Acid promoted cinnamyl ion mobility within peptide derived macrocycles

We are developing methods that restrict the conformational mobility of peptides and related heteropolymers while simultaneously altering their properties. Our experiments occur as processes wherein a conserved, lipophilic reagent is activated in stages to form composite products with unprotected polyamides in parallel. For each starting oligomer, the goal is to create not one, but rather a collection of products. The intent is for those materials to retain molecular recognition elements of the biopolymer, yet display that functionality as part of stable, cyclic structures having defined shapes and enhanced membrane solubility/permeability. Here we describe reagent 2 and its two-step integration into peptides to afford macrocyclic ethers (e.g., 4 when starting with W-W-Y). When those materials are treated with protic acid in anhydrous solvent, the cinnamyl unit migrates from the oxygen of tyrosine to distribute throughout the structure, forming new products via carbon/carbon bonding. These changes occur concomitantly with acid-promoted rearrangements/cyclizations of the dienyne appendage to generate mixtures containing unique macrocycles such as 15. Similar amalgamations of 2 with more diverse peptides is a means to begin accessing complex peptidomimetics systematically. From a library of screening fractions generated in this way, we have identified a small molecule that selectively promotes hippocampal neurogenesis in the adult mouse brain.     

Endolaryngeal changes during high-intensity phonation videolaryngoscopic observations

Using a five-part vocal figure and standard fiberoptic techniques, we have analyzed the laryngeal functions of a group of professional singers and have made five observations occurring during high-intensity phonation that contradict the accepted physiologic functioning of the larynx. We have analyzed these contradictions as they relate to the three endolaryngeal sphincters; this was accomplished by the development of a four-component vocal protocol to examine the changes in these laryngeal structures and the degree of independent control of each of these structures possible in this group of specialized subjects. We have attempted to explain our findings based on available data relating to the functions of the intrinsic and extrinsic laryngeal musculature (including the cricothyroideus muscle) and the neurologic mechanisms involved. Finally, we discuss this data as it relates to current vocal training.     

The contribution of aryepiglottic constriction to “ringing” voice quality—A videolaryngoscopic study with acoustic analysis

Fiberscopic video laryngoscopy was performed on five professional singers to determine the presence or absence of aryepiglottic narrowing as a function of voice quality. Each sang “Happy Birthday” and parts of the “Star Spangled Banner” in six different voice qualities: speech, falsetto, sob (a low larynx with a vocal tract expanded by relaxing the middle constrictors), twang, belting, and opera. Several features were found to be common among the subjects and related to specific qualities. Aryepiglottic constriction was present in all singers in twang, belting, and opera qualities. Spectrographic analysis related the constriction to the presence of the “singer's formant.” The presence of this type of constrictive behavior will require further research to ascertain the possible benefits to those for whom a louder voice is essential and to understand the relationship of this constrictive maneuver to the natural closure functions of the larynx.     

Nachweis des Aluminiums

Ohne Zusammenfassung     

Development of proneurogenic, neuroprotective small molecules

Degeneration of the hippocampus is associated with Alzheimer's disease and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apoptotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile, and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive toward increases in activity and regions subject to modification. We have discovered compounds that are orally available, nontoxic, stable in mice, rats, and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photo-cross-linking.     

Geospatial model of COVID-19 spreading and vaccination with event Gillespie algorithm

We have developed a mathematical model and stochastic numerical simulation for the transmission of COVID-19 and other similar infectious diseases that accounts for the geographic distribution of population density, detailed down to the level of location of individuals, and age-structured contact rates. Our analytical framework includes a surrogate model optimization process to rapidly fit the parameters of the model to the observed epidemic curves for cases, hospitalizations, and deaths. This toolkit (the model, the simulation code, and the optimizer) is a useful tool for policy makers and epidemic response teams, who can use it to forecast epidemic development scenarios in local settings (at the scale of cities to large countries) and design optimal response strategies. The simulation code also enables spatial visualization, where detailed views of epidemic scenarios are displayed directly on maps of population density. The model and simulation also include the vaccination process, which can be tailored to different levels of efficiency and efficacy of different vaccines. We used the developed framework to generate predictions for the spread of COVID-19 in the canton of Geneva, Switzerland, and validated them by comparing the calculated number of cases and recoveries with data from local seroprevalence studies.