Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells

Transplantation of exogenous dopaminergic neuron (DA neurons) is a promising approach for treating Parkinson's disease (PD). However, a major stumbling block has been the lack of a reliable source of donor DA neurons. Here we show that a combination of five transcriptional factors Mash1, Ngn2, Sox2, Nurr1, and Pitx3 can directly and effectively reprogram human fibroblasts into DA neuron-like cells. The reprogrammed cells stained positive for various markers for DA neurons. They also showed characteristic DA uptake and production properties. Moreover, they exhibited DA neuron-specific electrophysiological profiles. Finally, they provided symptomatic relief in a rat PD model. Therefore, our directly reprogrammed DA neuron-like cells are a promising source of cell-replacement therapy for PD

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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