Total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone C for photoaffinity labeling of β-tubulin

The total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone C is described as a potential photoaffinity probe to elucidate the β-tubulin binding site. A sequential Suzuki-aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C1–C6 fragment. The C22-functionalized analog exhibited good activity in microtubule assembly assays, but cytotoxicity was significantly reduced. Molecular modeling simulations indicated that excessive steric bulk in the C22 position is accommodated by the large hydrophobic pocket of the binding site. Photoaffinity labeling studies were inconclusive suggesting non-specific labeling

Estratégia de marketing: contribuições para a teoria em marketing

O artigo aborda o tema estratégia de marketing, enfocando sua formulação e implementação. Apresenta o desenvolvimento de um modelo teórico de formação da estratégia de marketing e suas contribuições para a teoria em Marketing. Para tanto, analisou-se a literatura sobre estratégia e estudaram-se dois modelos de formação da estratégia de marketing. Além desses modelos, agregou-se uma pesquisa exploratória realizada em algumas empresas, a qual permitiu que fosse elaborada uma estrutura inicial de um modelo evolutivo, validada por um grupo de executivos das empresas pesquisadas a partir dos resultados da modelagem de equações estruturais. A análise dos resultados da pesquisa sugere as variáveis significativas, bem como as suas relações para a formação da estratégia de marketing. Esse modelo contribui para o estudo da estratégia de marketing por apresentar reflexões sobre formulação e implementação de estratégias, elaborando um construto a partir das várias visões de estratégia

A Horizon Scan to Support Chemical Pollution–Related Policymaking for Sustainable and Climate‐Resilient Economies

While chemicals are vital to modern society through materials, agriculture, textiles, new technology, medicines, and consumer goods, their use is not without risks. Unfortunately, our resources seem inadequate to address the breadth of chemical challenges to the environment and human health. Therefore, it is important we use our intelligence and knowledge wisely to prepare for what lies ahead. The present study used a Delphi‐style approach to horizon‐scan future chemical threats that need to be considered in the setting of chemicals and environmental policy, which involved a multidisciplinary, multisectoral, and multinational panel of 25 scientists and practitioners (mainly from the United Kingdom, Europe, and other industrialized nations) in a three‐stage process. Fifteen issues were shortlisted (from a nominated list of 48), considered by the panel to hold global relevance. The issues span from the need for new chemical manufacturing (including transitioning to non‐fossil‐fuel feedstocks); challenges from novel materials, food imports, landfills, and tire wear; and opportunities from artificial intelligence, greater data transparency, and the weight‐of‐evidence approach. The 15 issues can be divided into three classes: new perspectives on historic but insufficiently appreciated chemicals/issues, new or relatively new products and their associated industries, and thinking through approaches we can use to meet these challenges. Chemicals are one threat among many that influence the environment and human health, and interlinkages with wider issues such as climate change and how we mitigate these were clear in this exercise. The horizon scan highlights the value of thinking broadly and consulting widely, considering systems approaches to ensure that interventions appreciate synergies and avoid harmful trade‐offs in other areas. We recommend further collaboration between researchers, industry, regulators, and policymakers to perform horizon scanning to inform policymaking, to develop our ability to meet these challenges, and especially to extend the approach to consider also concerns from countries with developing economies

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

A Fab-Selective Immunoglobulin-Binding Domain from Streptococcal Protein G with Improved Half-Life Extension Properties.

Half-life extension strategies have gained increasing interest to improve the pharmacokinetic and pharmacodynamic properties of protein therapeutics. Recently, we established an immunoglobulin-binding domain (IgBD) from streptococcal protein G (SpGC3) as module for half-life extension. SpGC3 is capable of binding to the Fc region as well as the CH1 domain of Fab arms under neutral and acidic conditions.Using site-directed mutagenesis, we generated a Fab-selective mutant (SpGC3Fab) to avoid possible interference with the FcRn-mediated recycling process and improved its affinity for mouse and human IgG by site-directed mutagenesis and phage display selections. In mice, this affinity-improved mutant (SpGC3FabRR) conferred prolonged plasma half-lives compared with SpGC3Fab when fused to small recombinant antibody fragments, such as single-chain Fv (scFv) and bispecific single-chain diabody (scDb). Hence, the SpGC3FabRR domain seems to be a suitable fusion partner for the half-life extension of small recombinant therapeutics.The half-life extension properties of SpGC3 can be retained by restricting binding to the Fab fragment of serum immunoglobulins and can be improved by increasing binding activity. The modified SpGC3 module should be suitable to extend the half-life of therapeutic proteins and, thus to improve therapeutic activity

Click-Chemistry as a Mix-and-Match Kit for Amphiphile Synthesis

A small library of amphiphilic compounds was synthesized in an array using the Huisgen 1,3-dipolar cycloaddition of terminal alkynes with azides (CuAAC or click reaction). The self-assembling properties of these compounds were evaluated by polarizing microscopy and synchrotron small-angle X-ray scattering analysis

Synthesis of Skeletally Diverse and Stereochemically Complex Library Templates Derived from Isosteviol and Steviol

We have applied a diversity-oriented approach for the synthesis of skeletally diverse and stereochemically complex templates for small-molecule library production by performing Beckmann rearrangement and Beckmann fragmentation reactions on the bicyclo[3.2.1]octane rings of steviol and isosteviol, aglycones derived from the diterpene natural product stevioside. The optimization of these two reaction pathways is presented along with the successful application of a photo-Beckmann rearrangement. This work also led to the discovery of cyano-Prins-type and Thorpe–Ziegler-type cyclization reactions

Determination binding kinetics by quartz crystal microbalance measurements.

<p>Specificity and affinity of scDb-SpG_C3, scDb-SpG_C3Fab, and scDb-SpG_C3FabRR for human and mouse serum IgG, Fc Fragments, and Fab fragments were determined by QCM measurements at pH 7.4. Two-fold dilutions were added, starting at a concentration of 1,000 nM.</p

Effector cell retargeting and activation by bispecific scDb fusion proteins determined by IL–2 release.

<p>CEA positive target cells (LS174T) were incubated with scDb-SpG_C3 variants together with or without 100 μg/ml human IgG 1 h prior to addition of PBMCs. Cell free supernatant was analyzed after 24 h for released IL-2 by ELISA.</p

Affinity determination by QCM (K_D values in nM).

<p>Affinity determination by QCM (K_D values in nM).</p