Synthesis and Screen of a Proline-Rich Combinatorial Library Towards the Identification of Sickle Cell Hemoglobin Polymerization Inhibitors

Sickle cell disease is a genetic disorder that affects the hemoglobin within red blood cells. A point mutation in the gene coding for the β-subunit of hemoglobin allows the mutant chain to interact with a hydrophobic pocket of another hemoglobin in a deoxygenated environment, causing polymerization of the proteins. This creates the characteristic sickle-shape of the diseased blood cells that can clog capillaries, leading to tissue damage and cell death. Currently, there are limited options for those affected with sickle cell disease. The research to be presented is focused on discovering peptides that can interact with the mutated hemoglobin and prevent aggregation. A novel proline-rich peptide ligand, ZSF39, was identified through a phage display against deoxygenated sickle cell hemoglobin. A combinatorial peptide library based on the structure of ZSF39 was synthesized and screened for binding affinity using an ELISA. A tightly binding peptide, LHSl, was discovered through the ELISA and found to have a significant inhibitory effect on the polymerization of sickle cell hemoglobin. This work represents a novel approach for the discovery of therapeutics for this debilitating disorder

Yes, It Is Polyphony and a Map: Revisiting the 72 Verses of St. Martial

The enigmatic 72 Verses for St. Martial is one of the many works by Ademar de Chabannes (989–1034) crafted to promote the false narrative that St. Martial of Limoges, rather than being a third-century bishop, was actually a first-century apostle. The composition is visually striking due to the acrostic formed from the first letter of each tercet, MARCIALIS APOSTOLVS XRISTI, and its two overlapping melodies, one in black ink and the other in red. The relationship between the two notations is the subject of debate: Paul Hooreman’s conclusion that they are two variations of the same monophonic chant is countered by Manuel Pedro Ferreira, who argues that Hooreman’s reasoning is insufficient to rule out polyphony. I use Ferreira’s assessment as a jumping-off point for the current analysis, which investigates the compositional processes underlying the creation of the 72 Verses. Hooreman describes many details in the chant as subject to disorganization, scribal error, lack of ability, etc., but when the chant is analyzed polyphonically, these problems resolve. Beyond the music itself, the chant’s unusual polyphonic structure features reveals that the chant is structured around medieval maps, moving between a mappa mundi and the celestial spheres

Don't judge a fish by its fins: species delineation of Congolese Labeo (Cyprinidae)

Conspicuous characters are often useful in species identification. Yet, identification and delineation are two different processes, and such characters do not necessarily provide the best basis on which species can be delineated. This is illustrated by the case of the Labeo with papillary lips from the Congo basin. Traditionally, species delineation in this group was based on a conspicuous trait: the shape of the dorsal fin, which shows a profound degree of differentiation. Morphometric analyses were performed on 185 specimens both with and without measurements taken on this fin. The groups obtained using these two approaches were compared with those obtained through DNA barcoding. For this, 24 sequences of the standard barcoding COI gene were obtained. Species delineations based on morphological and molecular results were in agreement when the shape of the dorsal fin was ignored. This suggested that of the five nominal species known from the Congo basin, L. altivelis, L. rosae, L. lineatus, L. weeksii and L. maleboensis, only the former three remain valid. Consequently, L. weeksii was synonymised with L. altivelis and L. maleboensis with L. lineatus. The sole Congo basin endemic is L. lineatus as L. altivelis and L. rosae also occur in more southern basins. The use of the shape of the dorsal fin in morphological studies has previously led to overestimates of species diversity in this group. This is due to the fact that L. altivelis shows a remarkable amount of geographical variation for this trait. The large amount of intra- and interspecific variation in this character was caused by differential allometric growth in different parts of the dorsal fin

Don’t judge a fish by its fins: species delineation of Congolese Labeo (Cyprinidae)

Conspicuous characters are often useful in species identification. Yet, identification and delineation are two different processes, and such characters do not necessarily provide the best basis on which species can be delineated. This is illustrated by the case of the Labeo with papillary lips from the Congo basin. Traditionally, species delineation in this group was based on a conspicuous trait: the shape of the dorsal fin, which shows a profound degree of differentiation. Morphometric analyses were performed on 185 specimens both with and without measurements taken on this fin. The groups obtained using these two approaches were compared with those obtained through DNA barcoding. For this, 24 sequences of the standard barcoding COI gene were obtained. Species delineations based on morphological and molecular results were in agreement when the shape of the dorsal fin was ignored. This suggested that of the five nominal species known from the Congo basin, L. altivelis, L. rosae, L. lineatus, L. weeksii and L. maleboensis, only the former three remain valid. Consequently, L. weeksii was synonymised with L. altivelis and L. maleboensis with L. lineatus. The sole Congo basin endemic is L. lineatus as L. altivelis and L. rosae also occur in more southern basins. The use of the shape of the dorsal fin in morphological studies has previously led to overestimates of species diversity in this group. This is due to the fact that L. altivelis shows a remarkable amount of geographical variation for this trait. The large amount of intra- and interspecific variation in this character was caused by differential allometric growth in different parts of the dorsal fin.status: publishe

Synergy of Advanced Experimental and Modeling Tools to Underpin the Synthesis of Static Step-Growth-Based Networks Involving Polymeric Precursor Building Blocks

The strength of combining experimental design and advanced kinetic Monte Carlo (kMC) modeling to understand step-growth network synthesis, commencing with a linear/star polymeric precursor, is illustrated considering three chemistries: (i) para-fluoro-thiol reaction (PFTR); (ii) nitrile imine-mediated tetrazole-ene cycloaddition (NITEC); and (iii) star poly(ethylene oxide-stat-propylene oxide) (sPEG)-amine-epoxy click reaction. Chemical parameters are determined based on small-molecule systems (monofunctional analogues) and diffusion parameters based on literature data and higher-network-yield data. Overall model validation is performed considering molar mass and spectroscopic experimental data. As basic support, kMC modeling provides the evolution of the complete size exclusion chromatography trace for both the soluble and the insoluble fraction at any time. In more detail, kMC modeling allows one to construct, whenever desired, two-dimensional traces such as the distribution of species with a given molar mass and number of cross-linking points (CPs) of a given type (e.g., with at least three cross-links), still differentiating between the soluble and insoluble fractions. Ultimately, postprocessing of kMC modeling results allows one to calculate distributions regarding distances between specific functional groups and the molecular pore size distribution upon considering a three-dimensional representation of the molecular buildup of individual network molecules. Also, the (relative) importance of reaction pathways can be assessed. It is, for instance, shown that diffusional limitations on intermolecular reactions determine how far a polymer network yield can be pushed, with a strong effect due to an intrinsically fast maleimide incorporation step, specifically for NITEC. Too long linear precursor building blocks should be avoided as they induce too prominent diffusional limitations. Too short linear precursor building blocks promote intramolecular reactions. With the sPEG building blocks, a well-defined structure is obtained, as confirmed by the narrow distribution regarding the distances between dye molecules added in the polymerization recipe. </p