Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Modeling Ion Channel Kinetics with HPC

Abstract — Performance improvements for computational sciences such as biology, physics, and chemistry are critically dependent on advances in multicore and manycore hardware. However, these emerging systems require substantial investment in software development time to migrate, optimize, and validate existing science models. The focus of our study is to examine the step-by-step process of adapting new and existing computational biology models to multicore and distributed memory architectures. We analyze different strategies that may be more efficient in multicore vs. manycore environments. Our target application, Kingen, was developed to simulate AMPAR ion channel activity and to optimize kinetic model rate constants to biological data. Kingen uses a genetic algorithm to stochastically search parameter space to find global optima. As each individual in the population describes a rate constant parameter set in the kinetic model and the model is evaluated for each individual, there is significant computational complexity and parallelism in even a simple model run. Keywords- multicore; cluster; workload characterization; application profiling; kinetic modeling; scientific application; high performance computation; ion channel kinetics I

FRD-2023-0011 - presentation - Recommendations for managing diarrhea from trofinetide use in individuals with Rett syndrome: a plain language summary

What is this summary about?Rett syndrome is a rare genetic disorder that affects the way the brain develops. The medication trofinetide (DAYBUE™) was studied in a large clinical trial called LAVENDER, where it showed a benefit in reducing symptoms of Rett syndrome versus placebo (placebo did not contain medication but looked the same as trofinetide and was taken in the same way). The most common side effect in the trial was diarrhea (frequent and/or watery bowel movements). In order to help caregivers and healthcare providers, experts created recommendations on how to prevent and manage diarrhea if it occurs during trofinetide treatment.What were the results?In the LAVENDER trial, no characteristics were found that could help to identify people who may develop diarrhea when taking trofinetide.What were the recommendations?The diarrhea management recommendations include:Keep a diary of the frequency (how often) of bowel movements and their consistency (shape, hardness/softness) before starting trofinetideOn starting trofinetide, discuss stopping or reducing medicines for constipation with the healthcare provider– Ask the healthcare provider to swap other liquid medications with sugar alcohols to a pill form if possible– Introduce dietary fiberAt the first sign of diarrhea, contact the healthcare provider and start antidiarrheal medication– A stool (feces) diary should be kept, noting frequency and consistency along with monitoring how much liquid the person is drinkingFollow a regular diet when taking trofinetide– Those with mild dehydration can be given an oral rehydration solution, but the healthcare provider should be contacted for moderate or severe dehydrationWhat do the results mean?These practical recommendations may help caregivers to manage diarrhea so people can continue to take trofinetide, allowing individuals with Rett syndrome and their caregivers to experience its benefits.</p

Mathematical modelling of non-stationary fluctuation analysis for studying channel properties of synaptic AMPA receptors

The molecular properties of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are an important factor determining excitatory synaptic transmission in the brain. Changes in the number (N) or single-channel conductance (γ) of functional AMPA receptors may underlie synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). These parameters have been estimated using non-stationary fluctuation analysis (NSFA).The validity of NSFA for studying the channel properties of synaptic AMPA receptors was assessed using a cable model with dendritic spines and a microscopic kinetic description of AMPA receptors. Electrotonic, geometric and kinetic parameters were altered in order to determine their effects on estimates of the underlying γ.Estimates of γ were very sensitive to the access resistance of the recording (RA) and the mean open time of AMPA channels. Estimates of γ were less sensitive to the distance between the electrode and the synaptic site, the electrotonic properties of dendritic structures, recording electrode capacitance and background noise. Estimates of γ were insensitive to changes in spine morphology, synaptic glutamate concentration and the peak open probability (Po) of AMPA receptors.The results obtained using the model agree with biological data, obtained from 91 dendritic recordings from rat CA1 pyramidal cells. A correlation analysis showed that RA resulted in a slowing of the decay time constant of excitatory postsynaptic currents (EPSCs) by approximately 150 %, from an estimated value of 3.1 ms. RA also greatly attenuated the absolute estimate of γ by approximately 50-70 %.When other parameters remain constant, the model demonstrates that NSFA of dendritic recordings can readily discriminate between changes in γvs. changes in N or Po. Neither background noise nor asynchronous activation of multiple synapses prevented reliable discrimination between changes in γ and changes in either N or Po.The model (available online) can be used to predict how changes in the different properties of AMPA receptors may influence synaptic transmission and plasticity

Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study

Abstract Objective Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders. Methods Caregivers of participants enrolled in the US Natural History Study of RTT and RTT-related disorders (n = 925) were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2. Results The top caregiver concerns for classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The frequency of the top caregiver concerns for classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. Caregivers of participants with increased seizure severity often ranked seizures as the first concern, whereas caregivers of participants without active seizures often ranked hand use or communication as the top concern. Comparison across disorders found commonalities in the top caregiver concerns between classic RTT, atypical RTT, MECP2 duplication syndrome, CDKL5 deficiency disorder, and FOXG1 syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features. Conclusion The top caregiver concerns for individuals with RTT and RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers

Additional file 1 of Top caregiver concerns in Rett syndrome and related disorders: data from the US natural history study

Additional file 1: Table S1. MECP2 mutation distribution for Classic and Atypical RTT