Edouard de Castro

Stirring science news/topics

Researchers found, in cultured cells, that N-acetylcysteine, a widely-used “drug” / food complement – “soaking up” reactive oxygen (among other things) – could prevent (some of?) the molecular damages occurring in Hutchinson Gilford progeria – a condition where children age up to eight times too quickly.
It hasn’t yet been given to children with the illness… A real full randomised clinical trial of the drug is not possible as the condition is so rare (78 cases worldwide!), but it could/will be tried.

(metal rust © youthedesigner.com)

Our findings suggest that un-repaired Reactive oxygen species – induced DNA double-strand breaks [= DNA damages] contribute significantly to the [restrictive dermopathy] RD and [Hutchinson Gilford progeria syndrome] HGPS phenotypes and that inclusion of [N-acetylcysteine] NAC in a combinatorial therapy might prove beneficial to HGPS patients.

BBC News article

original publication:
The accumulation of un-repairable DNA damage in laminopathy progeria fibroblasts is caused by ROS generation and is prevented by treatment with N-acetyl cysteine, Human Molecular Genetics (2011) 20 (20): 3997-4004. doi: 10.1093/hmg/ddr327

p.s. Jan 2012

Stem cell-like progenitor cells (derived from the muscle of young healthy mice) injection doubles progeric mice lifespan: science daily article

A paradigm shift: Adult stem cells can be rejuvenated

Researchers from the Buck institute and Georgia Tech found that while young adult stem cells are able to suppress the transcriptional activity of “junk” ALU genomic elements (integrated remains of old viral infections in Supraprimates) and deal with the damage to the DNA, older adult stem cells are not able to scavenge this transcription. By suppressing the accumulation of toxic transcripts from those ALU elements, they were able to reverse the process of human adult stem cell aging in culture!

image © genomicenterprise.com

Our results demonstrate that the cytotoxicity of induced Alu repeats is functionally relevant for the human adult stem cell aging. Stable suppression of Alu transcription can reverse the senescent phenotype, reinstating the cells’ self-renewing properties and increasing their plasticity by altering so-called “master” pluripotency regulators.

This is a major finding: cellular senescence and ultimately cellular aging, is not an irreversible process!

They used lenti-virus delivering Alu inhibitory shRNA (Small hairpin RNA) to “silence” / knockdown Alu transcription…
Not yet usable in live humans (although siRNA – without the need to pass via an shRNA precursor expressed by a virus – could be injected ~directly c.f. Performing RNAi Experiments in Animals), but this study represents a paradigm shift!

I think that future studies will have to be performed to determine if those rejuvenated cells are completely equivalent to “young” ones (and do not become cancerous) ...

sciencedaily.com article
medicalxpress.com article

original publication:
Inhibition of activated pericentromeric SINE/Alu repeat transcription in senescent human adult stem cells reinstates self-renewal, Cell Cycle, Volume 10, Issue 17, September 1, 2011 (PMID 21862875)

[Nov 2 2011] in the same vein, a new study (published in Nature journal!) as shown that removing senescent cells somehow rejuvenates mice! Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders

to summary: removing trash (junk genetic element expression, senescent cells) is good for you! ;-)

Researchers at the University of Nottingham and the University of Maastricht have improved the use of genetically engineered bacteria to destroy cancer cells.
Spores of the Clostridium sporogenes anaerobic bacteria injected into patients will only grow in solid tumours (where there is no/low oxygen). Later, an anti-cancer drug is then injected as an inactive “pro-drug” form. When the pro-drug reaches the site of the tumour, a bacterial genetically engineered enzyme activates the drug, killing nearby tumor cells. As the bacteria grew only in tumor tissues, the enzyme is only present there, therefore the pro-drug will only become active in tumors.

When Clostridia spores are injected into a cancer patient, they will only grow in oxygen-depleted environments, ie the centre of solid tumours.
This is a totally natural phenomenon, which requires no fundamental alterations and is exquisitely specific. We can exploit this specificity to kill tumour cells but leave healthy tissue unscathed.

This therapy will kill all types of tumour cell. The treatment is superior to a surgical procedure, especially for patients at high risk or with difficult tumour locations

We anticipate that the strain we have developed will be used in a clinical trial in 2013 led by Jan Theys and Philippe Lambin at the University of Maastricht in The Netherlands.

The work was presented to the Society of Microbiology’s autumn conference at the University of York. (= unpublished results so far!... what is the used pro-drug/enzyme “combo”?... + looks that it was only tested on animals…)

physorg article
sciencedaily artcile
BBC news article

A revolution in the treatment of viral infections

Researchers at MIT’s Lincoln laboratory have developed a new antiviral drug named DRACO (double-stranded RNA activated caspase oligomerizers) that is effective against ~all viruses.
It was tested on human and animal cells and was effective against 15 tested viruses including some rhinoviruses (common cold), H1N1 influenza (flu), a polio virus, a stomach virus, dengue fever and several other hemorrhagic fever viruses.

H1N1 influenza A (flu) virus CGI. © proactiveinvestors.com

The drug can identify cells that have been infected by a virus – by targeting a type of RNA produced only by infected cells – then kill those cells to terminate the infection! It combine a dsRNA-binding protein with another protein that induces cells to undergo apoptosis (programmed cell suicide). It also includes a “delivery tag” (taken from naturally occurring proteins) that allows it to cross cell membranes and enter inside cells. However, if no dsRNA is present, DRACO leaves the cell unharmed.
Could be on pharmacy shelves in a decade!...

In theory, it should work against all viruses

Most of the tests reported in this study were done in human and animal cells cultured in the lab, but the researchers also tested DRACO in mice infected with the H1N1 influenza virus. When mice were treated with DRACO, they were completely cured of the infection. The tests also showed that DRACO itself is not toxic to mice.

Rider says he hopes to license the technology for trials in larger animals and for eventual human clinical trials.

n.b. As the drug is not directly targeting the virus but the infected host cells, it will be very difficult for the virus to become resistant! (unless it doesn’t provoke any reaction from the infected cells … by being harmless!) ... it’s the “perfect” drug… except maybe for wide spread infections where killing all the infected cells might kill the host! (is probably just for early-stage treatment!)

p.s. Couldn’t this kind of system be used to target and kill cancer cells!? ... but it’s not easy to find and track a molecular target that is exclusively cancer specific.

Broad-Spectrum Antiviral Therapeutics (PLOS one article)

MITnews article

A new (or revived) theory / view on cancer

In a Cell Cycle journal article, researchers propose that cancer formation is akin to the evolution of a new species and that carcinogenesis is fulled by aneuploidy – losses or gains of chromosomes – [and other chromosomal damages] altering the expression and stability of the whole genome. Aneuploidy itself could be caused by carcinogens, certain replication errors (c.f. mitotic catastrophe) [and genome destabilizing mutations].
The Proponents of the classic mutation theory claim that aneuploidy is the consequence of cancer, here the researchers argue that it is the cause.

Spectral karyotyping of highly aneuploid (69 chromosomes!) human cell line UMSCC 81 © clincancerres.aacrjournals.org

Driven by their inherent genetic instability, aneuploid cells evolve random karyotypes automatically. Most of these cell die, but a very small minority acquires reproductive autonomy and immortality [with enrichment in proto-oncogenes and tumor suppressor genes mutations]. Selection for reproductive survival stabilizes new cancer cells against the inherent instability of aneuploidy within specific margins of variation.
Genetic divergence, selection, then stabilization of a new karyotype: this looks like a speciation process.

In few words: Aneuploidy is not a wasteful side effect of being an immortal cancer cell harboring few cancer causing mutations, but the “root” of the cancer: messing the whole genome, and providing a pool of unstable = fast evolving parasitic cells – representing new species – ready to evolve against/around most treatments.
n.b. All cancer cells are aneuploid!
n.b. Some tumors are transmissible + with a distinct karyotype = they literally represent autonomous parasitic species! c.f. transmissible cancer wikipedia article

[but few mutations might induce/favor aneuploidy, so the classical “mutation theory” might be kind of right! just not starting with tumor suppressor gene / proto-oncogene mutations]

Cell Cycle paper: Is carcinogenesis a form of speciation?

news-medical.net article

sciencedaily.com article

“I think Duesberg is correct by criticizing mutation theory, which sustains a billion-dollar drug industry focused on blocking these mutations,” said Vincent, a medical oncologist. “Yet very, very few cancers have been cured by targeted drug therapy, and even if a drug helps a patient survive six or nine more months, cancer cells often find a way around it.”

[yes, but maybe there is only a finite number of “ways” a cell can be immortal and invasive, so blocking several – actual and potential – key mutations at the same time could some day keep most cancers at bay?]

because the disrupted chromosomes of newly evolved cancers are visible in a microscope, it may be possible to detect cancers earlier

[it’s known since ages isn’t it?... but ‘looks like it’s not that easy to put a tiny microscope inside our bodies to visit each cell ;-)]

science20.com article

The inability to grow blood vessel networks is the bigest problem in regenerative medicine today as without blood supply, you cannot make a large tissue structure (thicker than a couple hundred microns)!

capillary network (credit: Image courtesy of Rice University, taken from sciencedaily.com)

To mimic the body’s extracellular matrix, where blood vessels could grow, researchers from Rice University and other Texas Medical Center institutions, used modified polyethylene glycol (PEG) gel, 3D engraved by “two-photon lithography” – an ultrasensitive way of using light to create intricate three-dimensional patterns within the soft PEG hydrogels – infused with living cells and growth factors to grow blood capillaries throughout the gel matrix.
Doing so they have broken one of the major roadblocks on the path to growing transplantable tissue in the lab!

To test these new vascular networks, the researchers implanted the gels into the corneas of mice (where no natural vasculature exists). After injecting a tracing dye into the mice’s bloodstream, the researchers could confirm normal blood flow in the newly grown capillaries.

A major development! The first step in real tissue / organ engineering!?...

RiceUniversity video
media.rice.edu announce

physorg.com article
sciencedaily article
Acta Biomaterialia original paper

Researchers at the Stanford University School of Medicine have identified calreticulin (CRT) as the pro-phagocytic (“eat me”) signal that is highly expressed on the surface of several human cancers, but was minimally expressed on most normal cells.
They’ve also shown that this signal should be counterbalanced by the expression of an anti-phagocytic (“don’t eat me”) signal identified as CD47 in order for the (CRT positive) cancer cells to survive.

Calreticulin (pdb 1hhn) skeleton structure © wikipedia.org

CD47 is a cell surface protein that serves as a signal inhibiting phagocytosis through ligation to its receptor SIRPα (signal regulatory protein &alpha) on phagocytic cells.
Blocking CD47-SIRPα interaction with a monoclonal antibody against CD47 results in phagocytosis of cancer cells and leads to in vivo tumor elimination! Yet normal cells remain mostly unaffected as they don’t display the “eat me” signal (Cell surface CRT is expressed on cancer, but not most normal, stem and progenitor cells).

The researchers also found that the most aggressive cancers were the ones making the most CRT: CRT expression is associated with tumor progression and worse clinical outcome across several tumor types. This raises hopes that some of aggressive cancer cells may be the most vulnerable to therapies targeting CD47 and CRT.

If all (aggressive) cancer cells have to make CRT (conferring them some survival advantage!?) then just blocking the counterbalancing signal CD47 would make a very promising, ~simple and ~side effect free therapy! (but it’s more likely that there will be selection for mutant cancer cells that can thrive without CRT but at least it’s another weapon against cancer)

Science Daily article
Science Translational Medicine article

Telomere reactivation and partial reversal of aging in mice

Researchers at Harvard, manipulated telomerase activity in mice to study its effect on aging.

(green) telomeres at the tips of (blue) chromosomes [image taken from wired.com]

Telomerase less mice do age prematurely and are infertile with small brains, damaged intestines and poor senses of smell. Activating telomerase for a month (the used mutants have their telomerase gene “replaced” by an artificial construct expressing a telomerase protein fused to an estrogen receptor, that could only become active in the presence of a special form of estrogen) not only stopped premature aging, but rejuvenated the treated mice, with cells returning to a growth state, reversal of tissue degeneration, and increase in size of the spleen, testes, and brain.

Short lived mutant mice lacking telomerase activity do not age “normally” per se, but rejuvenation is anyhow a spectacular result. Data on (temporary) telomerase over-activation on mice with a normal telomerase activity is probably on its way… but will take more time!

article on harvard gazette
nature article

Proteasome and protein rejuvenation

French researchers from CNRS/ENS Lyon, instead of comparing old cells / organism versus young ones as everybody, decided to study aging from another perspective: looking at natural examples of rejuvenation: why / how / when germ cells become ‘young’ again!

Understanding aging by studying reproduction: the protein “damage” signal (white) drops sharply (white arrow) at a precise stage of the maturation of the oocytes destined to become embryos [image taken from physorg.com]

They monitored the cellular oxidation level during germ cell maturation (in C. elegans they developed a novel immunofluorescence technique to in situ visualize the level of protein carbonylation) and observed that:
1) the germline (of gametes) is damaged – precluding the idea that the germline does not age (the germline looks even more oxidized than the surrounding somatic tissues)!
2) at a precise stage of maturation of the oocytes the level of oxidation dropped suddenly!

Before reproduction, the proteins in our gametes are therefore “cleansed” and rejuvenated. Inhibition of the proteasome (which serves to degrade proteins) prevents this protein rejuvenation, hinting that correct protein degradation – via the proteasome – is an important process against cellular aging... (about protein degradation and aging, see also below: Stopping protein buildup and aging)

It would be nice if they could also visualize telomere lenght and/or telomerase activity in situ!

‘would be nice to be able to boost proteasome activity with drugs (e.g. oleuropein found in olive oil!) ... maybe acting on proteasome activator proteins and/or PARP-1

physorg.com article
Aging Cell article

Boeing subsidiary Spectrolab to mass produce record breaking 39.2 percent efficiency solar cell.

I’m really not into the “green” obsession, but this is really high tech and exciting!

a photovoltaic solar cell © wikimedia

Spectrolab is the world’s leading supplier of solar cells for satellites. Boeing hopes to transfer that success to the terrestrial solar cell market with those new high efficiency solar cells (existing ones achieve only around 10% of efficiency) that are expected to be available from January.
The US Solar America Initiative plan is to make solar energy cost-competitive with conventional electricity generation by 2015.

Free, limitless energy source…
Solar power + high efficiency batteries: bye bye “wired” charging!?

physorg.com article

The Spectrolab scientists also predict that with theoretical efficiencies of 58% in cells with more than three junctions using improved materials and designs, concentrator solar cells could achieve efficiencies of more than 45% or even 50% in the future.

gizmag article

11 years of radial velocity observations of the nearby red dwarf star Gliese 581 by a team of planet hunters from the University of California Santa Cruz, and the Carnegie Institution of Washington led to the discovery a new planet named Gliese 581g.

The newly discovered planet Gliese 581g (not shown) lies in the middle of the habitable zone! © ESO/Franck Selsis, University of Bordeaux taken from hellofromearth.net

This earth like planet – 3.1 to 4.3 times the mass of the Earth and a radius of 1.3 to 2.0 times that of Earth – is revolving tidally locked with a period of 36.6 days around the red dwarf star Gliese 581, 20.5 light years away from earth (in the constellation Libra). It is believed to be the first discovered planet that falls within a star’s habitable zone (Goldilocks, where the existence of liquid water is considered a strong possibility) ever found, the most Earth-like planet, and the best exoplanet candidate with the potential for harboring life found to date!

Its mass indicates that it is probably a rocky planet with a definite surface and that it has enough gravity to hold on to an atmosphere, likely one that is denser than Earth’s.
With one side of the planet always facing the star (tidal lock), temperatures could range from blazing hot in the light side to freezing cold in the dark side, with continuous Earth-like temperatures imaginable along the area between the bright and the dark side (where the sun would always be near the horizon). n.b. What a strange (for us) world!

Personally, given the ubiquity and propensity of life to flourish wherever it can, I would say that, my own personal feeling is that the chances of life on this planet are 100% [polemic]. I have almost no doubt about it… Life on other planets doesn’t mean E.T. Even a simple single-cell bacteria or the equivalent of shower mold would shake perceptions about the uniqueness of life on Earth.
(Steven Vogt, first author)

The fact that we were able to detect this planet so quickly and so nearby tells us that planets like this must be really common.
(Steven Vogt)

Gliese 581g wikipedia article
National Science Foundation News article
The Astrophysical Journal article

Oct 22, 2010:

Controversy

First Goldilocks Exoplanet May Not Exist

Since publishing the data set the American group had used, the Swiss had extended their record to 6.5 years, including a total of 180 measurements. “We do not see any evidence for a fifth planet … as announced by Vogt et al.,” Pepe wrote to Science in an e-mail from the meeting. On the other hand, he added, “we can’t prove there is no fifth planet.”

If those orbits are in fact circular, as the American group believes, the supposed elongation could mask the presence of a smaller fifth planet. But even if data-analysis issues are not ironed out, all agree, a few more years of observation should do the trick.

Feb 2011:

not about Gliese but exoplanet hunt:

NASA spots 54 potentially life-friendly planets

In just a year of peering out at a small slice of the galaxy, the Kepler telescope has spotted 1,235 possible planets outside our solar system. Amazingly, 54 of them are seemingly in the zone that could be hospitable to life

NASA Finds Earth-Size Planet Candidates in Habitable Zone, Six Planet System

Of the 54 new planet candidates found in the habitable zone, five are near Earth-sized. The remaining 49 habitable zone candidates range from super-Earth size – up to twice the size of Earth – to larger than Jupiter.

Researchers at the California Institute of Technology (Caltech), are developing a mutation specific treatment for cancer relying on synthetic small RNAs that will “stick” specifically to mutated RNAs in cancer cells and trigger cell auto-destruction.
Will this treatment work in patients? won’t it select cancer cells that lack any self destruction response? (and therefore are resistant to this treatment): to be determined, but this represents a step in the right direction as the “ultimate” – specific cancer treatment should be: kill cells if – and only if – they had been “diagnosed” with a certain mutation, leaving the rest of the organism unharmed.

small conditional RNAs (light and dark blue) bind to a targeted RNA cancer mutation (orange and green), triggering self-assembly of a long double-stranded RNA polymer that activates an innate immune response (gray turns to red) leading to cell death. [from physorg.com]

image courtesy of Suvir Venkataraman, William M. Clemons, Jr. and Niles A. Pierce (Caltech)

This approach effectively eliminates lab-grown human brain, prostate and bone cancer cells in a mutation-specific manner. Future experiments will determine whether the treatment is effective in patients.

The first small RNA will open up if – and only if – it finds the cancer mutation. A positive “diagnosis” exposes a signal that was previously hidden within the small RNA. Once this small RNA is open, a second small RNA binds to it, setting off a chain reaction in which these RNA molecules continue to combine to form a longer chain. The length of the chain is an important part of the “treatment”. Longer chains trick the cell into thinking it has been invaded by a virus, tripping a self-destruct response.

physorg.com article
sciencedaily article

slated to appear online the week of September 6 2010 in Proceedings of the National Academy of Sciences (PNAS)

Unlike measuring radial velocity, this “new” exoplanet detection method is supposedly sensitive enough to find planets the size of Earth, orbiting around other stars with regular earth based telescopes!

If a planet passes in front of its parent star the observed star visual brightness drops by a small amount. Once a planet has been detected by the transit method, measures of variations in the timing of those transits could allow extremely sensitive detection of additional planets in the system with sizes potentially as small as Earth-sized planets!

An Earth-mass planet could cause deviations in the transit timing of a typical gas giant planet orbiting close to its star by up to 1 minute. This is a big enough effect to be detected with small 1m diameter telescopes! Discoveries can be followed up / confirmed with larger instruments.

(original paper accepted at Monthly Notices of the Royal Astronomical Society)
preprint: Transit timing variation in exoplanet WASP-3b

For final interpretation not only transit timing but also photometric observations of the transit of the predicted second planet and the high precision radial-velocity data are needed.

science daily article

2005 science report (theoretical?) article

Earlier research suggested that there was no interbreeding between Humand and Neanderthals, but these early results were not based on an analysis of the complete Neanderthal genome… (now the first draft of the complete neanderthal genome is ready; will be final soon [final/published May 2010, see link below]).

Now [April 20 2010] a genetic analysis of nearly 2,000 people from around the world indicates that humans interbred with extinct species twice, leaving their genes within the DNA of people today!

The researchers arrived at that conclusion by studying genetic data from 1,983 individuals from 99 populations in Africa, Europe, Asia, Oceania and the Americas. Sarah Joyce, a doctoral student working with Long, analyzed 614 microsatellite positions, which are sections of the genome that can be used like fingerprints. She then created an evolutionary tree to explain the observed genetic variation in microsatellites. The best way to explain that variation was if there were two periods of interbreeding between humans and an archaic species, such as Homo neanderthalensis or H. heidelbergensis.

Using projected rates of genetic mutation and data from the fossil record, the researchers suggest that the interbreeding happened about 60,000 years ago in the eastern Mediterranean and, more recently, about 45,000 years ago in eastern Asia. Those two events happened after the first H. sapiens had migrated out of Africa, says Long. His group didn’t find evidence of interbreeding in the genomes of the modern African people included in the study.

Note about Homo sapiens and neanderthalensis ancestor from wikipedia (Homo heidelbergensis page):

Heidelbergensis is the direct ancestor of H. sapiens and H. neanderthalensis. Neanderthals diverged from H. heidelbergensis probably some 300,000 years ago in Europe, during the Wolstonian Stage; H. sapiens probably diverged between 200,000 and 100,000 years ago in Africa.
Homo neanderthalensis retained most of the features of H. heidelbergensis after its divergent evolution. Though shorter, Neanderthals were more robust, had large brow-ridges, a slightly protruding face and lack of prominent chin. They also had a larger brain than all other hominins [1200–1900 cm3 skull capacity vs ~ 1350 cm3 for human]. Homo sapiens, on the other hand, has the smallest brows of any known hominin, was tall and lanky, and had a flat face with a protruding chin. H. sapiens has a larger brain than H. heidelbergensis, and a smaller brain than H. neanderthalensis

see also: Comparing Neanderthals and modern humans

references:

Nature News report

May 6 2010 updates:
(not about the microsatellite study but based on the complete genome. They arrive at the same conclusion!)

Neanderthal genes ‘survive in us’ (BBC News)

A Draft Sequence of the Neandertal Genome (Science)

The data suggest that between 1 and 4% of the genomes of people in Eurasia are derived from Neandertals.
...
A striking observation is that Neandertals are as closely related to a Chinese and Papuan individual as to a French individual, even though morphologically recognizable Neandertals exist only in the fossil record of Europe and western Asia. Thus, the gene flow between Neandertals and modern humans that we detect most likely occurred before the divergence of Europeans, East Asians, and Papuans. This may be explained by mixing of early modern humans ancestral to present-day non-Africans with Neandertals in the Middle East before their expansion into Eurasia.

Targeted Investigation of the Neandertal Genome by Array-Based Sequence Capture (Science)

we have identified 88 amino acid substitutions that have become fixed in humans since our divergence from the Neandertals.

Dec. 22 2010

Sequencing of Denisova hominin (based on nuclear DNA extracted from a finger boneand a tooth!) shows that it interbreed with Asian human population (itself, like all non african populations, having interbreed with Neandertals) around 50,000 years ago.
bbc news article
nature article – Human origins: Shadows of early migrations

© bbc.co.uk

July 2011

Genetic research confirms that non-Africans are part Neanderthal

When the Neanderthal genome was sequenced in 2010, they quickly compared 6000 chromosomes from all parts of the world to the Neanderthal haplotype. The Neanderthal sequence was present in peoples across all continents, except for sub-Saharan Africa, and including Australia.
There is little doubt that this haplotype is present because of mating with our ancestors and Neanderthals.

Researchers from the Massachusetts General Hospital provide data supporting an in vivo function for Amyloid beta (Aβ) – the primary constituent of the plaques found in the brains of Alzheimer’s disease (AD) patients – as an antimicrobial peptide (AMP)!
These small amyloid beta proteins might be part of the innate immune system, which provides broad defense against a wide range of pathogens.

Amyloid protein loop ©UCLA Newsroom

Amyloid beta is toxic to neurons, and the protein’s accumulation / clumping as plaques in the brains of Alzheimer’s patients is thought to induce the neurodegeneration characterizing the disorder. The protein is generated when a larger parent molecule called the amyloid precursorprotein (APP) is cleaved by enzymes. Several different types of Aβ can be generated by the cleavage; the more common Aβ 40 and Aβ 42 forms are particularly prone to aggregate into toxic plaques. It was thought for years that the amyloid beta were just metabolic garbage. The team found that Aβ 40 and mostly 42 have an anti-microbial activity (and has similarities with the human cathelicidin antimicrobial peptide LL-37).

Our findings suggest Aβ is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of Aβ-mediated pathology and has important implications for ongoing and future AD treatment strategies.

It looks like factors that trigger hyperactivity of the innate immune system – not only infection but also traumatic brain injury and stroke, which are already known to increase the risk for Alzheimer’s – could cause excessive deposition of A-beta…

The Alzheimer’s Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide [PLoS one article]

Science Daily article

p.s. Sept 2010:
Function found for the amyloid precursor protein
is an iron oxidase! (n.b. the precursor, not the beta amyloid)

Researchers from the UCLA AIDS Institute have found that a chemical from the plant Astragalus membranaceus root, frequently used in Chinese herbal therapy, can prevent or slow the progressive shortening of telomeres, which could make it a key weapon in the fight against HIV (where some T cells are driven into ~ exhaustion/senescence by over ~ stimulation/replication) and by extension – potentially – against aging.

Structure of parallel quadruplexes that can be formed by human telomeric DNA (© Wikipedia )

[from Wikipedia article] “A telomere is a region of repetitive DNA” (TTAGGG x n in Vertebrates) “at the end of chromosomes, which protects the end of the chromosome from destruction.” “The telomere is a disposable buffer, which is consumed during cell division and is replenished by an enzyme: the telomerase (reverse transcriptase TERT).” “Human somatic cells lacking telomerase gradually lose telomeric sequences as a result of incomplete replication.”
This shortening of telomeres places a limit on the number of times that most body cells can divide, the so-called Hayflick limit.

In the study, immune cells drawn from people with HIV were treated with a telomerase activator (from Geron / TAsciences) – a simple extract from Astragalus root named “TAT2” (cycloastragenol, CAS Registry no. 84605-18-5). The treated cells killed viruses better, divided longer and acted more youthful.

As for telomerase activity role in aging: the latest evidence in mammals surfaced in a study from Spain: Mice that were bred to have enhanced levels of telomerase (through genetic engineering) lived 26% longer.
Now a simple plant extract can enhance telomerase activity!... Let the testing and patenting (and fighting) with the activator (and putative – more active, more easily patentable – chemical synthetic derivatives) begin…

jimmunol article [Telomerase-Based Pharmacologic Enhancement of Antiviral Function of Human CD8+ T Lymphocytes]
cell article [Telomerase Reverse Transcriptase Delays Aging in Cancer-Resistant Mice]
sciencedaily article
mentioned in newsweek article

Sept 2010:
A Natural Product Telomerase Activator As Part
of a Health Maintenance Program

Scientists from the ATR Computational Neuroscience Laboratories have developed a new brain analysis technology that can “extract” images directly from the human brain (visual cortex) using software analyzing multivoxel patterns of fMRI 2 seconds single volume scans.
They succeeded in catching the visual cortex signals and then reconstructing the presented 10×10 patches black and white images (contrast patterns)!

In their experiment, the researchers first trained their system by “recording” individual brain patterns on known 400 different still images, then showed people the 6 letters in the word “neuron” and finally succeeded in reconstructing the presented letters.

By combining the outputs of local decoders that predicted local contrasts of multiple scales, we were able to reconstruct a large variety of images using only several hundred random images to train the reconstruction model.

Note: they “used” only 2 subjects. Obviously, the whole system is subject specific (I think!) ... training on one subject could not resolve images seen by another subject.

It was the first time in the world that it was possible to visualise what people see directly from the brain activity.

More interesting are attempts to reconstruct subjective states that are elicited without sensory stimulation, such as visual imagery, illusions, and dreams.

Neuron article [Visual Image Reconstruction from Human Brain Activity using a Combination of Multiscale Local Image Decoders]
ArsTechnica article

Researchers have ‘stopped’ the aging process in an entire organ for the first time

Researchers at Albert Einstein College of Medicine in New York City have shown that Chaperone-mediated autophagy (CMA) could be enhanced to allow mice to continuously degrade and recycle ‘damaged’ proteins that accumulate with old age. The team has previously found that CMA activity declines in aged organisms and has proposed that this failure in cellular clearance could contribute to aging via the accumulation of altered proteins.

Old mice with extra LAMP-2A show less protein buildup in their liver cells (right) than normal mice at the same age. © sciencenow.sciencemag.org, credit: Zhang and Maria Cuervo; Albert Einstein College of Medicine

Genetically manipulating the number of lysosomal receptors for CMA (receptor for ‘damaged’ proteins complexed to hsc70 chaperone) LAMP-2A – to compensate their age related loss, they showed that the livers of old mice with a preserved CMA system worked as well as those in younger animals.

Although this marked functional improvement surpassed our initial predictions, we do not think that a single protein, LAMP-2A, is responsible for the decline in liver function with age. Instead, we argue that our findings support the idea that restoration of one of the cellular quality control mechanisms— in this case, CMA—improves the intracellular milieu (by preventing accumulation of damaged proteins), and this slows down the deterioration of the other quality control mechanisms.
... In conclusion, to our knowledge, this work shows for the first time in vivo that maintenance of proper autophagic activity throughout life span prevents or slows down the functional failure associated with cellular proteotoxicity and accumulation of intracellular damage in aging
Zhang, Cuervo; Nature medecine

While her paper does not show increased survival rates among the mice, le Couteur, who has advised her recently on the research, says Cuervo does have data on improved survival rates which she intends to publish.
Cuervo is now working with pharmaceutical companies to identify drugs that will turn the receptors on, or make them more active. She believes maintaining efficient protein clearance may improve longevity and function in all the body’s tissues.
Discovery article

Cuervo suggested that studies of two dietary systems, the low fat and the calorie restricted diet, are suggesting evidence of a similar nature, that it’s to do with helping cells get rid of spent protein effectively.
Medicalnewstoday article

It looks the failure to remove damaged proteins is one cause, and not just the consequence of aging!

Could it be possible to achieve the same effect across the whole body!? and via drugs (or diet!)?

BBC News link
Nature medecine paper [Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function]
Nextbigfuture article
Sciencenow article [Long live the liver]
Discovery link
Medicalnewstoday link

Simple cancer cure soon to be tested in humans

Scientists have shown that transfusion of white blood cells from cancer-resistant mice can completely destroy tumours in mice, curing 100 percent of lab mice afflicted with advanced cancer! (See note below), and are about to embark on a human trial to test whether this technique also works in humans.

Granulocytes (among Platelets) © www.sciencemuseum.org.uk

Scientist have since identified similar cancer-killing activity in the white blood cells of some healthy humans (bbc news link). The anti-tumor activity seems to be primarily confered by granulocyte immune cells

In a small study of human volunteers, it was found that granulocytes cancer-killing activity was highest in people under age 50. They also found that this activity can be lowered by factors such as winter or emotional stress. Therefore the key to the success for the new therapy is to transfuse sufficient granulocytes from the best donors while their cancer-killing activities are at their peak level.

In mice, we’ve been able to eradicate even highly aggressive forms of malignancy with extremely large tumors … Hopefully, we will see the same results in humans. Our laboratory studies indicate that this cancer-fighting ability is even stronger in healthy humans (Zheng Cui).

Scientists at Wake Forest University Baptist Medical Center are about to embark on a human trial, and are currently recruiting 500 local potential donors who are 50 years old or younger and in good health to have their blood tested. Of those, 100 volunteers with high cancer-killing activity will be asked to donate white blood cells for the study. Cell recipients will include 22 cancer patients who have solid tumors that either didn’t respond originally, or no longer respond, to conventional therapies.

sciencentral link
sciencedaily link

Note: what about host rejection of foreign cells (graft-versus-host) ? It seems granulocytes don’t induce such rejection, but other immune cells that might could be injected by mistake during the transfusion (so the cells have to be extremely well sorted?)!

Caloric restriction and stress response… again… but this time not “for” aging but as a “magic shield” – chemo boost – against cancer!

Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy

Starvation induces healthy cells to go into “protective” mode. It looks that cancer cells are not being able to respond to that [my hypothesis: because they have their mitochondria turned off?], and just continue on their normal pro-growth track, leaving them differentially more sensitive to oxydative/chemo stress.

US and Italian researchers found that starvation could potentially boost the effectiveness of chemotherapy used on cancer patients. Mice given a high dose of chemotherapy after fasting continued to thrive. The same dose killed half the normally fed mice! The hyper aggresive chemotherapy worked as intended on cancer, extending the lifespan of mice injected with aggressive human tumors.

(from PNAS article abstract) Short-term starved S. cerevisiae or cells lacking proto-oncogene homologs were up to 1,000 times better protected against oxidative stress or chemotherapy drugs than cells expressing the oncogene homolog Ras2val19. Low-glucose or low-serum media also protected primary glial cells but not six different rat and human glioma and neuroblastoma cancer cell lines against hydrogen peroxide or the chemotherapy drug/pro-oxidant cyclophosphamide. Finally, short-term starvation provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/prooxidant etoposide.

This is not just one more anti-cancer treatment that attacks the cancer cells. There is an important conceptual difference: Here the study focused instead on protecting all the other healthy cells!
This is a very important paper. It defines a novel concept in cancer biology. It’s a direction that’s worth pursuing in clinical trials in humans. said cancer researchers Pinchas Cohen, Felipe Sierra

A new way to fight cancer: the silver shield [physorg.com]

PNAS article [Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy]

Note:
Does FGF21 ‘starvation hormone’ (see FGF21 note) induce the same effect?

Muscle-enhancing drugs: tricking muscles into thinking they have been working out.

AMPK-PPARδ pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise; representing a novel pharmacologic target to reprogram muscle endurance.

Last year researcher from the Salk Institute for Biological Studies in San Diego have shown that genetically engineered mice with increased PPARδ (a master regulator of numerous genes) activity had almost double the running endurance of regular mice. Now the same team tested the effect of PPARδ and AMPK agonists.
One drug, Aicar (AMPK agonist), increased the mice’s running distance on a treadmill by 44 percent after just four weeks of treatment without any form of exercise training! A second drug, GW1516 (PPARδ agonist, developed by GlaxoSmithKline to raise levels of HDL), increases running distance by 70% but had to be combined with exercise to have any effect.

They showed that the AMP-mimetic AICAR can increase endurance in sedentary mice by genetically reprogramming muscle metabolism in a PPARδ – dependant manner.
Aicar appeard to change the physical composition of muscle, transforming the tissue from sugar-burning fast-twitch fibers to fat-burning slow-twitch ones, the same changes that occur through heavy endurance training.

5-aminoimidazole-4-carboxamideribonucleotide (AICAR)

Cell article [AMPK and PPARδ Agonists Are Exercise Mimetics]
sciencenow link
nytimes link
latimes link

~related story: Mighty Mice; myostatin and follistatin regulation of muscle build up: sciencedaily link

An innocuous-(but beautiful)-looking ctenophore (comb jelly) might be the direct progeny of the first animal on Earth. A massive analysis of the evolutionary biology of animals suggests that the earliest member of the metazoa kingdom was related to those comb jelly.
The jelly possesses distinct tissues and a nervous system! whereas the sponge (Porifera, “simplest true animal”), lacks both, showing that evolution doesn’t automatically means increasing complexity.

© hoxfulmonsters.com

The placement of ctenophores as the sister group to all other sampled metazoans is strongly supported in all our analyses.

If corroborated by further analyses, it would have major implications for early animal evolution, indicating either that sponges have been greatly simplified or that the complex morphology of ctenophores has arisen independently from that of other metazoans.

Sampled Ctenophores (in study):
Mertensiid sp.
Mnemiopsis leidyi (caspianenvironment.org link)

‘hope a complete sequenced genome will soon be available!...

Nature article [Broad phylogenomic sampling improves resolution of the animal tree of life]

Ctenophora entries in UniProt

Scientists at the University of Southern California have set a record for the single greatest lifespan extension yet produced in an organism.

www.genomenewsnetwork.org

The researchers were studying how caloric restriction extends life span in yeast [Caloric restriction (CR) is the only non-genetic intervention known to slow aging and extend (maximum and average) life span in organisms ranging from yeast to mice]. CR has been linked to the down-regulation of Tor, Akt, and Ras signaling.
The team showed that the deletion of both RAS2 and the Akt and S6 kinase homolog SCH9 genes in combination with caloric restriction caused a remarkable 10-fold life span extension!
It is believed that the mutations and the caloric restrictions push the organisms into a maintenance mode, enabling them to redirect energy from growth and reproduction into anti-aging systems until they can feed and breed again.

The researchers are also studying a human population isolated in the mountains of Ecuador that appears to have “equivalent mutations” to the genetically modified yeast. The humans have a mutation in their growth hormone receptor, which controls the genes that are analogous to the delete ones in yeast.
Two copies of the mutation result in a number of health problems (the correct expression of the genes is probably essential during development), but the scientists expect to find characteristics of disease-resistance and long-livedness amongst those with only one copy of the mutation (It looks that cancer is virtually unknown amongst this population).

Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras/PKA, Tor, and Sch9 [PLOS Genetics article]

sciencefriday link
msnbc link

Regulatory effects of small genetic variation

A study led by McGill University researchers has demonstrated that small DNA differences between individuals (single nucleotide polymorphisms – SNPs) can lead to dramatic differences in the way genes produce proteins. These, in turn, are (in part) responsible for the large differences in physical characteristics between individuals.

Majewski and his colleagues have demonstrated that the natural processing of messenger RNA (mRNA), via a process called splicing, is “modulated” by these SNPs. The SNPs in certain individuals lead to changes in splicing and result in the production of drastically altered forms of the encoded protein.

We detected 324 genes with significant associations between flanking SNPs and transcript levels. Of these, 39% reflected changes in whole gene expression and 55% reflected transcript isoform changes such as splicing variants (exon skipping, alternative splice site use, intron retention), differential 5’ UTR (initiation of transcription) use, and differential 3’ UTR (alternative polyadenylation) use.

mcgill link
Genome-wide analysis of transcript isoform variation in humans [Nature genetics link]

SNPs related and fun:
Eye Color Explained [discovermagazine]

Nuclear reprogramming, creates stem-like cells from the patient’s own cells!

Yamanaka and his colleagues have shown that their mouse technique (see Simple switch turns cells embryonic note) works with human cells as well.
Independently, James Thomson (university of Wisconsin, Madison) and his colleagues were also able to reprogram human cells, again by inserting just four genes (two of which are different from those Yamanaka uses).

(image from BBC News)

Yamanaka’s group used a retrovirus to express into adult cells OCT3/4, SOX2, KLF4, and c-MYC genes in order to reprogram cells (into stem cells) taken from the facial skin of a 36-year-old woman and from connective tissue from a 69-year-old man.
Thomson’s team used (identifying from scratch its own list of 14 candidate reprogramming genes): OCT3 and SOX2, as Yamanaka used, and two different genes, NANOG and LIN28.

Growing in a lab dish, the skin cells turned into ones that closely resemble embryonic stem cells, which have the potential to develop into every tissue of the body…
This could mean that stem cell research is no longer dependent on using cells from human embryos, which has proved highly controversial.

The induced cells do all the things embryonic stem cells do. It’s going to completely change the field (Professor James Thomson).

More work will be required to see how those cells differ from ‘normal’ stem cells and to find how to activate those genes without using a viral vector (that might cause problems).

BBC News link
sciencenow link
sciencedaily link

Nov. 30 2007: update: A simpler recipe for human stem cells
Yamanaka shows that he can make both human and mouse iPS cells with just three factors, without using c-myc (a known oncogene).

Advances in fluorescent gene reporting: Brain’s wiring seen in Technicolor

Researchers have developed a technique that will allow neurobiologists to draw a detailed wiring plan of the mammalian brain by inserting genes coding for fluorescent proteins into mice. Dubbed ‘Brainbow’, the system reveals individual neurons within the nervous system in up to 90 different colours.

from rsc.org (copyright Nature magazine)

The researchers inserted into mice a construct targeted (Cre/Lox system) to the central nervous system, with genes coding for 4 fluorescent protein emmiting ‘primary’ colours (red, yellow, cyan and orange) organized so that, randomly, only one of the genes are expressed per insertion. Depending on the number and ‘color’ of insertions (combinatorial expression), distinct cells will show distinct hues. Colours show how cells intertwine.

The research is showing the brain as we have never seen it before. This technique will allow neurobiologist to track changes in the neural circuitry up to the individual cell level; it could be also used to monitor the effects of therapies on the neural wiring, and more generally to (more precisely and easily) track tissue organisation changes in model organisms.

The transgenic mice and necessary research tools are now available for other scientists to use. The researchers plan to create transgenic fish, insects and nematode worms (C. elegans) using similar techniques.

rcs.org chemistryworld link
Nature news link
sciencefriday link [with video and bigger picts]

J Livet et al, Nature, 2007, 450, 56 [DOI:10.1038/nature06293]

Targeted virotherapeutic for the systemic treatment of cancer in humans

Researchers at Stanford University and Jennerex Biotherapeutics have engineered vaccinia virus (cousin of smallpox virus) into a cancer killing machine.
The virus was engineered from the strain of vaccinia virus that is the basis for the vaccine that has been used in hundreds of millions of people in vaccination against smallpox, so should therefore be safe for humans.

image from the-scientist.com

Viral genes were deleted in order to restrict virus replication to cancer cells (Western Reserve strain of vaccinia [WR] with deletions in the viral thymidine kinase [TK] and vaccinia growth factor [VGF]). The resulting virus infects cancer cells while leaving healthy cells alone. In addition, the researchers also spliced a gene (human GM-CSF) into the virus that makes it produce granulocyte-macrophage colony-stimulating factor (GM-CSF), which induces the body’s immune system to recognize and attack tumors infected by the virus, meaning that the virus also enhances the host immune response against cancer cells.
Granulocyte are now known to be an important factor in body’s responce to cancer, see: Rare People Have Extreme Anti-Cancer Immune Cells (15% of human may be especially resistant to cancer thanks to their granulocytes, see also my note about SR/CR mice).

One-Two Punch: After the virus has destroyed most of the tumors, it stimulates an elevated immune system response, that will mop up remaining cancer cells.

In a study appearing Thursday October 25 2007 in the Journal of Clinical Investigation, the researchers report that the new treatment resulted in the suppression of spleen tumors and (lung) metastasis in the rabbits on which it was tested. The virus is now headed toward phase II trials with human patients.

Scientists have been trying to genetically engineer viruses to selectively infect and destroy cancer cells for more than 10 years, but with limited success. Vaccinia represents a promising ‘platform’ for the design of oncolytic viruses (has a long history of human use during the smallpox eradication campaign, spread extremely rapidly within tissues, inherent tumor selectivity of certain strains, etc…). In addition, with the new JX-963 therapy, the virus doesn’t have to do the work alone – it elicits the body’s own defenses to mop up cancer cells.

Human trials (on patients with any form of solid tumor cancer) are expected to begin early next year.

Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963

sciencenow link
newscientist link
wired link

Scientists at the University of Rochester and the J. Craig Venter Institute have discovered a copy of the entire genome of a bacterial parasite – Wolbachia – inside the genome of its insects – Drosophila ananassae – host. The parasitic bacteria live inside its hosts’ cells, including the germ cells that give rise to eggs.

Wolbachia (red) inside fruit fly cells (DNA in green) – microbiology.ucsc.edu

The team found Wolbachia sequences in three wasp and four worm species genomes. Resequencing DNA from the tropical fruit fly Drosophila ananassae, the team discovered that the insect was carrying nearly the entire Wolbachia genome of more than 1 million DNA base pairs on one of its chromosomes. Most of the DNA appears to be nonfunctional, but the researchers found RNA transcripts from 30 Wolbachia genes!

The finding, suggests that lateral gene transfer – the movement of genes between unrelated species – might be much more widespread than previously thought and has serious repercussions for genome-sequencing projects; Bacterial DNA sequences are routinely discarded when (invertebrate) eukaryote genomes are assembled, yet these genes may indeed be part of the organism’s genome, and might even be responsible for functioning traits.

This study establishes the widespread occurrence and high frequency of a process that we would have dismissed as science fiction until just a few years ago.
W. Ford Doolittle – www.sciencedaily.com interview

Widespread Lateral Gene Transfer from Intracellular Bacteria to Multicellular Eukaryotes – Science article abstract

sciencedaily link
science news link

An 8-million-year-old bacterium was thawed out from the oldest known ice on Earth and brought back to life in the laboratory.

Kay Bidle of Rutgers University in New Jersey (USA) and his colleagues extracted DNA and bacteria from ice found between 3 to 5 metres beneath the surface of a glacier in the Beacon and Mullins valleys of Antarctica.

Whereas the “young” 100,000-year-old ice contained a variety of microorganisms – doubling in size every 7 days on average – the researchers found only one type of bacterium in the 8-million-year-old sample. It also grew in the laboratory but much more slowly, doubling only every 70 days.
Studies of isolated DNA from the samples showed that it had become increasingly fragmented as time went on.

By analysing samples of ice varying from 100,000 years to eight million years, they calculated a ‘DNA half-life’: the length of DNA fragments in the ice halves every 1.1 million years. The researchers believe the DNA is degraded by cosmic rays, which are particularly strong at the poles where the Earth’s magnetic field is at its weakest.

This half-life makes it unlikely that life on Earth was carried here on comets from outside our solar system, unless ice and rock could protect microbes deep inside from radiation.

Genetic popsicle [Nature news]
Eight-million-year-old bug is alive and growing [newscientist]

Note/update (Aug 27 2007): ~related subject
A new study shows that Bacteria can survive in deep freeze for hundreds of thousands of years by staying just alive enough (not as dormant spores) to keep their DNA in good repair. It seems that the best way to survive for a long time is to keep up metabolic activity and use it for continuous DNA repair…
National Geographic link

A new study came up with 2 gene variants which appear to confer some resistance to HIV infection.
The bearers of those variants have the ability to better keep the HIV virus load at bay.

Geneticists performed genome-wide analysis on ~30’000 people among which 486 were “resistant” and looked for polymorphisms associated with this resistance.

Individuals with one of the sequence variation dubbed rs9264942 of the HLA-C gene (human leukocyte antigen – C) have up to 90% less virus in their body than typically infected people.
The rs9264942 mutation appears to help fight HIV infection by increasing the amount of produced HLA-C protein. This protein helps alert the immune system to foreign particles, such as viruses, within cells. While HIV can disable similar proteins, known as HLA-A and HLA-B, it appears unable to do the same to HLA-C.

The other variation HLA-B*5701 is in the HCP5 gene which codes for a human endogenous retrovirus (a genetic fossil of a virus that inserted itself into human chromosomes long ago but no longer produces infectious progeny)!?

People infected with HIV have widely varying responses to the infection, with some falling sick quickly and others successfully fighting off full-blown AIDS for years or even decades. By understanding the determinants of this great variability, we might get hints on how to better fight the virus by finding new targets for anti-HIV drugs and new vaccine strategies.

This was the first time a genome-wide association analysis approach has been used for an infectious disease.

?This finding is detailed in the July 20 issue of Science?
DOI: 10.1126/science.1143767

sciencenow link

NewScientist article

A genetic modification that makes the brain less responsive to insulin increases the life span of mice, showing that the brain can regulate life span independently of the body’s ability to respond to insulin.

Relations between caloric restriction, insuline and aging are well documented. Caloric restricted mice are skinny, live longer, use insulin efficiently, and have low amounts of insulin in their tissues.
Researchers wanted to know whether interfering with insulin signaling via the reduction of Irs2 – a protein that allows the cells to respond to insulin – expression (by inactivating half of its copies. note: inactivating both copies is probably lethal?) could extend life span.

Mice with lower Irs2 signaling throughout the body or just in the brain have their life span extended up to 18% but are fat and prediabetic at the same time! – showing that leanness does not cause life extension directly but is a just side effect in some other life extension interventions such as caloric restriction.
Lowering Irs2 signaling just in the brain is enough to promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice showing that the brain via its insuline sensitivity is a key regulator of aging.

Here the genetically modified mice use insulin less efficiently than normal mice, the opposite of mice under caloric-restriction! showing that there are several (contradictory at first sight? or all comming down to making the brain belive the body is starving ? e.g. FGF21 note) ways to extend life span.

sciencemag news link

Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis

FGF21, triggered in starving mice via a specific cellular receptor (PPAR-alpha) that controls the use of fat as energy, spurs a metabolic shift to burning stored fats instead of carbohydrates and induces a hibernation-like state of decreased body temperature and physical activity, all geared to promote survival.

Researchers found that liver and circulating levels of FGF21 increase in mice in response to both a low-carb, high-fat diet and fasting.
FGF21 injected in properly fed mice causes their body to ‘think’ it is starving and burn fat even when on a high calorie diet.

Adipocytes

Kliewer’s group showed that FGF21 is induced directly by PPAR in liver in response to fasting in mice. FGF21 in turn stimulates lipid breakdown in white adipose tissue and ketone body production in the liver.
During fasting, the liver hormone communicates with adipose tissue to send fat to the liver. It turns on the metabolism of fat into ketone bodies—and at the same time, it sensitizes the animals to going into torpor to conserve energy. It’s clear that FGF21 is a principal component of the fasting or starvation response.

The hormone – that also make blood sugar levels drop – may lead to treatments for people with type 2 diabetes or obesity.
In addition, the well known lifespan enhancing effect of caloric-restriction might also be mediated by FGF21.

Cellmetabolism article

ScienceDaily link
ScienceNow link

Research reported this by three different groups shows/confirms that normal (skin) cells can be reprogrammed to an embryonic state in mice. The race is now on to apply the surprisingly straightforward procedure to human cells.

Four genes (Oct4, Sox2, c-Myc, and Klf4, see Turning adult cells into ES cells note), which code for transcription factors, are transferred into the cells using retroviruses. The proteins trigger the expression of other genes that lead the cells to become pluripotent. Yamanaka calls them induced pluripotent stem cells (iPS cells).
The reprogrammed cells appear to have all the same traits as Embryonic Stem cells:
All three groups were able to produce chimaeric mice using iPS cells isolated in this way; and the mice passed iPS DNA on to their offspring, showing they behave like ‘real’ ES cells.
One group also produced fetuses whose cells were derived entirely from iPS cells!

Yamanaka’s method can use the most basic cells and can be accomplished with simple lab techniques.

Applying the method to human cells has yet to be successful it will probably require the use of additional transcription factors.

Nature news link

First “habitable” Earth like planet outside Solar System discovered

In a find­ing that if con­firmed could stand as a land­mark in history, as­tro­no­mers (led by Stephane Udry of the Geneva Observatory in Switzerland, using the HARP instrument on the European Southern Observatory’s 3.6m telescope – La Silla, Chile -) have dis­co­v­ered the most Earth-like plan­et out­side our So­lar Sys­tem to date – Gliese 581 C: a world that may have liq­uid oceans and thus life.

The planet has 1.5 times the Earth’s radius (5 Earths mass, 2x our gravity), orbits – in 13 days – a red dwarf – Gliese 581 located only 20.5 light-years away in the constellation Libra (“the Scales”) – that also appear to harbour a Neptune-mass planet (8x the Earth, orbiting in 84 days), and a bigger one (15 Earths, or­bit­ing in 5.4 days, discovered in 2005).
Gl 581 planets

It is 14 times closer to its star than the Earth is from the Sun. However as the star is smaller and colder than the Sun, the planet is not scorched by solar radiation and lies in the habitable zone. Its mean temperature is estimated to lie between 0 and 40 degrees Celsius (32 and 104 degrees Fahrenheit) where water (if any) is liquid!

Models predict (based on its size) that the planet should be either rocky or covered with oceans. It is most probably tidally locked (permanently presenting one face to the sun) so one face is frozen and the other is extremely hot! ... ‘not very good for complex life!?

Note: Red dwarfs are al­so ex­pected to live ex­traor­di­nar­ily long be­cause they burn fu­el slow­ly. A red dwarf one-third the Sun’s mass, like Gliese 581, would typ­i­cal­ly shine for some 130 bil­lion years, out­liv­ing the Sun by thir­teen times!

Note: Even though Gliese 581 offers such promise, it is impossible for mankind/probes to reach it using current technology. Chemical rockets generate only a fraction of the speed needed to get there within a human timescale… (solution ?: nuclear pulse propulsion)

space.com link
BBC News link
Astronomy & Astrophysics paper (pdf)

Note: May 3 2007; exactly the opposite news! as­tro­no­mers just found the – so far – most massive exoplanet : Weird New Planet Weighs as Much as 2,500 Earths
HAT-P-2b is only slightly larger than Jupiter, it weighs around eight times as much! — equivalent to the mass of 2,500 Earths! A giant solid (iron?) planet!

May 9 2007; HD 149026b (Saturn-sized world orbiting a star about 256 light-years away) is 90 times more massive than Earth, has a temp. of 2000 degrees Celsius, and reflects almost no light!

‘looks like there is a lot of diversity in the exoplanet bestiary!

A 20-residue peptide, designated VIRUS-INHIBITORY PEPTIDE (VIRIP), corresponding to the C-proximal region of α1-antitrypsin (the most abundant circulating serine protease inhibitor) inhibits a wide variety of HIV-1 strains including those resistant to current antiretroviral drugs. It was found by screening (for anti viral activity) a comprehensive peptide library generated from human hemofiltrate.

Tweaks to its amino acid components boosted its anti-HIV potency by two orders of magnitude!
Tests also showed that some derivatives of the molecule are highly stable in (ex-vivo) human blood plasma, and non-toxic (for cell cultures) even at very high concentrations.
A synthetic version of VIRIP also proved effective at blocking HIV, excluding the possibility that some other factor was responsible.

VIRIP blocks HIV-1 entry by interacting with the gp41 fusion peptide.
VIRIP may lead to the development of a new class of antiretroviral drugs.

Cell article
BBC news article

Cancers are now believed to arise from cancer stem cells (CSCs). Instead of rapidly dividing like their million-fold-more-plentiful “normal” cancer cell companions (that they kick-started), these outliers grew slowly.
Killing those stem cells would prevent tumour growth/spread and might represent the ultimate weapon against cancer, yet “classic” chemotherapy has proven ineffective as it tends to kill only rapidly dividing cells (the bulk of normal cancer cells).

A new study has shown that endothelial (vascular) cells interact closely with self-renewing brain tumor cells and secrete factors that maintain these cells in a stem cell-like state, forming a perivascular niche for CSCs.

Model for the Role of the Vascular Niche in Cancer (top) Cancer stem cells (CSCs) reside in close proximity to blood vessels, where they receive signals that allow them to self-renew and to generate transit-amplifying cells. Transit-amplifying cells proliferate rapidly and make up the bulk of the tumor but cannot self-renew and only give rise to differentiated (postmitotic) cells. The continued generation of transit-amplifying cells from CSCs allows the tumor to keep growing. (bottom) Antiangiogenic therapies disrupt blood vessels, leading to disintegration of the vascular niche. Without this niche, CSCs cannot self-renew and instead only differentiate into transit-amplifying cells. As these cells exhaust themselves, the tumor gradually stops growing and involutes. [credit: sciencedirect.com, Cancer Cell]

They propose that an antiangiogenic drug [in this study Bevacizumab] together with an Epithelial Growth Factor Receptor inhibitor [Erlotinib] arrest brain tumor growth, at least in part, by disrupting a vascular niche microenvironment that is critical for the maintenance of CSCs.

Targeting both cancer stem cells and the bulk of “normal” cancer cells with combined drugs/therapies (e.g. antiangiogenics [recentin, etc…], chemotherapy, surgery … and maybe even capsaicin, dichloroacetate and resveratrol !?) might be the future of cancer treatment.

Cancer Cell article
sciencedirect article
sciencemag article

A new model suggests the rapid decay of radioactive elements within [Saturn moon] Enceladus shortly after it formed may have jump-started the long-term heating of the moon’s interior that continues today.

jpl press-release

(To me:) water + organic molecules + heat for billions of years = life ?

Analysis (by Cassini’s ion and neutral mass spectrometer) of the geyser eruptions plume revealed mostly water vapor but also minor amounts of gaseous nitrogen, methane, carbon dioxide, propane and acetylene [plume’s composition: April 2007 issue of the journal Icarus]

According to the theory, the remaining, more slowly decaying radioactivity in the core could continue to warm and melt the moon’s interior for billions of years, along with tidal forces from Saturn’s gravitational tug.

All the findings and the hot start model indicate that a warm, organic-rich mixture was produced below the surface of Enceladus and might still be present today, making the moon a promising kitchen for the cooking of primordial soup.

The only question: is their model correct?

When are we going to lauch some ‘serious’ ‘life-finder’ probes to those promising ice moons (Enceladus, Europa), instead of wasting money on crappy ‘low’-space shuttle, international space station ?...

Let’s just go through that plume and collect some nice material!

Enceladus’ plume: Compositional evidence for a hot interior

Two dark gullies turned bright as NASA’s now-lost Mars Global Surveyor (MGS) looked on, suggesting liquid water still flows on the red planet...

The discovery is unexpected because the planet’s temperatures and atmospheric pressure are too low to allow water to exist in liquid form for long.
It suggests geological activity could be heating water beneath the surface so that it is warm enough to flow for long enough to leave deposits behind.
This possibility is particularly exciting because water and a stable heat source are key precursors for the existence of life. This mean (if it was really water) there could be life on Mars now!?
This is really significant. It means we now know where to look for life.

It suggests there is some sort of geological heating process going on beneath the surface and that Mars is a more dynamic place than we had previously thought.

Large Hi-Res photograph of Mars water deposits

Now we are talking about liquid water on the surface today. That is a revolution in how we see Mars and how we talk about exploring Mars.

Note: Newly formed dust streaks have been observed, but are always dark. The formation of new gullies has been observed before also, but these were on the sides of sand dunes, and were more clearly related to avalanching sand.
Some scientists think it possible that gullies like this were caused not by water but by liquid carbon dioxide; which is unlikely owing to the difficulty in burying highly volatile CO2…

newscientist article
nasa.gov page
bbc new article
Telegraph article
M. Malin et al. Science 314: 1573-1577 (8 Dec. 2006)

Note:
European Space Agency said it will redirect the instruments on Mars Express — including a powerful spectrometer — to try to find out more…
The spectrometer will examine if sediment in the gullies pinpointed from the NASA pictures contains fine sediment such as clay, which would indicate they had been deposited by water… + its radar can penetrate to much greater depth below the planet’s surface…
International herald tribune article

Update March 2008:

too bad!:
Computer models rule out pure liquid water! An avalanche of dry debris is a much better match for their calculations and also what their computer model predicts.
sciencedaily link

Scientists have partially reconstructed the genome of a Neanderthal man who lived 38,000 years ago.

Studying the Neanderthal genome will shed light on the genetic changes that made our species what it is, after the evolutionary lineages of Neanderthals and modern humans diverged from one another.

We have identified a 38,000-year-old Neanderthal fossil that is exceptionally free of contamination from modern human DNA. Direct high-throughput sequencing of a DNA extract from this fossil has thus far yielded over one million base pairs of hominoid nuclear DNA sequences.

Comparison with the human and chimpanzee genomes reveals that modern human and Neanderthal DNA sequences diverged on average about 500,000 years ago.
Existing technology and fossil resources are now sufficient to initiate a Neanderthal genome-sequencing effort.

http://www.nature.com/nature/focus/neanderthaldna/index.html
http://news.bbc.co.uk/2/hi/science/nature/6146908.stm

Analysis of one million base pairs of Neanderthal DNA

NASA has selected Lockheed Martin Corp. as the prime contractor to design, develop, and build Orion spacecraft that will take humans (back!) to the Moon and later to Mars.
The first flight with astronauts aboard is planned for no later than 2014. Orion’s first flight to the moon is planned for no later than 2020.

Orion will have more than 2.5 times the interior volume of the three-seat Apollo capsules that carried astronaut crews to the moon for missions lasting only several hours to several days in the late 1960s and early 1970s. It will be able to carry 4-6 astronauts to the moon and support missions of up to six months.

nasa.gov orion_contract page
nasa.gov orion/index page

It’s sad to see how late we are!... 40 years after apollo, we’;re right at the same point! but at last, soon no more pathetic ‘space’; (is 200km altitude space?) shuttles…

Researchers at MIT and Hong Kong University have come up with a biodegradable liquid that can seal wounds in seconds.
When applied to an open wound, the liquid, which is composed of peptides, turns into a gel that seals the wound. The gel gradually breaks down (no need to worry about removing it) into amino acids that aid in tissue repair.

So far only tested on rats/hamsters, but when it makes its way to humans, it could revolutionize surgeries by making it much easier to control bleeding.

“Here we report the first use of nanotechnology to achieve complete hemostas is in less than 15 seconds, which could fundamentally change how much blood is needed during surgery of the future.“

The researchers said the liquid can be used in wet environments, and it did not produce an immune response in test animals.
The exact mechanism of the solutions’ action is still unknown, but the researchers believe the peptides interact with the structure that surrounds and supports cells in mammals, called the extracellular matrix.

Nano hemostat solution: immediate hemostasis at the nanoscale (nanomedjournal) :
[html]
[pdf]

cbc.ca article

Orion was also the code name of an atomic Spaceship project [from General Dynamics Corporation/General Atomics] started in 1957 and declared dead in 1965. A huge ship powered by hundreds of tiny atomic bombs! [Nuclear pulse propulsion] capable of much greater lift and efficiency than chemically driven rockets.
Orion’;s potential performance was stunning (could reach Pluto and return to Earth within year, or even travel to Proxima Centauri in 44 years at almost 10% the speed of light!). They hoped to put men on Mars by 1965 and on Saturn by 1970!
Obviously they were few little problems: fallouts and electromagnetic pulses!… (idea: if we could start those spaceships from the moon, then no more worries!?). Otherwise the system appeared to be entirely workable!
Struggles between NASA, the military, Congress, and other parties doomed Orion (+ Nuclear Test Ban Treaty of 1963 outlawed it).
In many respects, Orion may be the closest mankind has ever come to large-scale space travel (this technology is also one of very few known interstellar space drives that could be constructed with known technology).

”Project Orion: The True Story of the Atomic Spaceship” book by George Dyson

astronautix.com article

bombs would be ejected backwards from the vehicle, followed by solid-propellant disks [or propellant could be combined with the bombs into ‘pulse units’]. The explosions would vaporize the propellant, and the resulting plasma would impinge upon a pusher plate [as duration of high temperatures is so short, research showed that either simple aluminum or steel would be durable enough].
The advantage of this system is that no attempt is made to confine the explosions, implying that relatively high-yield (hence high-power) bombs may be used. Such a system is neither temperature- nor power-limited.

Does it make any sense [nowadays] to even think of reviving the nuclear-pulse concept? Economically the answer is yes. Pedersen says that 10,000-ton spaceships with 10,000-ton payloads are feasible. Spaceships like this could be relatively cheap compared to shuttle-like vehicles…

George Dyson video on youtube

At last something new in aging research besides stress resistance/caloric restriction/telomer shortening!

Wrinkled cell nuclei may make us age

In cells taken from the elderly, the nuclei tend to be wrinkled up, the DNA accumulates damage, and the levels of some proteins that package up DNA go askew, the team reports in Science1. This mirrors the same changes that they previously observed in cells from HGPS children.
The team suggests that healthy cells always make a trace amount of an aberrant form of lamin A protein, but that young cells can sense and eliminate it. Elderly cells, it seems, cannot.

Critically, blocking production of this deviant protein corrected all the problems with the nucleus. “You can take these old cells and make them young again”. Will it work on “full” organisms!?...

If further research confirms the link, we all suffer from laminopathies at some time. Treatments to keep nuclei in shape might help not just a child with HGPS but also a grandmother who can’t make it to the mailbox without a walker.

http://www.nature.com/news/2006/060424/full/060424-11.html

Cancer drug might help kids with fatal “aging” syndrome

A class of drugs known as farnesyl transferase inhibitors, or FTIs, can reverse an abnormality in laboratory-grown cells engineered to mimic cells from progeria patients.
The drug blocks the first step in processing the faulty protein that causes the syndrome.

FTIs prevent addition of farnesyl to all proteins that have a particular molecular tag. In cancer, the key target among these proteins is one called Ras, which is activated by the same farnesyl-triggered process as lamin A and which promotes cancerous growth when there’s too much of it.

http://www.hopkinsmedicine.org/Press_releases/2005/09_26b_05.html
http://en.wikipedia.org/wiki/Farnesyltransferase_inhibitor

A Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria

In 2003, Dr. Zheng Cui and his colleagues at the Comprehensive Cancer Center of Wake Forest University reported the discovery of mice with immune cells that rendered them invulnerable to cancer: they had been intentionally giving mice cancer by injecting them with virulent cancer cells as part of a separate study, when they discovered a single mouse in the colony that was completely immune to the invasive cells.

His curiosity piqued, Dr. Cui went on to show that it could resist multiple rounds of such injections, and were so impressed that they used him to father a whole colony of mice, all of whom shared this remarkable invulnerability to cancer. Based on that ability, he calls them spontaneous regression/complete resistance (SR/CR) mice.

Now, they’ve shown that the transplanted white blood cells from those mice can protect normal mice from what should have been lethal doses of highly aggressive new cancers.

The transplanted white blood cells included natural killer cells, and other white blood cells called neutrophils and macrophages that are part of the body’s “innate immune system.” This system forms a first line of host defense against pathogens, such as bacteria.

“Their activation requires no prior exposure, but rather depends on a pre-determined mechanism to recognize specific patterns on the cancer cell surface” the researchers said.

“The potency and selectivity for cancer cells are so high that, if we learned the mechanism, it would give us hope that this would work in humans” said Cui. “This would suggest that cancer cells send out a signal, but normal white blood cells can’t find them.”

http://www.sciencedaily.com/releases/2006/05/060509094714.htm
http://www1.wfubmc.edu/cancer/research/mice/summary.htm

http://www.discover.com/issues/aug-06/rd/areyouimmune
Even more promising, Cui has sampled a group of human volunteers and found that 10 to 15 percent have similar super cancer-fighting white blood cells. That could explain why some people never get cancer and why others’ tumors spontaneously regress.

Sept 2007:
‘Cancer-resistant’ people lend out their killer cell [newscientist article]
Granulocyte transfusion article on telegraph.co.uk
Cui has now discovered that a large sub-population of immune cells called granulocytes can kill cancer and that the effectiveness of these cells varies from person to person.
Such cells in some people can be almost 50 times more effective in fighting cancer than in others. Initial evidence suggests it may be possible to transfer the ability to fight off cancer between people.

His group is about to start a clinical trial on 22 humans to try to see if immune system components from people with super immune systems can defeat cancer when separated out and injected into people with cancer.

Boeing Spectrolab terrestrial solar cell surpasses 40 Percent Efficiency!
Common solar cells have an (energy conversion) efficiency of ~12% = only 12% of the potential light power is converted into electricity.

40% is the highest efficiency level any photovoltaic device has ever achieved!

The excellent performance of these materials hints at still higher efficiency in future solar cells!

A Solar future!?...

http://www.boeing.com/news/releases/2006/q4/061206b_nr.html
http://www.webwire.com/ViewPressRel.asp?aId=24666

Images from a camera orbiting Mars have shown 100mph jets of carbon dioxide erupt through ice at the planet’s south pole.
Sand and dust carried up in the jets could explain mysterious dark spots, streaks and spider-shaped features that reappear around the same time each year, the researchers say.

Artist’s impression (Ron Miller/ASU)

That finding was presented by an Arizona State University research team in the science journal Nature (vol 442, p.790 and p.793).

Newscientist Space article

from xkcd

;-)

bbc news article

Scientists studying pictures from Nasa’s Odyssey spacecraft have spotted what they think may be seven caves on the surface of Mars. The caves are on the flanks of the Arsia Mons volcano.

The researchers describe the candidate caves as “seven sisters” and have given them all names: Dena, Chloe, Wendy, Annie, Abbey, Nicki and Jeanne.

The cave entrances are between 100m and 252m wide (330-828ft), the researchers calculated they must extend between 73m and 96m (240-315ft) below the surface.

The caves may be the only natural structures capable of protecting primitive life forms from micrometeoroids, UV radiation, solar flares and high energy particles that bombard the planet’s surface.

discover article

Researchers at the Wistar Institute in Philadelphia, are studying a unique strain of mouse that can heal wounds by regeneration. After a hole is pierced in the mouse’s ear (a typical laboratory identification procedure), it closes with no evidence that a hole was ever present. These animals, known as Murphy/Roths/Large mice, or MRL mice, are so named to denote the two scientists who originally bred them, as well as their unusually large size. MRL mice are genetically unique, and scientists are researching them to elucidate the genetics of regeneration, hoping to gather information that can be used to help humans.

When the Wistar scientists induced heart injury in both MRL mice and typical mice, they found that the MRL mouse heart returned to normal, whereas the typical mouse heart was scarred. Human hearts scar following injury from heart attack, and the scarring response contributes to chronic heart disease and death. The healing response in the MRL mouse, however, differed greatly from that of the typical mouse. The MRL mouse displayed early movement of cardiomyocytes into the wound site, and DNA synthesis and proliferation of these cells. The MRL mouse heart also demonstrated better revascularization (restoration of blood supply) at the site of injury, which is necessary to help cells thrive and avoid death. According to the scientists, the MRL mouse studies demonstrate that “mammalian hearts have significant capacity to regenerate.”

The MRL mouse has even been shown to have some digit regrowth.

PNAS paper
BBC news article

Scientists in Japan reported that boosting the activity of just four genes can apparently turn mouse skin cells into cells that closely resemble ES cells.

Yamanaka and his colleagues wondered whether the factors that give ES cells their unique properties might also be able to reprogram adult cells to behave like ES cells. They identified 24 genes that are specifically expressed in mouse ES cells and used viral vectors to introduce extra copies of the genes into skin cells taken from mouse tail tips.
Through a process of elimination, the team whittled down the candidates to a suite of just four genes that, when introduced together into the tail-tip cells, could produce colonies of ES-like cells. As Yamanaka described, three of the four factors are old friends: Oct4, Sox2, and c-Myc are all key genes in both early embryos and ES cells. Yamanaka did not name the fourth gene, but he said it is a transcription factor that until now has not been recognized as playing a major role in ES cells.

It looks like we might one day be able to make ES cells without embryos!?

http://sciencenow.sciencemag.org/cgi/content/full/2006/703/1

Female mice undergoing IVF with sperm extracted from dead mice kept in the deep freeze for 15 years, had healthy, fertile pups!

The team, led by Atsuo Ogura of the Institute of Physical and Chemical Research Bioresource Center in Tsukuba, Japan did not use hi-tech cryo-protection techniques, simply storing whole testes or bodies in a freezer!

The sperm appeared lifeless when thawed out but researchers were surprised to find that they produced viable offspring.

If spermatozoa of extinct mammalian species (eg woolly mammoths) can be retrieved from animal bodies that were kept frozen for millions of years in permanent frost, live animals might be restored by injecting them into oocytes from females of closely related species.

http://news.bbc.co.uk/2/hi/science/nature/4793915.stm
reported in Proceedings of the National Academy of Sciences (could not find ref.?)

The traditional light bulb’s days could be numbered, according to scientists who have taken an important step towards making white organic light-emitting diodes (OLEDs) commercially viable. The material, described in the journal Nature, can be printed in wafer thin sheets that could transform walls, ceilings or even furniture into lights.

The OLEDs do not heat up like today’s light bulbs and so are far more energy efficient and should last longer. They also produce a light that is more akin to natural daylight than traditional bulbs.

In terms of the technology, we could do this today. We just can’t make it for a reasonable price. But we are marching down a path that will make it practical.

http://www.nature.com/news/2006/060410/full/060410-8.html
http://news.bbc.co.uk/1/hi/sci/tech/4906188.stm
http://en.wikipedia.org/wiki/OLED

[March 2007] 1000 Lumens white (“classic”) LED:

http://www.ledsmagazine.com/news/4/2/10

Osram has developed a small light-emitting diode spotlight [named Ostar, contains six 1 mm2 power LED chip] that achieves an output of more than 1,000 lumens for the first time (like a 100w light bulb).
Last 50 times longer than incandescent lamps!

So LEDs are bright enough to light our houses and last 10 times longer than even halogen technology. We’re ready to upgrade!

a market launch is planned for summer 2007

2010: a luminous flux of 1913 lumens and a luminous efficacy of 135 lumens per watt at 1 amp

White LEDs with super-high luminous efficacy could satisfy all general lighting needs

Stem cells from a mouse embryo have been coaxed into producing both eggs and sperm in the same dish. The eggs and sperm are the most mature yet grown in the lab, and the advance brings researchers closer to their ultimate aim: producing human eggs and sperm from adult body cells.

That means: in the future, infertile men and women might have their own children; there might be an easy and unlimited egg source to produce embryonic stem-cell lines…
(scary? but interesting!)

http://www.nature.com/news/2006/060619/full/060619-13.html