Reverse-Engineering a Transcriptional Enhancer: A Case Study in Drosophila

Abstract Enhancers, or cis-regulatory elements, are the principal determinants of spatiotemporal patterning of gene expression. For reasons of clinical and research utility, it is desirable to build customized enhancers that drive novel gene expression patterns, but currently, we largely rely on “found” genomic elements. Synthetic enhancers, assembled from transcription factor binding sites taken from natural signal-regulated enhancers, generally fail to behave like their wild-type counterparts when placed in transgenic animals, suggesting that important aspects of enhancer function are still unexplored. As a step toward the creation of a truly synthetic regulatory element, we have undertaken an extensive structure–function study of an enhancer of the Drosophila decapentaplegic (dpp) gene that drives expression in the developing visceral mesoderm (VM). Although considerable past efforts have been made to dissect the dppVM enhancer, transgenic experiments presented here indicate that its activity cannot be explained by the known regulators alone. dppVM contains multiple, previously uncharacterized, regulatory sites, some of which exhibit functional redundancy. The results presented here suggest that even the best-studied enhancers must be further dissected before they can be fully understood, and before faithful synthetic elements based on them can be created. Implications for developmental genetics, mathematical modeling, and therapeutic applications are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63213/1/ten.tea.2008.0074.pd

Reduced specificity of autobiographical memory and depression: The role of executive control

It has been widely established that depressed mood states and clinical depression, as well as a range of other psychiatric disorders, are associated with a relative difficulty in accessing specific autobiographical information in response to emotion-related cue words on an Autobiographical Memory Test (AMT; J. M. G. Williams & K. Broadbent, 1986). In 8 studies the authors examined the extent to which this relationship is a function of impaired executive control associated with these mood states and clinical disorders. Studies 1-4 demonstrated that performance on the AMT is associated with performance on measures of executive control, independent of depressed mood. Furthermore, Study 1 showed that executive control (as measured by verbal fluency) mediated the relationship between both depressed mood and a clinical diagnosis of eating disorder and AMT performance. Using a stratified sample in Study 5, the authors confirmed the positive association between depressed mood and impaired performance on the AMT. Studies 6-8 involved experimental manipulations of the parameters of the AMT designed to further indicate that reduced executive control is to a significant extent driving the relationship between depressed mood and AMT performance. The potential role of executive control in accounting for other aspects of the AMT literature is discussed. (PsycINFO Database Record (c) 2007 APA, all rights reserved)

Recognize fish as food in policy discourse and development funding

The international development community is off-track from meeting targets for alleviating global malnutrition. Meanwhile, there is growing consensus across scientific disciplines that fish plays a crucial role in food and nutrition security. However, this ‘fish as food’ perspective has yet to translate into policy and development funding priorities. We argue that the traditional framing of fish as a natural resource emphasizes economic development and biodiversity conservation objectives, whereas situating fish within a food systems perspective can lead to innovative policies and investments that promote nutrition-sensitive and socially equitable capture fisheries and aquaculture. This paper highlights four pillars of research needs and policy directions toward this end. Ultimately, recognizing and working to enhance the role of fish in alleviating hunger and malnutrition can provide an additional long-term development incentive, beyond revenue generation and biodiversity conservation, for governments, international development organizations, and society more broadly to invest in the sustainability of capture fisheries and aquaculture

Advancing biological understanding and therapeutics discovery with small-molecule probes

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines but also highlight the need to innovate the science of therapeutic discovery

Measurement of CPCP asymmetries in D±→η′π±D^{\pm}\rightarrow \eta^{\prime} \pi^{\pm} and Ds±→η′π±D_s^{\pm}\rightarrow \eta^{\prime} \pi^{\pm} decays

See paper for full list of authors - All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-041.html - Submitted to Phys. Lett. BInternational audienceA search for CP violation in D±→η′π± and D±s→η′π± decays is performed using proton-proton collision data, corresponding to an integrated luminosity of 3 fb−1, recorded by the LHCb experiment at centre-of-mass energies of 7 and 8 TeV. The measured CP-violating charge asymmetries are ACP(D±→η′π±)=(−0.61±0.72±0.55±0.12)% and ACP(D±s→η′π±)=(−0.82±0.36±0.24±0.27)%, where the first uncertainties are statistical, the second systematic, and the third are the uncertainties on the ACP(D±→K0Sπ±) and ACP(D±s→ϕπ±) measurements used for calibration. The results represent the most precise measurements of these asymmetries to date