Can the meiotic sex ratio explain the sex ratio bias in adult populations in the dioicous moss Drepanocladus lycopodioides?

Sex ratio variation is commonly observed in natural populations of many organisms with separate sexes and genetic sex determination, including bryophytes. Most bryophyte populations exhibit female-skewed expressed adult sex ratios, generally inferred from counts of sexually mature plants. For the rarely sexually reproducing perennial dioicous moss Drepanocladus lycopodioides, we showed that a female bias also exists in the genetic adult sex ratio, using a specifically designed molecular sex-associated marker. Here, we investigated whether the meiotic spore sex ratio contributes to the observed bias in genetic adult sex ratio in natural populations. Earlier attempts to study meiotic sex ratios have involved commonly cultivated ruderals that rapidly express sex in the laboratory. We established single-spore cultures from field-collected sporophytes from these populations and used the marker to assess the sex of individual sporelings. Spore germinability was (near) complete, and mortality among sporelings was virtually absent. The true meiotic sex ratio did not differ from equality, but strongly differed both from the observed genetic sex ratios in the natural adult populations, and from the European scale genetic sex ratio. We conclude that the biased population sex ratios in this species arise at life cycle stages after spore germination. Sexual dimorphism may selectively favour female proliferation during some phase of gametophyte development. Based on methodological progress, we successfully used a perennial study species with rare sexual reproduction, which significantly broadens the life history spectrum investigated in bryophyte sex ratio studies.     

Design,synthesis, biological evaluation,and molecular modeling studies of chalcone-rivastigmine hybrids as cholinesterase inhibitors

A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC₅₀ to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer’s disease (AD) treatment.     

Start Codon Targeted (SCoT) markers provide new insights into the genetic diversity analysis and characterization of Tunisian Citrus species

Start Codon Targeted markers were used to establish phylogenetic relationship among seven species from Citrus L. genus. Twelve SCoT primers were used for their ability to reveal polymorphism of the targeted codon of initiation. A total of 132 amplicons were generated and 93.9% of them were polymorphic. The polymorphism information content of 0.884 and the resolving power of 75.22 illustrate the efficiency of the tested SCoT primers in highlighting polymorphism. The average Nei's (1973) gene diversity (0.376), the Schannon's index (0.548) and the Gst parameter (0.346) describe an important polymorphism at the interspecies level in Citrus genus. Analysis of molecular variance suggested significant genetic differences within species. In fact, 84% of variance occurs within the species, whereas 16% of the variation was recorded among the species of Citrus. The limited gene flow (Nm = 0.941) was recognized as a major factor to explain the partition of the observed diversity. The principal coordinates analyses, Neighbor Joining and the Bayesian clustering approach based on the SCoT markers also confirm the discrimination of the species of Citrus. Our results confirm the relevance and suggest the effectiveness of the SCoT markers for assessing genetic diversity, characterization and identification of the species of Citrus.     

The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization

This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor–water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.     

Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking

Bromodomains (BRDs) recognize acetyl-lysine modified histone tails mediating epigenetic processes. BRD4, a protein containing two bromodomains, has emerged as an attractive therapeutic target for several types of cancer as well as inflammatory diseases. Using a fragment-based in silico screening approach, we identified two small molecules that bind to the first bromodomain of BRD4 with low-micromolar affinity and favorable ligand efficiency (0.37 kcal/mol per non-hydrogen atom), selectively over other families of bromodomains. Notably, the hit rate of the fragment-based in silico approach is about 10% as only 24 putative inhibitors, from an initial library of about 9 million molecules, were tested in vitro.     

Synthesis,in vitro α-glucosidase inhibitory potential and molecular docking study of thiadiazole analogs

α-Glucosidase is a catabolic enzyme that regulates the body’s plasma glucose levels by providing energy sources to maintain healthy functioning. 2-Amino-thiadiazole (1–13) and 2-amino-thiadiazole based Schiff bases (14–22) were synthesized, characterized by ¹H NMR and HREI-MS and screened for α-glucosidase inhibitory activity. All twenty-two (22) analogs exhibit varied degree of α-glucosidase inhibitory potential with IC₅₀ values ranging between 2.30 ± 0.1 to 38.30 ± 0.7 μM, when compare with standard drug acarbose having IC₅₀ value of 39.60 ± 0.70 μM. Among the series eight derivatives 1, 2, 6, 7, 14, 17, 19 and 20 showed outstanding α-glucosidase inhibitory potential with IC₅₀ values of 3.30 ± 0.1, 5.80 ± 0.2, 2.30 ± 0.1, 2.70 ± 0.1, 2.30 ± 0.1, 5.50 ± 0.1, 4.70 ± 0.2, and 5.50 ± 0.2 μM respectively, which is many fold better than the standard drug acarbose. The remaining analogs showed good to excellent α-glucosidase inhibition. Structure activity relationship has been established for all compounds. The binding interactions of these compounds were confirmed through molecular docking.     

Justification for the generic status of Courtoisina (Cyperaceae)

In the past, the two species of Courtoisina were placed either in Cyperus L., Mariscus Vahl, or in Courtoisia Nees (now Courtoisina Sojak). While these species show undoubted external similarities to both Cypm and Muriscus , they differ by their widely winged glumes and the arrangement of the veins of the glumes. They also differ profoundly from Mariscus and most species of Cypm in anatomical characteristics, and it is concluded that these differences warrant separate generic status.