Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA).

Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.

Microbial Functional Gene Diversity Predicts Groundwater Contamination and Ecosystem Functioning.

Contamination from anthropogenic activities has significantly impacted Earth's biosphere. However, knowledge about how environmental contamination affects the biodiversity of groundwater microbiomes and ecosystem functioning remains very limited. Here, we used a comprehensive functional gene array to analyze groundwater microbiomes from 69 wells at the Oak Ridge Field Research Center (Oak Ridge, TN), representing a wide pH range and uranium, nitrate, and other contaminants. We hypothesized that the functional diversity of groundwater microbiomes would decrease as environmental contamination (e.g., uranium or nitrate) increased or at low or high pH, while some specific populations capable of utilizing or resistant to those contaminants would increase, and thus, such key microbial functional genes and/or populations could be used to predict groundwater contamination and ecosystem functioning. Our results indicated that functional richness/diversity decreased as uranium (but not nitrate) increased in groundwater. In addition, about 5.9% of specific key functional populations targeted by a comprehensive functional gene array (GeoChip 5) increased significantly (P < 0.05) as uranium or nitrate increased, and their changes could be used to successfully predict uranium and nitrate contamination and ecosystem functioning. This study indicates great potential for using microbial functional genes to predict environmental contamination and ecosystem functioning.IMPORTANCE Disentangling the relationships between biodiversity and ecosystem functioning is an important but poorly understood topic in ecology. Predicting ecosystem functioning on the basis of biodiversity is even more difficult, particularly with microbial biomarkers. As an exploratory effort, this study used key microbial functional genes as biomarkers to provide predictive understanding of environmental contamination and ecosystem functioning. The results indicated that the overall functional gene richness/diversity decreased as uranium increased in groundwater, while specific key microbial guilds increased significantly as uranium or nitrate increased. These key microbial functional genes could be used to successfully predict environmental contamination and ecosystem functioning. This study represents a significant advance in using functional gene markers to predict the spatial distribution of environmental contaminants and ecosystem functioning toward predictive microbial ecology, which is an ultimate goal of microbial ecology.

Effect of meal size and body size on specific dynamic action and gastric processing in decapod crustaceans.

Meal size and animal size are important factors affecting the characteristics of the specific dynamic action (SDA) response across a variety of taxa. The effects of these two variables on the SDA of decapod crustaceans are based on just a couple of articles, and are not wholly consistent with the responses reported for other aquatic ectotherms. Therefore, the effects of meal size and animal size on the characteristics of SDA response were investigated in a variety of decapod crustaceans from different families. A 6 fold increase in meal size (0.5%-3% body mass) resulted a pronounced increase in the duration of increased oxygen consumption, resulting in an increase in the SDA of Callinectes sapidus, Cancer gracilis, Hemigrapsus nudus, Homarus americanus, Pugettia producta and Procambarus clarkii. Unlike many other aquatic ectotherms a substantial increase between meal sizes was required, with meal size close to their upper feeding limit (3% body mass), before changes were evident. In many organisms increases in both duration and scope contribute to the overall SDA, here changes in scope as a function of meal size were weak, suggesting that a similar amount of energy is required to upregulate gastric processes, regardless of meal size. The SDA characteristics were less likely to be influenced by the size of the animal, and there was no difference in the SDA (kJ) as a function of size in H. americanus or Cancer irroratus when analysed as mass specific values. In several fish species characteristics of the SDA response are more closely related to the transit times of food, rather than the size of a meal. To determine if a similar trend occurred in crustaceans, the transit rates of different sized meals were followed through the digestive system using a fluoroscope. Although there was a trend towards larger meals taking longer to pass through the gut, this was only statistically significant for P. clarkii. There were some changes in transit times as a function of animal size. The foregut clearance times for Cancer magister increased with increasing body size, while smaller Carcinus maenas cleared the hindgut region at a faster rate than larger individuals. Unlike fish there was no clear relationship between transit rates and any of the SDA characteristics. While the fluoroscopy method is useful for assessing foregut activity and food passage, it is limited when inferring connections between nutrient assimilation and post-absorptive processes in crustaceans. Therefore, at least with respect to meal size, transit rates do not make a good proxy for determining the SDA characteristics in crustaceans.