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

School Psychologists\u27 Confidence Level with Suicide Intervention and Prevention in the Schools

Schools psychologists are often called upon to work with suicidal students regardless of previous training or the comfort levels that they possess in this area (Debski, Spadafore, Jacob, Poole, and Hixon, 2007; Oordt, Jobes, Fonseca, and Schmidt, 2009). This study evaluates the results of a survey created by this study’s investigator. It was disseminated to members of the National Association of School Psychologists’ Listserv (NASP-Listserv) and gathers general and demographic data as well as information that contribute to the assessment of suicide intervention and prevention experience and training received by the participants. Also investigated was whether or not suicide intervention and prevention is typically a part of a school psychologist’s role. Specific attention was paid to any relationship between the levels of suicide intervention and prevention experience and training and school psychologists’ self-perceived confidence levels in these areas. Results reveal that more experience and comprehensive training in the area of suicide intervention and prevention help school psychologists feel more confident in working with students at-risk for suicidal behaviors. In addition, this research supports the hypothesis that school psychologists often have an active role in suicide intervention and prevention in schools. Because results find that most psychologists gain knowledge via workshops, implications for graduate training programs for school psychologists and school districts will be discussed. Directions for future research will also be addressed

Neurochemical compartmentalization within the pigeon basal ganglia

The goals of this study were to use multiple informative markers to define and characterize the neurochemically distinct compartments of the pigeon basal ganglia, especially striatum and accumbens. To this end, we used antibodies against 12 different neuropeptides, calcium-binding proteins or neurotransmitter-related enzymes that are enriched in the basal ganglia. Our results clarify boundaries between previously described basal ganglia subdivisions in birds, and reveal considerable novel heterogeneity within these previously described subdivisions. Sixteen regions were identified that each displayed a unique neurochemical organization. Four compartments were identified within the dorsal striatal region. The neurochemical characteristics support previous comparisons to part of the central extended amygdala, somatomotor striatum, and associational striatum of mammals, respectively. The medialmost part of the medial striatum, however, has several unique features, including prominent pallidal-like woolly fibers and thus may be a region unique to birds. Four neurochemically distinct regions were identified within the pigeon ventral striatum: the accumbens, paratubercular striatum, ventrocaudal striatum, and the ventral area of the lateral part of the medial striatum that is located adjacent to these regions. The pigeon accumbens is neurochemically similar to the mammalian rostral accumbens. The pigeon paratubercular and ventrocaudal striatal regions are similar to the mammalian accumbens shell. The ventral portions of the medial and lateral parts of the medial striatum, which are located adjacent to accumbens shell-like areas, have neurochemical characteristics as well as previously reported limbic connections that are comparable to the accumbens core. Comparisons to neurochemically identified compartments in reptiles, mammals, and amphibians indicate that, although most of the basic compartments of the basal ganglia were highly conserved during tetrapod evolution, uniquely avian compartments may exist as well

Prototyping to Leverage Learning in Product Manufacturing Environments

AbstractRooted in the automotive industry, this article discusses the topic of leveraging tacit knowledge through prototyping. After first providing an overview on learning and knowledge, the Socialization, Externalization, Combination and Internalization (SECI) model is discussed in detail, with a clear distinction between tacit and explicit knowledge. Based on this model, we propose a framework for using said reflective and affirmative prototyping in an external vs. internal learning/knowledge capturing and transfer setting. Contextual examples from select automotive manufacturing R&D projects are given to demonstrate the importance and potential in applying more effective strategies for knowledge transformation in engineering design

Group i metabotropic glutamate receptors: A potential target for regulation of proliferation and differentiation of an immortalized human neural stem cell line

© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Human neural stem cells (NSCs) from the developing embryo or the subventricular zone of the adult brain can potentially elicit brain repair after injury or disease, either via endogenous cell proliferation or by cell transplantation. Profound knowledge of the diverse signals affecting these cells is, however, needed to realize their therapeutic potential. Glutamate and group I metabotropic glutamate receptors (mGluRs) affect proliferation and survival of rodent NSCs both during embryonic and post-natal development. To investigate the role of group I mGluRs (mGluR1 and mGluR5) on human NSCs, we differentiated an immortalized, forebrain-derived stem cell line in the presence or absence of glutamate and with addition of either the group I mGluR agonist DHPG or the selective antagonists, MPEP (mGluR5) and LY367385 (mGluR1). Characterization of differentiated cells revealed that both mGluR1 and mGluR5 were present on the cells. Addition of glutamate to the growth medium significantly increased cell proliferation and reduced cell death, resulting in increased cell numbers. In the presence of glutamate, selective activation of group I mGluRs reduced gliogenesis, whereas selective inhibition of group I mGluRs reduced neurogenesis. Our results substantiate the importance of glutamate signalling in the regulation of human NSCs and may as such be applied to promote proliferation and neuronal differentiation.This research was supported by the Danish Parkinson Association, IMK Almene Fond, Hørslev-Fonden, Kirsten og Freddy Johansens Fond, Grosserer Brogaard og Hustrus Mindefond and Fonden for Lægevidenskabens Fremme.Peer Reviewe

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

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

Storage capacity of a constructive learning algorithm

Upper and lower bounds for the typical storage capacity of a constructive algorithm, the Tilinglike Learning Algorithm for the Parity Machine [M. Biehl and M. Opper, Phys. Rev. A {\bf 44} 6888 (1991)], are determined in the asymptotic limit of large training set sizes. The properties of a perceptron with threshold, learning a training set of patterns having a biased distribution of targets, needed as an intermediate step in the capacity calculation, are determined analytically. The lower bound for the capacity, determined with a cavity method, is proportional to the number of hidden units. The upper bound, obtained with the hypothesis of replica symmetry, is close to the one predicted by Mitchinson and Durbin [Biol. Cyber. {\bf 60} 345 (1989)].Comment: 13 pages, 1 figur

Parisi Phase in a Neuron

Pattern storage by a single neuron is revisited. Generalizing Parisi's framework for spin glasses we obtain a variational free energy functional for the neuron. The solution is demonstrated at high temperature and large relative number of examples, where several phases are identified by thermodynamical stability analysis, two of them exhibiting spontaneous full replica symmetry breaking. We give analytically the curved segments of the order parameter function and in representative cases compute the free energy, the storage error, and the entropy.Comment: 4 pages in prl twocolumn format + 3 Postscript figures. Submitted to Physical Review Letter