Culture

Priorities in a Sick Culture or One Child Left Behind

When my daughter Caitlin was at Peace Dale Elementary School we asked that her glucose level be checked by the nurse before lunch on alternate days. At the time there was only one part time nurse in the school. The need for Caitlin to have her glucose tested before lunch was necessary to help maintain good control of her diabetes. Caitlin's physician at the Joslin Center in Boston determined that the midday numbers were essential for any possible change in the amount of insulin she required. My request, made several times, finally received a response from the superintendent at the time. He said to me during a phone conservation that my request was a "no can do, Jeff." Aside from the flippant and cavalier response, I was appalled that the school would put a child at risk, any child, and expose itself to considerable liabilty. As an employee of the SK School Department I naively believed that our schools would be outspoken advocates for the health and safety of our children. Sadly this was not true in my daughter's case. If you were the parent in this case, what would you do next?

School risk for diabetes children
The health of many children with type 1 diabetes is threatened due to poor care in primary schools, say campaigners.
Diabetes UK claims 6,500 pupils in England are not covered by school medication policies which ensure they get insulin injections when needed.
This means parents often need to visit during the school day to administer injections.
The charity wants ministers to force school inspectors to keep checks on the care of children with diabetes.
It is unacceptable for medication regimes to be changed to fit around school hours Douglas Smallwood Diabetes UK
Thousands of children in the UK have type I diabetes, caused by the sudden loss of insulin-producing cells in the pancreas.
Most are wholly dependent on regular blood testing and insulin injections to avoid severe complications - which can include diabetic coma and even death.
In the long term, poor control of diabetes can increase the risk of heart disease, stroke, kidney failure and amputation.
There is already evidence that blood glucose levels are poorly managed, with research in 2007 suggesting that only one in five children had their levels properly under control.
Injection regimes are a particular problem at younger ages, when children do not have the skills or confidence to carry out testing and injections.
Diabetes UK says its research suggests only 16% of primary schools in England have medication policies which allow them to administer insulin.
Toilet trauma
This can mean that treatment regimes are changed to fit around school hours, or that children are not cared for properly in school.
The charity said that parents had told it of instances in which children had to inject insulin in school toilets, or, in one case, wait outside the gates for the arrival of a nurse.
Douglas Smallwood, its chief executive, said: "It is unacceptable for medication regimes to be changed to fit around school hours.
"Children must have the most appropriate treatment for their diabetes and be properly supported in managing their condition.
"Where parents have to step in to give insulin injections during school hours, we hear all too often that they are unable to work because they have to go into school every day - this can put heartbreaking strain on families both financially and emotionally."
He said that the government needed to strengthen legislation to include the well-being of children with long-term conditions - and to make sure that school inspections included the presence or absence of a medication policy.
A spokesman for the Department for Children, Schools and Families, said there was no legal duty on schools to administer medicines, but most assisted on a voluntary basis.
In Scotland, a similar survey suggested just one in ten primary schools had a policy on giving medication and were prepared to follow it.

Redox Molecules and Liver Injury

Mechanisms of Liver Injury. III. Role of glutathione redox status in liver injury
Derick Han, Naoko Hanawa, Behnam Saberi, and Neil Kaplowitz
University of Southern California (USC) Research Center for Liver Diseases, USC-University of California-Los Angeles Research Center for Alcohol Liver and Pancreatic Diseases, Keck School of Medicine, USC, Los Angeles, California

Submitted 4 January 2006 ; accepted in final form 6 February 2006


ABSTRACT
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ABSTRACT
GSH and Cell Redox...
Cellular GSH levels and...
Nernst potential determines...
Mechanisms That Alter GSH...
GSH and Regulation of...
Redox Regulation of Apoptosis...
Redox Regulation of Liver...
Modulation of Fas-Induced...
Effect of Redox Changes...
Redox Changes in APAP-Induced...
Mitochondria Redox Changes in...
Perspectives
GRANTS
REFERENCES


GSH is the most abundant redox molecule in cells and thus the most important determinant of cellular redox status. Thiols in proteins can undergo a wide range of reversible redox modifications (e.g., S-glutathionylation, S-nitrosylation, and disulfide formation) during times of increased exposure to reactive oxygen and nitrogen species, which can affect protein activity. These reversible thiol modifications regulated by GSH may be nanoswitches to turn on and off proteins, similar to phosphorylation, in cells. In the cytoplasm, an altered redox state can activate (e.g., MAPKs and NF-E2-related factor-2) and inhibit (e.g., phosphatases and caspases) proteins, whereas in the nucleus, redox alterations can inhibit DNA binding of transcription factors (e.g., NF-B and activator protein-1). The consequences include the promotion of expression of antioxidant genes and alterations of hepatocyte survival as well as the balance between necrotic versus apoptotic cell death. Therefore, the understanding of the redox regulation of proteins may have important clinical ramifications in understanding the pathogenesis of liver diseases.


thiol; disulfide; S-glutathionylation



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THE UTILIZATION OF OXYGEN IN METABOLISM is associated with the generation of reactive oxygen species (ROS; e.g., O2–·, H2O2, HO·) that can oxidize macromolecules and damage cells. Protein redox modifications can decrease the activity of important enzymes and transcription factors that may be important in affecting apoptotic signaling pathways and cell viability. The tripeptide glutathione (GSH) is the major antioxidant and redox regulator in cells that is important in combating oxidation of cellular constituents. Cells spend a great deal of energy to maintain high levels of reduced GSH, which in turn helps to keep proteins in a reduced state. Drugs, infections, and inflammation in the liver can increase ROS generation and/or decrease GSH levels and cause a shift in the cellular redox status of hepatocytes to become more oxidized. An alteration of the normal redox balance can alter cell signaling pathways in hepatocytes and may thus be an important mechanism in mediating the pathogenesis of many liver diseases.

GSH and Cell Redox Status
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ABSTRACT
GSH and Cell Redox...
Cellular GSH levels and...
Nernst potential determines...
Mechanisms That Alter GSH...
GSH and Regulation of...
Redox Regulation of Apoptosis...
Redox Regulation of Liver...
Modulation of Fas-Induced...
Effect of Redox Changes...
Redox Changes in APAP-Induced...
Mitochondria Redox Changes in...
Perspectives
GRANTS
REFERENCES


Redox status has historically been used to describe the ratio of interconvertible reduced/oxidized forms of a molecule. The thiol group in the cysteine residue of GSH can become oxidized to form a disulfide (reaction 1):


(1)
To define a cellular redox state, the ratios of important and abundant redox molecules such as NAD+/NADH, NADP+/NADPH, and GSH/GSSG can be measured. However, because it is difficult to measure all linked redox couples in cells, a representative redox couple is generally measured. GSH/GSSG is the most important and commonly measured redox couple used to obtain an estimate of cellular redox state because 1) it is found at high levels in cells, far higher (100–10,000 greater) than most redox active compounds; and 2) the GSH/GSSG ratio is important in determining the redox status of proteins, thus influencing protein function and activity. An assessment of the GSH/GSSG ratio therefore provides a reliable estimation of cellular redox status in cells and is thus frequently measured as an indicator of oxidative stress.


Cellular GSH levels and compartmentation
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ABSTRACT
GSH and Cell Redox...
Cellular GSH levels and...
Nernst potential determines...
Mechanisms That Alter GSH...
GSH and Regulation of...
Redox Regulation of Apoptosis...
Redox Regulation of Liver...
Modulation of Fas-Induced...
Effect of Redox Changes...
Redox Changes in APAP-Induced...
Mitochondria Redox Changes in...
Perspectives
GRANTS
REFERENCES


GSH is synthesized by two enzymes: glutamate-cysteine ligase (GCL) and GSH synthetase, with the former catalyzing the rate-limiting step and being a point of feedback for GSH regulation (Fig. 1). A compartmentation of GSH occurs in cells, with mitochondria, the endoplasmic reticulum, and possibly the nucleus containing separate GSH pools. Mitochondrial GSH, which comprises about 10% of hepatic GSH, is generally considered more important than cytoplasmic GSH levels for cell survival. It is generally accepted that the GSH/GSSG ratio in cells is >100:1 under normal circumstances, but the redox ratio can shift to <4:1 during times of severe oxidative stress. The GSH/GSSG ratio is maintained by the enzyme GSSG reductase, which uses the reducing power of NADPH to convert GSSG to GSH. The GSH/GSSG ratio is thus ultimately tied to NADPH levels, which are determined by the energy status of the cell. Hepatocytes also export GSH through sinusoidal transport into plasma (Fig. 1) or into bile through canalicular transport.





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Fig. 1. Regulation of hepatic GSH. The maintenance of hepatic GSH is a dynamic process achieved by a balance between rates of GSH synthesis, GSH and GSSG efflux, GSH reactions with reactive oxygen species (ROS) and reactive nitrogen species (RNS), and utilization by GSH peroxidase. 1: glutamate-cysteine ligase (GCL) is the rate-limiting step in GSH synthesis that catalyzes the formation of -glutamylcysteine. 2: GSH synthetase catalyzes the final step in GSH synthesis. 3: GSSG reductase utilizes the reducing power of NADPH to reduce GSSG to GSH. 4: GSH peroxidase reduces H2O2 and lipid peroxides to water and alcohols using the reducing power of GSH. 5: GSH transferases detoxify xenobiotic compounds through conjugation with GSH. 6: GSNO reductase removes GSNO, resulting in the formation of GSSG (not shown). GSSG reductase is needed to regenerate GSSG formed by GSNO reductase. NO·, nitric oxide (NO) radical.





Nernst potential determines redox status
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ABSTRACT
GSH and Cell Redox...
Cellular GSH levels and...
Nernst potential determines...
Mechanisms That Alter GSH...
GSH and Regulation of...
Redox Regulation of Apoptosis...
Redox Regulation of Liver...
Modulation of Fas-Induced...
Effect of Redox Changes...
Redox Changes in APAP-Induced...
Mitochondria Redox Changes in...
Perspectives
GRANTS
REFERENCES


The Nernst equation, which estimates the reduction potential between redox couples in an electrochemical cell, can be used to determine the redox potential of GSH in cells, thus providing an estimate of cellular redox status. The voltage of an electrochemical cell (E) can be determined by the following:


where Eo is the electromotive force under standard conditions, R is the gas constant (equal to 8.314 J·K–1·mol–1), T is the temperature (in Kelvin), F is the Faraday constant (equal to 9.6485 x 104 C/mol), n is the number of electrons exchanged, and Q is the mass action expression, which for GSH would be defined by [GSH]2/[GSSG] (24). At pH 7, Eo becomes –240 mV for GSH, and, under standard conditions and temperature, the redox potential (E) of GSH can be defined as follows (24):



One of the advantages of using the Nernst potential to determine the cellular GSH redox potential over just estimating the GSH/GSSG ratio is that the Nernst equation takes into account the actual concentration of GSH and GSSG. Because two GSH molecules are needed to form one GSSG molecule, the reaction is second order for GSH and, therefore, [GSH] is squared in the Nernst equation. Thus any changes in the absolute concentration of [GSH] will change the redox potential, even without changes in the GSH/GSSG ratio. For example, a hepatocyte that has 10 mM GSH and a GSH/GSSG of 100:1 would have a potential of –330 mV. A cell with just 1 mM GSH with a similar GSH/GSSG of 100:1 would have a potential of –300 mV, even though the GSH/GSSG ratio remained the same. This would suggest that cells with more GSH, such as hepatocytes, have a greater redox buffering capacity than cells with lower GSH levels, such as neurons.


Mechanisms That Alter GSH Redox Status
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ABSTRACT
GSH and Cell Redox...
Cellular GSH levels and...
Nernst potential determines...
Mechanisms That Alter GSH...
GSH and Regulation of...
Redox Regulation of Apoptosis...
Redox Regulation of Liver...
Modulation of Fas-Induced...
Effect of Redox Changes...
Redox Changes in APAP-Induced...
Mitochondria Redox Changes in...
Perspectives
GRANTS
REFERENCES


GSH plays a key role in the detoxification of peroxides, reactive nitrogen species [RNS; e.g., peroxynitrite (ONOO–) and N2O3], and xenobiotic compounds (such as reactive electrophilic molecules) in cells (Fig. 1). Because the cellular GSH redox potential is affected by both GSH levels and the GSH/GSSG ratio, the cellular redox status can be altered by an increase in ROS or RNS generation (i.e., inflammation) that decreases the GSH/GSSG ratio and/or by the metabolism of drugs or other xenobiotic substances that deplete GSH. The GSH S-transferase family catalyzes the conjugation of GSH to many xenobiotic compounds (generally reactive electrophiles) to aid in their removal from cells. High levels of drugs and xenobiotic compounds that are detoxified by GSH can cause severe GSH depletion, and a dramatic shift in the cellular redox can occur. If mitochondrial GSH is depleted to levels below a certain threshold (30–40% depletion), an increase in H2O2 release from mitochondria will occur, because GSH needed by GSH peroxidase to detoxify H2O2 becomes limiting. Thus a fall in GSH levels will lower the cellular redox status either directly, from a loss of GSH needed to maintain the redox buffer, or indirectly, by allowing increased exposure of cells to ROS that can oxidize cellular constituents because the GSH needed to detoxify peroxides becomes limiting. The maintenance of hepatic GSH and cellular redox status is therefore a dynamic process achieved by a balance between rates of GSH synthesis, GSH and GSSG efflux, GSH utilization by various enzymes, and NADPH levels (Fig. 1).


GSH and Regulation of Protein Redox Status
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ABSTRACT
GSH and Cell Redox...
Cellular GSH levels and...
Nernst potential determines...
Mechanisms That Alter GSH...
GSH and Regulation of...
Redox Regulation of Apoptosis...
Redox Regulation of Liver...
Modulation of Fas-Induced...
Effect of Redox Changes...
Redox Changes in APAP-Induced...
Mitochondria Redox Changes in...
Perspectives
GRANTS
REFERENCES


Protein oxidation.

The oxidation of proteins has become an important field of investigation in liver disease because of the potential of protein oxidation to disrupt cell signaling pathways, particularly those involving cell death cascades. Protein oxidation may entail a wide range of chemical modifications including hydroxylation of amino acids, such as tyrosine and phenylalanine hydroxylation, methionine oxidation to methionine sulfoxide, and oxidation of thiols in cysteine residues to disulfides. The thiols in cysteine residues of proteins can undergo various reversible and irreversible redox alterations in response to ROS and RNS stress (Fig. 2) that may be a central mechanism of protein regulation. Because many redox alterations to thiols are readily reversible through mechanisms involving GSH, thiol redox alteration, like phosphorylation, has been suggested to be an important mechanism of turning on and off proteins, particularly in response to oxidative and nitrosative stress.





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Fig. 2. Redox modifications of thiols. Thiols in cysteine residues can undergo various reversible and irreversible modifications after reactions with ROS and RNS. NO, through the formation of higher nitrogen species (e.g., N2O3), can cause the S-nitrosylation of thiols. GSSG can undergo disulfide exchange with protein thiols and cause the S-glutathionylation of protein. ROS such as H2O2 can cause the S-hydroxylation of thiols to form sulfenic acid. Sulfenic acid can further oxidize to sulfinic or sulfonic acids, which represent irreversible oxidations of thiols. ROS can also cause vicinal thiols or thiols from different proteins to undergo intra- or intermolecular disulfide bridge formation, respectively. GSH reacts with sulfenic acids or nitrosothiols to remove these bonds and causes S-glutathionylation.




Protein thiol modifications by ROS and RNS.
ROS and RNS can oxidize thiols in proteins both directly and indirectly. Oxidants like ONOO– and H2O2 can causes thiols to become sulfenic, sulfinic, and sulfonic acids (Fig. 2). Although sulfenic acid formation is readily reversible by GSH, it is unstable and can undergo further oxidation to sulfinic and sulfonic acids, which represent irreversible modifications. Recently, it has been shown that treatment of the mitochondrial protein aconitase with ONOO– results in sulfonic acid formation on cysteines residues and an inhibition of activity (9). ROS or RNS can also cause vicinal thiols or thiols from different proteins to undergo intra- or intermolecular disulfide bridge formation, respectively. Nitric oxide (NO), through the formation of higher nitrogen species such as N2O3, has been shown to S-nitrosylate protein thiols and also GSH. The nitrosylation of protein thiols may be an important mechanism, besides those involving guanylyl cyclase, by which NO affects cell signaling. ROS can also modulate protein function indirectly through GSSG formation. Increases in H2O2 or ONOO– in cells will cause increased GSSG formation, which in turn can undergo mixed disulfide exchange and S-glutathionylate proteins (Fig. 2). For this reason, GSSG is rapidly converted to GSH by GSSG reductase or actively transported out of cells. The localized environment of neighboring amino acids (pH, charge, etc.) determine the reactivity of the thiols to different stresses.

Changes in protein activity after thiol modifications.

All the modifications to protein thiols outlined in Fig. 2 can potentially affect protein activity, with the degree depending on the importance of the cysteine residue in carrying out protein function. Many metabolic enzymes, kinases, phosphatases, and transcription factors contain critical cysteine residues that, if modified, can alter protein activity. Transcription factors such as NF-B and c-jun [activator protein-1 (AP-1)] contain critical cysteine residues that are needed for binding to DNA (18). The modification of thiols of cysteine residues can potentially affect binding to DNA and thus transcriptional activity. NF-B has been shown to be S-glutathionylated and S-nitrosylated, both modifications causing a decrease in transcriptional activity. Some proteins may not contain cysteine residues important in protein function; however, modification of thiols may cause a conformational change that alters protein activity. Thus, like phosphorylation, the reversible modification of thiols, such as glutathionylation, may be a mechanism to turn on or off signaling pathways through modification of important cysteine residues or through the induction of conformational changes in the protein.

The exposure of cells to ROS is known to activate or inhibit many signaling cascades, including c-Jun NH2-terminal protein kinase (JNK), protein kinase C (PKC), and tyrosine kinase signaling. ROS such as H2O2 have been suggested to be second messengers in many signaling pathways in cells. However, to date, no receptor for H2O2 has been found in cells. H2O2 signaling may therefore depend on the oxidation of critical thiols in key signaling proteins, which results in a change of activity. Thiol modifications may also be a mechanism by which cells sense and regulate cellular redox status. The transcription factor NF-E2-related factor-2 (Nrf2) plays an essential role in the response to oxidative stress through the induction of antioxidant genes, including GCL, to upregulate GSH levels. Nrf2 is normally found in the cytoplasm bound to the inhibitory protein Kelch-like ECH-associated protein 1 (Keap 1). Thiols in Keap 1 act as redox sensors. Oxidation of thiols in Keap 1 will cause Nrf2 dissociation and translocation to the nucleus (5). Thus Keap 1 and Nfr2 act together to sense changes in cellular redox status, and, if redox alterations occur, genes necessary to restore cellular redox status are transcribed.

Regulation of protein redox status by GSH.

The regulation of protein redox by GSH occurs through two mechanisms: 1) by buffering and protecting thiols on proteins from ROS and RNS and 2) by reversing disulfides bonds and nitrosthiols that can occur during times of oxidative and nitrosative stress. GSH will intercept ROS and RNS, such as N2O3, that nitrosylate thiols of proteins. The reaction of N2O3 with GSH results in the formation of GSNO (Fig. 1). Because GSNO can potentially S-nitrosylate thiols in proteins, like GSSG, GSNO is rapidly reduced in cells by GSNO reductase.

The deglutathionylation of proteins can be accomplished directly by GSH, but the process is relatively slow. Therefore, in cells, deglutathionylation is catalyzed by glutaredoxin, a disulfide reductase [reaction 2 (15)]


(2)
Similarly, GSH can reduce intra- and interprotein disulfide cross-links of proteins, but this process is (again) relatively slow. In cells, the reduction of disulfides is catalyzed by thioredoxin (Trx). Trx contains vicinal thiols that react with and reduce disulfide cross-links (reaction 3)


(3)



(4)
The enzyme Trx reductase uses the reducing power of NADPH to regenerate Trx-S2H2 from Trx-S2 (15). Trx has been shown to be particularly important in keeping the thiols of NF-B reduced in the nucleus so that it can effectively bind to DNA (14).

The high levels of GSH, along with redox-regulating enzymes [Trx, glutaredoxin, GSSG reductase, GSNO reductase, and other redox proteins (e.g., redox factor-1 and peroxiredoxins)] maintain proteins in cells in the reduced thiol form. This is in contrast to the extracellular environment in which GSH levels are low and proteins contain disulfides to maintain structural integrity (i.e., immunoglobins) in an oxidized environment. The cell spends a great deal of energy in the form of NADPH to keep the intracellular environment reduced.


Redox Regulation of Apoptosis and Necrosis
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ABSTRACT
GSH and Cell Redox...
Cellular GSH levels and...
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Cell death is the crucial event leading to the clinical manifestation of hepatotoxicity from drugs, viruses, and alcohol. The redox alterations caused by ROS and RNS or agents that deplete GSH [e.g., diethylmaleate (DEM) and buthionine sulfoximine (BSO)] have been shown to induce apoptosis and necrosis in hepatocytes and other cells. This is because many proteins that modulate cell survival and death, such as NF-B, JNK, PKC, and caspases, are redox regulated. Caspases, for example, are cysteine proteases that have been shown to be inactivated by nitrosylation or through the oxidation of thiols to disulfides (8, 18).

A common observation in many cell lines is that low levels of ROS such as H2O2 can induce apoptosis, whereas higher levels lead to necrosis (1). Because critical cysteines on different proteins have different redox potentials, low levels of oxidants may be causing thiol oxidation in some proteins while not affecting other proteins. Thus low levels of oxidants may promote apoptosis by causing redox alterations that activate proapoptotic factors such as JNK and inhibit prosurvival proteins such as NF-B (inhibiting DNA binding) without altering the redox status of proapoptotic caspases. In HL-60 cells, it has been estimated that a change in the redox potential by +72 mV promotes apoptosis (2). High levels of oxidants likely favor necrosis by inhibiting caspases needed to mediate apoptosis (8). Large redox changes caused by high amounts of oxidants such as H2O2 or severe GSH depletion will cause necrosis in primary cultured hepatocytes, whereas modest redox changes have not been shown to promote apoptosis in hepatocytes. However, changes in the intracellular environment by oxidants or GSH-depleting agents can regulate the response of hepatocytes to tumor necrosis factor- (TNF) and Fas-induced apoptosis. Thus redox alterations in hepatocytes may be important in regulating the cell death pathways that mediate many liver pathologies.

Alterations in Response to TNF by Redox Changes in Hepatocytes

TNF in liver diseases. The cytokine TNF is an important regulator of inflammation in the liver. However, TNF is also believed to promote liver injury during inflammation. Several studies have shown that liver damage caused by exogenous agents such as carbon tetrachloride and chronic ethanol are dramatically decreased in mice lacking the TNF receptor. It is believed that sustained elevated levels of TNF promote apoptosis and necrosis in hepatocytes and, consequently, liver damage. TNF-induced apoptosis and necrosis of hepatocytes is believed to mediate, at least in part, liver damage during inflammation in alcoholic liver disease, liver ischemia, and liver toxicity caused by exogenous toxins, such as carbon tetrachloride.

TNF is a well-characterized antineoplastic agent that, upon exposure, triggers apoptosis and necrosis in many types of transformed cells. Hepatocytes, like most nontransformed cells, are resistant to TNF. The injection of TNF in vivo generally causes a proliferative response in the liver rather than a cytotoxic one. The resistance of hepatocytes to TNF has been attributed to the activation of NF-B and transcription of NF-B-dependent survival genes [such as inhibitor of apoptosis (IAP), inducible NO synthase (iNOS), and Bcl-XL] that protect hepatocytes from TNF. iNOS expression may be antiapoptotic because NO production can lead to the nitrosylation and inactivation of caspases. The sensitization of hepatocytes to TNF can be achieved by interfering with NF-B activation and/or transcription of NF-B-dependent survival genes by treatment with agents such as actinomycin D (RNA synthesis inhibitor) (20).

The resistance of hepatocytes to the lethal actions of TNF has lead to the question of how TNF promotes hepatocellular injury in various pathologies. Two possibilities can be considered: 1) TNF's proinflammatory actions indirectly lead to hepatocellular injury and/or 2) TNF has a direct lethal effect on hepatocytes that have somehow been sensitized, possibly as a consequence of inflammation. Although interference with RNA or protein synthesis can sensitize cells to TNF-induced apoptosis in vitro and in vivo (blocking NF-B survival gene expression), it is less clear as to what could be the mechanism of sensitization in liver diseases.

Sensitization of hepatocytes to TNF-induced apoptosis by changes in cellular redox status. Work done in our laboratory suggests that the redox alterations due to increased ROS and/or consequent GSH depletion that may occur during inflammation or caused by drug treatment may be an important mechanism in sensitizing hepatocytes to TNF-induced apoptosis (21, 22). Previous work from our laboratory has shown that GSH-depleting agents [e.g., acetaminophen (APAP), phorone, and DEM] at doses that deplete mitochondrial GSH levels will induce necrosis in primary cultured hepatocytes. However, more modest doses of GSH-depleting agents that result mainly in cytoplasmic GSH depletion (cytoplasmic GSH depletion results in a minimal change in cell viability) were found to sensitize hepatocytes to TNF-induced apoptosis by inhibiting NF-B-dependent survival gene expression (21, 22). Similarly, sublethal levels of H2O2 and redox-modulating agents such as diamide also sensitized primary cultured hepatocytes to TNF-induced apoptosis (10). The most redox-sensitive step in the pathway from IKK-mediated phosphorylation of IB- to the transactivation of NF-B-dependent genes was the latter, presumably due to altered DNA binding of p50 and p65 subunits; this occurred after a modest selective depletion of cytosol GSH (40–50%). More severe, selective depletion of cytosol GSH (70–80%) or exposure to oxidants led to an inhibition of IB- phosphorylation (10, 21, 22). Thus redox alteration caused by GSH depletion or oxidants inhibits TNF-induced NF-B-dependent expression of survival genes and thus promotes apoptosis.

On the basis of these findings, a dose relationship of the effect of H2O2 or decreases in GSH on hepatocyte apoptosis and necrosis can be proposed (Fig. 3). Moderate sublethal levels of H2O2 or depletion of cytoplasmic GSH cause cellular redox changes that interfere with NF-B signaling, sensitizing hepatocytes to TNF-induced apoptosis. There is probably a redox range in which apoptosis can be initiated by TNF treatment of hepatocytes. High doses of H2O2 or substantial decreases in mitochondrial GSH ultimately cause necrosis in hepatocytes regardless of the presence of TNF through extensive oxidative damage that may overwhelm or even inhibit apoptotic signaling pathways, including caspase activity by oxidation of critical thiols. Therefore, massive necrosis caused by H2O2 or decreased GSH levels occurs after a certain critical redox threshold is passed, and, below this threshold, redox changes sensitize cells to TNF-induced apoptosis by inhibiting NF-B activation and/or transactivation. Redox changes in hepatocytes caused by inflammation and drugs (i.e., APAP) may therefore be an important mechanism for sensitizing hepatocytes to TNF-induced apoptosis and promoting liver disease.





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Fig. 3. Cell redox potential in determining apoptosis and necrosis: the role of tumor necrosis factor- (TNF). A moderate change in cellular redox potential caused by moderate sublethal levels of H2O2 or depletion of cytoplasmic GSH levels sensitizes cells to TNF-induced apoptosis through interference with NF-B signaling. Large redox changes caused by high doses of H2O2 or substantial decreases in the GSH cause necrosis in hepatocytes, regardless of the presence of TNF. Therefore, massive necrosis caused by H2O2 or decreased GSH levels occurs after a certain critical redox threshold is passed, and below this threshold redox changes sensitize cells to TNF-induced apoptosis.





Redox Regulation of Liver Regeneration: Role of TNF
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The plating of primary cultured hepatocytes under low density stimulates hepatocytes to undergo a shift from the G0 to G1 phase in the cell cycle and an increase in GSH levels. The increase in GSH is a result of increase synthesis of GCL in hepatocytes. Similarly, GSH levels after partial hepatectomy doubled due to increased GCL expression and activity (16). This suggests that redox changes may be important in regulating hepatocyte division. The increased GSH in the liver after partial hepatectomy was not associated with a change in the GSH/GSSG ratio. With the use of the Nernst equation, the cellular redox of liver cells goes from –330 to –340 mV after partial hepatectomy, assuming a GSH level of 10 mM and no changes in the GSH/GSSG ratio. This suggests a strong reducing environment is necessary for cell replication. In support of this notion is the observation that liver regeneration was inhibited by GSH depletion. The alteration in redox potential may be a common feature in dividing cells, because ROS have been suggested to modulate the cell cycle in many cell lines. Because TNF is secreted and NF-B activation is essential for hepatocyte survival after partial hepatectomy (4), an increased reducing environment caused by increased GSH may be generated to ensure proper NF-B activity and hepatocyte survival.

Modulation of Fas-Induced Apoptosis by Redox Alterations
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Fas ligand belongs to the TNF/nerve growth factor superfamily that transduces apoptotic signals through activation of caspases. Treatment of mice with agonistic anti-Fas antibody triggers apoptosis in hepatocytes and liver failure. The notion that Fas signaling could be altered by redox changes arose from the observation that acute GSH depletion by phorone treatment prevented apoptosis induced by anti-Fas treatment (13). GSH esters but not antioxidants were found to restore the susceptibility of GSH-depleted mice against Fas-mediated apoptosis, suggesting that redox changes were important in modulating Fas signaling. The inhibition of apoptosis caused by GSH depletion by phorone was likely due to the redox modulation of caspase 3, which has thiols essential for mediating apoptosis. However, Fas signaling is complex and involves many redox-regulated proteins. Other researchers have observed that GSH depletion from feeding animals a sulfur amino acid-deficient diet (a slow, prolonged GSH depletion) exacerbated Fas-mediated apoptosis through increased p53 and Bax expression (11). This suggests that acute and prolonged redox changes may affect different redox proteins and thus may have varying effects on cell signaling pathways.


Effect of Redox Changes in Various Liver Injury Models
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Liver injury can be studied using various toxins such as galactosamine (Gal) cotreated with either TNF or LPS, concanavalin A, LPS alone, and -amanitin. Hentze et al. (12) observed that liver injury caused by the above agents could be inhibited by acute GSH depletion caused by phorone treatment (12). Because many of these toxins mediate liver injury through mechanisms independent of caspase 3, the results suggest that other signal proteins, besides caspases, that mediate liver injury are regulated by redox changes. Another factor in in vivo studies is different consequences of inhibition of the NF-B pathway in different cell types; whereas GSH depletion inhibits survival gene expression, sensitizing cells to TNF-induced apoptosis in hepatocytes, inhibition of NF-B in nonparenchymal cells may exert an anti-inflammatory effect by inhibiting the expression of cytokines, chemokines, and adhesion molecules (17). Although an acute shift from a reduced to a more oxidized state protected the liver from various toxins, the protection is probably not universal. Xu et al. (25) observed that GSH depletion with BSO treatment (a slower and prolonged means of GSH depletion) increased liver damage caused by Gal/LPS. This again points out that acute and long-term redox changes may affect cell signaling pathways differently and switch on and off different proteins.


Redox Changes in APAP-Induced Liver Injury and JNK Activation
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The importance of GSH in hepatocyte survival is demonstrated in APAP-induced liver injury. The cytochrome P-450 system in hepatocytes metabolizes APAP to N-acetyl-p-benzoquinone (NAPQI), which is detoxified by conjugation with GSH. An overdose of APAP causes severe GSH depletion, ROS generation, and covalent binding of NAPQI to protein, resulting in cell death. Nrf2, through redox alterations, is activated after APAP treatment so that GSH synthesis can be increased in hepatocytes. N-acetylcysteine, which can replenish GSH, is effective in treating patients with APAP-induced liver injury. Not surprisingly, GSH depletion by phorone or other agents potentiated APAP-induced liver injury in vivo.

Recent studies have suggested that cell death caused by GSH depletion and ROS generation is not sufficient for APAP-induced hepatotoxicity. Indeed, activation of redox-regulated proteins such as JNK may be necessary to mediate hepatocyte death caused by APAP (7). JNK and upstream kinases such as apoptosis signal-regulating kinase-1 are inhibited by Trx and GSH transferase subunits ( and others) (23). ROS and GSSG can oxidize these inhibitors and release active kinases. In addition, protein tyrosine phosphatases, including JNK phosphatase, have active site thiolate cysteines, which readily undergo oxidation by H2O2 to sulfenic acids (which inhibit these enzymes, thus favoring the persistence of activated phosphokinases). The understanding of how redox alterations activate JNK and other signaling proteins is an important question in understanding APAP-induced liver injury.


Mitochondria Redox Changes in Liver Diseases
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GSH and Cell Redox...
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Mitochondrial GSH is much more important for hepatocyte survival than cytoplasmic GSH. The mitochondrial redox status has profound effects on the cellular redox status as a whole, because the depletion of mitochondrial GSH can cause increased release of H2O2 from the mitochondrial matrix that can oxidize cytoplasmic proteins and affect cell signaling. Chronic ethanol treatment and hepatitis C infection (19) have been shown to cause mitochondrial GSH depletion. Chronic ethanol treatment is believed to selectively deplete mitochondrial GSH by decreasing GSH transporter activity through ethanol-induced changes in inner membrane fluidity due to cholesterol accumulation (6). In addition, the change in the mitochondrial redox potential caused by mitochondrial GSH depletion may also be important in regulating mitochondrial permeability transition (MPT). MPT is the opening of the mitochondrial megapore [composed of voltage-dependent anion channels, adenine nucleotide transporter (ANT), and other proteins] that may be important in necrosis and apoptosis, because it results in the loss of bioenergetics and release of proapoptotic proteins such as cytochrome c. ANT and other components of the megapore are believed to have thiols that are important in regulating pore opening and closing (3). Disulfide formation on ANT will favor pore opening and a consequent loss of mitochondrial function. The redox regulation of MPT may be important in mediating APAP-induced liver injury. APAP treatment will trigger MPT in hepatocytes likely through redox alterations in ANT and other mitochondrial proteins, which mediates hepatocyte necrosis. Mitochondrial GSH changes may have profound effects on cellular redox status through modulating ROS generation, as well as necrosis and apoptosis through the regulation of MPT, and thus may be an important mechanism of mediating liver injury.


Perspectives
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GSH and Cell Redox...
Cellular GSH levels and...
Nernst potential determines...
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GSH is the most abundant redox molecule in cells and thus the most important determinant of cellular redox status. Both the levels of GSH and GSH/GSSG ratio determine the redox status of proteins in cells. Thiols in proteins can undergo a wide range of reversible redox modifications during times of increased exposure to ROS and RNS, which can affect protein activity. These reversible thiol modifications regulated by GSH may be nanoswitches to turn on and off proteins, similar to phosphorylation, in cells. In the cytoplasm, an altered redox state can activate (MAPKs, PKC, and Nrf-2) and inhibit (protein phosphatases, caspases, and IKK) proteins, whereas in the nucleus redox alterations can inhibit DNA binding of transcription factors (NF-B and AP-1). The consequences include the promotion of expression of antioxidant genes and alterations of cell survival as well as the balance between necrotic versus apoptotic cell death. Many liver diseases involve redox changes caused by GSH depletion or increased ROS and RNS generation. Therefore, understanding the redox regulation of proteins may have important clinical ramifications in understanding the pathogenesis of liver diseases and developing therapeutic approaches.


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GSH and Cell Redox...
Cellular GSH levels and...
Nernst potential determines...
Mechanisms That Alter GSH...
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Redox Regulation of Liver...
Modulation of Fas-Induced...
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This work was supported by National Institutes of Health Grants RO1-DK-067215, P30-DK-48522, and P50-AA-11999.



FOOTNOTES


Address for reprint requests and other correspondence: D. Han, Research Center for Liver Diseases, Keck School of Medicine, Univ. of Southern California, 2011 Zonal Ave., HMR 101, Los Angeles, CA 90089-9121 (e-mail: derickh@usc.edu)


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Redox Regulation of Liver...
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Apotosis in Hepatocytes

Genomic Analysis Reveals a Potential Role for Cell Cycle Perturbation in HCV-Mediated Apoptosis of Cultured Hepatocytes
ArticleRelated ContentComments: 0.Formal Correction: This article has been formally corrected to address the following errors.

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Abstract
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Introduction
Results
Discussion
Materials and Methods
Supporting Information
Acknowledgments
Author Contributions
References
Kathie-Anne Walters1#, Andrew J. Syder2#, Sharon L. Lederer1, Deborah L. Diamond1, Bryan Paeper1, Charles M. Rice2, Michael G. Katze1*

1 Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, United States of America, 2 Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, Rockefeller University, New York, New York, United States of America

Abstract Top
The mechanisms of liver injury associated with chronic HCV infection, as well as the individual roles of both viral and host factors, are not clearly defined. However, it is becoming increasingly clear that direct cytopathic effects, in addition to immune-mediated processes, play an important role in liver injury. Gene expression profiling during multiple time-points of acute HCV infection of cultured Huh-7.5 cells was performed to gain insight into the cellular mechanism of HCV-associated cytopathic effect. Maximal induction of cell-death–related genes and appearance of activated caspase-3 in HCV-infected cells coincided with peak viral replication, suggesting a link between viral load and apoptosis. Gene ontology analysis revealed that many of the cell-death genes function to induce apoptosis in response to cell cycle arrest. Labeling of dividing cells in culture followed by flow cytometry also demonstrated the presence of significantly fewer cells in S-phase in HCV-infected relative to mock cultures, suggesting HCV infection is associated with delayed cell cycle progression. Regulation of numerous genes involved in anti-oxidative stress response and TGF-β1 signaling suggest these as possible causes of delayed cell cycle progression. Significantly, a subset of cell-death genes regulated during in vitro HCV infection was similarly regulated specifically in liver tissue from a cohort of HCV-infected liver transplant patients with rapidly progressive fibrosis. Collectively, these data suggest that HCV mediates direct cytopathic effects through deregulation of the cell cycle and that this process may contribute to liver disease progression. This in vitro system could be utilized to further define the cellular mechanism of this perturbation.

Author Summary Top
Chronic HCV infection is associated with progressive liver injury and subsequent development of fibrosis/cirrhosis. The cellular mechanisms by which HCV replication, and subsequent virus–host interactions, may mediate liver injury are unclear. Microarray experiments were performed to characterize the host transcriptional response to HCV infection of cultured hepatocytes in an attempt to gain insight into the mechanism of HCV-associated cell death. Analysis of the gene expression data revealed that many differentially regulated genes function to induce apoptosis in response to cell cycle arrest, possibly in response to DNA damage and oxidative stress. Labeling of dividing cells in culture followed by flow cytometry also demonstrated the presence of significantly fewer cells in S-phase in HCV-infected cultures relative to mock cultures, suggesting HCV infection is associated with delayed cell cycle progression. Finally, many of the cell-death–related genes whose expression changes in response to HCV infection of cultured hepatocytes were also differentially regulated in liver tissue from HCV-infected patients with histological evidence of fibrosis. In summary, HCV may mediate direct cytopathic effects through perturbation of the cell cycle which potentially contributes to liver disease progression.





And another regrettable thing about death
is the ceasing of your own brand of magic,
which took a whole life to develop and market-
the quips, the witticisms, the slant
adjusted to a few, those loved ones nearest
the lip of the stage, their soft faces blanched
in the footlight glow, their laughter close to tears,
their tears confused with their diamond earrings,
their warm pooled breath in and out with your heartbeat,
their response and your performance twinned.
The jokes over the phone. The memories packed
in rapid-access file. The whole act.
Who will do it again? That's it: no one;
imitators and descendants aren't the same.
- John Updike who passed away on 1/30/09

TNF Receptor

Clinical Significance of Soluble TNF Receptor in Japanese Patients with Non-Alcoholic Steatohepatitis
Katsutoshi Tokushige 1 , Etsuko Hashimoto 1 , Noriko Tsuchiya 1 , Hiroyuki Kaneda 1 , Makiko Taniai 1 , Keiko Shiratori 1
Tokyo, Japan; Fax: 81-3-5269-7430; E-mail: drs-hashimoto@mti.biglobe.ne.jp
Copyright 2005 The Research Society on Alcoholism
KEYWORDS
Soluble TNF Receptor • NASH
ABSTRACT

Background: Soluble tumor necrosis factor receptor (sTNFR) is reported to be a good indicator of TNF production and severity in inflammatory diseases. To investigate the clinical significance of sTNFR in non-alcoholic steatohepatitis (NASH), we measured the serum levels of soluble TNF receptor-1 and -2.
Patients and Methods: We analyzed 82 NASH patients and 15 healthy subjects (control). The grades of fibrosis, inflammation and fatty deposit were evaluated on liver biopsy. The serum levels of sTNFR-1 and -2 were measured by ELISA.
Results: There was significant correlation between platelet count and sTNFRs. The titers of sTNFR-2 in NASH patients with diabetes mellitus (DM) were higher than in those without DM. The serum levels of sTNFRs in NASH patients with advanced fibrosis were increased compared with those of control and NASH patients with low-grade fibrosis. Soluble TNFRs in patients with moderate inflammation were increased compared to those of control and patients with mild inflammation. There was no significant association between fatty deposit grade and sTNFRs.

E-mail Response From Faustman Lab

MGH Diabetes Clinical Trial to me show details 10:45 AM (4 hours ago) Reply

Dear Jeff, Thank you for your e-mail and interest in our research! To learn more about Dr. Faustman’s ground-breaking research please view our new website www.faustmanlab.org. Here you can find Dr. Faustman's latest update, our fall/winter 2008 newsletter, our most recent publication in PNAS, and information on how to give monetary and research blood donations. Please look this information over and get back to me with any questions you may have. In order for Caitlin's information to be entered into our clinical trial database, we need you to fill out the Faustman Lab Patient Information Sheet (attached or found on our website) and send/e-mail/fax the form back to me. By returning this form, you will be included in our database (which will be scanned for future trial phase eligibility) and will also receive our newsletter, about 2 times per year. I would love to schedule you for a research blood donation appointment. Information about this is provided on our website. We take blood donations every Mon., Tues, and Thurs. morning. Please let me know if you are interested and your availability and I would be more than happy to help you schedule an appointment. Again, thank you for your interest and I look forward to hearing from you! Take care, Melissa Melissa Pierre, BA Clinical Research Coordinator Massachusetts General Hospital Immunology Lab - Diabetes Research CNY, 13th Street, Building 149, Room 3603 Charlestown, MA 02129 Phone: 617-726-4084

Spider Decoys: Natural Selection Tops Itself Again

If this doesn't kindle your childilke sense of awe and wonder, than nothing will. Imagine an organism that makes a life-like replica of itself to deter predators. The existence and functionality of behavioral genes is not new, even though there is still so much to learn about how complex behaviors can be influenced by genes- the bower bird, for example. But this takes animal behavior and genetic oversight to dizzying new heights. How does a trait like model building evolve, and survive the scrutiny of natural selection? The latter question is perhaps not so difficult, but the former is perplexing and awesome ( literal meaning). Has any one seen R. Dawkins in the house?

Spider builds life-sized decoys Matt Walker Editor, Earth News
There is a species of spider that builds models of itself, which it uses as decoys to distract predators.
The spider may be the first example of an animal building a life-size replica of its own body.
So believe the scientists who made the discovery, which is published in the journal Animal Behaviour.
The arachnid's behaviour also offers one explanation for why many spiders like to decorate their webs with strange-looking ornaments.
Many animals try to divert the attentions of predators by becoming masters of disguise.
Some try to avoid being seen altogether by using camouflage to blend in against a background, such as the peppered moth evolving motley wings that blend into tree bark, or stick insects that look like sticks.
Others evolve more conspicuous ornaments designed to distract a predator, such as butterflies that grow large eyespots or lizards that quickly move colourful tails, which they detach from their bodies if grabbed.
This latter strategy has puzzled biologists, because attracting predators in the first place is usually a bad idea.
One hypothesis is that animals which grow conspicuous ornaments benefit overall, because directing a predator to attack an expendable part of the body, such as the lizard's tail, outweighs the costs of attracting the attention of the predator in the first place.
Under attack
But animals do not tend to actually build life-like replica models of themselves to act as decoys.
However, that is exactly what a species of orb spider called Cyclosa mulmeinensis does, biologists Ling Tseng and I-Min Tso of Tunghai University in Taichung, Taiwan, have discovered.
This and other related spiders in the same genus decorate their webs with material such as detritus, plant parts, prey remains or egg sacs.
Because such detritus is often of a similar colour to the spider, researchers suspected it might help camouflage the arachnid.
Our study seems to be the first to empirically demonstrate the function of animal-made decoys Spider specialist I-Min Tso
Initially Tseng and Tso decided to test the idea by videoing another related species called Cyclosa confusa living in the wild. They measured how often predatory wasps attacked the spiders in webs decorated with detritus compared with those in undecorated webs.
"We predicted that spiders with prey carcass decorations on webs should receive fewer wasp attacks because spiders should be well camouflaged by such objects," says Tso. "To our surprise, spiders on decorated webs received far more attacks than those on undecorated webs."
That confirmed that the decorations attracted predators rather than acting as camouflage.
However, Tseng and Tso suspected that these decorations might also redirect enough attacks to make them worthwhile.
Life-like decoys
So they tested the idea on another species Cyclosa mulmeinensis living on Orchid Island off the southeast coast of Taiwan. This species decorates its web with both the remains of dead insect prey and egg sacs.
Intriguingly, the spiders made prey pellets and egg sacs that were the same size as its own body.
The researchers also found that these decorations appeared to wasps to be the same colour, and reflect light in the same way, as the spider's body.
In short, the spider made decorations that were of the same size, shape and appearance as itself.
"Our results show that this vulnerable spider protects itself from predator attacks by constructing decoys that increase the conspicuousness of the web, and resemble its own appearance in size and colour," the researchers write in Animal Behaviour.
"When both spiders and web decorations are present on the same web, they look like a string of nearly identical oval objects to the predators."
"I don't know of any animal that actively builds a decoy of itself. Our study seems to be the first to empirically demonstrate the function of animal-made decoys," says Tso.
The decoys worked, too. More often than not, a wasp would attack a decoy rather than the spider, thinking it to be a tasty meal.
But all wasp strikes on spiders living on undecorated webs were directed straight at the spider.
"Decorations built by Cyclosa spiders function as a conspicuous anti-predator device instead of a camouflaging device. The benefit of successful escape from predator attack seems to outweigh the cost of increased detection," says Tso.
Web decorations
Scientists have been trying to answer the question of why many species decorate their webs for more than 100 years.
Tso suspects that there is no single answer.
"I think that the functions of web decorations might be very diverse and differ from taxa to taxa. Different spiders seem to decorate their webs for different reasons," he says.
For example, spiders often decorate their webs with silk ornaments, which might strengthen the web, act as a warning signal to predators, to deter large animals from accidentally walking into the web, destroying it, or to act as a visual signal to attract prey.
Others, including Cyclosa species, may use non-silk decorations primarily as anti-predator devices.

And another regrettable thing about death
is the ceasing of your own brand of magic,
which took a whole life to develop and market-
the quips, the witticisms, the slant
adjusted to a few, those loved ones nearest
the lip of the stage, their soft faces blanched
in the footlight glow, their laughter close to tears,
their tears confused with their diamond earrings,
their warm pooled breath in and out with your heartbeat,
their response and your performance twinned.
The jokes over the phone. The memories packed
in rapid-access file. The whole act.
Who will do it again? That's it: no one;
imitators and descendants aren't the same.
- John Updike who passed away on 1/30/09

Israel in Gaza

We attacked Iraq, a country that had no capacity to defend itself, on numerous fabrications, the most recent of which was to bring democracy to the oppressed people of Iraq. The end result has been the death and maiming of thousands of of American soldiers as well as the deaths of hundreds of thousands of Iraqi civilians. We, the American people have been silent co-conspirators in our acquiescence to the criminal Bush policies.

The Israeli invasion of Gaza was another crime against a "country" with even less capability to defend itself. American weapons and approval made this slaughter of innocents possible. The American media, as usual, functioned as an approving cheerleader for the Israeli attrocities in Gaza. We must hold our politcians accountable for murderous policies that perpetuate injustice. A good place to start is to pull American funding for future Israeli war crimes.

Published on Thursday, July 2, 2009 by Agence France Presse
Amnesty Accuses Israel of Using Human Shields in Gaza
by - Amnesty accused Israeli forces on Thursday of war crimes in Gaza, saying they used children as human shields and conducted wanton attacks on civilians, in a report rejected as "unbalanced" by Israel.
sraeli soldiers stand on a tank along the border with the Gaza Strip in February 2009. Amnesty International has accused Israeli forces of war crimes in Gaza, saying they used children as human shields and conducted wanton attacks on civilians, in a report rejected as "unbalanced" by Israel. (AFP photo)The London-based human rights group also accused Hamas of war crimes, but said it found no evidence to support Israeli claims that Gaza's Islamist rulers used civilians as human shields during Israel's massive 22-day offensive.
It reiterated its call for international arms embargoes against Israel and Hamas, and called for "criminal investigations in national courts" under universal jurisdiction wherever there is sufficient evidence of war crimes.
"Much of the destruction was wanton and resulted from direct attacks on civilian objects," Amnesty said in a report on the December-January war on the Gaza Strip.
In numerous cases, Israeli troops forced Palestinians to stay in one room of their home while turning the rest of the house into a base and sniper position, "effectively using the families, both adults and children, as human shields and putting them at risk," the group said.
"Intentionally using civilians to shield a military objective, often referred to as using 'human shields' is a war crime," Amnesty said.
One Palestinian was quoted as saying Israeli troops forced him to go into a house to check whether gunmen holed up inside were still alive. They were, and threatened to kill him if he returned. The soldiers later forced him to check on the fighters two more times.
The report said it found no evidence Palestinian fighters directed civilians to shield military objectives from attacks, forced them to stay in buildings used by militants or prevented them from leaving commandeered buildings.
But it said Palestinian armed groups fired hundreds of rockets into southern Israel which "constitute war crimes."
Amnesty also accused Hamas of endangering Palestinian civilians by firing rockets from residential areas and storing weapons and ammunition there.
More than 1,400 Palestinians and 13 Israelis died during the offensive Israel launched in response to rocket fire by militants in the impoverished and overcrowded territory.
Amnesty said 300 children were among those killed.
It said hundreds of civilians were killed with high-precision weapons. "Others, including women and children, were shot at short range when posing no threat to the lives of the Israeli soldiers," it said.
"Wilful killings of unarmed civilians are war crimes," Amnesty said.
It said Israel's use of white phosphorus shells was also a clear breach of international law.
White phosphorus is not illegal if used as a smokescreen in open areas "but it should not be used in a densely populated area as it was used here," said Donatella Rovera, who led an Amnesty mission to Gaza and southern Israel.
The Israeli military called the report "unbalanced" and "distorted."
"The slant of their report indicates that the organisation succumbed to the manipulations of the Hamas terror organisation," a statement said.
The military insisted its forces used "fighting methods and advanced technology to minimise harm to the civilian population while engaging terrorists who were operating from densely populated areas and using the local population as 'human shields'."
It also accused Amnesty of ignoring "the blatant violations of international law perpetrated by Hamas."
Hamas also sharply criticised the report.
"It falsely accuses Hamas while playing down the seriousness of the crimes committed by the Israeli occupation," Sami Abu Zuhri, a spokesman for the Islamist movement.
"It puts the executioner and the victim on the same footing," he said.

Epigenetics: Partial Vindication for Lamarck

Genes have long been considered the only way biological traits are passed down through generations of organisms. Now we know that non-genetic variations acquired during the lifespan of a plant or animal can be passed along to its offspring.
The phenomenon is known as epigenetic inheritance. We don't yet know how prolific this mechanism is. But a new study in The Quarterly Review of Biology lists more than 100 well-documented cases of epigenetic inheritance between generations of organisms.
In other words, non-DNA inheritance happens a lot more than we thought. For example:
Fruit flies exposed to certain chemicals transmit changes—bristly outgrowths on their eyes—down at least 13 generations.
Exposing a pregnant rat to a chemical that alters reproductive hormones leads to generations of sick offspring.
People malnourished in adolescence transmit higher rates of heart disease and diabetes to their children and grandchildren.
In these and 97 other cases the changes in subsequent generations were not from changes in DNA but from epigenetics.
There are four known mechanisms for epigenetic inheritance. The best known involves on-off switches (sort of) that render genes active or inactive—without actually changing the DNA. The revelations of epigenetics are rewriting the study of evolution. And no, epigentics does not make creationism right.
The rewrite is a vindication of sorts for 18th-century naturalist Jean Baptiste Lamarck, whose writings predated Charles Darwin's and who believed that evolution was driven in part by the inheritance of acquired traits.
His wonkiest supposition: Giraffe ancestors reached with their necks to munch leaves high in trees, stretching their necks to become slightly longer—a trait passed on to descendants.
More accurate: All the stuff we're synthesizing and creating from plastics to nanomaterials is going to live in our bodies and take its toll down the generations for a long, long time.

Speciation

Darwin's finches are an excellent example of the way in which species' gene pools have adapted in order for long term survival via their offspring. The Darwin's Finches diagram below illustrates the way the finch has adapted to take advantage of feeding in different ecological niche's.
Their beaks have evolved over time to be best suited to their function. For example, the finches who eat grubs have a thin extended beak to poke into holes in the ground and extract the grubs. Finches who eat buds and fruit would be less successful at doing this, while their claw like beaks can grind down their food and thus give them a selective advantage in circumstances where buds are the only real food source for finches.
Industrial Melanism the existence of two distinctly different groups of a species that still belong to the same species. Alleles for these organisms over time are governed by the theory of natural selection, and over this time the genetic differences between groups in different environments soon become apparent, as in the case of industrial melanism.
Industrial melanism occurs in a species called the peppered moth, where the occurrence has become of more frequent occurrence since the beginning of the industrial age. The following argument elaborates the basis of principles involved in natural selection as far as industrial melanism is concerned.
Pollution, which is more common in today's world since the industrial age causes a change in environment, particularly in the 1800's when soot would collect on the sides of buildings from chimneys and industries and make them a darker colour.
The resultant effect was that the peppered moth, which had a light appearance was more visible against the darker backgrounds of sooty buildings.
This meant that predators of the peppered moth could find them more easily as they are more visible against a dark background.
Due to mutations, a new strain of peppered moth came to existence, where their phenotype was darker than that of the white peppered moth.
This meant that these new, darker peppered moths were once again harder to track down by their prey in environments where industry has taken its toll.
In this instance, natural selection would favour the darker moths in polluted environments and the whiter moths in the lesser polluted environments due to their ability to merge in with their environmental colours and lessen the chances of them being prone to a predator.
Sickle Cell Trait
Consider this argument of natural selection in the case of sickle cell trait, a genetic defect common in Africa.
Sickle cell trait is a situation that occurs in the presence of a recessive allele coding for haemoglobin, a substance in the blood responsible for the transport of gases like oxygen. The presence of the allele is either partially expressed recessively (sickle cell), or fully expressed by a complete recessive expression which results in full blown anaemia. If this particular allele is dominant, no sickle cell trait is expressed in the phenotype.
The above occurrences in the case of a recessive allele result in structural defects of red blood cells, severely reducing the organisms capacity to uptake oxygen.
It was pointed out that in Africa, there is a high frequency of this mutation, where cases of malaria were high.
A substantiated link was made noting those who suffer sickle cell trait or anaemia were immune to the effects of malaria.
This is yet again natural selection at work. Although sickle cell trait or anaemia are not advantageous characteristics on their own, they prove to be advantageous in areas where malaria proves to be a greater threat to preserving the genome (i.e. surviving).
The incomplete dominance of this genetic expression proves favourable either way.
This is how science has understood natural
Polymorphism pertains to the existence of

Adaptive Radiation: Darwin's Finches
There are now at least 13 species of finches on the Galapagos Islands, each filling a different niche on different islands. All of them evolved from one ancestral species, which colonized the islands only a few million years ago. This process, whereby species evolve rapidly to exploit empty ecospace, is known as adaptive radiation.
Click for larger image
Resource Type:Image
Format:Graphic
Topics Covered:Adaptation and Natural Selection
Backgrounder
Adaptive Radiation: Darwin's Finches:
When Charles Darwin stepped ashore on the Galapagos Islands in September 1835, it was the start of five weeks that would change the world of science, although he did not know it at the time. Among other finds, he observed and collected the variety of small birds that inhabited the islands, but he did not realize their significance, and failed to keep good records of his specimens and where they were collected. It was not until he was back in London, puzzling over the birds, that the realization that they were all different, but closely related, species of finch led him toward formulating the principle of natural selection.In his memoir, The Voyage of the Beagle, Darwin noted, almost as if in awe, "One might really fancy that, from an original paucity of birds in this archipelago, one species had been taken and modified for different ends."Indeed, the Galapagos have been called a living laboratory where speciation can be seen at work. A few million years ago, one species of finch migrated to the rocky Galapagos from the mainland of Central or South America. From this one migrant species would come many -- at least 13 species of finch evolving from the single ancestor. This process in which one species gives rise to multiple species that exploit different niches is called adaptive radiation. The ecological niches exert the selection pressures that push the populations in various directions. On various islands, finch species have become adapted for different diets: seeds, insects, flowers, the blood of seabirds, and leaves.The ancestral finch was a ground-dwelling, seed-eating finch. After the burst of speciation in the Galapagos, a total of 14 species would exist: three species of ground-dwelling seed-eaters; three others living on cactuses and eating seeds; one living in trees and eating seeds; and 7 species of tree-dwelling insect-eaters.Scientists long after Darwin spent years trying to understand the process that had created so many types of finches that differed mainly in the size and shape of their beaks. Most recently, Peter and Rosemary Grant have spent many years in the Galapagos, seeing changing climatic conditions from year to year dramatically altering the food supply. As a result, certain of the finches have lived or died depending on which species' beak structure was best adapted for the most abundant food -- just as Darwin would have predicted.

Top Ten Discoveries

Steam engine
V2 rocket engine
Electric telegraph
Stephenson's Rocket
X-ray machine
Model T Ford
Penicillin
Pilot ACE Computer
DNA double helix
Apollo 10 capsule

Hummingbirds Impress the Ladies

Faster than a fighter jet" - the hummingbird in action (footage slowed down)
Male hummingbirds, swooping in an effort to impress females, achieve speeds higher than fighter jets, according to a study.
A US researcher has captured the birds' dives with super-fast cameras. He lured them into their impressive displays using stuffed models of female birds.
The feathered acrobats reached speeds of almost 400 body lengths per second.
The findings are reported in the journal Proceedings of the Royal Society B.

Males were driven to spectacular displays by model females
Christopher Clark from the University of California Berkeley filmed the courtship dives of male Anna's hummingbirds on cameras able to capture 500 frames per second.
Their top speed, he said, was "greater than [that] of a fighter jet with its afterburners on, or the space shuttle during atmospheric re-entry".
Jet fighters, however, are able to out-accelerate the little birds.
In the latter stages of their dives, when they spread their wings to pull up, the hummingbirds' "instantaneous acceleration" was, said Mr Clark, "greater than any organism previously recorded undergoing aerial manoeuvres".
And that was all without the help of a powerful jet engine.
The study, Mr Clark said, was an example of how such displays, triggered by the prospect of a mate, could be used to study the very limits of animals' abilities.

The CO2 Lag

What does the lag of CO2 behind temperature in ice cores tell us about global warming?
Filed under:
FAQ
Greenhouse gases
Paleoclimate— group @ 9:42 AM - ()
This is an issue that is often misunderstood in the public sphere and media, so it is worth spending some time to explain it and clarify it. At least three careful ice core studies have shown that CO2 starts to rise about 800 years (600-1000 years) after Antarctic temperature during glacial terminations. These terminations are pronounced warming periods that mark the ends of the ice ages that happen every 100,000 years or so.
Does this prove that CO2 doesn't cause global warming? The answer is no.
The reason has to do with the fact that the warmings take about 5000 years to be complete. The lag is only 800 years. All that the lag shows is that CO2 did not cause the first 800 years of warming, out of the 5000 year trend. The other 4200 years of warming could in fact have been caused by CO2, as far as we can tell from this ice core data.
The 4200 years of warming make up about 5/6 of the total warming. So CO2 could have caused the last 5/6 of the warming, but could not have caused the first 1/6 of the warming.
It comes as no surprise that other factors besides CO2 affect climate. Changes in the amount of summer sunshine, due to changes in the Earth's orbit around the sun that happen every 21,000 years, have long been known to affect the comings and goings of ice ages. Atlantic ocean circulation slowdowns are thought to warm Antarctica, also.
From studying all the available data (not just ice cores), the probable sequence of events at a termination goes something like this. Some (currently unknown) process causes Antarctica and the surrounding ocean to warm. This process also causes CO2 to start rising, about 800 years later. Then CO2 further warms the whole planet, because of its heat-trapping properties. This leads to even further CO2 release. So CO2 during ice ages should be thought of as a "feedback", much like the feedback that results from putting a microphone too near to a loudspeaker.