6-Methylquinazolin-4(3H)-one Based Compounds as BRD9 Epigenetic Reader Binders: A Rational Combination of in silico Studies and Chemical Synthesis

6-methylquinazolin-4(3H)-one-based compounds were here identified and synthesized as novel binders of bromodomain-containing protein 9 (BRD9) epigenetic reader. Accounting a fast and efficient synthetic route aimed to easily obtain differently 2- and 8-disubstituted 6-methylquinazolin-4(3H)-one derivatives, a virtual library of synthesizable items was built and submitted to molecular docking experiments. Based on two 3D structure-based pharmacophore models recently developed by us on BRD9, 16 compounds were selected and synthesized, using mild conditions with good yields in relatively short reaction times. Among them, 14, 16, 18, 22, and 26 emerged as the most potent compounds of these series, able to bind BRD9 at the low micromolar range of concentrations. These molecules also showed a promising selective behavior when tested against BRD4 bromodomain. These results highlighted the quinazolin-4(3H)-one chemical core as a valuable scaffold for developing promising BRD9 binders

“Discovery of promising 1,2,4-oxadiazoles hits for the development of new anti-inflammatory agents interfering with eicosanoid biosynthesis pathways”

Prostaglandin E2 (PGE2) is an inflammatory mediator that plays a pivotal role in the evolvement and progression of inflammatory and tumor diseases.1The identification of novel inhibitors of eicosanoids biosynthesis with unexplored scaffolds is of great demand to develop a next generation of anti-inflammatory or anti-cancer drugs. Following a multidisciplinary protocol that involves virtual combinatorial screening, chemical synthesis, and validation of the biological activities we afforded to the identification of 1,2,4-oxadiazole-based hits, as a novel class of anti-inflammatory agents able to inhibit several enzymes involved in the progression of inflammation. 1,2,4-oxadiazoles represent a versatile “privileged scaffold” in drug discovery, due to the possibility of modifying and opportunely decorating the nucleus,2 and are never explored for their inhibitory activity on eicosanoid biosynthesis. This multidisciplinary scientific approach led to the identification of a multi-target inhibitor of cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1). Moreover, in vivo studies on the disclosed hit demonstrate that it attenuates leukocytes migration in a model of zymosan-induced peritonitis and modulates the production of IL-1β and TNF-α. These promising outcomes pave the way toward a medicinal chemistry optimization campaign of the disclosed hit characterized by a promising and safer pharmacological profile

Infall of gas as the formation mechanism of stars up to 20 times more massive than the Sun

Theory predicts and observations confirm that low-mass stars (like the Sun) in their early life grow by accreting gas from the surrounding material. But for stars ~ 10 times more massive than the Sun (~10 M_sun), the powerful stellar radiation is expected to inhibit accretion and thus limit the growth of their mass. Clearly, stars with masses >10 M_sun exist, so there must be a way for them to form. The problem may be solved by non-spherical accretion, which allows some of the stellar photons to escape along the symmetry axis where the density is lower. The recent detection of rotating disks and toroids around very young massive stars has lent support to the idea that high-mass (> 8 M_sun) stars could form in this way. Here we report observations of an ammonia line towards a high-mass star forming region. We conclude from the data that the gas is falling inwards towards a very young star of ~20 M_sun, in line with theoretical predictions of non-spherical accretion.Comment: 11 pages, 2 figure

Multiple ATR-Chk1 Pathway Proteins Preferentially Associate with Checkpoint-Inducing DNA Substrates

The ATR-Chk1 DNA damage checkpoint pathway is a critical regulator of the cellular response to DNA damage and replication stress in human cells. The variety of environmental, chemotherapeutic, and carcinogenic agents that activate this signal transduction pathway do so primarily through the formation of bulky adducts in DNA and subsequent effects on DNA replication fork progression. Because there are many protein-protein and protein-DNA interactions proposed to be involved in activation and/or maintenance of ATR-Chk1 signaling in vivo, we systematically analyzed the association of a number of ATR-Chk1 pathway proteins with relevant checkpoint-inducing DNA structures in vitro. These DNA substrates included single-stranded DNA, branched DNA, and bulky adduct-containing DNA. We found that many checkpoint proteins show a preference for single-stranded, branched, and bulky adduct-containing DNA in comparison to undamaged, double-stranded DNA. We additionally found that the association of checkpoint proteins with bulky DNA damage relative to undamaged DNA was strongly influenced by the ionic strength of the binding reaction. Interestingly, among the checkpoint proteins analyzed the checkpoint mediator proteins Tipin and Claspin showed the greatest differential affinity for checkpoint-inducing DNA structures. We conclude that the association and accumulation of multiple checkpoint proteins with DNA structures indicative of DNA damage and replication stress likely contribute to optimal ATR-Chk1 DNA damage checkpoint responses

The stellar and sub-stellar IMF of simple and composite populations

The current knowledge on the stellar IMF is documented. It appears to become top-heavy when the star-formation rate density surpasses about 0.1Msun/(yr pc^3) on a pc scale and it may become increasingly bottom-heavy with increasing metallicity and in increasingly massive early-type galaxies. It declines quite steeply below about 0.07Msun with brown dwarfs (BDs) and very low mass stars having their own IMF. The most massive star of mass mmax formed in an embedded cluster with stellar mass Mecl correlates strongly with Mecl being a result of gravitation-driven but resource-limited growth and fragmentation induced starvation. There is no convincing evidence whatsoever that massive stars do form in isolation. Various methods of discretising a stellar population are introduced: optimal sampling leads to a mass distribution that perfectly represents the exact form of the desired IMF and the mmax-to-Mecl relation, while random sampling results in statistical variations of the shape of the IMF. The observed mmax-to-Mecl correlation and the small spread of IMF power-law indices together suggest that optimally sampling the IMF may be the more realistic description of star formation than random sampling from a universal IMF with a constant upper mass limit. Composite populations on galaxy scales, which are formed from many pc scale star formation events, need to be described by the integrated galactic IMF. This IGIMF varies systematically from top-light to top-heavy in dependence of galaxy type and star formation rate, with dramatic implications for theories of galaxy formation and evolution.Comment: 167 pages, 37 figures, 3 tables, published in Stellar Systems and Galactic Structure, Vol.5, Springer. This revised version is consistent with the published version and includes additional references and minor additions to the text as well as a recomputed Table 1. ISBN 978-90-481-8817-

Timeless Links Replication Termination to Mitotic Kinase Activation

The mechanisms that coordinate the termination of DNA replication with progression through mitosis are not completely understood. The human Timeless protein (Tim) associates with S phase replication checkpoint proteins Claspin and Tipin, and plays an important role in maintaining replication fork stability at physical barriers, like centromeres, telomeres and ribosomal DNA repeats, as well as at termination sites. We show here that human Tim can be isolated in a complex with mitotic entry kinases CDK1, Auroras A and B, and Polo-like kinase (Plk1). Plk1 bound Tim directly and colocalized with Tim at a subset of mitotic structures in M phase. Tim depletion caused multiple mitotic defects, including the loss of sister-chromatid cohesion, loss of mitotic spindle architecture, and a failure to exit mitosis. Tim depletion caused a delay in mitotic kinase activity in vivo and in vitro, as well as a reduction in global histone H3 S10 phosphorylation during G2/M phase. Tim was also required for the recruitment of Plk1 to centromeric DNA and formation of catenated DNA structures at human centromere alpha satellite repeats. Taken together, these findings suggest that Tim coordinates mitotic kinase activation with termination of DNA replication

Comparative genome analysis of PHB gene family reveals deep evolutionary origins and diverse gene function

<p>Abstract</p> <p>Background</p> <p>PHB (Prohibitin) gene family is involved in a variety of functions important for different biological processes. PHB genes are ubiquitously present in divergent species from prokaryotes to eukaryotes. Human PHB genes have been found to be associated with various diseases. Recent studies by our group and others have shown diverse function of PHB genes in plants for development, senescence, defence, and others. Despite the importance of the PHB gene family, no comprehensive gene family analysis has been carried to evaluate the relatedness of PHB genes across different species. In order to better guide the gene function analysis and understand the evolution of the PHB gene family, we therefore carried out the comparative genome analysis of the PHB genes across different kingdoms.</p> <p>Results</p> <p>The relatedness, motif distribution, and intron/exon distribution all indicated that PHB genes is a relatively conserved gene family. The PHB genes can be classified into 5 classes and each class have a very deep evolutionary origin. The PHB genes within the class maintained the same motif patterns during the evolution. With<it> Arabidopsis</it> as the model species, we found that PHB gene intron/exon structure and domains are also conserved during the evolution. Despite being a conserved gene family, various gene duplication events led to the expansion of the PHB genes. Both segmental and tandem gene duplication were involved in Arabidopsis PHB gene family expansion. However, segmental duplication is predominant in Arabidopsis. Moreover, most of the duplicated genes experienced neofunctionalization. The results highlighted that PHB genes might be involved in important functions so that the duplicated genes are under the evolutionary pressure to derive new function.</p> <p>Conclusion</p> <p>PHB gene family is a conserved gene family and accounts for diverse but important biological functions based on the similar molecular mechanisms. The highly diverse biological function indicated that more research needs to be carried out to dissect the PHB gene function. The conserved gene evolution indicated that the study in the model species can be translated to human and mammalian studies.</p

Bioreactor for microalgal cultivation systems: strategy and development

Microalgae are important natural resources that can provide food, medicine, energy and various bioproducts for nutraceutical, cosmeceutical and aquaculture industries. Their production rates are superior compared to those of terrestrial crops. However, microalgae biomass production on a large scale is still a challenging problem in terms of economic and ecological viability. Microalgal cultivation system should be designed to maximize production with the least cost. Energy efficient approaches of using light, dynamic mixing to maximize use of carbon dioxide (CO2) and nutrients and selection of highly productive species are the main considerations in designing an efficient photobioreactor. In general, optimized culture conditions and biological responses are the two overarching attributes to be considered for photobioreactor design strategies. Thus, fundamental aspects of microalgae growth, such as availability of suitable light, CO2 and nutrients to each growing cell, suitable environmental parameters (including temperature and pH) and efficient removal of oxygen which otherwise would negatively impact the algal growth, should be integrated into the photobioreactor design and function. Innovations should be strategized to fully exploit the wastewaters, flue-gas, waves or solar energy to drive large outdoor microalgae cultivation systems. Cultured species should be carefully selected to match the most suitable growth parameters in different reactor systems. Factors that would decrease production such as photoinhibition, self-shading and phosphate flocculation should be nullified using appropriate technical approaches such as flashing light innovation, selective light spectrum, light-CO2 synergy and mixing dynamics. Use of predictive mathematical modelling and adoption of new technologies in novel photobioreactor design will not only increase the photosynthetic and growth rates but will also enhance the quality of microalgae composition. Optimizing the use of natural resources and industrial wastes that would otherwise harm the environment should be given emphasis in strategizing the photobioreactor mass production. To date, more research and innovation are needed since scalability and economics of microalgae cultivation using photobioreactors remain the challenges to be overcome for large-scale microalgae production

“Long lasting inflammatory effects of ammonium glycyrrhizinate: an integrated study of pharmacology and computational analysis”

The object of the study was to estimate the long-lasting effects induced by ammonium glycyrrhizinate (AG) after a single administration in mice using animal models of pain and inflammation together with biochemical and docking studies. A single intraperitoneal injection of AG was able to produce anti-inflammatory effects in zymosan-induced paw edema and peritonitis. Moreover, in several animal models of pain, such as the writhing test, the formalin test, and hyperalgesia induced by zymosan, AG administered 24 h before the tests was able to induce a strong antinociceptive effect. Molecular docking studies revealed that AG possesses higher affinity for microsomal prostaglandin E synthase type-2 compared to type-1, whereas it seems to locate better in the binding pocket of cyclooxygenase (COX)-2 compared to COX-1. These results demonstrated that AG induced anti-inflammatory and antinociceptive effects until 24-48 h after a single administration thanks to its ability to bind the COX/mPGEs pathway. Taken together, all these findings highlight the potential use of AG for clinical treatment of pain and/or inflammatory-related diseases