Important new molecule in the biology of dementia

Anthony L. Komaroff, NEJM Journal Watch, April 8, 2014

Two molecules — β-amyloid and tau — are important in the biology of Alzheimer disease. Yet, high concentrations of them, either alone or together, do not seem to be sufficient to cause the disease.

In a study in the March 27 issue of Nature (http://dx.doi.org/10.1038/nature13163), researchers evaluated the molecules produced in the brains of older people with preserved cognitive function or with dementia and identified a candidate molecule called REST, which is important in embryonic brain development. The production of REST is silenced after embryonic development is completed, but is turned back on in aging brains. The researchers discovered that production continues in healthy older people with preserved cognition — but switches off in people with mild cognitive impairment, Alzheimer disease, or one of several other dementing diseases. REST deficiency was most striking in areas that are most affected in Alzheimer disease. Experiments showed that REST protects neurons from the toxic effects of β-amyloid and oxidative stress and protects against apoptosis (which is programmed cell death). Deleting the gene for REST in mice led to age-related neurodegeneration.

The REST molecule might protect the brain against age-related degenerative diseases, including Alzheimer disease. This molecule now becomes an important focus in understanding the underlying biology of dementia, as well as a target for therapeutics. Not all new and exciting putative disease-related molecules stand the test of time, but many experts are betting that this one will.

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REST and stress resistance in ageing and Alzheimer’s disease

Tao Lu, Liviu Aron, Joseph Zullo, Ying Pan, Haeyoung Kim, Yiwen Chen, Tun-Hsiang Yang, Hyun-Min Kim, Derek Drake, X. Shirley Liu, David A. Bennett, Monica P. Colaiácovo & Bruce A. Yankner

Nature 507, 448–454 (27 March 2014) doi:10.1038/nature13163

Abstract

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer’s disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer’s disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer’s disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

The Wall, by Marlen Haushofer (1968)

I had washed my hair, and it now floated, light and bushy, around my head. The rainwater had made it soft and smooth. Looking in the mirror I cut it short so that it just covered my ears, and I contemplated my tanned face under its sun-bleached cap of hair. It looked very strange, thin, with slight hollows in the cheeks. Its lips had grown narrower, and I felt this strange face was marked by a secret need. As there were no human beings left alive to love this face it struck me as quite superfluous. It was naked and pathetic, and I was ashamed of it and wanted nothing to do with it. My animals were fond of my familiar smell, my voice and my movements. I could easily cast off my face; it was needed no longer. At this thought a feeling of emptiness rose up in me, which I had to get rid of at any price. I looked for some kind of work to do, and told myself that in my situation it was childish to mourn a face, but the tormenting sense that I had lost something important would not be driven away.

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I have always been fond of animals, in the slight and superficial way in which city people feel drawn to them. When they were suddenly all I had, everything changed. There are said to have been prisoners who have tamed rats, spiders and flies and begun to love them. I think they acted in accordance with their situation. The barriers between animal and human come down very easily. We belong to a single great family, and if we are lonely and unhappy we gladly accept the friendship of our distant relations. They suffer as we do if pain is inflicted on them, and like myself they need food, warmth and a little tenderness.

[[[ ]]]
But if time exists only in my head, and I’m the last human being, it will end with my death. The thought cheers me. I may be in a position to murder time. The big net will tear and fall, with its sad contents, into oblivion. I’m owed some gratitude, but no one after my death will know I murdered time. Really these thoughts are quite meaningless. Things happen, and, like millions of people before me, I look for a meaning in them, because my vanity will not allow me to admit that the whole meaning of an event lies in the event itself. If I casually step on a beetle, it will not see this event, tragic for the beetle, as a mysterious concatenation of universal significance. The beetle was beneath my foot at the moment when my foot fell; a sense of well-being in the daylight, a short, shrill pain and then nothing. But we’re condemned to chase after a meaning that cannot exist. I don’t know whether I will ever come to terms with that knowledge. It’s difficult to shake off an ancient, deep-rooted megalomania. I pity animals, and I pity people, because they’re thrown into this life without being consulted. Maybe people are more deserving of pity, because they have just enough intelligence to resist the natural course of things. It has made them wicked and desperate, and not very lovable. All the same, life could have been lived differently. There is no impulse more rational than love. It makes life more bearable for the lover and the loved one. We should have recognized in time that this was our only chance, our only hope for a better life. For an endless army of the dead, mankind’s only chance has vanished for ever. I keep thinking about that. I can’t understand why we had to take the wrong path. I only know it’s too late.

(translated by Shaun Whiteside)

The importance of reduced meat and dairy consumption for meeting stringent climate change targets

Abstract
For agriculture, there are three major options for mitigating greenhouse gas (GHG) emissions: 1) productivity improvements, particularly in the livestock sector; 2) dedicated technical mitigation measures; and 3) human dietary changes. The aim of the paper is to estimate long-term agricultural GHG emissions, under different mitigation scenarios, and to relate them to the emissions space compatible with the 2 °C temperature target. Our estimates include emissions up to 2070 from agricultural soils, manure management, enteric fermentation and paddy rice fields, and are based on IPCC Tier 2 methodology. We find that baseline agricultural CO₂-equivalent emissions (using Global Warming Potentials with a 100 year time horizon) will be approximately 13 Gton CO₂eq/year in 2070, compared to 7.1 Gton CO₂eq/year 2000. However, if faster growth in livestock productivity is combined with dedicated technical mitigation measures, emissions may be kept to 7.7 Gton CO₂eq/year in 2070. If structural changes in human diets are included, emissions may be reduced further, to 3–5 Gton CO₂eq/year in 2070. The total annual emissions for meeting the 2 °C target with a chance above 50 % is in the order of 13 Gton CO₂eq/year or less in 2070, for all sectors combined. We conclude that reduced ruminant meat and dairy consumption will be indispensable for reaching the 2 °C target with a high probability, unless unprecedented advances in technology take place.

Fredrik Hedenus, Stefan Wirsenius, Daniel J. A. Johansson
Department of Energy and Environment, Chalmers University of Technology, Gothenburg, Sweden

Climatic Change. Published online 28 March 2014.
doi:10.1007/s10584-014-1104-5

environment, environmentalism, animal rights, vegetarianism, veganism

The real agenda of school choice opponents: protecting privilege

Perhaps Steve Nelson should have heeded his feelings of “caution and ambivalence” before submitting his jeremiad against school choice (“Real Agenda of School-Choice Advocates,” Valley News [West Lebanon, N.H.], January 5). It is difficult to imagine a more awkward and inappropriate source of such a lamentation than the head of an expensive private school in Manhattan [The Calhoun School].

Nelson is rightly concerned about quality, but erroneously states, “The one comprehensive study done to date shows that charters on balance do slightly worse than the public schools they replaced.” Assuming that he is referring to the “National Charter School Study” by the Stanford University Center for Research on Education Outcomes (CREDO), the 2013 report actually states that “charter schools now advance the learning gains of their students more than traditional public schools in reading[, and] academic growth of charter students in math [...] is now comparable to the learning gains in traditional public schools.” CREDO also separately studied Louisiana, which Nelson singled out for condemnation: “The charter school sector in Louisiana has a trend of strong results.”

Obviously, not all private or charter schools are commendable, voucher systems are far from ideal, and profiteers exploiting a real need are rightly decried. But students who are failed by their public school don’t have time to wait for improvements. They need those alternatives now. It certainly doesn’t help to accuse their parents of tearing apart “the connective tissue of our nation” for trying to do what’s best for their children.

Since Nelson defended his own alternative school as decidedly not rending “America’s social fabric,” he would have done better to suggest more progressive ways to expand such options for others. As noted by Ginia Bellafante in the same day’s New York Times, Mayor Bill De Blasio’s newly appointed Schools Chancellor, Carmen Fariña, has high praise for a network of charter schools serving the poorest neighborhoods of Brooklyn. And the cover story of the Valley News featured the Ledyard Charter School, which impressively meets the needs of many area students for an alternative to the regular high schools. Not only the schools and students, but society as a whole would clearly benefit from more support for such alternatives.

A progressive approach to education requires choice for all, not just the rich.

human rights, Vermont

Three-dimensional chess

While U.S. President Obama denies involvement in Ukraine yet decries the remarkably restrained government response to violent protesters as repressive and antidemocratic, even as his Assistant Secretary of State for European Affairs is recorded going over her plans for regime change, and nonsensically insists that (democratically elected) Ukraine President Yanukovich has refused to negotiate with protesters when it is clearly the other way around, here are a few pieces from Counterpunch about this week's state of the great game (of hypocrisy).

Masking Tragedy in Ukraine, by Chris Floyd

Obama Pushes for Regime Change in Venezuela, by Mark Weisbrot

Do We Care About People If They Live in Bahrain? by David Swanson

human rights, anarchism, anarchosyndicalism

More on science fetishization

The corporate bullies of GMOs, wind power, “smart” meters, etc. invariably appeal to “science” to dismiss concerns of harm and tout the claims of good. But the actual good is invariably the benefit to their companies’ or research teams’ viability and profits. There is no questioning of their necessity or consideration of what is to be lost or taken away (e.g., farming freedom, open and wild spaces, privacy, etc.).

Their appeal to science is amoral. Their defenders apparently believe that a conclusion is “good” simply for being reached logically. And that criticism of science, however logical, can not in fact be so, because logic has already determined that it is good.

The problem, of course, is an infantile division of human thought between “rational” and “emotional”. Both religion and science operate with both, but the latter claims the exclusive mantle of “reason” and then self-servingly stops there. Any questioning of what science does in the name of reason, or what companies do under the name of science, is called an attack on reason itself, even when it is itself quite reasonable.

The business of science, as its own gatekeeper, is often deaf to reason outside its own self-serving logic. A prime example is the swallowing by GMO supporters of the claim that Roundup-Ready crops would reduce pesticide use, when they are expressly designed to tolerate the company’s own pesticide, thus removing an important check on that pesticide’s use. The result has indeed been an increase in pesticide use, and the “anti-science fear-mongers” who warned of super-weeds and the threat to monarch butterflies have been proved correct. While “golden rice” has been talked about for many years without any practical results, the actual results of GMO “research” have been “terminator” genes to prevent seed saving and plants that produce their own pesticides, as well as pesticide-tolerant crops. Even if golden rice were a beneficial reality, it has nothing to do with all that is wrong with the GMO business.

The assertion that humans have always manipulated the genes of plants and animals illustrates the amoral logic that actually, in the service of corporate science, avoids thought. There is a big difference between selecting the results of a plant or animal’s own natural processes and splicing genes between species and even kingdoms. The latter represents a violation of the natural order that science purports to study.

Reason without consideration of ethics or morals, or simply without considering potential harms or seriously assessing actual benefits, is a mark of a sociopath. Human reason is not a good in itself. It is ultimately self-serving: hence the term “rationalization”. And rationalization of corporate depredation and profit — along with demonization of those who question it — is not science.

wind power, wind energy, environment, environmentalism, human rights, animal rights, anarchism, ecoanarchism, anarchosyndicalism

Social aspects of wind energy development

“When people are talking about changing the way we harness and use energy, industrial wind instead entrenches a centralized and inefficient system. When people are talking about reducing the burning of fossil fuels, industrial wind entrenches the grid’s dependence on them. When people are talking about moderating the corporate control of society, industrial wind entrenches the worst of predatory and crony capitalism that works to move more public money into private hands, transfering the common wealth of the many into the pockets of a few without regard for human, societal, or environmental cost. Big wind operates much like — and is often firmly embedded in — the military-industrial-banking complex subverting democracy and fairness by making politics a stepping stone to private riches, with the frisson of riding a wave of green-technology utopianism. Only those who have sworn allegiance to their program are citizens of their country. The rest of us are only resources to exploit and barriers to overcome.”

—from Wind Energy Primer

wind power, wind energy, wind turbines, wind farms, environment, environmentalism, human rights, animal rights, , anarchism, ecoanarchism, anarchosyndicalism