A human MAP kinase interactome.

Mitogen-activated protein kinase (MAPK) pathways form the backbone of signal transduction in the mammalian cell. Here we applied a systematic experimental and computational approach to map 2,269 interactions between human MAPK-related proteins and other cellular machinery and to assemble these data into functional modules. Multiple lines of evidence including conservation with yeast supported a core network of 641 interactions. Using small interfering RNA knockdowns, we observed that approximately one-third of MAPK-interacting proteins modulated MAPK-mediated signaling. We uncovered the Na-H exchanger NHE1 as a potential MAPK scaffold, found links between HSP90 chaperones and MAPK pathways and identified MUC12 as the human analog to the yeast signaling mucin Msb2. This study makes available a large resource of MAPK interactions and clone libraries, and it illustrates a methodology for probing signaling networks based on functional refinement of experimentally derived protein-interaction maps

Large-scale replication study reveals a limit on probabilistic prediction in language comprehension

Do people routinely pre-activate the meaning and even the phonological form of upcoming words? The most acclaimed evidence for phonological prediction comes from a 2005 Nature Neuroscience publication by DeLong, Urbach and Kutas, who observed a graded modulation of electrical brain potentials (N400) to nouns and preceding articles by the probability that people use a word to continue the sentence fragment (‘cloze’). In our direct replication study spanning 9 laboratories (N=334), pre-registered replication-analyses and exploratory Bayes factor analyses successfully replicated the noun-results but, crucially, not the article-results. Pre-registered single-trial analyses also yielded a statistically significant effect for the nouns but not the articles. Exploratory Bayesian single-trial analyses showed that the article-effect may be non-zero but is likely far smaller than originally reported and too small to observe without very large sample sizes. Our results do not support the view that readers routinely pre-activate the phonological form of predictable words.Additional co-authors: Simon Busch-Moreno, Xiao Fu, Jyrki Tuomainen, Eugenia Kulakova, E Matthew Husband, Zdenko Kohút, Shirley-Ann Rueschemeyer, Falk Huetti

A practical drug discovery project at the undergraduate level

A practical drug discovery project for third-year undergraduates is described. No previous knowledge of medicinal chemistry is assumed. Initial lecture-workshops cover the basic principles; then students are asked to improve the profile of a weakly potent, poorly soluble PI3K inhibitor (1). Compound array design, molecular modelling and screening data analysis are followed by laboratory work in which each student, as part of a team, attempts to synthesise at least two target compounds. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. Forty-eight target compounds have been prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and 10-fold, respectively

Communications Biophysics

Contains research objectives and reports on six research projects split into three sections.National Institutes of Health (Grant 5 P01 NS13126-07)National Institutes of Health (Training Grant 5 T32 NS07047-05)National Institutes of Health (Training Grant 2 T32 NS07047-06)National Science Foundation (Grant BNS 77-16861)National Institutes of Health (Grant 5 R01 NS1284606)National Institutes of Health (Grant 5 T32 NS07099)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 5 R01 NS14092-04)Gallaudet College SubcontractKarmazin Foundation through the Council for the Arts at M.I.T.National Institutes of Health (Grant 1 R01 NS1691701A1)National Institutes of Health (Grant 5 R01 NS11080-06)National Institutes of Health (Grant GM-21189

In vitro and in vivo antifungal profile of a novel and long acting inhaled azole, PC945, on Aspergillus fumigatus infection

The profile of PC945, a novel triazole antifungal, designed for administration via inhalation, hasbeen assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tight-binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B)activity.In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945, and thenwashed, PC945 was found to be quickly absorbed into both target and non-target cells and toproduce persistent antifungal effects. In temporarily neutropenic immunocompromised miceinfected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treatedintranasally with PC945 at 0.56 μg/mouse, while posaconazole showed similar effects (44%) at14 μg/mouse. This profile affirms that topical treatment with PC945 should provide potentantifungal activity in the lung

Communications Biophysics

Contains reports on nine research projects split into four sections.National Institutes of Health (Grant 5 PO1 NS13126)National Institutes of Health (Grant 5 KO4 NS00113)National Institutes of Health (Training Grant 5 T32 NS07047)National Institutes of Health (Training Grant 1 T32 NS07099)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 5 ROI NS10916)National Institutes of Health (Grant 5 RO1 NS12846)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 1 RO1 NS14092)Edith E. Sturgis FoundationHealth Sciences FundNational Institutes of Health (Grant 2 R01 NS11680)National Institutes of Health (Fellowship 5 F32 NS05327)National Institutes of Health (Grant 2 ROI NS11080)National Institutes of Health (Training Grant 5 T32 GM07301

Communications Biophysics

Contains reports on eight research projects split into four sections.National Institutes of Health (Grant 5 P01 NS13126)National Institutes of Health (Grant 5 K04 NS00113)National Institutes of Health (Training Grant 5 T32 NS07047)National Science Foundation (Grant BNS80-06369)National Institutes of Health (Grant 5 ROl NS11153)National Institutes of Health (Fellowship 1 F32 NS06544)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 5 R01 NS10916)National Institutes of Health (Grant 5 RO1 NS12846)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 1 R01 NS14092)National Institutes of Health (Grant 2 R01 NS11680)National Institutes of Health (Grant 5 ROl1 NS11080)National Institutes of Health (Training Grant 5 T32 GM07301

Communications Biophysics

Contains reports on seven research projects split into three sections, with research objective for the final section.National Institutes of Health (Grant 2 PO1 NS 13126)National Institutes of Health (Grant 5 RO1 NS 18682)National Institutes of Health (Grant 1 RO1 NS 20322)National Institutes of Health (Grant 1 RO1 NS 20269)National Institutes of Health (Grant 5 T32 NS 07047)Symbion, Inc.National Institutes of Health (Grant 5 RO1 NS10916)National Institutes of Health (Grant 1 RO1 NS16917)National Science Foundation (Grant BNS83-19874)National Science Foundation (Grant BNS83-19887)National Institutes of Health (Grant 5 RO1 NS12846)National Institutes of Health (Grant 5 RO1 NS21322)National Institutes of Health (Grant 5 RO1 NS 11080

Communications Biophysics

Contains reports on seven research projects split into three sections.National Institutes of Health (Grant 5 PO1 NS13126)National Institutes of Health (Grant 1 RO1 NS18682)National Institutes of Health (Training Grant 5 T32 NS07047)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 1 F33 NS07202-01)National Institutes of Health (Grant 5 RO1 NS10916)National Institutes of Health (Grant 5 RO1 NS12846)National Institutes of Health (Grant 1 RO1 NS16917)National Institutes of Health (Grant 1 RO1 NS14092-05)National Science Foundation (Grant BNS 77 21751)National Institutes of Health (Grant 5 R01 NS11080)National Institutes of Health (Grant GM-21189

Communications Biophysics

Contains research objectives and reports on eight research projects split into three sections.National Institutes of Health (Grant 2 PO1 NS13126)National Institutes of Health (Grant 5 RO1 NS18682)National Institutes of Health (Grant 5 RO1 NS20322)National Institutes of Health (Grant 1 RO1 NS 20269)National Institutes of Health (Grant 5 T32 NS 07047)Symbion, Inc.National Institutes of Health (Grant 5 R01 NS10916)National Institutes of Health (Grant 1 RO NS 16917)National Science Foundation (Grant BNS83-19874)National Science Foundation (Grant BNS83-19887)National Institutes of Health (Grant 5 RO1 NS12846)National Institutes of Health (Grant 1 RO1 NS21322-01)National Institutes of Health (Grant 5 T32-NS07099-07)National Institutes of Health (Grant 1 RO1 NS14092-06)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 5 RO1 NS11080