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The development of sustainable C(sp3)–H functionalization methods is of great interest to the pharmaceutical and agrochemical industries. Anodic oxidation is an efficient means of producing benzylic cations that can undergo subsequent in situnucleophilic attack to afford functionalized benzylic products. Herein, we demonstrate the suitability of carboxylic acids as nucleophiles to yield benzylic esters. This method employs a series of secondary benzylic substrates and functionalized carboxylic acids and is demonstrated on a gram scale in flow.

Dichloromeldrum’s acid is introduced as a bench-stable, nonvolatile reagent for the dichloroacetylation of anilines and alkyl amines to produce α,α-dichloroacetamides, which are important motifs for medicinal chemistry. Products are formed in good to excellent yields with reagent grade solvents, and, as the only byproducts are acetone and CO2, no column chromatography is required. Thus, this reagent is practical, efficient, and green for the dichloroacetylation of primary amines.

The reactors are an essential component of electrosynthetic reactions. As the electron transfer processes are heterogeneous, the reactors have a significant impact on reaction outcomes. This has resulted in reaction reproducibility being problematic, which commercial reactors alleviate somewhat but are expensive and cannot be optimized or iterated upon. Using 3D printing, rapid prototyping of bespoke reactors should facilitate investigation of the sensitivity of key reactor parameters, enable reactor optimization, and improved reproducibility through sharing of the print files. However, the bottleneck to this approach is the Computer Aided Design (CAD) of the reactors, which typically requires specialist knowledge and training to do. This has resulted in 3D printing not being typically used in the field of electrosynthesis. Herein, we showcase the development and application of a user-friendly, open-source software tool that can be used to produce Electrochemical Reactor CAD (ERCAD) designs simply and easily by nonexperts. We demonstrate its use to design and print reactors for the analysis, optimization, screening, and scaleup of electrosynthetic reactions. Using this parametric design tool, chemists with no design experience or skills can now easily create, print, test, and share their reactors.

Introduction:Following a US National Academy of Sciences report in 2007 entitled “Toxicity Testing of the 21st Century: a Vision and a Strategy,” significant advances within translational drug safety sciences promise to revolutionize drug discovery and development. The purpose of this review is to outline why investigative safety science is a competitive advantage for the pharmaceutical industry.Areas covered:The article discusses the essential goals for modern investigative toxicologists including: cross-species target biology; molecular pathways of toxicity; and development of predictive tools, models and biomarkers that allow discovery researchers and clinicians to anticipate safety problems and plan ways to address them, earlier than ever before. Furthermore, the article emphasizes the importance of investigating unanticipated clinical safety signals through a combination of mechanistic preclinical studies and/or molecular characterization of clinical samples from affected organs.Expert opinion:The traditional boundaries between pharma industry teams focusing on safety/efficacy and preclinical/clinical development are rapidly disappearing in favor of translational safety science-centric organizations with a vision of bringing more effective medicines forward safely and quickly. Comparative biology and mechanistic toxicology approaches facilitate: i) identifying translational safety biomarkers; ii) identifying new drug targets/indications; and iii) mitigating off-target toxicities. These value-adding safety science contributions will change traditional toxicologists from side-effect identifiers to drug development enablers.

Introduction:The goal of early predictive safety assessment (PSA) is to keep compounds with detectable liabilities from progressing further in the pipeline. Such compounds jeopardize the core of pharmaceutical research and development and limit the timely delivery of innovative therapeutics to the patient. Computational methods are increasingly used to help understand observed data, generate new testable hypotheses of relevance to safety pharmacology, and supplement and replace costly and time-consuming experimental procedures.Areas covered:The authors survey methods operating on different scales of both physical extension and complexity. After discussing methods used to predict liabilities associated with structures of individual compounds, the article reviews the use of adverse event data and safety profiling panels. Finally, the authors examine the complexities of toxicology data from animal experiments and how these data can be mined.Expert opinion:A significant obstacle for data-driven safety assessment is the absence of integrated data sets due to a lack of sharing of data and of using standard ontologies for data relevant to safety assessment. Informed decisions to derive focused sets of compounds can help to avoid compound liabilities in screening campaigns, and improved hit assessment of such campaigns can benefit the early termination of undesirable compounds.

Aluminum-lithium (Al-Li) alloys are of interest to the aerospace and aeronautical industries as rising fuel costs and increasing environmental restrictions are promoting reductions in vehicle weight. However, Al-Li alloys suffer from several issues during fusion welding processes including solute segregation and depletion. Solid freeform fabrication (SFF) of materials is a repair or rapid prototyping process, in which the deposited feedstock is built-up via a layering process to the required geometry. Recent developments have led to the investigation of SFF processes via Gas Metal Arc Welding (GMAW) capable of producing functional metallic components. A SFF process via GMAW would be instrumental in reducing costs associated with the production and repair of Al-Li components. Furthermore the newly developed Controlled-Short-Circuit-MIG (CSC-MIG) process provides the ability to control the weld parameters with a high degree of accuracy, thus enabling the optimization of the solidification parameters required to avoid solute depletion and segregation within an Al-Li alloy. The objective of this study is to develop the welding parameters required to avoid lithium depletion and segregation. In the present study weldments were produced via CSC-MIG process, using Al-Li 2199 sheet samples as the filler material. The residual lithium concentration within the weldments was then determined via Atomic Absorption (AA) and X-ray Photoelectron Spectroscopy (XPS). The microstructure was analyzed using High Resolution Scanning Electron Microscopy (HR-SEM). Finally the mechanical properties of welded samples were determined through the application of hardness and tensile testing.

The author discusses his construction of an observatory in his home in Amarillo, Texas. He provides a brief background of his interest in astronomy. Some features of his dream observatory are discussed, including a pier and beam construction and 5-foot high walls to allow viewing with the main telescope. He started the construction of his observatory in 2007 with the help of his wife, Amy.

The formation of J-aggregates in Langmuir monolayers of a neat merocyanine dye (3-carboxymethyl-5-[2-(3-octadecyl-2-benzothiazolinyldene)ethylidene]-2-thioxo-4-thiazolidinone) has been examined by measuring the normal incidence absorption spectra. Five types of J-aggregates were found to be formed, depending on the temperature and the concentration and type of cations present in the subphase. The shift in the absorption peak wavelength on the J-aggregates formation is accounted for in terms of the number and the geometrical arrangement of the chromophores in each J-aggregate. The spectral shifts were analyzed numerically using both a point dipole model and a transition density model. These calculations indicate that the five different J-aggregates are linear ones with aggregation numbers ranging from 2 to 6.

Yeast SUG1 was originally characterized as a transcriptional mediator for the GAL4 transactivator. A similar role in vertebrates was suggested by the ligand-enhanced interaction between mammalian homologues of yeast SUG1 and the ligand-dependent activating domain (AF-2) of nuclear receptors. SUG1 was also shown to be a component of the PA700 regulatory complex of the 26 S proteasome and a member of a large family of putative ATPases. However, no catalytic function has yet been attributed to SUG1. We show here that SUG1 is a 3′-5′ DNA helicase whose activity is dependent on an intact ATP binding domain. The sedimentation heterogeneity of mammalian SUG1 suggests that it may be associated with distinct protein complexes and therefore play multiple roles.

The chronic relapsing nature of heroin addiction can be explained from a family systems viewpoint. The addiction cycle is part of a family pattern involving a complex homeostatic system of interlocking feedback mechanisms. These serve to maintain the addiction and consequently the overall family stability. Drug-taking usually starts at adolescence. It is related to an intense fear of separation experienced by the family in response to the addict's attempts at individuation. The family becomes stuck at a particular developmental stage. Heroin provides a solution at several levels to the dilemma of whether or not to allow him independence. Paradoxically, it permits him to simultaneously be both close and distant, "in" and "out," competent and incompetent, relative to his family of origin. This is pseudoindividuation. An understanding of these concepts, and their integration into a homeostatic model, can provide the basis for effective treatment.

Synthetic organic chemistry is increasingly automated, data rich and intelligent. At the Automated Synthesis Forum, industry and academia showcased their recent progress towards this augmented future.

The genes transcribed by RNA polymerase (pol) III can be placed into four distinct groups based on the nature and position of their promoter elements. In the higher eukaryotes equivalent genes usually belong to the same sub-type of pol III promoters and there are few examples of genes which have changed promoter type during evolution. In this work we demonstrate that the promoter of the Arabidopsis thaliana 7SL RNA gene is located upstream of the coding region and Is identical to the promoters of pol Ill-specific plant U-small nuclear RNA (U-snRNA) genes. Sequence analysis of two different 7SL genes from A.thallana revealed that both genes contain two sequence elements in their 5′ flanking regions identical In sequence and position to the highly conserved USE and TATA elements of the pol Ill-transcribed plant U-snRNA genes. Mutational analysis of these elements in the At7SL-2 gene Indicates that the USE and TATA elements are both necessary and account for ≥90% of the transcriptional activity of this gene In transfected plant protoplasts. Within the coding region of both genes there is a sequence element which is a 10/11 nt match to the consensus B-box element of tRNA genes, however, this element Is not important for gene activity. These findings distinguish the plant genes from the human 7SL gene, which has both internal and upstream promoter elements and its upstream elements are different from those found in the human U-snRNA genes.