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Ehlers M.D.,Biogen
Cell | Year: 2016

The conversion of basic biology into new therapeutics requires scientific activities in both academia and industry. Successful drug discovery projects span disciplines, sectors, and institutions and tightly couple laboratory and clinical experiments. Here, Ehlers describes conceptions and misconceptions about how science is conducted in industry versus academia. © 2016 Elsevier Inc.

Crotti A.,Biogen | Glass C.K.,University of California San Diego
Trends in Immunology | Year: 2015

Currently, the concept of 'neuroinflammation' includes inflammation associated with neurodegenerative diseases, in which there is little or no infiltration of blood-derived immune cells into the brain. The roles of brain-resident and peripheral immune cells in these inflammatory settings are poorly understood, and it is unclear whether neuroinflammation results from immune reaction to neuronal dysfunction/degeneration, and/or represents cell-autonomous phenotypes of dysfunctional immune cells. Here, we review recent studies examining these questions in the context of Huntington's disease (HD), where mutant Huntingtin (HTT) is expressed in both neurons and glia. Insights into the cellular and molecular mechanisms underlying neuroinflammation in HD may provide a better understanding of inflammation in more complex neurodegenerative disorders, and of the contribution of the neuroinflammatory component to neurodegenerative disease pathogenesis. © 2015 Elsevier Ltd.

Heppner F.L.,Charite - Medical University of Berlin | Ransohoff R.M.,Biogen | Becher B.,University of Zurich
Nature Reviews Neuroscience | Year: 2015

The past two decades of research into the pathogenesis of Alzheimer disease (AD) have been driven largely by the amyloid hypothesis; the neuroinflammation that is associated with AD has been assumed to be merely a response to pathophysiological events. However, new data from preclinical and clinical studies have established that immune system-mediated actions in fact contribute to and drive AD pathogenesis. These insights have suggested both novel and well-defined potential therapeutic targets for AD, including microglia and several cytokines. In addition, as inflammation in AD primarily concerns the innate immune system-unlike in 'typical' neuroinflammatory diseases such as multiple sclerosis and encephalitides-the concept of neuroinflammation in AD may need refinement. © 2015 Macmillan Publishers Limited. All rights reserved.

Arya R.,Comprehensive Epilepsy Center | Kothari H.,Unterberg Childrens Hospital at Monmouth Medical Center | Zhang Z.,University of Cincinnati | Han B.,Biogen | And 3 more authors.
Neurology | Year: 2015

Objective: This is a network meta-analysis of nonvenous drugs used in randomized controlled trials (RCTs) for treatment of acute convulsive seizures and convulsive status epilepticus. Methods: Literature was searched according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for RCTs examining treatment of acute convulsive seizures or status epilepticus with at least one of the study arms being a nonvenous medication. After demographic and outcome data extraction, a Bayesian network meta-analysis was performed and efficacy results were summarized using treatment effects and their credible intervals (CrI). We also calculated the probability of each route-drug combination being the most clinically effective for a given outcome, and provided their Bayesian hierarchical ranking. Results: This meta-analysis of 16 studies found that intramuscular midazolam (IM-MDZ) is superior to other nonvenous medications regarding time to seizure termination after administration (2.145 minutes, 95% CrI 1.308-3.489), time to seizure cessation after arrival in the hospital (3.841 minutes, 95% CrI 2.697-5.416), and time to initiate treatment (0.779 minutes, 95% CrI 0.495-1.221). Additionally, intranasal midazolam (IN-MDZ) was adjudged most efficacious for seizure cessation within 10 minutes of administration (90.4% of participants, 95% CrI 79.4%-96.9%), and persistent seizure cessation for ≥1 hour (78.5% of participants, 95% CrI 59.5%-92.1%). Paucity of RCTs produced evidence gaps resulting in small networks, routes/drugs included in some networks but not others, and some trials not being connected to any network. Conclusions: Despite the evidence gaps, IM-MDZ and IN-MDZ exhibit the best efficacy data for the nonvenous treatment of acute convulsive seizures or status epilepticus. © 2015 American Academy of Neurology.

Huttlin E.L.,Harvard University | Ting L.,Harvard University | Bruckner R.J.,Harvard University | Gebreab F.,Harvard University | And 25 more authors.
Cell | Year: 2015

Summary Protein interactions form a network whose structure drives cellular function and whose organization informs biological inquiry. Using high-throughput affinity-purification mass spectrometry, we identify interacting partners for 2,594 human proteins in HEK293T cells. The resulting network (BioPlex) contains 23,744 interactions among 7,668 proteins with 86% previously undocumented. BioPlex accurately depicts known complexes, attaining 80%-100% coverage for most CORUM complexes. The network readily subdivides into communities that correspond to complexes or clusters of functionally related proteins. More generally, network architecture reflects cellular localization, biological process, and molecular function, enabling functional characterization of thousands of proteins. Network structure also reveals associations among thousands of protein domains, suggesting a basis for examining structurally related proteins. Finally, BioPlex, in combination with other approaches, can be used to reveal interactions of biological or clinical significance. For example, mutations in the membrane protein VAPB implicated in familial amyotrophic lateral sclerosis perturb a defined community of interactors. © 2015 Elsevier Inc.

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