This work offers a comprehensive approach to understanding the phenomena underlying vesicular exocytosis, a process involved in vital functions of living organisms such as neuronal and neuroendocrine signaling. The kinetics of release of most neuromediators that modulate these functions in various ways can be efficiently monitored using single-cell amperometry (SCA). Indeed, SCA at ultramicro- or nanoelectrodes provides the necessary temporal, flux, and nanoscale resolution to accurately report on the shape and intensity of single exocytotic spikes. Rather than characterizing amperometric spikes using standard descriptive parameters (e.g., amplitude and half-width), however, this study summarizes a modeling approach based on the underlying biology and physical chemistry of single exocytotic events. This approach provides deeper insights into intravesicular phenomena that control vesicular release dynamics. The ensuing model’s intrinsic parsimony makes it computationally efficient and friendly, enabling the processing of large amperometric traces to gain statistically significant insights.

This work poses and partially explores an astrobiological hypothesis: might polymeric sulfur and phosphorus-based oxides form heteropolymers in the acidic cloud decks of Venus’ atmosphere? Following an introduction to the emerging field of computational astrobiology, we demonstrate the use of quantum chemical methods to evaluate basic properties of a hypothetical carbon-free heteropolymer that might be sourced from feedstock in the Venusian atmosphere. Our modeling indicates that R-substituted polyphosphoric sulfonic ester polymers may form via multiple thermodynamically favorable pathways and exhibit sufficient kinetic stability to persist in the Venusian clouds. Their thermodynamic stability compares favorably to polypeptides, whose formation is slightly thermodynamically unfavored relative to amino acids in most known abiotic conditions. We propose a combined approach of vibrational spectroscopy and mass spectrometry to search for related materials in Venus’s atmosphere but note that none of the currently planned missions are well suited for their detection. While predicted Ultraviolet–Visible spectra suggest that the studied polymers are unlikely candidates for Venus’s unidentified UV absorbers, the broader possibility of sulfuric acid–based chemistry supporting alternative biochemistries challenges the traditional carbon-centric models of life. We argue that such unconventional lines of inquiry are warranted in the search for life beyond Earth.

G-quadruplexes and i-motifs are non-canonical secondary structures of DNA that act as conformational switches in controlling genomic events. Within the genome, G- and C-rich sequences with the potential to fold into G-quadruplexes and i-motifs are overrepresented in important regulatory domains, including, but not limited to, the promoter regions of oncogenes. We previously have shown that some promoter sequences can adopt coexisting duplex, G-quadruplex, i-motif, and coiled conformations; moreover, their distribution can be modelled as a dynamic equilibrium in which the fractional population of each conformation is determined by the sequence and local conditions. On that basis, we proposed a hypothesis in which the level of expression of a gene with G- and C-rich sequences in the promoter is regulated thermodynamically by fine-tuning the duplex-to-G-quadruplex ratio, with the G-quadruplex modulating RNA polymerase activity. Any deviation from the evolutionarily tuned, gene-specific distribution of conformers, such as might result from mutations in the promoter or a change in cellular conditions, may lead to under- or overexpression of the gene and pathological consequences. We now expand on this hypothesis in the context of supporting evidence from molecular and cellular studies and from biophysico-chemical investigations of oligomeric DNA. Thermodynamic control of transcription implies that G-quadruplex and i-motif structures in the genome form as thermodynamically stable conformers in competition with the duplex conformation. That is in addition to their recognized formation as kinetically trapped, metastable states within domains of single-stranded DNA, such as a transcription bubble or R-loop, that are opened in a prior cellular event.