μOrgano: A Lego?-Like Plug & Play System for Modular Multi-Organ-Chips

Human organ-on-a-chip systems for drug screening have evolved as feasible alternatives to animal models, which are unreliable, expensive, and at times erroneous. While chips featuring single organs can be of great use for both pharmaceutical testing and basic organ-level studies, the huge potential of the organ-on-a-chip technology is revealed by connecting multiple organs on one chip to create a single integrated system for sophisticated fundamental biological studies and devising therapies for disease. Furthermore, since most organ-on-a-chip systems require special protocols with organ-specific media for the differentiation and maturation of the tissues, multi-organ systems will need to be temporally customizable and flexible in terms of the time point of connection of the individual organ units. We present a customizable Lego^®-like plug & play system, μOrgano, which enables initial individual culture of single organ-on-a-chip systems and subsequent connection to create integrated multi-organ microphysiological systems. As a proof of concept, the μOrgano system was used to connect multiple heart chips in series with excellent cell viability and spontaneously physiological beat rates.     

The SbcC and SbcD homologs of the cyanobacterium <Emphasis Type="Italic">Anabaena</Emphasis> sp. strain PCC7120 (Alr3988 and All4463) contribute independently to DNA repair

The ubiquitous SbcCD exonuclease complex has been shown to perform an important role in DNA repair across prokaryotes and eukaryotes. However, they have remained uncharacterized in the ancient and stress-tolerant cyanobacteria. In the cyanobacterium Anabaena sp. strain PCC7120, SbcC and SbcD homologs, defined on the basis of the presence of corresponding functional domains, are annotated as hypothetical proteins, namely Alr3988 and All4463 respectively. Unlike the presence of sbcC and sbcD genes in a bicistronic operon in most organisms, these genes were distantly placed on the chromosome in Anabaena, and found to be negatively regulated by LexA. Both the genes were found to be essential in Anabaena as the individual deletion mutants were non-viable. On the other hand, the proteins could be individually overexpressed in Anabaena with no effect on normal cell physiology. However, they contributed positively to enhance the tolerance to different DNA damage-inducing stresses, such as mitomycin C and UV- and γ-radiation. This indicated that the two proteins, at least when overexpressed, could function independently and mitigate the damage caused due to the formation of DNA adducts and single- and double-strand breaks in Anabaena. This is the first report on possible independent in vivo functioning of SbcC and SbcD homologs in any bacteria, and the first effort to functionally characterize the proteins in any cyanobacteria.     

Protein A chromatography resin lifetime—impact of feed composition

Adsorbent lifetime during protein A chromatography is not readily predicted or understood, representing a key challenge to be addressed for biopharmaceutical manufacturers. This article focuses on the impact of feed composition on the performance of a typical agarose‐based protein A resin across a lifetime of 50 cycles. Cycling studies were performed using three different feed materials with varying levels of feed components including proteases, histones, DNA, and nonhistone proteins. Changes in the process and quality attributes were measured. The DBCs were not seen to vary between conditions although there was a reduction in particle porosity in all cases. Fluorescence spectroscopy and LC‐MS/MS were used to identify the contribution and extent of fouling to the observed capacity loss. Residual protein A ligand density and deposition of foulants (HCP, residual mAb, and DNA) varied between the three feed materials. Resins cycled in feed materials containing high concentrations of HCP and histones were seen to have greater extents of capacity loss. The mode of performance loss, capacity loss, or impact on product quality was seen to vary depending on the feed material. The results indicate that feed material composition may be correlated to the rate and mode of resin aging as a basis for improved process understanding. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:412–419, 2018     

Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.