Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha

Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+?breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays.     

Overview and recommendations for regionalized life cycle impact assessment

The International Journal of Life Cycle Assessment - Regionalized life cycle impact assessment (LCIA) has rapidly developed in the past decade, though its widespread application, robustness, and...     

Core-shell encapsulation formulations to stabilize desiccated Bradyrhizobium against high environmental temperature and humidity

Engineered materials to improve the shelf-life of desiccated microbial strains are needed for cost-effective bioaugmentation strategies. High temperatures and humidity of legume-growing regions challenge long-term cell stabilization at the desiccated state. A thermostable xeroprotectant core and hydrophobic water vapour barrier shell encapsulation technique was developed to protect desiccated cells from the environment. A trehalose core matrix increased the stability of desiccated Bradyrhizobium by three orders of magnitude over 20 days at 32°C and 50% relative humidity (RH) compared to buffer alone; however, the improvement was not deemed sufficient for a shelf-stable bioproduct. We tested common additives (skim milk, albumin, gelatin and dextran) to increase the glass transition temperature of the desiccated product to provide further stabilization. Albumin increased the glass transition temperature of the trehalose-based core by 40°C and stabilized desiccated Bradyrhizobium for 4 months during storage at high temperature (32°C) and moderate humidity (50% RH) with only 1 log loss of viability. Although the albumin-trehalose core provided exceptional protection against high temperature, it was ineffective at higher humidity conditions (75%). We therefore incorporated a paraffin shell, which protected desiccated cells against 75% RH providing proof of concept that core and shell encapsulation is an effective strategy to stabilize desiccated cells.     

Attraction of Fruit-Eating Bats with Essential Oils of Fruits: A Potential Tool for Forest Restoration

Previous tests with essential oils from ripe chiropterochoric fruits suggested they can be used to attract and capture fruit-eating bats inside forest remnants. Here we evaluated the efficiency of these oils to attract frugivorous bats to open areas. We performed field tests with artificial fruits impregnated with essential oils of the genera Piper or Ficus that were attached to two groups of mist-nets set 50 m outside the border of a forest remnant. One group of artificial fruits received the corresponding oil isolated through hydrodistillation and the other received water only. Fruits with oils attracted significantly more fruit-eating bats, especially Artibeus lituratus that regularly crosses open habitats to reach other forest remnants. The highly significant attraction of A. lituratus by the oil of Piper was unexpected, since this bat is a specialist on Ficus fruits. We hypothesize that in habitats with no fruit available it is possible to attract frugivorous bats with the odor of several ripe fruit species. Furthermore, we verified that almost half of the individuals captured defecated seeds, indicating that the oils also attract recently fed bats, even when their preferred food is available nearby. This technique potentially may increase seed rain at specific locations, being particularly promising to restoration projects.     

Study of involvement of ImuB and DnaE2 in stationary-phase mutagenesis in Pseudomonas putida

Several bacterial species carry in their genomes a so-called "mutagenesis" gene cluster encoding ImuB which is similar to Y-family DNA polymerases, and DnaE2 related to the catalytic subunit DnaE of Pol III. Y-family DNA polymerases are known to be involved in stationary-phase mutagenesis and DnaE2 homologues characterized so far have expressed a mutator phenotype. In this study, we raised a question about the involvement of ImuB and DnaE2 in stationary-phase mutagenesis. Here, we show that Pseudomonas putida ImuB and DnaE2 have antagonistic effects on stationary-phase mutagenesis. ImuB facilitated accumulation of stationary-phase mutants up to two-fold. In contrast to that, DnaE2 had no significant effect on emergence of 1-bp deletion mutants and moreover, it acted as an anti-mutator in accumulation of base substitution mutants in starving bacteria. Similar antagonistic effects of DnaE2 and ImuB on mutagenesis appeared also in UV-mutagenesis study. This data distinguishes the DnaE2 of P. putida from its homologues studied in other organisms.     

Inundation,Hydrodynamics and Vegetation Influence Carbon Dioxide Concentrations in Amazon Floodplain Lakes

Ecosystems - Extensive floodplains and numerous lakes in the Amazon basin are well suited to examine the role of floodable lands within the context of the sources and processing of carbon within...     

Length–weight relationships of eight fish species from Guyana coastal drainages,Amapá, Brazil

The present study provides the length–weight relationships (LWR) for eight fish species in 19 streams from the Pedreira River basin, a small tributary of the Guyana coastal drainages from Amapá State, Brazil. Fishes were collected at two occasions, one in November 2016, the other in July 2018, using hand nets, with 0.5 mm of mesh size and 0.25 m² of mouth area, and trawl nets, with 0.5 mm of mesh size and 3 m long. Standard length and total weight were measured to determine the LWRs. The results show that the coefficient b varied between 2.798 and 3.380 and thus the values were within the expected range.     

Functional reconstitution of Arabidopsis thaliana plant uncoupling mitochondrial protein (AtPUMP1) expressed in Escherichia coli

The Arabidopsis thaliana uncoupling protein (UCP) gene was expressed in Escherichia coli and isolated protein reconstituted into liposomes. Linoleic acid-induced H+ fluxes were sensitive to purine nucleotide inhibition with an apparent K(i) (in mM) of 0.8 (GDP), 0.85 (ATP), 0.98 (GTP), and 1.41 (ADP); the inhibition was pH-dependent. Kinetics of AtPUMP1-mediated H+ fluxes were determined for lauric, myristic, palmitic, oleic, linoleic, and linolenic acids. Properties of recombinant AtPUMP1 indicate that it represents a plant counterpart of animal UCP2 or UCP3. This work brings the functional and genetic approaches together for the first time, providing strong support that AtPUMP1 is truly an UCP.     

Interactions of 5-deazapteridine derivatives with Mycobacterium tuberculosis and with human dihydrofolate reductases

There are major differences between the structures of human dihydrofolate reductase (hDHFR) and Mycobacterium tuberculosis dihydrofolate reductase (mtDHFR). These differences may allow us to design more selective mtDHFR inhibitors. In this paper we study the reactions of six different compounds derived from 5-deazapteridine with human and bacterial enzymes. Results suggest that the addition of hydrophobic groups to the aminophenyl ring would increase mtDHFR-inhibitor affinity and selectivity.