9 research outputs found
Somatic Maintenance Resources in the Honeybee Worker Fat Body Are Distributed to Withstand the Most Life-Threatening Challenges at Each Life Stage
<div><p>In a global transcriptome analysis of three natural and three manipulated honeybee worker phenotypes at different ages, we have investigated the distribution of investment in somatic maintenance of the fat body. Gene expression is modulated so that the bees are able to resist the most life-threatening challenges at the actual life stage. Different modes of maintenance and repair are regulated, apparently to meet the environmental challenges most detrimental to survival and reproductive potential for the hive. We observed a broad down-regulation of genomic and cellular maintenance in the short-lived foragers and nurse bees compared to the long-lived winter bees. Our results show that survival and reproduction of the entire hive is given priority over the individual bees, hence supporting the idea of the honeybee society as a superorganism. Our results also fit the disposable soma theory of aging.</p></div
Number of differently expressed genes with a cut-off of q = 10% in all comparisons of worker phenotypes.
<p>Number of differently expressed genes with a cut-off of q = 10% in all comparisons of worker phenotypes.</p
qPCR validation of SOLiD whole transcriptome data.
<p>There was a very good correlation between the experimental data and the qPCR in all comparisons apart from nurse bees versus <i>vg</i>knockdowns. Omitting this data point gave a correlation of 0.93435774 for the rest of the genes in this comparison.</p
The resulting extraction of 12 clusters from the unsupervised hierarchical clustering analysis of all 8640 transcripts.
<p>Only foragers, nurses and the winter bee pools were included in the analysis. The x axis denotes the fold change and the y axis the individual bees within each worker group. Two clusters were up-regulated in winter bee pools (a, e), whereas four clusters were down-regulated in this worker phenotype (f, g, h and i). Four clusters were up-regulated in nurse bees (b, c, j, and l); one cluster was up-regulated in foragers (k) and one down-regulated (d). Abbreviations: (F1-5) foragers, (N1-5) nurses bee, (Wp1-5) winter bee pools, (FC) fold change.</p
Expressed genes within the insulin-insulin like signalling pathway.
<p>Comparison between worker phenotypes, only expressed genes with a fold change above 2 was considered. Abbreviations: F (foragers), N (nurse bees), Wb (winter bees).</p
Elevated Intraocular Pressure After Intravitreal Steroid Injection in Diabetic Macular Edema: Monitoring and Management
<p><b>Article full text</b></p>
<p><br></p>
<p>The full text of this article can
be found here<b>.</b> <a href="https://link.springer.com/article/10.1007/s40123-016-0052-8?view=classic">https://link.springer.com/article/10.1007/s40123-016-0052-8?view=classic</a></p><p></p>
<p><br></p>
<p><b>Provide enhanced content for this
article</b></p>
<p><br></p>
<p>If you are an author of this
publication and would like to provide additional enhanced content for your
article then please contact <a href="http://www.medengine.com/Redeem/âmailto:[email protected]â"><b>[email protected]</b></a>.</p>
<p><br></p>
<p>The journal offers a range of
additional features designed to increase visibility and readership. All
features will be thoroughly peer reviewed to ensure the content is of the
highest scientific standard and all features are marked as ‘peer reviewed’ to
ensure readers are aware that the content has been reviewed to the same level
as the articles they are being presented alongside. Moreover, all sponsorship
and disclosure information is included to provide complete transparency and
adherence to good publication practices. This ensures that however the content
is reached the reader has a full understanding of its origin. No fees are
charged for hosting additional open access content.</p>
<p><br></p>
<p>Other enhanced features include,
but are not limited to:</p>
<p><br></p>
<p>• Slide decks</p>
<p>• Videos and animations</p>
<p>• Audio abstracts</p>
<p>• Audio slides</p
Discovery of Tetrahydropyrazolopyridine as Sphingosine 1‑Phosphate Receptor 3 (S1P<sub>3</sub>)‑Sparing S1P<sub>1</sub> Agonists Active at Low Oral Doses
FTY720 is the first oral small molecule
approved for the treatment
of people suffering from relapsing–remitting multiple sclerosis.
It is a potent agonist of the S1P<sub>1</sub> receptor, but its lack
of selectivity against the S1P<sub>3</sub> receptor has been linked
to most of the cardiovascular side effects observed in the clinic.
These findings have triggered intensive efforts toward the identification
of a second generation of S1P<sub>3</sub>-sparing S1P<sub>1</sub> agonists.
We have recently disclosed a series of orally active tetrahydroisoquinoline
(THIQ) compounds matching these criteria. In this paper we describe
how we defined and implemented a strategy aiming at the discovery
of selective structurally distinct follow-up agonists. This effort
culminated with the identification of a series of orally active tetrahydropyrazolopyridines
The Discovery of I‑BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor
Through
their function as epigenetic readers of the histone code,
the BET family of bromodomain-containing proteins regulate expression
of multiple genes of therapeutic relevance, including those involved
in tumor cell growth and inflammation. BET bromodomain inhibitors
have profound antiproliferative and anti-inflammatory effects which
translate into efficacy in oncology and inflammation models, and the
first compounds have now progressed into clinical trials. The exciting
biology of the BETs has led to great interest in the discovery of
novel inhibitor classes. Here we describe the identification of a
novel tetrahydroquinoline series through up-regulation of apolipoprotein
A1 and the optimization into potent compounds active in murine models
of septic shock and neuroblastoma. At the molecular level, these effects
are produced by inhibition of BET bromodomains. X-ray crystallography
reveals the interactions explaining the structure–activity
relationships of binding. The resulting lead molecule, I-BET726, represents
a new, potent, and selective class of tetrahydroquinoline-based BET
inhibitors
Optimization of Sphingosine-1-phosphate‑1 Receptor Agonists: Effects of Acidic, Basic, and Zwitterionic Chemotypes on Pharmacokinetic and Pharmacodynamic Profiles
The efficacy of the recently approved
drug fingolimod (FTY720)
in multiple sclerosis patients results from the action of its phosphate
metabolite on sphingosine-1-phosphate S1P<sub>1</sub> receptors, while
a variety of side effects have been ascribed to its S1P<sub>3</sub> receptor activity. Although S1P and phospho-fingolimod share the
same structural elements of a zwitterionic headgroup and lipophilic
tail, a variety of chemotypes have been found to show S1P<sub>1</sub> receptor agonism. Here we describe a study of the tolerance of the
S1P<sub>1</sub> and S1P<sub>3</sub> receptors toward bicyclic heterocycles
of systematically varied shape and connectivity incorporating acidic,
basic, or zwitterionic headgroups. We compare their physicochemical
properties, their performance in <i>in vitro</i> and <i>in vivo</i> pharmacokinetic models, and their efficacy in peripheral
lymphocyte lowering. The campaign resulted in the identification of
several potent S1P<sub>1</sub> receptor agonists with good selectivity
vs S1P<sub>3</sub> receptors, efficacy at <1 mg/kg oral doses,
and developability properties suitable for progression into preclinical
development