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Cyclic imides are commonly encountered structural motifs in natural and synthetic molecules with remarkable pharmacological properties. They are also used widely for further functionalization through various chemical transformations. Currently, renewed focus has been devoted worldwide on this important class of compounds for their potential new applications especially in the area of medicinal / pharmaceutical chemistry as well as in drug discovery. Consequently, their syntheses have attracted considerable interest. Various innovative methodologies have recently been developed in order to access and functionalize this class of compounds. For example, the combination of classical as well as modern reactions allowed synthetic chemists to perform the straight forward and direct synthesis of diversity based library of compounds, often in 1-2 steps. The present report will cover the relevant and recent advances in the field of occurrences, synthesis and chemical reactions of cyclic imides mainly from 1980 to the end of 2015.

Tyrosyl-DNA phosphodiesterase 2 repairs irreversible topoisomerase II-mediated cleavage complexes generated by anticancer topoisomerase-targeted drugs and processes replication intermediates for picornaviruses (VPg unlinkase) and hepatitis B virus. There is currently no TDP2 inhibitor in clinical development. Here, we report a series of deazaflavin derivatives that selectively inhibit the human TDP2 enzyme in a competitive manner both with recombinant and native TDP2. We show that mouse, fish, and C. elegansTDP2 enzymes are highly resistant to the drugs and that key protein residues are responsible for drug resistance. Among them, human residues L313 and T296 confer high resistance when mutated to their mouse counterparts. Moreover, deazaflavin derivatives show potent synergy in combination with the topoisomerase II inhibitor etoposide in human prostate cancer DU145 cells and TDP2-dependent synergy in TK6 human lymphoblast and avian DT40 cells. Deazaflavin derivatives represent the first suitable platform for the development of potent and selective TDP2 inhibitors.

Wheat blast is a serious disease caused by the fungus Magnaporthe oryzae(Triticumpathotype) (MoT). The objective of this study was to determine the effect of the 2NS translocation from Aegilops ventricosa(Zhuk.) Chennav on wheat head and leaf blast resistance. Disease phenotyping experiments were conducted in growth chamber, greenhouse, and field environments. Among 418 cultivars of wheat (Triticum aestivumL.), those with 2NS had 50.4 to 72.3% less head blast than those without 2NS when inoculated with an older MoT isolate under growth chamber conditions. When inoculated with recently collected isolates, cultivars with 2NS had 64.0 to 80.5% less head blast. Under greenhouse conditions when lines were inoculated with an older MoT isolate, those with 2NS had a significant head blast reduction. With newer isolates, not all lines with 2NS showed a significant reduction in head blast, suggesting that the genetic background and/or environment may influence the expression of any resistance conferred by 2NS. However, when near‐isogenic lines (NILs) with and without 2NS were planted in the field, there was strong evidence that 2NS conferred resistance to head blast. Results from foliar inoculations suggest that the resistance to head infection that is imparted by the 2NS translocation does not confer resistance to foliar disease. In conclusion, the 2NS translocation was associated with significant reductions in head blast in both spring and winter wheat.

Background: Bilateral intracerebroventricular (ICV) administration of streptozotocin (STZ) causes Alzheimer’s disease (AD)-type neurodegeneration in rats. The model is increasingly used for investigating pathology and therapeutic strategies for AD. Objective: The present study investigated cognitive abilities in rats infused with STZ-ICV in relation to hippocampal and cortical mitochondrial functions during a period of 60 days. Methods: Cognitive functions were assayed in rats employing various mazes. Mitochondrial state-3-respiration, complex-I activity and dynamin related protein-1 (DRP-1) expression were measured respectively by oxygraph, spectrophotometry and immunoblot assay. Amyloidosis was investigated employing Congo red staining. Results: One-time ICV-STZ infused animals exhibited body-weight loss and impaired cognitive ability from 14th day post-infusion. A significant loss of mitochondrial electron transport chain complex-I activity in the hippocampi and cortices was found by 14 days, and persisted up to 60 days following ICV-STZ infusion. Mitochondrial state-3 respiration was unaltered in these brain regions by 14 days, but significantly decreased from 21 days after STZ administration. DRP-1 expression was significantly increased in the hippocampi and cortices of these animals 21 days after infusion, but persisted only in the hippocampi up to 60 days. Congophilic granules indicative of amyloidosis were detected in the hippocampus by 21 days. Conclusion: Our results suggest that the non-genetic sporadic AD (sAD) rat model developed by single-time STZ-ICV infusion exhibits protein aggregation and dementia probably resulting from increased mitochondrial fragmentation and functional aberrations. The present study reinforces the validity of this model for studying pathogenesis and potential therapies of sAD.

Faults on overhead distribution feeders have significant impact on the distribution reliability. Literature review on outages shows that overhead lines are highly susceptible to environmental factors such as weather, trees and animal. Historical analysis of outage data recorded by utility in Kansas showed that the occurrences of animal-caused outages are dependent on weather conditions and time of the year. This paper proposes models based on neural network combined with boosting algorithms based on AdaBoost to estimate weekly animal-related outages. Effectiveness of the proposed models is evaluated using actual data for four cities of different sizes in Kansas. Performance of the proposed models are compared with each other and with neural network without boosting, and previously implemented models. The results clearly show that boosting reduces mean square error and mean absolute error, and increases correlation between the estimated outages and observed outages. Additionally, AdaBoost+ performs better than AdaBoost.RT with lower errors and higher correlations.

A Standing Contact Fatigue (SCF) test set up has been developed in order to facilitate quick testing of contact fatigue resistance of material surfaces. In this method the sample is pressed against a hard ball rapidly and the resulting crack formation is studied in order to evaluate the SCF resistance. Induction hardened surfaces of cam-ring steel and steels with pearlitic, martensitic, bainitic, ausferritic and quench and tempered microstructures have been studied. Characterization was performed by optical microscopy, scanning electron microscopy and hardness measurements. Ring-cone cracks were found at the edge of the indentations but inside the indent in the surface hardened cam-ring steel samples. Sectional views revealed that these cracks also grow underneath the indentation. Radial cracks were found in non-surface hardened samples. The test of the SCF resistance of steels with different microstructures showed that the ausferritic microstructures tested shoved better SCF resistance than the quench and tempered samples with similar hardness. A comparison between different tempering temperatures of surface hardened steels showed that samples tempered at the higher temperature 240 oC resulted in better SCF resistance.

The recognition that few human diseases are thoroughly addressed by mono-specific, monoclonal antibodies (mAbs) continues to drive the development of antibody therapeutics with additional specificities and enhanced activity. Historically, efforts to engineer additional antigen recognition into molecules have relied predominantly on the reformatting of immunoglobulin domains. In this report we describe a series of fully functional mAbs to which additional specificities have been imparted through the recombinant fusion of relatively short polypeptides sequences. The sequences are selected for binding to a particular target from combinatorial libraries that express linear, disulfide-constrained, or domain-based structures. The potential for fusion of peptides to the N- and C- termini of both the heavy and light chains affords the bivalent expression of up to four different peptides. The resulting molecules, called zybodies, can gain up to four additional specificities, while retaining the original functionality and specificity of the scaffold antibody. We explore the use of two clinically significant oncology antibodies, trastuzumab and cetuximab, as zybody scaffolds and demonstrate functional enhancements in each case. The affect of fusion position on both peptide and scaffold function is explored, and penta-specific zybodies are demonstrated to simultaneously engage five targets (ErbB2, EGFR, IGF-1R, Ang2 and integrin αvβ3). Bispecific, trastuzumab-based zybodies targeting ErbB2 and Ang2 are shown to exhibit superior efficacy to trastuzumab in an angiogenesis-dependent xenograft tumor model. A cetuximab-based bispecific zybody that targeting EGFR and ErbB3 simultaneously disrupted multiple intracellular signaling pathways; inhibited tumor cell proliferation; and showed efficacy superior to that of cetuximab in a xenograft tumor model.

Novel succinimide derivatives based on nimesulide were designed as potential anticancer agents and their synthesis was carried out using a straightforward and atom economic method. The key step of this methodology involved an Aza-Michael addition of several nitrogen nucleophiles to the corresponding N-aryl maleimide derivatives prepared efficiently from nimesulide via a two-step process. A number of compounds containing -NHX (X Ar, NHCOR, NHAr etc) at the C-3 of the succinimide were prepared in good yields. A number of compounds synthesized were tested for their cytotoxicity in vitro against human colon cancer cell lines and some of them showed promising activities.

Despite the clinical success of anti-tumor necrosis factor (TNF) therapies in the treatment of inflammatory conditions such as rheumatoid arthritis, Crohn disease and psoriasis, full control of the diseases only occurs in a subset of patients and there is a need for new therapeutics with improved efficacy against broader patient populations. One possible approach is to combine biological therapeutics, but both the cost of the therapeutics and the potential for additional toxicities needs to be considered. In addition to the various mediators of immune and inflammatory pathways, angiogenesis is reported to contribute substantially to the overall pathogenesis of inflammatory diseases. The combination of an anti-angiogenic agent with anti-TNF into one molecule could be more efficacious without the risk of severe immunosuppression. To evaluate this approach with our Zybody technology, we generated bispecific antibodies that contain an Ang2 targeting peptide genetically fused to the anti-TNF antibody adalimumab (Humira®). The bispecific molecules retain the binding and functional characteristics of the anti-TNF antibody, but with additional activity that neutralizes Ang2. In a TNF transgenic mouse model of arthritis, the bispecific anti-TNF-Ang2 molecules showed a dose-dependent reduction in both clinical symptoms and histological scores that were significantly better than that achieved by adalimumab alone.

The topic of spinal cord compression is presented in 2 issues: Part I, Volume 34, Number 7; and Part II, Volume 34, Number 8.

A number of α,β-unsaturated carboxylic acids were reacted with electron rich arenes or heteroarene in the presence of trifluoroacetic anhydride (TFAA) and H3PO4 at room temperature to give a variety of chalcone derivatives in good to excellent yields. The methodology was used to prepare novel compounds of potential pharmacological significances.

In this paper, a biomechanical basis for pedestrian protection is presented based on reviews of epidemiological and biomechanical studies conducted over the last three decades. Epidemiological studies reveal the nature and cause of pedestrian crashes and injuries sustained in the field. The various factors that influence pedestrian crashes and fatalities such as pedestrian demographics, time and location of crash, type of vehicles involved and their design characteristics, impact speeds, and nature and severity of injuries sustained are covered in the epidemiology section. The biomechanical studies identify the injury mechanisms and the biomechanical tolerances. Several biomechanical studies that attempt to identify the injury mechanisms and quantify the tolerances are critically reviewed in this paper, and the existing gaps in literature are identified. Further, the three primary injury mechanisms for pedestrian lower extremity injuries are highlighted, and an injury mechanism for depressed tibial fracture is hypothesised. The effect of exterior vehicle parameters such as bumper height, bumper stiffness, hood length, hood stiffness, bumper lead angle on the nature and severity of injuries sustained are also discussed. The biomechanical injury criteria and tolerance values in a proposed draft ECE pedestrian regulation are also presented. Finally, conclusions are drawn based on the epidemiological and biomechanical studies, which lead to a proposal for future work.

The nimesulide based novel glycolamide esters were designed and synthesized for the first time via a three-step method starting from nimesulide. Structures of the synthesized compounds were confirmed by spectroscopic analysis. All the synthesized compounds were examined for their cytotoxic effects in vitro, some of which showed significant cytotoxic activities against HCT-15 human colon cancer cell line.

A series of α,β‐unsaturated carboxylic acids (I) are reacted with electron rich arenes and hetarenes (II) in the presence of TFAA to give a variety of chalcone derivatives (III) in good to high yields.

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