The Roles of H19 in Regulating Inflammation and Aging.

Accumulating evidence suggests that long non-coding RNA H19 correlates with several aging processes. However, the role of H19 in aging remains unclear. Many studies have elucidated a close connection between H19 and inflammatory genes. Chronic systemic inflammation is an established factor associated with various diseases during aging. Thus, H19 might participate in the development of age-related diseases by interplay with inflammation and therefore provide a protective function against age-related diseases. We investigated the inflammatory gene network of H19 to understand its regulatory mechanisms. H19 usually controls gene expression by acting as a microRNA sponge, or through mir-675, or by leading various protein complexes to genes at the chromosome level. The regulatory gene network has been intensively studied, whereas the biogenesis of H19 remains largely unknown. This literature review found that the epithelial-mesenchymal transition (EMT) and an imprinting gene network (IGN) might link H19 with inflammation. Evidence indicates that EMT and IGN are also tightly controlled by environmental stress. We propose that H19 is a stress-induced long non-coding RNA. Because environmental stress is a recognized age-related factor, inflammation and H19 might serve as a therapeutic axis to fight against age-related diseases

Genomic and phenotypic signatures of climate adaptation in an Anolis lizard

Integrated knowledge on phenotype, physiology and genomic adaptations is required to understand the effects of climate on evolution. The functional genomic basis of organismal adaptation to changes in the abiotic environment, its phenotypic consequences, and its possible convergence across vertebrates, are still understudied. In this study, we use a comparative approach to verify predicted gene functions for vertebrate thermal adaptation with observed functions underlying repeated genomic adaptations in response to elevation in the lizard Anolis cybotes. We establish a direct link between recurrently evolved phenotypes and functional genomics of altitude-related climate adaptation in three highland and lowland populations in the Dominican Republic. We show that across vertebrates, genes contained in this interactome are expressed within the brain and during development. These results are relevant to elucidate the effect of global climate change across vertebrates, and might aid in furthering insight into gene-environment relationships under disturbances to external homeostasis

Hot topics in epigenetic mechanisms of aging: 2011

Aging is a complex process that results in compromised biological functions of the organism and increased susceptibility to disease and death. Although the molecular basis of aging is currently being investigated in many experimental contexts, there is no consensus theory to fully explain the aging process. Epigenetic factors, including DNA methylation, histone modifications, and microRNA expression, may play central roles in controlling changes in gene expression and genomic instability during aging. In this Hot Topic review, we first examine the mechanisms by which these epigenetic factors contribute to aging in diverse eukaryotic species including experimental models of yeasts, worms, and mammals. In a second section, we will emphasize in the mammalian epigenetic alterations and how they may affect human longevity by altering stem cell function and/or somatic cell decline. The field of aging epigenetics is ripe with potential, but is still in its infancy, as new layers of complexity are emerging in the epigenetic network. As an example, we are only beginning to understand the relevance of non-coding genome to organism aging or the existence of an epigenetic memory with transgenerational inheritance. Addressing these topics will be fundamental for exploiting epigenetics phenomena as markers of aging-related diseases or as therapeutic targets

Critical dynamics in homeostatic memory networks

Critical behavior in neural networks characterized by scale-free event distributions and brought about by self-regulatory mechanisms such as short-term synaptic dynamics or homeostatic plasticity, is believed to optimize sensitivity to input and information transfer in the system. Although theoretical predictions of the spike distributions have been confirmed by in-vitro experiments, in-vivo data yield a more complex picture which might be due to the in-homogeneity of the network structure, leakage in currents or massive driving inputs which has so far not been comprehensively covered by analytical or numerical studies.

We address these questions by the study of a neural model of memory that allows for storage and retrieval of patterns and for recombining such patterns as needed for search in problem solving. The model features critical dynamics in the neural assembly as a result of the interplay of synaptic depression and facilitation (Levina e.a 2007, 2009). Model simulations show that the prolonged consolidation of memory patterns induces a bias towards the memories which affects the scale-free spike-frequency distribution. However, selective modification of neuronal circuitry in the form of controlled homeostatic regulation in the form of recalibration of the synaptic weights towards the critical value preserved criticality although characterized by fluctuations between learned random patterns, as observed by the dynamics of stored pattern retrieval quality. The resulting spike statistics depends on the assumed coding scheme, but even sparse or orthogonal memory patterns introduce a typical event size which is incompatible with critical dynamics below the maximal memory capacity. Specifically results obtained for de-correlated patterns show an immediate jump from the sub-critical regime to a state of super-criticality in contrast to a more structured wave-like formation in the avalanche dynamics obtained from a general set of random patterns, pointing towards an eventual evolution of the network connectivity and the optimization of the critical regime. Specifically results obtained for de-correlated patterns show an immediate jump from the sub-critical regime to a state of super-criticality in contrast to a more structured wave-like formation in the avalanche dynamics obtained from a general set of random patterns, pointing towards an eventual evolution of the network connectivity and the optimization of the critical regime (Pearlmutter and Houghton, 2009).

The combination of memory and ongoing dynamics in the model was chosen for its implications in the context of cognitive aging. Following the paradigm of aging as a multi-criteria optimization process, we posit aging effects as a result of an increasing incompatibility of learning goals. In aging, a shift from fluid intelligence (flexibility to recombine memory content) towards crystalline intelligence (optimal memory organization) appears as a lifelong trend against the general decrease of resources. We show that in young age memory and criticality can be maintained simultaneously by a homeostatic leveling of the synaptic conductances. This balance is lost in the aging brain where the memory attractors cannot be kept sufficiently shallow due to neural and synaptic loss, a reduction of activity while experiencing a growth in memories. The value of the memory organization is therefore protected on the cost of the partial loss of the capability of recombining memory patterns in a task-dependent way

Neuronal Correlation Parameter in the Idea of Thermodynamic Entropy of an N-Body Gravitationally Bounded System

Understanding how the brain encodes information and performs computation requires statistical and functional analysis. Given the complexity of the human brain, simple methods that facilitate the interpretation of statistical correlations among different brain regions can be very useful. In this report we introduce a numerical correlation measure that may serve the interpretation of correlational neuronal data, and may assist in the evaluation of different brain states. The description of the dynamical brain system, through a global numerical measure may indicate the presence of an action principle which may facilitate a application of physics principles in the study of the human brain and cognition

Lithium alters expression of RNAs in a type-specific manner in differentiated human neuroblastoma neuronal cultures, including specific genes involved in Alzheimer's disease.

Lithium (Li) is a medication long-used to treat bipolar disorder. It is currently under investigation for multiple nervous system disorders, including Alzheimer's disease (AD). While perturbation of RNA levels by Li has been previously reported, its effects on the whole transcriptome has been given little attention. We, therefore, sought to determine comprehensive effects of Li treatment on RNA levels. We cultured and differentiated human neuroblastoma (SK-N-SH) cells to neuronal cells with all-trans retinoic acid (ATRA). We exposed cultures for one week to lithium chloride or distilled water, extracted total RNA, depleted ribosomal RNA and performed whole-transcriptome RT-sequencing. We analyzed results by RNA length and type. We further analyzed expression and protein interaction networks between selected Li-altered protein-coding RNAs and common AD-associated gene products. Lithium changed expression of RNAs in both non-specific (inverse to sequence length) and specific (according to RNA type) fashions. The non-coding small nucleolar RNAs (snoRNAs) were subject to the greatest length-adjusted Li influence. When RNA length effects were taken into account, microRNAs as a group were significantly less likely to have had levels altered by Li treatment. Notably, several Li-influenced protein-coding RNAs were co-expressed or produced proteins that interacted with several common AD-associated genes and proteins. Lithium's modification of RNA levels depends on both RNA length and type. Li activity on snoRNA levels may pertain to bipolar disorders while Li modification of protein coding RNAs may be relevant to AD

Redundancy and Aging of Efficient Multidimensional MDS-Parity Protected Distributed Storage Systems

The effect of redundancy on the aging of an efficient Maximum Distance Separable (MDS) parity--protected distributed storage system that consists of multidimensional arrays of storage units is explored. In light of the experimental evidences and survey data, this paper develops generalized expressions for the reliability of array storage systems based on more realistic time to failure distributions such as Weibull. For instance, a distributed disk array system is considered in which the array components are disseminated across the network and are subject to independent failure rates. Based on such, generalized closed form hazard rate expressions are derived. These expressions are extended to estimate the asymptotical reliability behavior of large scale storage networks equipped with MDS parity-based protection. Unlike previous studies, a generic hazard rate function is assumed, a generic MDS code for parity generation is used, and an evaluation of the implications of adjustable redundancy level for an efficient distributed storage system is presented. Results of this study are applicable to any erasure correction code as long as it is accompanied with a suitable structure and an appropriate encoding/decoding algorithm such that the MDS property is maintained.Comment: 11 pages, 6 figures, Accepted for publication in IEEE Transactions on Device and Materials Reliability (TDMR), Nov. 201

Impaired Auditory Temporal Selectivity in the Inferior Colliculus of Aged Mongolian Gerbils

Aged humans show severe difficulties in temporal auditory processing tasks (e.g., speech recognition in noise, low-frequency sound localization, gap detection). A degradation of auditory function with age is also evident in experimental animals. To investigate age-related changes in temporal processing, we compared extracellular responses to temporally variable pulse trains and human speech in the inferior colliculus of young adult (3 month) and aged (3 years) Mongolian gerbils. We observed a significant decrease of selectivity to the pulse trains in neuronal responses from aged animals. This decrease in selectivity led, on the population level, to an increase in signal correlations and therefore a decrease in heterogeneity of temporal receptive fields and a decreased efficiency in encoding of speech signals. A decrease in selectivity to temporal modulations is consistent with a downregulation of the inhibitory transmitter system in aged animals. These alterations in temporal processing could underlie declines in the aging auditory system, which are unrelated to peripheral hearing loss. These declines cannot be compensated by traditional hearing aids (that rely on amplification of sound) but may rather require pharmacological treatment