Small molecule inhibitors of bromodomain-acetyl-lysine interactions.

Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests that they function as "readers" of histone lysine acetylation, a component of the proposed "histone code". Bromodomain-containing proteins are often found as components of larger protein complexes with roles in fundamental cellular process including transcription. The publication of two potent ligands for the BET bromodomains in 2010 demonstrated that small molecules can inhibit the bromodomain-acetyl-lysine protein-protein interaction. These molecules display strong phenotypic effects in a number of cell lines and affect a range of cancers in vivo. This work stimulated intense interest in developing further ligands for the BET bromodomains and the design of ligands for non-BET bromodomains. Here we review the recent progress in the field with particular attention paid to ligand design, the assays employed in early ligand discovery, and the use of computational approaches to inform ligand design.

Phenotypic screening and fragment-based approaches to the discovery of small-molecule bromodomain ligands.

Bromodomains are protein modules that bind to acetylated lysine residues and hence facilitate protein-protein interactions. These bromodomain-mediated interactions often play key roles in transcriptional regulation and their dysfunction is implicated in a large number of diseases. The discovery of potent and selective small-molecule bromodomain and extra C-terminal domain bromodomain ligands, which show promising results for the treatment of cancers and atherosclerosis, has promoted intense interest in this area. Here we describe the progress that has been made to date in the discovery of small-molecule bromodomain ligands, with particular emphasis on the roles played by phenotypic screening and fragment-based approaches. In considering the future of the field we discuss the prospects for development of molecular probes and drugs for the non-bromodomain and extra C-terminal domain bromodomains.

Constitutive Extracellular Polysaccharide (EPS) Production by Specific Isolates of Crocosphaera watsonii.

Unicellular dinitrogen (N(2)) fixing cyanobacteria have only recently been identified in the ocean and recognized as important contributors to global N(2) fixation. The only cultivated representatives of the open ocean unicellular diazotrophs are multiple isolates of Crocosphaera watsonii. Although constituents of the genus are nearly genetically identical, isolates have been described in two size classes, large ∼5 µm and small ∼3 µm cell diameters. We show here that the large size class constitutively produces substantial amounts of extracellular polysaccharides (EPS) during exponential growth, up to 10 times more than is seen in the small size class, and does so under both N(2) fixing and non-N(2) fixing conditions. The EPS production exceeds the amount produced by larger phytoplankton such as diatoms and coccolithophores by one to two orders of magnitude, is ∼22% of the total particulate organic C in the culture, and is depleted in N compared to cellular material. The large difference in observed EPS production may be accounted for by consistently higher photochemical efficiency of photosystem II in the large (0.5) vs. small (∼0.35) strains. While it is known that Crocosphaera plays an important role in driving the biological carbon (C) pump through the input of new nitrogen (N) to the open ocean, we hypothesize that this species may also contribute directly to the C cycle through the constitutive production of EPS. Indeed, at two stations in the North Pacific Subtropical Gyre, ∼70% of large Crocosphaera cells observed were embedded in EPS. The evolutionary advantage of releasing such large amounts of fixed C is still unknown, but in regions where Crocosphaera can be abundant (i.e., the warm oligotrophic ocean) this material will likely have important biogeochemical consequences.

Survey of physicians' approach to food allergy, Part 2: Allergens, diagnosis, treatment, and prevention.

BACKGROUND: Food allergy (FA) practice varies widely. OBJECTIVE: To report differences between allergists and nonallergists regarding diagnosis, treatment, and prevention of FA. METHODS: A 2-page questionnaire was mailed to 3,000 allergists and 4,000 nonallergists. We previously published the findings on prevalence and manifestations. Herein, we report the findings on food allergens, diagnosis, treatment, and prevention. RESULTS: Responses were received from 584 (19.5%) of the allergists and 77 (1.9%) of the nonallergists. Because of the nonallergists' low response rate, descriptive comparisons were made without emphasis on statistical significance. Allergists and nonallergists differed in their rankings of the 5 most common food allergens. Nonallergists differed markedly from allergists in the diagnostic methods, using more leukocytotoxic tests (10.9% vs 0.3%), specific IgG4 tests (33.8% vs 6.0%), and intradermal tests (40.0% vs 9.5%), but fewer percutaneous skin tests (44.7% vs 98.9%), specific IgE tests (73.4% vs 97.8%), and challenges (61.1% vs 87.6%). They also differed in their use of open, single-blind, and double-blind challenge tests. Allergists were more likely to rely on elimination of proven food allergens and less likely to use conventional elimination diets, rotation diets, and sublingual or subcutaneous hyposensitization. Allergists were more likely to recommend a diet regimen during pregnancy (76.7% vs 35.3%) and lactation (91.1% vs 72.9%), breastfeeding (93.6% vs 84.3%), hydrolysate formulas (83.5% vs 64.3%), and withholding solids until the age of 6 months (89.4% vs 70.0%). CONCLUSION: Differences were noted between nonallergists and allergists regarding causes, diagnostic methods, treatment, and prevention of FA, indicating the need for more education in this area.

Survey of physicians' approach to food allergy, Part 1: Prevalence and manifestations.

INTRODUCTION: Food allergy (FA) prevalence is increasing and is being popularly claimed by the general population. OBJECTIVE: To evaluate attitudinal differences between allergists and nonallergists with regard to prevalence, manifestations, offending food component, and time of onset of FA reactions. METHODS: A 2-page questionnaire was mailed to 3,000 members of the American College of Allergy, Asthma and Immunology and 4,000 nonallergists (1,000 each of internists, pediatricians, family practitioners, and otolaryngologists). RESULTS: Responses were received from 584 allergists and 77 nonallergists. The overall estimated prevalence of FA was significantly higher for nonallergists than allergists (12.1% vs 4.6%) and in each age group. The most common gastrointestinal manifestation of FA was oropharyngeal itching according to allergists (67.2%) vs diarrhea according to nonallergists (42.5%). More nonallergists than allergists reported neurobehavioral manifestations, musculoskeletal symptoms, and upper airway symptoms as common in FA. On the other hand, more allergists than nonallergists considered atopic dermatitis, acute urticaria or angioedema, and anaphylaxis to be common. Nonallergists considered carbohydrates, fat, and additives as causing allergy much more than allergists did (34.4% vs 6.9%; P < .001). With regard to time of onset of FA, nonallergists had higher estimates than allergists for both late (25.5.% vs 13.0%; P < .001) and delayed (22.1% vs 4.5%; P < .001) reactions. CONCLUSION: Significant differences in attitudes toward FA were revealed between allergists and nonallergists, which highlights the need to enhance education in this area.

Further stable methods for the calculation of partition functions in the superconfiguration approach.

The extension to recursion over holes of the Gilleron and Pain method for calculating partition functions of a canonical ensemble of noninteracting bound electrons is presented as well as a generalization for the efficient computation of collisional line broadening.

Adverse reactions to food additives.

OBJECTIVES: To summarize the literature related to the classification of food additives and their reported adverse reactions and to provide a practical approach for evaluation of patients suspected of having such reactions. DATA SOURCES: Information was derived from selected reviews and original articles published in peer-reviewed journals and from authoritative textbook chapters, supplemented by the clinical experience of the authors. STUDY SELECTION: Priority was given to studies that used blinded, placebo-controlled oral challenges to confirm adverse reactions to food additives. In addition, selected, appropriately evaluated case reports are included. RESULTS: A large number of food additives are widely used in the food industry. Adverse reactions to additives seem to be rare but are likely underdiagnosed in part due to a low index of suspicion. Numerous symptoms have been attributed to food additive exposure, but the cause-and-effect relationship has not been well demonstrated in all. CONCLUSIONS: Reactions to food additives should be suspected in patients who report symptoms to multiple unrelated foods or to a certain food when commercially prepared but not when homemade and the allergy evaluation rules out a role for food protein. It is also prudent to investigate food additives in patients considered to have idiopathic reactions. There is a minor role for skin testing or in vitro testing. Oral challenge testing with common additives, preferably preceded by a trial of an additive-free diet, is the definitive procedure for detecting the offending agent. Once the specific additive is identified, management is basically avoidance of all its forms.

Generalization of super-transition-array methods to hot dense plasmas by using optimum independent particle reference systems.

The computation of superconfiguration partition functions relies upon independent electron statistics, with electron-electron contributions included as an average first-order correction factor. The decomposition into a first-order correction and reference independent electron system has degrees of freedom not exploited by current methods. We present a derivation for the conventional choice of decomposition and propose a different method for obtaining an optimal decomposition for each superconfiguration. This constitutes an alternative procedure to recomputing self-consistent fields for the refinement of superconfiguration partition functions. Numerical results are presented and discussed.