lunes, 16 de septiembre de 2013

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** Sciencescape Update
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All aboard! After an extensive summer of beta testing, feedback, and refinement,
Sciencescape (http://sciencescape.org) is rolling out to five Universities and
Institutions this fall. Select invites are going out at this very moment. If you
haven't gotten your account confirmation yet: it's coming in the very near future. A
huge thank you to everyone who has been testing the site, and who has contributed
such invaluable feedback. As ever, please send us an email
(mailto:support@sciencescape.org?subject=Feedback&body=Hi%20Team%20Sciencescape%2C%0A)
with any feedback or suggestions - we love hearing from you!



** Weekly Research Highlights
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September 13th, 2013

As we ramp up to a full public launch, Sciencescape (http://sciencescape.org) will
be bringing you snapshots of key papers published in the biomedical sciences. Each
week, our team of scientific editors at Sciencescape (http://sciencescape.org) will
filter through the overwhelming volume of new research to highlight and summarize
important work you need to know about.



Papers are chosen to showcase breakthroughs in trending fields like cancer
genomics, synthetic biology, and stem cells. Our first review of Weekly Research
Highlights is attached below - we hope that you are inspired to share it with your
colleagues!





** Human Genetics [AR]
** Metachromatic leukodystrophy patients benefit from new gene therapy approach
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Scientists led by Alessandra Biffi and Luigi Naldini of Milan, Italy, have developed
a gene therapy protocol to treat metachromatic leukodystrophy (MLD), an inherited
lysosomal storage disease caused by ARSA gene mutations that result in a deficiency
of the enzyme arylsulfatase A (ARSA). Children with MLD experience severe
progressive motor and cognitive impairment, and many die within a few years of
symptom onset. In this study, the researchers used an approach on human patients
that they showed was successful in mice a few years ago. They removed hematopoietic
stem cells from three children, transferred lentiviruses modified to contain the
ARSA gene into the cells, and put the cells back into the patients. Although the
children in the trial were presymptomatic, they were biochemically characterized as
being ARSA deficient, carried mutations associated with late-infantile MLD, and had
one or more older siblings with late-infantile MLD. Following the ARSA gene transfer
therapy, the patients produced normal amounts of the ARSA protein and showed no
manifestation of the disease seven to 21 months beyond their predicted age of
disease onset. While the therapy appears promising, longer follow-ups will be
necessary to fully assess the safety and success of the approach.


** Original article A. Biffi, E. Montini, L. Lorioli, M. Cesani, F. Fumagalli, T.
Plati, C. Baldoli, et al., Lentiviral hematopoietic stem cell gene therapy benefits
metachromatic leukodystrophy, Science 341 (6148), p. 864, 2013.
doi:10.1126/science.1233158 (http://www.sciencemag.org/content/341/6148/1233158)
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** Chemical Biology [JMW]
** New small-molecule melanopsin antagonists discovered
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Melanopsin is a photopigment of the opsin family of G protein-coupled receptors. It
is expressed in a subset of ganglion cells of the retina and mediates a variety of
non-visual responses to light, including pupil diameter, sleep, and circadian
rhythms. In a collaboration between Lundbeck Research (NJ, USA) and the Salk
Institute for Biological Studies (CA, USA), researchers screened 80,000 compounds
for activity against melanopsin. Several sulfonamide-containing compounds were
initially identified as showing promising antagonistic activity, and further
analogues were either purchased or synthesized. Six of the so-called opsinamides
inhibited melanopsin photoactivation, and two of them were evaluated further owing
to their drug-like properties and lack of interaction with rhodopsin (a related
opsin responsible for visual responses). In vivo studies in mice demonstrated that
opsinamides specifically and reversibly modified melanopsin-mediated light
responses, without affecting
the related rod- and cone-mediated function. The identification of potent, highly
specific synthetic melanopsin antagonists opens the possibility of treating
light-modulated disorders of the central nervous system, such as migraine and
photophobia.


** Original article K. A. Jones, M. Hatori, L. S. Mure, J. R. Bramley, R.
Artymyshyn, S.-P. Hong, M. Marzabadi, et al., Small-molecule antagonists of
melanopsin-mediated phototransduction, Nat. Chem. Biol., published online 25 August
2013, doi:10.1038/nchembio.1333
(http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.1333.html)
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** Synthetic Biology [JMW]
** Escherichia coli engineered for improved tolerance to short-chain alcohols
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Biofuels obtained from engineered microbes are attracting much interest as possible
alternatives to fossil fuels. Unfortunately, some of the desired fuel products are
actually toxic to the bacteria and yeast engineered to produce them, limiting their
growth and, in turn, limiting biofuel production. The Tullman-Ercek group at the
University of California, Berkeley, reports the engineering of Escherichia coli to
confer improved tolerance to n-butanol, isobutanol, and other straight-chain
alcohols. Through a directed evolution strategy, the researchers generated variants
of the E. coli inner membrane efflux pump protein AcrB. Efflux proteins actively
pump unwanted (toxic) substances out of the cell. The AcrB pump variants generated
were able to act on non-natural substrates, conferring greater tolerance to many
short-chain alcohols by actively transporting them out of the cell.  Directed
evolution of membrane transporters for specificity to non-native substrates is a
valuable
tool for controlling small molecule concentration gradients across the cell, whether
for biofuel or other chemical production.


** Original article M. A. Fisher, S. Boyarskiy, M. R. Yamada, N. Kong, S. Bauer, D.
Tullman-Ercek.  Enhancing tolerance to short-chain alcohols by engineering the
Escherichia coli AcrB efflux pump to secrete the non-native substrate n-butanol, ACS
Synth. Biol., published online 30 August 2013, doi:10.1021/sb400065q
(http://pubs.acs.org/doi/abs/10.1021/sb400065q?journalCode=asbcd6)
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** Stem Cells [SP]
** Building a brain
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The extraordinary complexity of the human brain makes its study very appealing, yet
incredibly difficult. Unsurprisingly, news that the Knoblich lab have cultivated
brain-like structures—termed cerebral organoids—from human pluripotent stem cells,
has been met with much excitement. The researchers attribute their success to a new
culture protocol, which involves providing the cells with a gel scaffold and
maintaining the developing tissue in a spinning, rather than stationary, bioreactor.
Although only about 4mm in size, cerebral organoids are organized much like the
developing human brain; researchers demonstrated forebrain, midbrain, and hindbrain
regions, as well as other more-specialized brain structures that include cerebral
cortex, choroid plexus, and retina. Strikingly, neurons present in the cerebral
cortex showed evidence of electrical activity. To demonstrate their utility for the
study of brain development, Knoblich and his team cultured cerebral organoids from a
patient with microcephaly, a disorder characterized by markedly reduced brain size.
These organoids recapitulated the disease much more accurately than mouse models
have previously been able to. This key advance in the culture of brain tissue holds
great potential for the study of brain development and disorders in the future.


** Original article M. A. Lancaster, M. Renner, C.-A. Martin, D. Wenzel, L. S.
Bicknell, M. E. Hurles, T. Homfray, J. M. Penninger, A. P. Jackson, and J. A.
Knoblich, Cerebral organoids model human brain development and microcephaly, Nature,
published online 28 August 2013, doi:10.1038/nature12517
(http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12517.html)
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** Developmental Biology [SP]
** Muscling in on the gut
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The gut lining is a highly folded structure comprising numerous projections called
villi, which provide a large surface area for optimal absorption of nutrients. In
humans, villi are formed in three discrete steps—longitudinal ridges develop, then
fold into zigzags, which subsequently transform into individual villi. New findings
from Cliff Tabin’s laboratory reveal a link between these morphological stages and
sequential differentiation of the surrounding smooth muscle. The research team
report that a circular layer of smooth muscle forms around the gut tube during the
first stage of villi formation, which compresses the underlying tissue, causing
luminal folds to develop. Differentiation of a second layer of muscle, situated
longitudinally, exerts pressures that cause the previously formed ridges to buckle
into zigzags, and the subsequent development of a third longitudinal layer of muscle
is responsible for the final patterning of villi. Blocking smooth muscle contraction
did not affect morphology, suggesting that peristalsis is not involved. With help
from the Applied Math Lab at Harvard University, the investigators constructed a
mathematical model of the process, which could be used to simulate the different
patterns of villi formation that are observed between species.


** Original article A. E. Shyer, T. Tallinen, N. L. Nerurker, Z. Wei, E. S. Gil, D.
L. Kaplan, C. J. Tabin, and L. Mahadevan, Villification: how the gut gets its villi,
Science, published online 29 August 2013, doi:10.1126/science.1238842
(http://www.sciencemag.org/content/early/2013/08/28/science.1238842)






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