We develop a general method to explore how the function performed by a biological network can constrain both its structural and dynamical network properties. This approach is orthogonal to prior studies which examine the functional consequences of a given structural feature, for example a scale free architecture. A key step is to construct an algorithm that allows us to efficiently sample from a maximum entropy distribution on the space of Boolean dynamical networks constrained to perform a specific function, or cascade of gene expression. Such a distribution can act as a "functional null model" to test the significance of any given network feature, and can aid in revealing underlying evolutionary selection pressures on various network properties. Although our methods are general, we illustrate them in an analysis of the yeast cell cycle cascade. This analysis uncovers strong constraints on the architecture of the cell cycle regulatory network as well as significant selection pressures on this network to maintain ordered and convergent dynamics, possibly at the expense of sacrificing robustness to structural perturbations.

Single-cell microscopy and computational modeling offer novel mechanistic insight into the G1/S switch that initiates DNA replication in budding yeast, revealing a Clb5/6-Cdk1 and Sic1 feedback loop and new rules of biochemical circuit design.

Objective. Bruton's tyrosine kinase (BTK) plays a critical role in B cell development and function. We recently described a selective BTK inhibitor, RN486, that blocks B cell receptor (BCR) and Fc␥ receptor signaling and is efficacious in animal models of arthritis. The aim of this study was to examine the potential efficacy of BTK in systemic lupus erythematosus (SLE), using an NZB ؋ NZW mouse model of spontaneous SLE.Methods. Mice received RN486 or its vehicle (administered in chow) at a final concentration of 30 mg/kg for 8 weeks, starting at 32 weeks of age.Results

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Summary Background Multiple actinic keratosis (AK) lesions may arise from the cancerization of large, sun‐damaged skin areas. Although photodynamic therapy (PDT) is considered the most effective therapeutic option, the efficacy and safety of field treatment of multiple AK lesions with PDT has never before been tested in a pivotal trial. Objectives To evaluate the efficacy, safety and cosmetic outcome of BF‐200 ALA (a nanoemulsion formulation containing 10% aminolaevulinic acid hydrochloride) combined with the BF‐RhodoLED® lamp for the field‐directed treatment of mild‐to‐moderate AK with PDT. Methods The study was performed as a randomized, multicentre, double‐blind, placebo‐controlled, parallel‐group, phase III trial with BF‐200 ALA and placebo in seven centres in Germany. A total of 94 patients were enrolled in this study; 87 were randomized (55 patients received BF‐200 ALA, 32 received placebo). Patients received one PDT. If residual lesions remained at 3 months after treatment, PDT was repeated. Illumination was performed with the PDT lamp BF‐RhodoLED (635 nm ± 9 nm) until a total light dose of 37 J cm−2 was achieved. Results BF‐200 ALA was superior to placebo with respect to patient complete clearance rate (91% vs. 22%, P < 0·0001) and lesion complete clearance rate (94·3% vs. 32·9%, P < 0·0001) after a maximum of two PDTs. The confirmatory analysis of all key secondary variables supported this superiority” should not be skipped since this is an important result. Treatment‐emergent adverse events (TEAEs) were experienced by 100% of the BF‐200 ALA group and 69% of the placebo group. The most commonly reported TEAEs were TEAEs of the application site. The cosmetic outcome was improved in the BF‐200 ALA group compared with placebo. Conclusions Field‐directed therapy with BF‐200 ALA and BF‐RhodoLED lamp is highly effective and well tolerated for multiple mild‐to‐moderate AK lesions, providing greatly improved skin quality.