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Featured
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News |
Hepatitis C mouse model a major milestone
Development paves the way for testing potential vaccines.
- Virginia Gewin
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News |
German E. coli outbreak leads to drug trial
Timely discovery of new use for expensive drug put to the test.
- Marian Turner
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Letter |
Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation
- Guillaume Lebon
- , Tony Warne
- & Christopher G. Tate
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Research Highlights |
Antibiotics aided by other drugs
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Spotlight |
Spotlight on Biotech/Pharma
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Letter |
Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity
- Jun R. Huh
- , Monica W. L. Leung
- & Dan R. Littman
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Letter |
FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR
Lung cancers with activating mutations in EGFR can be treated with EGFR inhibitors, but not all tumours respond and some develop resistance. In an RNAi screen, this study searches for modifiers of the EGFR inhibitor response. It is found that inhibition of FAS and NF-κB signalling enhances the response in vitro and in vivo. In a cohort of lung cancer patients treated with EGFR inhibitors, expression of the NF-κB inhibitor IκB is associated with a better response and longer survival, indicating that combining NF-κB pathway and EGFR inhibitors may prove clinically useful.
- Trever G. Bivona
- , Haley Hieronymus
- & Charles L. Sawyers
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Letter |
DHODH modulates transcriptional elongation in the neural crest and melanoma
In a zebrafish model of melanoma driven by activated BRAF, this study finds expression of a gene signature indicative of disrupted terminal differentiation of neural crest progenitors. A chemical screen led to the identification of leflunomide as an inhibitor of neural crest stem cells. Leflunomide inhibits dihydroorotate dehydrogenase and thereby transcriptional elongation, including genes involved in neural crest development and melanoma growth. Leflunomide has anti-melanoma activity in the zebrafish model and human melanoma xenografts, and might prove useful as an anticancer drug.
- Richard Mark White
- , Jennifer Cech
- & Leonard I. Zon
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News |
Female hormone could be key to male contraceptive
Progesterone-sensing molecule that guides sperm to egg offers fertility solution.
- Ewen Callaway
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Spotlight |
Spotlight on Biotech/Pharma
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Research Highlights |
Promoter predicts drug results
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Letter |
The structural basis for agonist and partial agonist action on a β1-adrenergic receptor
Here, the X-ray crystal structure of the β1 adrenergic receptor, a G-protein-coupled receptor, bound to four small molecules that either act as full agonists or partial agonists is solved. The structures show that agonist binding induces a contraction of the catecholamine-binding pocket relative to the antagonist-bound receptor. This work reveals the pharmacological differences between different ligand classes, which should facilitate the structure-based design of new drugs with predictable efficacies.
- Tony Warne
- , Rouslan Moukhametzianov
- & Christopher G. Tate
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World View |
Legal highs: the dark side of medicinal chemistry
Synthetic chemist David Nichols describes how his research on psychedelic compounds has been abused — with fatal consequences.
- David Nichols
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Outlook |
Interdisciplinary research: Big science at the table
Researchers are adopting the tools of bioinformatics and pharmaceuticals to study and interpret the ever-growing body of data on the interplay between diet and genes.
- Lucas Laursen
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Research Highlights |
Organic chemistry: Making maoecrystal V
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Research Highlights |
Medicine: Profiling for blood pressure
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Research Highlights |
Structural biology: Dopamine receptor revealed
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News |
Good news for 'good' cholesterol
Positive results inject life into strategy to treat heart disease.
- Alla Katsnelson
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News Feature |
Schizophrenia: The drug deadlock
The biology is too complicated. Pharma companies are quitting. Where are schizophrenia drugs going to come from?
- Alison Abbott
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News |
Key ingredient staves off marijuana memory loss
Cannabis composition determines effects on the brain.
- Arran Frood
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Letter |
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma
PLX4032 is a selective inhibitor of the B-RAF protein that has shown promising results in an early clinical trial in melanoma patients with an activating mutation in B-RAF. Now the structure and function of this inhibitor are described. Translational data from a phase I trial show that clinical efficacy requires a substantial degree of inhibition of the ERK pathway downstream of B-RAF. The data also show that BRAF-mutant melanomas are highly dependent on B-RAF activity.
- Gideon Bollag
- , Peter Hirth
- & Keith Nolop
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Research Highlights |
Neuroscience: Quick mood lift
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News |
How an 1,800-year-old herbal mix heals the gut
An ancient Chinese medicine might ease side effects of cancer treatments.
- Ewen Callaway
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News |
GlaxoSmithKline strikes back over anti-ageing pills
Drugs do work as thought, says pharmaceutical giant.
- Ewen Callaway
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News |
Boost for drugs against hepatitis C
Promising clinical trial results point to the pharmaceutical industry's next blockbuster.
- Ewen Callaway
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Editorial |
Effective approach
The controversy surrounding diabetes drugs highlights the importance of comparative studies.
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News |
Party drug could ease trauma long term
Pilot studies demonstrate effectiveness of MDMA for post-traumatic stress disorder.
- Lizzie Buchen
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News & Views |
Closing in on an oral treatment
At present, only injectable drugs are available for treating multiple sclerosis. So clinical trials indicating that the drug fingolimod might be a step towards an oral treatment for the disease are exciting indeed.
- Roland Martin
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Article |
Neural bases for addictive properties of benzodiazepines
Benzodiazepines, such as valium, are used both in clinics and for recreational purposes, but lead to addiction in some individuals. Addictive drugs increase the levels of dopamine and trigger synaptic adaptations in the mesolimbic reward system, but the neural basis for the addictive nature of benzodiazepines remains elusive. Here, they are shown to increase firing of dopamine neurons in the ventral tegmental area through GABAA receptor activation in nearby interneurons.
- Kelly R. Tan
- , Matthew Brown
- & Christian Lüscher
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News & Views |
Lack of inhibition leads to abuse
Chronic drug use can lead to addiction, which is initiated by specific brain circuits. The mystery of how one class of drugs, the benzodiazepines, affects activity in this circuitry has finally been solved.
- Arthur C. Riegel
- & Peter W. Kalivas
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Authors |
Abstractions
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News |
Head of German drug agency to leave post
Board calls time on embattled director of pharmaceutical evaluation institute.
- Quirin Schiermeier
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Research Highlights |
Neuropharmacology: Beating depression
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News |
Health benefits of red-wine chemical unclear
Sceptics continue to ask whether resveratrol really can delay the effects of ageing.
- Lizzie Buchen
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Article |
Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors
GNF-2 is a recently discovered, selective allosteric Bcr–Abl inhibitor. Solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry are now used to show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. The results show that the combination of allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.
- Jianming Zhang
- , Francisco J. Adrián
- & Nathanael S. Gray