Analyzing Single-Molecule Time Series via Nonparametric Bayesian Inference

The ability to measure the properties of proteins at the single-molecule level offers an unparalleled glimpse into biological systems at the molecular scale. The interpretation of single-molecule time series has often been rooted in statistical mechanics and the theory of Markov processes. While existing analysis methods have been useful, they are not without significant limitations including problems of model selection and parameter nonidentifiability. To address these challenges, we introduce the use of nonparametric Bayesian inference for the analysis of single-molecule time series. These methods provide a flexible way to extract structure from data instead of assuming models beforehand. We demonstrate these methods with applications to several diverse settings in single-molecule biophysics. This approach provides a well-constrained and rigorously grounded method for determining the number of biophysical states underlying single-molecule data.     

Impacts of co-occurring environmental changes on Alaskan stream fishes

1. Freshwater fishes are now facing unprecedented environmental changes across their northern ranges, especially due to rapid warming occurring at higher latitudes. However, empirical research that examines co-occurring environmental effects on northern fish communities remains limited.
2. We used fish community data from 1587 Alaskan stream sites to examine the potential combined and interacting effects of climate change, current weather, habitat, land use, and fire on two community-level metrics (species richness, relative abundance), and on the distributions of three Alaskan fish species.
3. Our models were 71–76% accurate in predicting the distribution of Alaskan stream fishes using a combination of climate and habitat variables. In contrast to other freshwater ecosystems that are most threatened by land use pressures, we did not detect any evidence for the potential stress of anthropogenic land use or fire on stream fishes.
4. Warming temperatures increased overall community richness and abundance but produced differing responses at the species level. Juvenile salmon presence was positively associated with several climate variables including warmer spring and autumn temperatures and wetter summers. In comparison, warmer seasonal temperatures contributed to declines for northern-adapted species such as Arctic grayling and Dolly Varden.
5. This study highlights the overarching role of current and changing climate in regulating northern stream fish biodiversity. Although many fish species may benefit from climate change across their northern ranges, localised declines are likely to occur and may prove detrimental for communities with limited fishing portfolios. Climate change adaptation and mitigation strategies customised for rapidly changing northern ecosystems will play an essential role in preserving ecologically unique northern species.

     

Juvenile foraging among the Hadza: Implications for human life history

The longstanding view that children among foraging populations are largely dependent on the food collection efforts of others is an assumed and implicit characteristic of several models of human life history and family formation. The evolution of protracted juvenility in humans is often explained using the “embodied capital model” which argues that prolonged investment in growth and delayed reproduction evolved because a long training period is required to learn difficult foraging tasks and become a self-sufficient forager. The model suggests that if juvenile investment in growth and learning yields an increase in adult productivity, then selection will favor delayed maturity, long life span, and increased brain size. Here, we test the embodied capital model with naturalistic foraging and consumption data among juvenile Hadza hunter–gatherers of Tanzania to determine the extent to which children self-provision. We found that sex had a significant effect on both the type and the amount of food brought back to camp and consumed while out foraging; compared to their male counterparts, young female foragers consumed less while foraging and returned to camp with more food. A wide variation in caloric returns was seen across all foragers in the sample. When analyzing only food brought back to camp, age was not a significant predictor. When combining the amount of food back to camp and the amount consumed while out foraging, however, older children consistently collected more food. The data presented here suggest that although older children do appear to have greater overall foraging success, even very young children are capable of collecting a considerable amount of food. Our data, although lending support to the embodied capital model, suggest that although foraging efficiency increases with age, it remains difficult to determine if this efficiency is a byproduct of learning, strength, or perhaps individual motivation. In addition, our results indicate that juvenile self-provisioning may have played a key role in the evolution of food sharing and cooperation during hominin evolution.     

Alterations in the expression and gating of Drosophila sodium channels by mutations in the para gene

Mutations in the para gene specifically affect the expression of sodium currents in Drosophila. While 65% of wild-type embryonic neurons in culture express sodium currents, three distinct mutations in the para locus resulted in a decrease in the fraction of cells from which sodium currents could be recorded. This reduction was allele-dependent: macroscopic sodium currents were exhibited in 49% of the neurons in parats1 cultures, 35% in parats2, and only 2% in paraST76. Voltage-clamp experiments demonstrated that the parats2 mutation also affected the gating properties of sodium channels. These results provide convincing evidence that para, a gene recently shown to exhibit sequence similarity to vertebrate sodium channels alpha subunits, encodes functional sodium channels in Drosophila. The finding that one para allele (paraST76) can virtually eliminate the expression of sodium currents strongly argues that the para gene codes for the majority of sodium channels in cultured embryonic neurons.     

Editorial

The American Peptide Symposium has been a forum for new research in peptide science for almost thirty years. For young scientists it has provided an opportunity to present their experimental results and to learn more about ongoing research in this rapidly changing field. The 15th American Peptide Symposium, held in Nashville, Tennessee, U.S.A. in June, 1997, highlighted the research of young scientists in two ways. Graduate students and postdoctoral fellows competed in the Young Investigators Poster Competition for awards for the most outstanding posters. The Young Investigators Mini-Symposium on the first day of the meeting provided an opportunity for selected young scientists to give oral presentations on their research. This special issue of Letters in Peptide Science highlights some of the results presented by young scientists as part of these two forums. The papers included exemplify the diversity of research in peptide science, from synthetic methodology to peptide structure to novel peptide design and biological activity. The outstanding quality of the research performed by these young scientists shows our field will be in good hands for the years to come.     

Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers

Spinal muscular atrophy (SMA) is a neurodegenerative disorder that results from mutations in the SMN1 gene, leading to survival motor neuron (SMN) protein deficiency. One therapeutic strategy for SMA is to identify compounds that enhance the expression of the SMN2 gene, which normally only is a minor contributor to functional SMN protein production, but which is unaffected in SMA. A recent high-throughput screening campaign identified a 3,4-dihydro-4-phenyl-2(1H)-quinolinone derivative (2) that increases the expression of SMN2 by 2-fold with an EC₅₀?=?8.3?µM. A structure-activity relationship (SAR) study revealed that the array of tolerated substituents, on either the benzo portion of the quinolinone or the 4-phenyl, was very narrow. However, the lactam ring of the quinolinone was more amenable to modifications. For example, the quinazolinone (9a) and the benzoxazepin-2(3H)-one (19) demonstrated improved potency and efficacy for increase in SMN2 expression as compared to 2.     

A theoretical study of receptor site models for trimethylammonium group interaction

A model system, depicting the interactions of the trimethylammonium and ammonium groups with possible receptor features has been constructed. The interaction energies of these two onium groups with seven receptor models have been calculated, using the interaction energy procedure of Claverie &; Rein (1969). The change of the energy of binding due to the structural change has been predicted for each receptor model. A ranking of receptor models has been constructed on this basis. The relationship of this change of binding energy to loss of potency of drug molecules containing these two structural features has been examined.