Evolution analyses of 115 aging-related genes exploring natural longevity in mammals -Positively selected genes & rapidly evolved genes enriched in IIS and immune pathways -Convergent mutations in genes associated with cancer in long-lived species -Evolution of longevity through cancer resistance in long-lived mammals ll www.cell.com/the-innovation

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Production of monoclonal antibodies (mAbs) receives considerable attention in the pharmaceutical industry. There has been an increasing interest in the expression of mAbs in Escherichia coli for analytical and therapeutic applications in recent years. Here, a modular synthetic biology approach is developed to rationally engineer E. coli by designing three functional modules to facilitate high-titer production of immunoglobulin G (IgG). First, a bicistronic expression system is constructed and the expression of the key genes in the pyruvate metabolism is tuned by the technologies of synthetic sRNA translational repression and gene overexpression, thus enhancing the cellular material and energy metabolism of E. coli for IgG biosynthesis (module 1). Second, to prevent the IgG biodegradation by proteases, the expression of a number of key proteases is identified and inhibited via synthetic sRNAs (module 2). Third, molecular chaperones are co-expressed to promote the secretion and folding of IgG (module 3). Synergistic integration of the three modules into the resulting recombinant E. coli results in a yield of the full-length IgG ≈150 mg L −1 in a 5L fed-batch bioreactor. The modular synthetic biology approach could be of general use in the production of recombinant mAbs.

The design and synthesis of a series of substituted 6-amino-4-(2,4-dimethoxyphenyl)-[1,2]dithiolo[4,3-b]-pyrrol-5-ones are described. All the synthesized compounds were evaluated for raising leukocyte count activities in normal mice. Four compounds (8a, b, d, h) exhibited raising leukocyte count activities close or higher than positive control recombinant human granulocyte colony stimulating factor (rhG-CSF), and some (8e-g, k, p, r) had a moderate effect. Among them, the most potent compound 8a was evaluated for its antileukopenia activity in cyclophosphamide (CTX) treated mice. Interestingly, 8a exhibited significant antileukopenia activity as compared to rhG-CSF. The results suggest that this kind of compounds might be utilized for the development of new candidate for treatment of leukocytopenia. and from other organisms since that time.2-4) This group of compounds includes thiolutin, aureothricin, isobutyropyrrothin, holomycin, xenorhabdins and thiomarinols A-G 5-9) ( Fig. 1). Dithiolopyrrolones are reported with diverse biological activities including against various Gram-positive and Gram-negative bacteria, yeasts, fungi and amoeboid parasites.10-12) Dithiolopyrrolones have also been reported to have anticancer activity. 13,14)The modifications of the dithiolopyrrolones have been extensively reported in literature. [15][16][17][18][19][20][21] However, all the modifications were intended to improve the antibacterial or anticancer activity. In our previous work, we first observed that ZL-004 (Fig. 2) exhibited antileukopenia activity, 22) which can significantly raise the white blood cells (WBC) count in normal mice and chemotherapy-induced mice. The mechanism of ZL-004 23) is to act on the mouse bone marrow causing proliferation and differentiation, the elevation of WBC is due to an increase in the absolute neutrophil count, which could promote the recovery of hemopoiesis. Also, it can raise WBC count in a dose-dependent manner without significant changes in erythrocyte, platelet counts or hemoglobin concentrations.In order to better understand the structure-activity relationship (SAR) and discover novel antileukopenia agents with higher potency and good safety profiles, we embarked on design and synthesis of analogues of ZL-004. In this study, we reported the practical synthesis, the SAR, the raising leukocyte count activity in normal mice and the antileukopenia activity in CTX-treated mice of the newly synthesized dithiolopyrrolones. 24,25) Results and DiscussionChemistry The synthesis of the target compounds was accomplished by the procedures shown in Chart 1. 1,3-Bis(tert-butylthio)propan-2-one was prepared from 1,3-dichloroacetone in the presence of potassium carbonate in acetone, which was coupled with 2,4-dimethoxyanile in toluene utilizing p-toluenesulfonic acid as catalyst. The reaction mixture was refluxed for 5h, and then the mixture was allowed to cool to −5°C, oxayl chlorite was added to the reaction mixture to generate the compound 3 in 75% yield. Ammonization of 3 by in situ synthesis of amm...

BackgroundThe transition from land to sea by the ancestor of cetaceans approximately 50 million years ago was an incredible evolutionary event that led to a series of morphological, physiological, and behavioral adaptations. During this transition, bone microstructure evolved from the typical terrestrial form to the specialized structure found in modern cetaceans. While the bone microstructure of mammals has been documented before, investigations of its genetic basis lag behind. The increasing number of cetaceans with whole-genome sequences available may shed light on the mechanism underlying bone microstructure evolution as a result of land to water transitions.ResultsCetacean bone microstructure is consistent with their diverse ecological behaviors. Molecular evolution was assessed by correlating bone microstructure and gene substitution rates in terrestrial and aquatic species, and by detecting genes under positive selection along ancestral branches of cetaceans. We found that: 1) Genes involved in osteoclast function are under accelerated evolution in cetaceans, suggestive of important roles in bone remodeling during the adaptation to an aquatic environment; 2) Genes in the Wnt pathway critical for bone development and homeostasis show evidence of divergent evolution in cetaceans; 3) Several genes encoding bone collagens are under selective pressure in cetaceans.ConclusionsOur results suggest that evolutionary pressures have shaped the bone microstructure of cetaceans, to facilitate life in diverse aquatic environments.