Microwave-assisted synthesis of 3-aminobenzo[b]thiophene scaffolds for the preparation of kinase inhibitors

Microwave irradiation of 2-halobenzonitriles and methyl thioglycolate in the presence of triethylamine in DMSO at 130 °C provides rapid access to 3-aminobenzo[b]thiophenes in 58–96% yield. This transformation has been applied in the synthesis of the thieno[2,3-b]pyridine core motif of LIMK1 inhibitors, the benzo[4,5]thieno[3,2-e][1,4]diazepin-5(2H)-one scaffold of MK2 inhibitors and a benzo[4,5]thieno[3,2-d]pyrimidin-4-one inhibitor of the PIM kinases

Fortification and health: challenges and opportunities.

Fortification is the process of adding nutrients or non-nutrient bioactive components to edible products (e.g., food, food constituents, or supplements). Fortification can be used to correct or prevent widespread nutrient intake shortfalls and associated deficiencies, to balance the total nutrient profile of a diet, to restore nutrients lost in processing, or to appeal to consumers looking to supplement their diet. Food fortification could be considered as a public health strategy to enhance nutrient intakes of a population. Over the past century, fortification has been effective at reducing the risk of nutrient deficiency diseases such as beriberi, goiter, pellagra, and rickets. However, the world today is very different from when fortification emerged in the 1920s. Although early fortification programs were designed to eliminate deficiency diseases, current fortification programs are based on low dietary intakes rather than a diagnosable condition. Moving forward, we must be diligent in our approach to achieving effective and responsible fortification practices and policies, including responsible marketing of fortified products. Fortification must be applied prudently, its effects monitored diligently, and the public informed effectively about its benefits through consumer education efforts. Clear lines of authority for establishing fortification guidelines should be developed and should take into account changing population demographics, changes in the food supply, and advances in technology. This article is a summary of a symposium presented at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2014 on current issues involving fortification focusing primarily on the United States and Canada and recommendations for the development of responsible fortification practices to ensure their safety and effectiveness

(Contravariant) Koszul duality for DG algebras

A DG algebras $A$ over a field $k$ with $H(A)$ connected and $H_{<0}(A)=0$ has a unique up to isomorphism DG module $K$ with $H(K)\cong k$. It is proved that if $H(A)$ is degreewise finite, then RHom_A(?,K): D^{df}_{+}(A)^{op} \equiv D_{df}^{+}}(RHom_A(K,K)) is an exact equivalence of derived categories of DG modules with degreewise finite-dimensional homology. It induces an equivalences of $D^{df}_{b}(A)^{op}$ and the category of perfect DG $RHom_A(K,K)$-modules, and vice-versa. Corresponding statements are proved also when $H(A)$ is simply connected and $H^{<0}(A)=0$.Comment: 33 page

Response to Kamath et al 'A syncretic approach can yield dividends'

We welcome the response from Kamath et al. and their insight into the issues and culture within medicine in India, and their thoughts about how to address these issues. We also agree that a drama-based approach is not sufficient on its own to deal with entrenched power issues which affect students adversely. As we have indicated, we believe “a multipronged approach is needed to generate systemic change.” These authors similarly advocate that student mistreatment be dealt with “in a comprehensive manner” including a ‘grievance redressal system’ and other measures to withhold accreditation where there are issues of abuse of power. Nevertheless, we note that Kamath et al. have responded positively to our approach—as a part of that mix—and it would be of great interest to see whether drama-based workshops could support medical students developing embodied acting skills in their institution and whether they may have similar transformative effects. We’d like to refer the authors to an excellent Medical Humanities paper we referenced that outlined drama-based activities in medical education in India: Gupta S, Singh S. Confluence: understanding medical humanities through street theatre. Medical Humanities. 2011;37(2):127-128. Despite the above article, the authors note that medical education in India has not embraced the medical humanities. We would draw a distinction within the medical humanities between activities which are primarily studious (reading literature, studying medical history) and workshops that are based on participative and embodied activity. Our experience has indicated the effectiveness of drama-based workshops in addressing both the cognitive and emotive aspects of harmful practices and we believe that it is the embodied nature of acting skills workshops that is transformative

A variable amplitude fretting fatigue life estimation technique: formulation and experimental validation

The aims of the research work summarised in this paper are twofold. The first goal is to make available a large number of new experimental results generated by testing specimens of grey cast iron under both constant and variable amplitude fretting fatigue loading. The second goal is to formulate an advanced fretting fatigue design approach based on the combined use of the Modified Wӧhler Curve Method, the Theory of Critical Distances and the Shear Stress-Maximum Variance Method. The validation exercise based on the experimental results being produced demonstrates that the proposed methodology is a powerful tool suitable for designing mechanical assemblies against fretting fatigue

How Common is Energetic ^3He in the Inner Heliosphere?

Using data from the SIS and ULEIS instruments on the Advanced Composition Explorer (ACE) we have identified periods during which energetic ^3He is present in near-Earth interplanetary space between November 1997 and May 2002. The data, which cover the energy intervals 0.2–1 MeV/nuc (ULEIS) and 4.5–16.3 MeV/nuc (SIS), show that ^3He is present a significant fraction of the time, as would be required if these suprathermal particles were the major source of the ^3He being accelerated by shocks in the interplanetary medium. Specifically, we find that energetic ^3He is present at least ~ 60% of the time, and perhaps significantly more often

Computationally designed libraries of fluorescent proteins evaluated by preservation and diversity of function

To determine which of seven library design algorithms best introduces new protein function without destroying it altogether, seven combinatorial libraries of green fluorescent protein variants were designed and synthesized. Each was evaluated by distributions of emission intensity and color compiled from measurements made in vivo. Additional comparisons were made with a library constructed by error-prone PCR. Among the designed libraries, fluorescent function was preserved for the greatest fraction of samples in a library designed by using a structure-based computational method developed and described here. A trend was observed toward greater diversity of color in designed libraries that better preserved fluorescence. Contrary to trends observed among libraries constructed by error-prone PCR, preservation of function was observed to increase with a library's average mutation level among the four libraries designed with structure-based computational methods