Crosstalk between age accumulated DNA-damage and the SIRT1-AKT-GSK3ß axis in urine derived renal progenitor cells

The aging process is manifested by a multitude of inter-linked biological processes. These processes contribute to genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, de-regulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The mammalian ortholog of the yeast silent information regulator (Sir2) SIRT1 is a NAD+-dependent class III histone deacetylase and has been recognized to be involved in many of the forementioned processes. Furthermore, the physiological activity of several Sirtuin family members has been connected to the regulation of life span of lower organisms (Caenorhabditis elegans and Drosophila melanogaster) as well as mammals. In the present study, we provide evidence that SIX2-positive urine derived renal progenitor cells-UdRPCs isolated directly from human urine show typical hallmarks of aging. This includes the subsequent transcriptional downregulation of SIRT1 and its downstream targets AKT and GSK3ß with increased donor age. This transcriptional downregulation is accompanied by an increase in DNA damage and transcriptional levels of several cell cycle inhibitors such as P16. We provide evidence that the renal progenitor transcription factor SIX2 binds to the coding sequence of SIRT1. Furthermore, we show that the SIRT1 promoter region is methylation sensitive and becomes methylated during aging, dividing them into SIRT1-high and -low expressing UdRPCs. Our results highlight the importance of SIRT1 in DNA damage repair recognition in UdRPCs and the control of differentiation by regulating the activation of GSK3β through AKT

Model architecture for associative memory in a neural network of spiking neurons

AbstractA synaptic connectivity model is assembled on a spiking neuron network aiming to build up a dynamic pattern recognition system. The connection architecture includes gap junctions and both inhibitory and excitatory chemical synapses based on Hebb’s hypothesis. The network evolution resulting from external stimulus is sampled in a properly defined frequency space. Neurons’ responses to different current injections are mapped onto a subspace using Principal Component Analysis. Departing from the base attractor, related to a quiescent state, different external stimuli drive the network to different fixed points through specific trajectories in this subspace

Retrieval behavior and thermodynamic properties of symmetrically diluted Q-Ising neural networks

The retrieval behavior and thermodynamic properties of symmetrically diluted Q-Ising neural networks are derived and studied in replica-symmetric mean-field theory generalizing earlier works on either the fully connected or the symmetrical extremely diluted network. Capacity-gain parameter phase diagrams are obtained for the Q=3, Q=4 and $Q=\infty$ state networks with uniformly distributed patterns of low activity in order to search for the effects of a gradual dilution of the synapses. It is shown that enlarged regions of continuous changeover into a region of optimal performance are obtained for finite stochastic noise and small but finite connectivity. The de Almeida-Thouless lines of stability are obtained for arbitrary connectivity, and the resulting phase diagrams are used to draw conclusions on the behavior of symmetrically diluted networks with other pattern distributions of either high or low activity.Comment: 21 pages, revte

Quantitative Characterization of Smooth Pursuit Eye Movements in School-Age Children Using a Child-Friendly Setup

Purpose: It could be argued that current studies investigating smooth pursuit development in children do not provide an optimal measure of smooth pursuit characteristics, given that a significant number have failed to adjust their setup and procedures to the child population. This study aimed to characterize smooth pursuit in children using child-friendly stimuli and procedures. Methods: Eye movements were recorded in 169 children (4–11 years) and 10 adults, while a customized, animated stimulus was presented moving horizontally and vertically at 6°/s and 12°/s. Eye movement recordings from 43 children with delayed reading, two with nystagmus, two with strabismus, and two with unsuccessful calibration were excluded from the analysis. Velocity gain, proportion of smooth pursuit, and the number and amplitude of saccades during smooth pursuit were calculated for the remaining participants. Median and quartiles were calculated for each age group and pursuit condition. ANOVA was used to investigate the effect of age on smooth pursuit parameters. Results: Differences across ages were found in velocity gain (6°/s P 0.05). Conclusions: Using child-friendly methods, children over the age of 7 to 8 years demonstrated adultlike smooth pursuit. Translational Relevance: Child-friendly procedures are critical for appropriately characterizing smooth pursuit eye movements in children

Effect of Stimulus Type and Motion on Smooth Pursuit in Adults and Children

PURPOSE: This study presents a two-degree customized animated stimulus developed to evaluate smooth pursuit in children and investigates the effect of its predetermined characteristics (stimulus type and size) in an adult population. Then, the animated stimulus is used to evaluate the impact of different pursuit motion paradigms in children. METHODS: To study the effect of animating a stimulus, eye movement recordings were obtained from 20 young adults while the customized animated stimulus and a standard dot stimulus were presented moving horizontally at a constant velocity. To study the effect of using a larger stimulus size, eye movement recordings were obtained from 10 young adults while presenting a standard dot stimulus of different size (1° and 2°) moving horizontally at a constant velocity. Finally, eye movement recordings were obtained from 12 children while the 2° customized animated stimulus was presented after three different smooth pursuit motion paradigms. Performance parameters, including gains and number of saccades, were calculated for each stimulus condition. RESULTS: The animated stimulus produced in young adults significantly higher velocity gain (mean: 0.93; 95% CI: 0.90-0.96; P = .014), position gain (0.93; 0.85-1; P = .025), proportion of smooth pursuit (0.94; 0.91-0.96, P = .002), and fewer saccades (5.30; 3.64-6.96, P = .008) than a standard dot (velocity gain: 0.87; 0.82-0.92; position gain: 0.82; 0.72-0.92; proportion smooth pursuit: 0.87; 0.83-0.90; number of saccades: 7.75; 5.30-10.46). In contrast, changing the size of a standard dot stimulus from 1° to 2° did not have an effect on smooth pursuit in young adults (P > .05). Finally, smooth pursuit performance did not significantly differ in children for the different motion paradigms when using the animated stimulus (P > .05). CONCLUSIONS: Attention-grabbing and more dynamic stimuli, such as the developed animated stimulus, might potentially be useful for eye movement research. Finally, with such stimuli, children perform equally well irrespective of the motion paradigm used

Differential DNA Methylation of THOR and hTAPAS in the Regulation of hTERT and the Diagnosis of Cancer

BACKGROUND Although DNA methylation in the gene promoters usually represses gene expression, the TERT hypermethylated oncological region (THOR) located 5' of the hTERT gene is hypermethylated when hTERT is expressed in diverse cancer types, including urothelial cancer (UC). METHODS Comprehensive MeDIP and DNA methylation array analyses complemented by the technically independent method of bisulfite genomic sequencing were applied on pathologically reviewed and classified urothelial carcinoma specimens and healthy urothelial tissue samples to reveal the methylation status of THOR in detail. RESULTS The detailed DNA methylation profiles reveal the exact positions of differentially methylated CpG dinucleotides within THOR in urothelial cancer and provide evidence ofa diverging role of methylation of these CpGs in the regulation of hTERT. In particular, our data suggest a regulating mechanism in which THOR methylation acts on hTERT expression through epigenetic silencing of the lncRNA hTERT antisense promoter-associated (hTAPAS), which represses hTERT. CONCLUSIONS These findings precisely define the most differentially methylated CpGs of THOR in early urothelial cancer, enabling optimal design of Methylation-Specific PCR (MSPCR) primers to reliably probe these methylation differences for diagnostic and prognostic purposes. In addition, this strategy presents a prime example that is also applicable to many other malignancies. Finally, the first evidence for the underlying epigenetic mechanism regulating hTERT expression through the methylation status of THOR is provided

A canonical ensemble approach to graded-response perceptrons

Perceptrons with graded input-output relations and a limited output precision are studied within the Gardner-Derrida canonical ensemble approach. Soft non- negative error measures are introduced allowing for extended retrieval properties. In particular, the performance of these systems for a linear and quadratic error measure, corresponding to the perceptron respectively the adaline learning algorithm, is compared with the performance for a rigid error measure, simply counting the number of errors. Replica-symmetry-breaking effects are evaluated.Comment: 26 pages, 10 ps figure