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Children’s complex thinking skills begin forming before they go to school

By William Harms

January 23, 2013

New research at the University of Chicago and the University of North Carolina at Chapel Hill shows that children begin to show signs of higher-level thinking skills as young as age 4 ½. Researchers have previously attributed higher-order thinking development to knowledge acquisition and better schooling, but the new longitudinal study shows that other skills, not always connected with knowledge, play a role in the ability of children to reason analytically.

The findings, reported in January in the journal Psychological Science, show for the first time that children’s executive function has a role in the development of complicated analytical thinking. Executive function includes such complex skills as planning, monitoring, task switching, and controlling attention. High early executive function skills at school entry are related to higher than average reasoning skills in adolescence.

Growing research suggests that executive function may be trainable through pathways, including preschool curriculum, exercise and impulse control training. Parents and teachers may be able to help encourage development of executive function by having youngsters help plan activities, learn to stop, think, and then take action, or engage in pretend play, said lead author of the study, Lindsey Richland, assistant professor of comparative human development at the University of Chicago.

Although important to a child’s education, “little is known about the cognitive mechanisms underlying children’s development of the capacity to engage in complex forms of reasoning,” Richland said.

The new research is reported in the paper “Early Executive Function Predicts Reasoning Development” and follows the development of complex reasoning in children from before the time they go to school until they are 15. Richland’s co-author is Margaret Burchinal, senior scientist at the Frank Porter Graham Child Development Institute at the University of North Carolina at Chapel Hill.

The two studied the acquisition of analogical thinking, one form of complex reasoning. “The ability to see relationships and similarities between disparate phenomena is fundamental to analytical and inductive reasoning, and is closely related to measurements of general fluid intelligence,” said Richland. Developing complex reasoning ability is particularly fundamental to the innovation and adaptive thinking skills necessary for a modern workforce, she pointed out.

Richland and Burchinal studied a database of 1,364 children who were part of the Early Child Care and Youth Development study from birth through age 15. The group was fairly evenly divided between boys and girls and included families from a diverse cross-section of ethnic and income backgrounds.

The current study examined tests children took when they were 4 ½, when they were in first grade, third grade, and when they were 15.  Because the study was longitudinal, the same children were tested at each interval. Among the tests they took were ones to measure analytical reasoning, executive function, vocabulary knowledge, short-term memory and sustained attention.

Children were tested at 4 ½ on their ability to monitor and control their automatic responses to stimuli. In first grade they worked on a test that judged their ability to move objects in a “Tower of Hanoi” game, in which they had to move disks between pegs in a specific order.

In third grade and at 15 years old, they were tested on their ability to understand analogies, asked in third grade for instance to complete the question “dog is to puppy as cat is to__?” As 15-year-olds they were asked to complete written tests of analogies.

The study found a strong relationship between high scores among children who as preschoolers had strong vocabularies and were good at monitoring and controlling their responses (executive function) to later ability on tests of understanding analogies.

“Overall, these results show that knowledge is necessary for using thinking skills, as shown by the importance of early vocabulary, but also inhibitory control and executive function skills are important contributors to children’s analytical reasoning development,” Richland said.

The National Academy of Education/Spencer Foundation, the Office of Naval Research and the National Science Foundation supported the research.

Tags

Early childhood development, Early Executive Function Predicts Reasoning Development, Lindsey Richland, Psychological science

Russian Academy of Sciences (RAS) confirms Ukrainian breakthrough in Alzheimer's treatment with Hydrated Fullerenes or C60-HYFNs or Water Soluble Buckyballs

Russian Academy of Sciences confirms Ukrainian break-though in treating Alzheimer’s
with Carbon 60 or C-60 or hydrated fullerenes (C60HYFns) or Buckeyballs. 

After the discovery of C-60 in 1985 and the awarding of the Nobel prize in 1995 to Kroto, Smalley and Curl, Ukrainian scientists, then discovered a way to make Carbon 60 or C-60 or fullerenes or buckeyballs water soluble about 15 years ago, have made progress on the Alzheimer’s front
treating it with Fullerene Water Solution (FWS) and with conventional treatment.
This was approved as a “dietary supplement” by the Ukrainian Ministry of Health
in 2010, and just several weeks ago they started producing a water drink in
Ukraine with .0002mg/100ml of C-60.

Walter  Derzko

WATER  SOLUBLE C60 FOR DEVELOPING ALZHEIMER'S DISEASE  TREATMENT

I.Ya.Podolskiy1) E.G.Makarova 1) R.Ya.Gordon2) V.V.Vorobev2) L.G.Bobyleva 1) A.G.Bobylev1)
Z.A.Podlubnaya1) , A.B.Geht3) O.A.Mishulina4)


1) Institute of Theoretical and Experimental Biophysics, Pushchino
2) Institute of Cell Biophysics, Pushchino
3) The Russian State Medical University, Moscow
4) National Research Nuclear University MEPI, Moscow


Creation of drugs for the  prevention and treatment of Alzheimer's disease (AD) is the most important
challenge to biomedical research in the XXI century. Synthesis of water-soluble
fullerenes and carbon nanotubes opened a new direction for drug development,
which is growing rapidly in the U.S., Europe and Asia.

* Rationale. One key element in the pathogenesis of Alzheimer's disease is increased formation of aggregated forms in the brain of amyloid β-peptide (1-42) (Aβ1-42). Create antiamiloid drugs is
the main thrust of development of asthma therapy.

^ The project aims to investigate the properties of stable antiamiloidn molecular colloidal aqueous
solution of fullerene C60HyFn.

Results. By transmission electron microscopy in vitro for the first time on a visual level, it was shown that
water-soluble C60 prevent and destroy the beta-amyloid. These findings led to
the conclusion that the fullerene in vitro anti-aggregation has a strong effect
on the β-amyloid peptides. Microinjection C60HyFn (0.46 nmol / μl) into the
hippocampus significantly reduced β-amyloid deposits in the pyramidal neurons of
hippocampal CA1 neurons and warned neurodegeneration. Fluorescence microscopy of
hippocampal pyramidal neurons with acridine orange and microfluoremetric
analysis will provide quantitative data on the restoration protein synthesizing
activity of pyramidal neurons in the hippocampus, impaired Aβ. Microinjection
C60HyFn (0.46 nmol/1μl) to prevent violations of spatial memory, due to the
introduction of the hippocampus Aβ1-42 (1.6 nmol / μl). On surviving hippocampal
slices fullerene increases the activity of pyramidal neurons in rats modified
EEG frontal cortex, impaired Aβ1-42.

Conclusion. Functionalized C60 direction slowly act on one of the key molecular targets of Alzheimer's disease, aggregated amyloid β-peptides, and are of great interest for the development of
Alzheimer's disease therapy. We assume that in the first half of the XXI century
will be based on fullerenes developed an effective prevention and treatment of
Alzheimer's disease.

This work was supported by a grant of the Presidium of RAS "basic sciences Medicine" and the state contract the Ministry of Higher Education and Science of the Russian Federation №
P1052.

http://rudocs.exdat.com/docs/index-417897.html?page=47

More in Russian

http://www.c60water.com/index.php?option=com_content&view=article&id=9&Itemid=33

Ukrainian scientists, who discovered a way to make Carbon 60 or C-60 or fullerenes or buckeyballs
water soluble about 15 years ago, have made progress on the Alzheimer’s front
treating it with Fullerene Water Solution (FWS) and with conventional treatment.
This was approved as a “dietary supplement” by the Ukrainian Ministry of Health
in 2010, and just several weeks ago they started producing a water drink in
Ukraine with .0002mg/100ml of C-60.

Below is a very rough
Google Translation from the Russian original.

Obviously, this
research is not on the radar of most western
researchers.

Walter
Derzko

http://www.c60water.com/index.php?option=com_content&view=article&id=9&Itemid=33

One of the diseases elderly is Alzheimer's disease or senile dementia.
More common after
sixty, but sick and young people. The disease is characterized by a steady
deterioration of memory until the complete disintegration of the personality.
Already in the beginning of the disease, recognizing the gradual loss of memory,
a person experiences great emotionally shaken. This neurodegenerative disease
affects more than thirty million people. Nicholas Sparks romantic drama "The
Notebook" and the same film shows the tragedy of close people who are sick of
this terrible disease.
Unfortunately, at present, has not yet found drugs
that can stop or reverse the development of cause neurodegenerative process.
Search for drugs for the treatment of this disease are engaged in the world. The
Institute of
Theoretical and
Experimental Biophysics studies in experimental models of Alzheimer's disease
are conducted under the direction of Igor Jakovljevic Podolsky. In 2007, he
first discovered the neuroprotective properties of water molecules with the most
beautiful. His work, published in January 2012, revealed the influence of
fullerene water very cause of the neurodegenerative process of memory
loss.
Alzheimer's disease is
associated with a decrease in the water content in the brain and increased
formation of amyloid protein (beta-amyloid peptide Aβ1-42). The threads of this
protein like vines entwine the neurons of the brain, disrupting their work and
worsening memory. In November 2011, Podolsky reported to the Presidium of RAS
results of their work done in accordance with the program "Fundamental science -
medicine." It was shown that the water has a fullerene antiamiloidnymi
properties. Microinjection of water prevents the formation of amyloid by
fullerene and destroyed "threads" of amyloid protein. This led to a reduction of
neurodegenerative changes in the brain of rats and restore lost
memory.
Interview with Igor Yakovlevich under "great discovery" was broadcast
on Channel One Russian TV from 18 to 23 March 2012.

The obtained results
allow us to begin clinical studies of fullerene water as a means for the
treatment and prevention of Alzheimer's disease. It is assumed that patients
will spray water fullerene as a spray in the nasal passages and to drink a
certain pattern.
Increased production of amyloid protein is the cause of not
only Alzheimer's disease. In addition to degenerative changes in the brain, it
can cause malfunction of other organs such as the pancreas, which is considered
as a possible cause of diabetes type. Amyloid proteins provoke the development
of many serious human diseases, the methods of treatment which at the moment
does not exist.
The Institute of Theoretical and Experimental Biophysics of
amyloidosis research conducted by Professor Zoya Alexandrovna Podlubnaya. Her
studies show that water prevents the formation of fullerene and destroying
amyloids in striated muscle. Antiamiloidnye fullerene properties of water can
allow the creation of new drugs for the treatment of previously incurable
diseases. This stimulates interest in studying biomedical properties of
fullerene water in many research centers. 

Oxygen Chamber Can Boost Brain Repair

Wednesday, January 23, 2013

Hyperbaric treatment has significantly resuscitated activity in damaged brains, TAU researchers find

Stroke, traumatic injury, and metabolic disorder are major causes of brain damage and permanent disabilities, including motor dysfunction, psychological disorders, memory loss, and more. Current therapy and rehab programs aim to help patients heal, but they often have limited success.

Now Dr. Shai Efrati of Tel Aviv University's Sackler Faculty of Medicine has found a way to restore a significant amount of neurological function in brain tissue thought to be chronically damaged — even years after initial injury. Theorizing that high levels of oxygen could reinvigorate dormant neurons, Dr. Efrati and his fellow researchers, including Prof. Eshel Ben-Jacob of TAU's School of Physics and Astronomy and the Sagol School of Neuroscience, recruited post-stroke patients for hyperbaric oxygen therapy (HBOT) — sessions in high pressure chambers that contain oxygen-rich air — which increases oxygen levels in the body tenfold.

Analysis of brain imaging showed significantly increased neuronal activity after a two-month period of HBOT treatment compared to control periods of non-treatment, reported Dr. Efrati in PLoS ONE. Patients experienced improvements such as a reversal of paralysis, increased sensation, and renewed use of language. These changes can make a world of difference in daily life, helping patients recover their independence and complete tasks such as bathing, cooking, climbing stairs, or reading a book.

Oxygen breathes new life into neurons

According to Dr. Efrati, there are several degrees of brain injury. Neurons impacted by metabolic dysfunction have the energy to stay alive, but not enough to fire electric signals, he explains. HBOT aims to increase the supply of energy to these cells.

The brain consumes 20 percent of the body's oxygen, but that is only enough oxygen to operate five to ten percent of neurons at any one time. The regeneration process requires much more energy. The tenfold increase in oxygen levels during HBOT treatment supplies the necessary energy for rebuilding neuronal connections and stimulating inactive neurons to facilitate the healing process, explains Dr. Efrati.

For their study, the researchers sought post stroke patients whose condition was no longer improving. To assess the potential impact of HBOT treatment, the anatomical features and functionality of the brain were evaluated using a combination of CT scans to identify necrotic tissue, and SPECT scans to determine the metabolic activity level of the neurons surrounding damaged areas.

Seventy-four participants spanning 6 to 36 months post-stroke were divided into two groups. The first treatment group received HBOT from the beginning of the study, and the second received no treatment for two months, then received a two-month period of HBOT treatment. Treatment consisted of 40 two-hour sessions five times weekly in high pressure chambers containing oxygen-rich air. The results indicate that HBOT treatment can lead to significant improvement in brain function in post stroke patients even at chronically late stages, helping neurons strengthen and build new connections in damaged regions.

A potential avenue for prevention

Although the study focuses on patients only through three years post-stroke, Dr. Efrati has seen similar improvement in patients whose brain injuries occurred up to 20 years before, belying the concept that the brain has a limited window for growth and change. "The findings challenge the leading paradigm since they demonstrate beyond any doubt that neuroplasticity can still be activated for months and years after acute brain injury, thus revealing that many aspects of the brain remain plastic into adulthood," says Prof. Ben-Jacob.

This study also "opens the gate into a new territory of treatment," adds Dr. Efrati. The researchers are currently conducting a study on the benefits of HBOT for those with traumatic brain injury. This treatment also has potential as an anti-aging therapy, applicable in other disorders such as Alzheimer's disease and vascular dementia at their early stages.

"It is now understood that many brain disorders are related to inefficient energy supply to the brain," explains Dr. Efrati. "HBOT treatment could right such metabolic abnormalities before the onset of full dementia, where there is still potential for recovery."

---

For more neuroscience news from Tel Aviv University, click here.

Keep up with the latest AFTAU news on Twitter: http://www.twitter.com/AFTAUnews.

 

Job Posting for Instructors/consultants to teach cognitive skills and opportunity recognition in a business /scientific environment

Job Posting for  Instructors/consultants  to teach cognitive skills and opportunity recognition
in a business /scientific environment

Job opening for part time instructors/ consultants to teach critical and creative cognitive skills in a
business and scientific environment, in various cities across  Canada  on a project/contract basis.

Experience in teaching in  the secondary school gifted program, entrepreneurship programs or a background  in cognitive science, complexity science, behavior economics or neuro-economics
desirable.

Send resume and cover  letter to  the Strategic Foresight Group, 116 Galley Ave Toronto,
Ontario M6R 1H1 by Feb 5, 2013

Massive animals may hold secrets of cancer suppression-Peto’s paradox

Theory suggests trade-off between cancer risk and reproductive potential.

• Virginia
       Gewin

21 January 2013

 

Large animals such as humpback whales may have evolved cancer-fighting mechanisms that smaller
animals lack — but one flip-side could be lower rates of reproduction.

Sue Flood / naturepl.com

 

If every living cell had an equal chance of becoming cancerous, whales and elephants should have a
greater risk of developing cancer than do humans or mice. But across species,
the occurrence of cancer does not show a correlation with body mass. According
to a new model, the paradox could be explained if animals were striking a
balance between reducing cancer risk and other priorities, such as maximising
the number of offspring.

 

The lack of correlation between body mass and cancer risk is known as Peto’s paradox, after epidemiologist Richard Peto of Oxford University in the UK, who noted it in the 1970s.
Evolutionary biologists think that it results from larger animals using
protective mechanisms that many smaller animals do not¹.

In an attempt to identify how greater body mass might foster such mechanisms, evolutionary biologist Benjamin Roche at the Institute of Research for Development in Montpellier, France, and
his colleagues created a theoretical model to simulate which of 100 possible
genetic-mutation strategies would become most prevalent over 4,000 generations.

The model included two gene types: proto-oncogenes, which can cause normal cells to become cancerous, and tumour-suppressor genes, which repair cellular damage that could otherwise lead
to cancer. For carcinogenesis to occur, the team assumed that proto-oncogenes
must be activated and tumour-suppressor genes must be rendered inactive.

“We found that tumour-suppressor genes and proto-oncogenes react differently along a gradient of body masses,” says Roche. “Their evolutionary dynamics are linked.” Proto-oncogene activation
decreased steadily with increasing body mass, the team found.

Cost–benefit ratio

In their model, evolution did not
always favour tumour-suppressor genes. Although these mechanisms could reduce
cancer mortality in any animal, they may come at a cost — reduced fertility, in
the case of the team's model. The result was that for intermediate-sized
animals, the evolutionary cost of having many tumour suppressor genes was
greater than the benefits of cancer protection they offered.

As a consequence, mutations would arise to keep tumour-suppressors in check.
“At this point, it is better for the population, evolutionarily, to tolerate
more deaths from cancer rather than investing in more costly mechanisms to
avoid cancer development,” says Roche.

The results, published in a special issue of Evolutionary Applications focused on cancer biology², could explain why, for example, the incidence of
cancer in humans stands at one in three, whereas it is only 18% in beluga whales³.

Roche and colleagues' is not the
only proposed explanation for Peto’s paradox. “There are a number of different
hypotheses,” says Carlo Maley, director of the Center for Evolution and Cancer
at the University of California, San
  Francisco. “For example, rather than body mass
influencing the number of tumour suppressors and oncogenes, maybe there are
less reactive oxygen species in larger organisms due to their lower metabolic
rate."

Maley and his colleagues are
sequencing the humpback whale genome, which they plan to compare with others,
including the elephant genome, to determine which hypotheses might be valid —
and whether nature has already come up with cancer-prevention mechanisms that
could be translated to the clinic.

Still, some biologists question
whether there is a paradox at all, saying that variations in cancer rates
across species — which range between 20% and 46% — are more similar than
different. “All species get cancer at about the same rate, typically in the
latter part of life span,” says James DeGregori, a molecular biologist at the University of Colorado
in Denver. “We
simply don’t have the data yet to back up the notion that larger animals have
come up with a way to avoid oncogenic mutations.”

Journal name:

Nature

DOI:

doi:10.1038/nature.2013.12258

References

1. 
   Caulin
   A.F., & Maley, C.C., Trends
   Ecol Evol 26, 175–182 (2011).

1.  
   • Article
   • ISI

Show context

1. 
   Roche, B., et
   al., Evo Appl. DOI: 10.1111/eva.12025 (2013).

Show context

1. 
   Martineau, D. et
   al. Environ Health Perspect. 110, 285–292 (2002).

1.  
   • Article
   • PubMed
   • ISI

Show context

 

 

Mathematicians aim to take publishers out of publishing

Episciences Project to launch series of community-run, open-access journals.

17 January 2013

Jean-Pierre Demailly is a leader in an effort to create a researcher-run publishing system.

Mathematicians plan to launch a series of free open-access journals that will host their peer-reviewed
articles on the preprint server arXiv. The project was publicly revealed yesterday in a blog post by Tim Gowers, a Fields Medal winner and mathematician at the University of Cambridge, UK.

 

The initiative, called the Episciences Project, hopes to show that researchers can organize the peer
review and publication of their work at minimal cost, without involving commercial publishers.

“It’s a global vision of how the research community should work: we want to offer an alternative to traditional mathematics journals,” says Jean-Pierre Demailly, a mathematician at the University of Grenoble, France, who is a leader in the effort. Backed by funding from the French government, the initiative may launch as early as April, he says.

Many mathematicians — and researchers in other fields — claim that they already do most of the work
involved in publishing their research. At no cost, they type up and format
their own papers, post them to online servers, join journal editorial boards
and review the work of their peers. By creating journals that publish links to
peer-reviewed work on servers such as arXiv, Demailly says, the community could
run its own publishing system. The extra expense involved would be the cost of
maintaining websites and computer equipment, he says.

That cost is not small, but it
could eventually be provided in part by the journals' users. The arXiv server,
for example, costs about US$826,000 a year to run, and is funded by the Cornell
University Library in Ithaca, New
York; the Simons Foundation in New York and institutional members.

Demailly says that he first thought of open-access electronic journals that overlay arXiv eight years ago, but the concept became a reality only last June, when he was contacted by the
Centre for Direct Scientific Communication (CCSD), based in Villeurbanne,
France. The CCSD, a unit of the French National Centre for Scientific Research,
develops open-access repositories such as the multidisciplinary archive HAL,
which mirrors the arXiv site.

For the Episciences Project, the CCSD plans to create a publishing platform that will support online
peer-reviewed journals. Each journal, or ‘epijournal’, would have its own
editor and editorial board, and authors could submit their arXiv-posted papers
to their journal of choice. The journal would then organize peer review,
perhaps using workflow software provided by the CCSD. Peer-reviewed papers
would be posted on arXiv alongside their un-reviewed versions. A central
committee (led by Demailly) would manage new journal candidates and make
recommendations on paper formatting, but each journal would be free to set its
own policies (including whether to charge for publication).

Gowers plans to start a journal in the interdisciplinary field of additive combinatorics; Demailly would not
say what other early epijournals might be. Gowers has strong views on shaking
up research publishing — last year, he kick-started
a boycott of the Dutch publishing giant Elsevier (see also Nature’s
profile of Gowers).

The idea of overlaying arXiv is
not new: some mathematics journals tried it in the early 2000s but scrapped the
idea because libraries began dropping print subscriptions, says Demailly.
Meanwhile, there are already some free, community-organized mathematics
journals, such as Documenta Mathematica, funded by the German Mathematical Society. “They are doing things on their own with a small website; we will have a global platform
capable of drastically reducing an individual journal’s administration costs,”
Demailly says.

Demailly says that he expects to adjust the concept with feedback from the mathematics community. “If people want larger reviews linked to papers, or the possibility of online comments and
blogs, we can offer this with only minor changes to the platform,” he says. At
the moment, the model's success or failure hinges on buy-in from mathematicians
— but the involvement of Gowers and other prominent mathematicians, such as
Terence Tao of the University of California, Los
  Angeles, may help to build support.

Journal name: Nature

DOI:doi:10.1038/nature.2013.12243

 

 

Four decades of business scenarios: what can experience teach?

Four decades of business scenarios: what can experience teach?

Authors: Stephen M. Millett

Article Type: Conceptual paper

Keywords: Future unknowns, Futuring and visioning, Long-term risk,
Research-based scenarios, Scenario learning, Scenario methodology, Scenarios,
Scenarios as hypotheses, Scenarios for desirable futures, Subject experts

Strategy & Leadership, Volume 41, Issue 1

Page Numbers: 29 - 33

Year: 2013

La Jolla Institute identifies molecular switch enabling immune cells to better fight disease

Finding on killer cells opens new avenue for combating AIDS, cancer and other diseases

SAN DIEGO – (January 20th, 2013) A research team led by the La Jolla Institute for Allergy & Immunology has discovered the mechanism that enables CD4 helper T cells to assume the more aggressive role of killer T cells in mounting an immune attack against viruses, cancerous tumors and other damaged or infected cells.   The finding, made in collaboration with researchers from the RIKEN Institute in Japan, could enable the development of more potent drugs for AIDS, cancer and many other diseases based on using this mechanism to trigger larger armies of killer T cells against infected or damaged cells. 

CD4 helper T cells, which normally assist other cells of the immune system during an infection, and CD8 killer T cells, which directly attack and eliminate infected cells, are two of the body's most important immune cells for defending against diseases.  Earlier research studies have shown that helper T cells can become killer cells in some instances.  However, the specific mechanism of action that allowed this to occur was not known until now.

"We have identified the molecular switch that enables CD4 T cells to override their programming as helper cells and transform into cytolytic (killer) cells," said La Jolla Institute scientist and study co-leader Hilde Cheroutre, Ph.D.  "Our team also showed that these transformed helper T cells represent a separate and distinct population of cells.  They are not a subset of TH-1 helper cells as previously thought."

Jay A. Berzofsky, M.D., Ph.D., chief of the Vaccine Branch at the National Cancer Institute's Center for Cancer Research, called the finding "a major advance" that provides new understanding about the cell's lineage and basic mechanisms.  Dr. Berzofsky was among the researchers whose work in the 1980s first demonstrated that helper cells could convert to killer cells.  "Understanding how these cells derive and what causes them to switch from helper T cells to cytolytic T cells is an important step to learning how to manipulate them in disease," he said, noting it could lead to novel approaches "either to turn these cells off in autoimmune disease or turn them on in infectious diseases."

He added that the finding could also have important implications in cancer. "We need all of the cytolytic machinery that we can get to try to destroy cancers," he said. "If we can learn to turn them on, I think it's reasonable to believe that these cytolytic T cells can play an important role in controlling cancer."

The findings were published today in Nature Immunology in a paper entitled "Transcriptional reprogramming of mature CD4 helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes."  Dr. Cheroutre is co-senior author on the study together with Dr. Ichiro Taniuchi of the RIKEN Research Center for Allergy and Immunology in Yokohama, Kanagawa, Japan.  First authors on the paper are: Mohammad Mushtaq Husain, Ph.D., of the La Jolla Institute; Daniel Mucida, Ph.D., formerly of the La Jolla Institute, now at Rockefeller University; Femke van Wijk, Ph.D., formerly of the La Jolla Institute, now at the University Medical Center Utrecht, The Netherlands, and Sawako Muroi, of the RIKEN Institute.

Mitchell Kronenberg, Ph.D., La Jolla Institute president & chief scientific officer, said the study reflects the very successful collaboration between the La Jolla Institute and RIKEN in Japan, which have joined efforts on a number of projects over the years.

In the study, the researchers found that a certain transcription factor, which are molecules in the cell nucleus that control  the activity of cells, continually suppresses the killer T cell lineage in helper T cells.  Using mice, the team showed that turning off this transcription factor (ThPOK) enabled the helper cells in the body's peripheral areas, like the blood, spleen and the intestine, to override their original programming and to become killer T cells.  "While our work focused on the intestines, we found that helper T cells in all tissues of the body have the potential to become killer cells in response to recognition of viral, tumor or other antigens in the context of cytokines such as IL-15," said Dr. Cheroutre.

Jonathan Braun, M.D., chair of the Department of Pathology and Laboratory Medicine at UCLA's David Geffen School of Medicine, praised the study as laying the groundwork for using T helper cells in a much more aggressive manner.  "Helper T cells are mainly understood for their role in regulating other immune cells," he said.  "This work reveals how they themselves can be triggered to become the action cells in the immune response.  This opens new possibilities for how to manipulate them therapeutically in disease."

Dr. Cheroutre said the transformation of CD 4 helper T cells into killer cells already occurs in the body naturally.  "Our finding could help to explain a number of occurrences that we haven't really understood up to this point, such as why some people can be chronically infected with HIV without developing AIDS."  In these instances, Dr. Cheroutre is convinced that CD4 helper T cells must be taking over the role of killer cells after the CD8 T cells become exhausted.  "It's like the helper cells can come in as reinforcements to keep the virus under control.  If we can develop ways to artificially trigger that process, we may be able to significantly help people with HIV and other chronic infections." 

While scientists would want to trigger a larger army of virus-specific killer cells in the case of infections, the opposite would be true in inflammation-fueled autoimmune diseases, like rheumatoid arthritis or multiple sclerosis, said Dr. Cheroutre.  "The CD4 T cells are the bad wolves in inflammatory diseases because they often trigger more pro-inflammatory cells which worsen these conditions," she said.  "With this knowledge, we may be able to prevent that by coaxing the CD4 killer cells to become regulatory cells instead, which is another one of their potential functions.  In regulatory mode, the CD4 T cells suppress the immune system.  This suppression reduces inflammatory cells, which is what we want to do in autoimmune diseases." 

However in cancer, the CD4 T cell's regulatory function becomes problematic because they inhibit the killer T cells from destroying cancerous cells.  This is because of their built-in mechanism to keep T cells from attacking the body's own cells, said Dr. Cheroutre.   "Cancer cells develop from our own cells and only look a little different from healthy cells," she explained.  "The killer T cells can sense that they are different and decide to eliminate them.  However, the CD4 regulatory T cells frequently suppress the killer T cells and prevent them from destroying the cancerous cells.  This is often how cancer cells can escape the immune system's normal action of stamping out bad cells."

Dr. Cheroutre said she believes it may be possible, using the newly discovered mechanism, to turn the CD4 regulatory T cells into killer cells that would aid, rather than block, the immune system's attack on cancerous cells.

 

###

 

Scripps Research Institute Chemists Devise Inexpensive, Benchtop Method for Marking and Selecting Cells

LA JOLLA, CA – January 8, 2013 - Chemists at The Scripps Research Institute (TSRI) have found an easier way to perform one of the most fundamental tasks in molecular biology. Their new method allows scientists to add a marker to certain cells, so that these cells may be easily located and/or selected out from a larger cell population.

The technique, which is described in a recent issue of the chemistry journal Angewandte Chemie International Edition,makes use of the tight binding of two proteins that are cheaply obtainable but are not found in human or other mammalian cells. As such, it has advantages over existing cell-marking techniques.

“This new technique is cheap, easy and sensitive,” said TSRI Institute Professor Richard A. Lerner, who is the senior author of the new report. “The method should be useful in a variety of applications that require separating out certain types of cells.”

Looking for a Better Way

The best-known cell marker in use today is GFP (green fluorescent protein), a jellyfish protein that emits a distinctive green light when illuminated by certain other light wavelengths. When scientists want to add a new gene to cells, for example to produce a therapeutic protein, they often construct a genetic sequence that also includes the GFP gene. Thus the cells that successfully produce the new protein will also produce GFP, whose fluorescence allows these cells to be identified and even sorted out from a larger population.

But fluorescence-based cell sorting is relatively expensive and cumbersome. Alternative cell-marking techniques use marker molecules to which antibodies or metals will bind tightly, but these are apt to have unwanted side effects on the cells that they mark. Lerner’s team, led by first author Yingjie Peng, a postdoctoral fellow, set out to invent a better method.

The new method exploits a special property of chitinase enzymes, which evolved to break down chitin—a tough, sugar-derived material found, for example, in crab shells, squid beaks and the cell walls of fungi. In addition to a main chitin-breaking domain, chitinases have another active structure, a “chitin binding domain”(ChBD). “It makes a super-strong bond with chitin,” said Peng. In recent years, scientists have begun to use this high-affinity binding of ChBD and chitin as a marker system, typically for selecting ChBD-tagged proteins in a lab dish. The new method uses ChBD to mark and select cells.

A Powerful Tool

In the basic technique, a new gene can be added to cells within a larger DNA vector that also includes the genetic sequences for ChBD and GFP. The ChBD molecule will be produced in such a way that it ends up being held on the outer surface of its host cell’s plasma membrane—and the GFP molecule will sit just inside the membrane. The GFP serves as a visual beacon, while the ChBD serves as a handy gripping point for cell selection.

After exposing a culture of test cells to this experimental ChBD-containing vector, the scientists was able to see, via the GFP tags, which cells were expressing them, and was able to select them out easily, with high sensitivity, using magnetic beads coated with chitin. “This is a relatively easy benchtop method,” Peng said. Importantly, these selected cells could produce progeny cells that seemed normal and healthy.

Because the ChBD marker, in the vector, is produced in a way that anchors it to a cell’s membrane, it also can serve as a powerful tool for selecting just the membrane fraction of a sample of cellular material. Peng and his colleagues demonstrated this using chitin beads to quickly isolate a pure fraction of membrane material from ChBD-marked test cells.

Cellulase enzymes, which break down the ubiquitous plant compound cellulose, also have a high-affinity cellulase-binding domain, which can be employed in the same way as the ChBD.

The scientists expect that the new cell-marking method will help to streamline another major molecular biology technique, which was pioneered by the Lerner laboratory in parallel with the group of Sir Gregory Winter at the Laboratory of Molecular Biology in Britain. This technique allows scientists to produce very large and diverse libraries of antibody arms, and to sift through them, or“pan”—as gold miners pan for nuggets—for those that might be of use, for example in therapies. ChBD-based markers should be useful in boosting the efficiency of this panning process, said Peng.

The Lerner laboratory is also investigating the potential use of ChBD-based cell marking in living animals, for example to track the fates of selected cell types throughout an animal’s lifespan.

Those interested in using the new technology are invited to contact TSRI’s Office of Technology Development, at (858) 784-8140 or through the department’s webpage at http://www.scripps.edu/research/technology/contactus.html.

Other contributors to the study, “Engineering Cell Surfaces for Orthogonal Selectability,”were Teresa M. Jones and Diana I. Ruiz of the TSRI Department of Chemistry, and Dae Hee Kim of the Scripps Korea Antibody Institute. For more information on the paper, see http://onlinelibrary.wiley.com/doi/10.1002/anie.201201844/abstract

The research was supported by a grant from Scripps Korea Antibody Institute.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. Over the past decades, TSRI has developed a lengthy track record of major contributions to science and health, including laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. The institute employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

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Researchers discover how underground rodent wards off cancer

 

Second mole rat species has different mechanism for resisting
cancer

Biologists at the University of Rochester have determined how blind mole
rats fight off cancer—and the mechanism differs from what they discovered three
years ago in another long-lived and cancer-resistant mole rat species, the
naked mole rat.

The team of researchers, led by Professor Vera Gorbunova and Assistant Professor Andrei Seluanov, found that abnormally growing cells in blind mole rats secrete the interferon beta
protein, which causes those cells to rapidly die. Seluanov and Gorbunova hope
the discovery will eventually help lead to new cancer therapies in humans.
Their findings are being published this week in the Proceedings of the
National Academy of Sciences.

Blind mole rats and naked mole rats—both subterranean rodents with long life spans—are the only
mammals never known to develop cancer. Three years ago, Seluanov and Gorbunova
determined the anti-cancer mechanism in the naked mole rat. Their research found
that a specific gene—p16—makes the cancerous cells in naked mole rats
hypersensitive to overcrowding, and stops them from proliferating when too many
crowd together.

"We expected blind mole rats to have a similar mechanism for stopping the spread of cancerous
cells," said Seluanov. "Instead, we discovered they've evolved their
own mechanism."

Gorbunova and Seluanov made their discovery by isolating cells from blind mole rats and forcing them
to proliferate in culture beyond what occurs in the animal. After dividing
approximately 15-20 times, all of the cells in the culture dish died rapidly.
The researchers determined that the rapid death occurred because the cells
recognized their pre-cancerous state and began secreting a suicidal protein,
called interferon beta. The precancerous cells died by a mechanism which kills
both abnormal cells and their neighbors, resulting in a "clean
sweep."

"Not only were the cancerous cells killed off, but so were the adjacent cells, which may also be
prone to tumorous behavior," said Seluanov.

"While people don't use the same cancer-killing mechanism as blind mole rats, we may be able
to combat some cancers and prolong life, if we could stimulate the same clean
sweep reaction in cancerous human cells," said Gorbunova.

The research team also included Christopher Hine, Xiao Tian, and Julia Ablaeva in Rochester,
Andrei Gudkov at Roswell Park Cancer Institute in Buffalo,
NY, and Eviatar Nevo at the University of Haifa
in Israel.

Gorbunova and Seluanov say they next want to find out exactly what triggers the secretion of
interferon beta after cancerous cells begin proliferating in blind mole rats.

Gorbunova believes the anti-cancer mechanism is an adaptation to subterranean life. "Blind mole
rats spend their lives in underground burrows protected from predators,"
said Gorbunova. "Living in this environment, they could perhaps afford to
evolve a long lifespan, which includes developing efficient anti-cancer
defenses."

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