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Big Data is no longer solely the purview of big organizations with big resources. Today's routine tools and experimental methods can generate large slices of data. For example, high-throughput sequencing can quickly interrogate biological systems for the expression levels of thousands of different RNAs, examine epigenetic marks throughout the genome, and detect differences in the genomes of individuals. Multichannel electrophysiology platforms produce gigabytes of data in just a few minutes of recording. Imaging systems generate videos capturing biological behaviors over the course of days. Thus, any researcher now has access to a veritable wealth of data. However, the ability of any given researcher to utilize that data is limited by her/his own resources and skills for downloading, storing, and analyzing the data. In this paper, we examine the necessary resources required to engage Big Data, survey the state of modern data analysis pipelines, present a few data repository case studies, and touch on current institutions and programs supporting the work that relies on Big Data. [ABSTRACT FROM AUTHOR]

Human cell adhesion molecules (CAMs) are essential for proper development, modulation, and maintenance of interactions between cells and cell-to-cell (and matrix-to-cell) communication about these interactions. Despite the differential functional significance of these roles, there have been surprisingly few systematic studies to enumerate the universe of CAMs and identify specific CAMs in distinct functions. In this paper, we update and review the set of human genes likely to encode CAMs with searches of databases, literature reviews, and annotations. We describe likely CAMs and functional subclasses, including CAMs that have a primary function in information exchange (iCAMs), CAMs involved in focal adhesions, CAM gene products that are preferentially involved with stereotyped and morphologically identifiable connections between cells (e.g., adherens junctions, gap junctions), and smaller numbers of CAM genes in other classes. We discuss a novel proposed mechanism involving selective anchoring of the constituents of iCAM-containing lipid rafts in zones of close neuronal apposition to membranes expressing iCAM binding partners. We also discuss data from genetic and genomic studies of addiction in humans and mouse models to highlight the ways in which CAM variation may contribute to a specific brain-based disorder such as addiction. Specific examples include changes in CAM mRNA splicing mediated by differences in the addiction-associated splicing regulator RBFOX1/A2BP1 and CAM expression in dopamine neurons. [ABSTRACT FROM AUTHOR]

This paper reviews quantitative and qualitative studies conducted to identify changes in the characteristics of hematopoietic stem/progenitor cells (HSCs/HPCs) with or without radiation exposure. The numerical recovery of HSCs/HPCs after radiation exposure is lower than for other types of cells, an effect that may depend on hierarchical ordering of generation age during blood cell differentiation, from primitive HSCs to various differentiated HPCs. Studies are in progress to evaluate gene expression in bone marrow cells and cells in the lineage-negative, c-Kit+, stem cell antigen+ (LKS) fraction from 21-month-old mice, with or without radiation exposure. Preliminary data suggest that cell cycle-related genes, that is, cyclin D1 ( Ccnd1), phosphatidylinositol 3 kinase regulatory subunit polypeptide 1 ( PiK3r1), and Fyn, are upregulated solely in the LKS fraction from 21-month-old mice irradiated at 6 weeks of age, compared with the LKS fraction from age-matched nonirradiated control mice. Additional studies may provide evidence that the aging phenotype is exaggerated following exposure to ionizing radiation, specifically in the LKS fraction. [ABSTRACT FROM AUTHOR]

Inferring gene regulatory networks from high-throughput genomic data is one of the central problems in computational biology. In this paper, we describe a predictive modeling approach for studying regulatory networks, based on a machine learning algorithm called MEDUSA. MEDUSA integrates promoter sequence, mRNA expression, and transcription factor occupancy data to learn gene regulatory programs that predict the differential expression of target genes. Instead of using clustering or correlation of expression profiles to infer regulatory relationships, MEDUSA determines condition-specific regulators and discovers regulatory motifs that mediate the regulation of target genes. In this way, MEDUSA meaningfully models biological mechanisms of transcriptional regulation. MEDUSA solves the problem of predicting the differential (up/down) expression of target genes by using boosting, a technique from statistical learning, which helps to avoid overfitting as the algorithm searches through the high-dimensional space of potential regulators and sequence motifs. Experimental results demonstrate that MEDUSA achieves high prediction accuracy on held-out experiments (test data), that is, data not seen in training. We also present context-specific analysis of MEDUSA regulatory programs for DNA damage and hypoxia, demonstrating that MEDUSA identifies key regulators and motifs in these processes. A central challenge in the field is the difficulty of validating reverse-engineered networks in the absence of a gold standard. Our approach of learning regulatory programs provides at least a partial solution for the problem: MEDUSA's prediction accuracy on held-out data gives a concrete and statistically sound way to validate how well the algorithm performs. With MEDUSA, statistical validation becomes a prerequisite for hypothesis generation and network building rather than a secondary consideration.

This paper studies a computational problem motivated by the modular response analysis method for reverse engineering of protein and gene networks. This set-cover problem is hard to solve exactly for large networks, but efficient approximation algorithms are given and their complexity is analyzed.

The reverse engineering of biochemical networks is a central problem in systems biology. In recent years several methods have been developed for this purpose, using techniques from a variety of fields. A systematic comparison of the different methods is complicated by their widely varying data requirements, making benchmarking difficult. Also, because of the lack of detailed knowledge about most real networks, it is not easy to use experimental data for this purpose. This paper contains a comparison of four reverse-engineering methods using data from a simulated network. The network is sufficiently realistic and complex to include many of the challenges that data from real networks pose. Our results indicate that the two methods based on genetic perturbations of the network outperform the other methods, including dynamic Bayesian networks and a partial correlation method.

Cingulin, paracingulin, and PLEKHA7 are proteins localized in the cytoplasmic region of the apical junctional complex of vertebrate epithelial cells. Cingulin has been detected at tight junctions (TJs), whereas paracingulin has been detected at both TJs and adherens junctions (AJs) and PLEKHA7 has been detected at AJs. One function of cingulin and paracingulin is to regulate the activity of Rho family GTPases at junctions through their direct interaction with guanidine exchange factors of RhoA and Rac1. Cingulin also contributes to the regulation of transcription of several genes in different types of cultured cells, in part through its ability to modulate RhoA activity. PLEKHA7, together with paracingulin, is part of a protein complex that links E-cadherin to the microtubule cytoskeleton at AJs. In this paper, we review the current knowledge about these proteins, including their discovery, the characterization of their expression, localization, structure, molecular interactions, and their roles in different developmental and disease model systems. [ABSTRACT FROM AUTHOR]

Polysaccharides (PS) have historically been viewed as T cell-independent antigens. However, in this paper I propose a new concept, based on substantial data from my laboratory over the previous 10 years, that during infections with PS-encapsulated extracellular bacteria, PS-specific IgG responses are largely CD4+ T cell dependent. Thus, capsular PS is typically encountered by the immune system covalently attached to the underlying subcapsular bacterial domain. I speculate that noncovalent association of PS with immunogenic proteins within the bacterial particle leads to recruitment of protein-specific CD4+ T cell help for the anti-PS response. However, differences in the composition and/or structure of the subcapsular domain of different extracellular bacteria may result in distinct anti-PS responses as well as differential effects on the immune response to coimmunizing soluble antigens. CD4+ T cell help for IgG anti-PS responses during infections with extracellular bacteria is likely to promote opsonic clearance of these rapidly growing pathogens. However, the expression of immunosuppressive components by certain bacteria may also serve to dampen such responses. [ABSTRACT FROM AUTHOR]

Over the last decades the burden of disease in Western countries has shifted from comparably easily treated infectious diseases to more complex diseases, such as the metabolic syndrome, cardiovascular disease, and psychiatric disorders. A common characteristic of these illnesses is the interplay of multiple genetic and nongenetic factors, which eventually results in the manifestation of disease symptoms. Large-scale epidemiological studies in humans have resulted in the identification of various environmental and genetic risk factors, which contribute to the onset, duration, and severity of disease. While tremendous progress has been made, it is still impossible to predict which combination of risk factors will result in the manifestation of a specific illness. This lack of knowledge is also frequently reflected in inadequate treatment strategies, which mainly focus on symptom reversal rather than targeting the cause of the diseases. One of the most prominent environmental risk factors described for numerous diseases is chronic exposure to stressful situations. In this paper we address clinical and preclinical evidence of chronic stress as a risk factor for disease and introduce a novel, high-throughput mouse model for chronic social stress. We can show that this model has a high degree of construct, face, and predictive validity in terms of physiological, behavioral, and gene expression changes. We further illustrate how novel animal models of chronic social stress can help to unravel the complex interaction of individual genetic vulnerability and environmental risk factors. [ABSTRACT FROM AUTHOR]

Stress triggers changes in gene expression mediating important adaptive and maladaptive responses. The full repertoire of genes whose expression in the adrenal medulla is altered by stress has not been previously determined. In this study, gene profiling (RAE 230 2.0 Affymetrix) was applied to elucidate global changes in gene expression in adrenal medulla of rats exposed to 2-h immobilization (IMO) stress once or repeatedly for 6 consecutive days. The number of transcripts significantly ( P < 0.01) altered with single IMO (651 up, 487 down) was more than with repeated IMO (370 up, 195 down). The annotated transcripts were further analyzed and categorized. The largest numbers of changes were in mRNA levels in the transcription factor and cell signaling categories. Robust changes were also observed in transcripts related to growth factors, apoptosis, neurosecretion/neuropeptides, heat shock proteins, structural proteins, chemokines, cytokines, metabolism/lipid-metabolism, and proteases. Many (>80%) were uniquely induced by single IMO. About half of transcripts changed by repeated IMO were also responsive to single IMO. Pathway analysis was applied to identify direct interactions and common targets among gene products altered by single and repeated IMO. In this paper, we briefly describe the most pronounced changes observed, with emphasis on those that may provide new insight into the common and distinct mechanisms whereby the adrenal medulla responses to a first encounter with stress compared to repeated exposure to the same stressor. [ABSTRACT FROM AUTHOR]

The obligate nature of Rickettsia prowazekii intracellular growth places severe restrictions on the analysis of rickettsial gene function and gene expression. Fortunately, this situation is improving as methods for the genetic manipulation and proteomic analysis of this fascinating human pathogen become available. In this paper, we review the current status of rickettsial genetics and the isolation of rickettsial mutants using a genetic approach. In addition, the examination of rickettsial gene expression through characterization of the rickettsial proteome will be described. This will include a description of a highthroughput, accurate mass approach that has identified 596 rickettsial proteins in a complex rickettsial protein sample. [ABSTRACT FROM AUTHOR]

DNA microarrays allow us to visualize simultaneously the expression of potentially all genes within a cell population or tissue sample—revealing the "transcriptome." The analysis of this type of data is commonly called "gene expression profiling" (GEP) because it provides a comprehensive picture of the pattern of gene expression in a particular biological sample. For this reason microarrays are revolutionizing life sciences research and are leading to the development of novel and powerful methods for investigating cancer biology, classifying cancers, and predicting clinical outcome of cancers. Several recent high-profile reports have revealed how clustering of GEP data can clearly identify clinically (and prognostically) important subtypes of cancer among patients considered by established clinicopathological criteria to have similar tumors. Accurate "prognostic signatures" can be obtained from GEP data, which represent relatively small numbers of genes. These signatures can be valuable in directing appropriate treatment and in predicting clinical outcome, and they generally outperform other systems based on clinical and histological criteria. In this paper the basic principles of DNA microarray technology and the different types of microarray platforms available will be introduced, and the power of the technique will be illustrated by reviewing some recent GEP studies on selected cancers, including a preliminary analysis of hepatocellular carcinoma from our Palermo laboratory. GEP is likely to be adopted in the future as a key decision-making tool in the clinical arena. However, several issues relating to data analysis, reproducibility, cross-comparability, validation, and cost need to be resolved before the technology can be adopted broadly in this context. [ABSTRACT FROM AUTHOR]

Environmental conditions in early life permanently alter the development of glucocorticoid receptor gene expression in the hippocampus and hypothalamic- pituitary-adrenal responses to acute or chronic stress. In part, these effects can involve an activation of ascending serotonergic pathways and subsequent changes in the expression of transcription factors that might drive glucocorticoid receptor expression in the hippocampus. This paper summarizes the evidence in favor of these pathways as well as recent studies describing regulatory targets within the chromatin structure of the promoter region of the rat hippocampal glucocorticoid receptor gene. [ABSTRACT FROM AUTHOR]

Most sex differences in brain function are attributed to sex differences in the effects of gonadal secretions. In addition, however, male and female cells differ because of differential effects of sex chromosome genes expressed within the cells themselves. The latter conclusion comes from numerous studies in which sexual phenotype appears to be insensitive to the effects of sex hormones during development or cases in which sex differences develop before the onset of sex-specific patterns of gonadal secretions. Recently, mouse models have become available in which the genetic sex of brain cells is independent of the gonadal type (testes vs. ovaries), which allows a test of the role of sex chromosome genes in brain development. This paper reviews the evidence that genetic sex of brain cells influences their sexual phenotype, and critically discusses the relative advantages of various experimental approaches to study this effect. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidoses (MPS) are a group of rare congenital metabolic disorders caused by the deficiency or low activity of enzymes required for glycosaminoglycans degradation. Mutations in the α‐l‐iduronidase gene (IDUA) are associated with mucopolysaccharidosis type I (MPS I). Our study here aims to identify an MPS‐related gene mutation in a typical patient with MPS and to further explore the possible pathogenic mechanism. We identified a homozygous c. 2T>C (p.M1T) change in IDUA as the pathogenic mutation in this individual (both parents were identified as carriers of the mutation), with IDUA enzyme activity significantly decreased. We further established an MPS I–related zebrafish model using IDUA‐specific morpholino (MO) to suppress gene expression, and found that IDUA‐MO zebrafish exhibited characteristic disease phenotypes with deficiency of IDUA. Transcriptome profiling of zebrafish larvae revealed 487 genes that were significantly altered when IDUA was depleted. TP53 signaling and LC3/GABARAP family protein‐mediated autophagy were significantly upregulated in IDUA‐MO zebrafish larvae. Moreover, leukotriene A4 hydrolase‐mediated arachidonic acid metabolism was also upregulated. Introduction of wild‐type human IDUA mRNA rescued developmental defects and aberrant signaling in IDUA‐MO zebrafish larvae. In conclusion, our study provides potential therapeutic targets for the treatment of MPS I. [ABSTRACT FROM AUTHOR]

Genes are often pleiotropic and plastic in their expression, features which increase and diversify the functionality of the genome. The foraging (for) gene in Drosophila melanogaster is highly pleiotropic and a long‐standing model for studying individual differences in behavior and plasticity from ethological, evolutionary, and genetic perspectives. Its pleiotropy is known to be linked to its complex molecular structure; however, the downstream pathways and interactors remain mostly elusive. To uncover these pathways and interactors and gain a better understanding of how pleiotropy and plasticity are achieved at the molecular level, we explore the effects of different for alleles on gene expression at baseline and in response to 4 h of food deprivation, using RNA sequencing analysis in different Drosophila larval tissues. The results show tissue‐specific transcriptomic dynamics influenced by for allelic variation and food deprivation, as well as genotype by treatment interactions. Differentially expressed genes yielded pathways linked to previously described for phenotypes and several potentially novel phenotypes. Together, these findings provide putative genes and pathways through which for might regulate its varied phenotypes in a pleiotropic, plastic, and gene‐structure‐dependent manner. [ABSTRACT FROM AUTHOR]

Nongenetic information implies all the forms of biological information not related to genes and DNA in general. Despite the deep scientific relevance of the concept, we currently lack reliable knowledge about its carriers and origins; hence, we still do not understand its true nature. Given that genes are the targets of nongenetic information, it appears that a parsimonious approach to find the ultimate source of that information is to trace back the sequential steps of the causal chain upstream of the target genes up to the ultimate link as the source of the nongenetic information. From this perspective, I examine seven nongenetically determined phenomena: placement of locus‐specific epigenetic marks on DNA and histones, changes in snRNA expression patterns, neural induction of gene expression, site‐specific alternative gene splicing, predator‐induced morphological changes, and cultural inheritance. Based on the available evidence, I propose a general model of the common neural origin of all these forms of nongenetic information in eumetazoans. [ABSTRACT FROM AUTHOR]

The studies reviewed above provide strong evidence for the concept that IGF-I plays an essential role in mediating the growth-promoting actions of GH, and thus, they support the central elements of the "somatomedin hypothesis." The data, however, also point to actions of each GH and IGF-I that are not linked. Many hormones and factors, other than GH, are known to regulate the expression of IGF-I, as well as its binding proteins (modulators of its actions), in a tissue-specific fashion. Some of these influences, e.g., estrogens, thyroid hormone, and nutritional factors, also effect GH synthesis and/or secretion. This complex and precise regulation undoubtedly plays a key role in coordinating the somatic and visceral growth stimulated by GH and IGF-I. The evidence that GH and IGF-I actions are not always coupled, therefore, is not surprising. The challenge is to dissect the precise role(s) of GH and IGF-I, as well as other hormones and growth factors, in the control of growth. Study of transgenic animals provides a powerful way to approach these issues in vivo. These studies demonstrate that IGF-I is capable of stimulating in vivo brain growth. The transgene IGF-I-stimulated increase in brain size appears to result both from an increase in cell number and, as demonstrated by Carson et al., from an increase in myelin content, which in turn may result from proliferation of oligodendrocytes. Other roles for IGF-I in brain growth and development, however, are possible and amply supported by numerous studies of brain-derived cultured cells (see other papers herein). Because IGF-I is normally expressed in brain, it seems reasonable to assume that the IGF-I-stimulated brain growth observed in these transgenic mice represents a response to IGF-I overexpression rather than a pharmacologic response that is not indicative of a normal IGF-I function. Study of this IGF-I transgenic line cannot address the developmental period(s) when IGF-I normally stimulates brain growth, but this transgenic line provides a model to investigate IGF-I's specific role and its mechanisms of action.

The pathogenesis of chronic rhinosinusitis (CRS) is largely unknown, but accumulating evidence supports the role of the airway epithelium in its pathophysiology. In our study here, we evaluated whether epidermal growth factor (EGF) regulates a hypoxia‐inducible factor 1α (HIF‐1α)–microRNA‐21 (miR‐21)–aquaporin 4 (AQP4) axis in nasal epithelial cells from CRS patients. We found that, compared with normal sinus mucosa, EGF, HIF‐1α, and miR‐21 were upregulated and AQP4 was downregulated in sinus mucosa from patients with CRS and in a CRS mouse model. It was established that EGF upregulated HIF‐1α and miR‐21 expression, that HIF‐1α regulated miR‐21 transcription, and that the AQP4 gene was a target of miR‐21. Knockdown of EGF and HIF‐1α mRNAs and of miR‐21, or overexpression of AQP4 mRNA, inhibited proliferation and promoted apoptosis of hypoxia‐exposed human nasal epithelial cells, effects that were associated with reduced levels of α‐SMA, fibronectin, and vimentin, as well as promoted caspase‐3 activity and E‐cadherin levels. In the mouse CRS model, EGF elevation increased in vivo production of inflammatory IL‐4 and IFN‐γ to promote CRS, which was reversed by AQP4 elevation. Collectively, EGF upregulates HIF‐1α and miR‐21 expression to inhibit AQP4 expression, thereby promoting the proliferation of nasal epithelial cells and the development of CRS. [ABSTRACT FROM AUTHOR]

This paper studies the functional and regulatory role of RecA, but further investigations are necessary to clarify the control mechanism of the SOS response gene expression in C. burnetii. [ABSTRACT FROM AUTHOR]

Vocal learning, the ability to produce modified vocalizations via learning from acoustic signals, is a key trait in the evolution of speech. While extensively studied in songbirds, mammalian models for vocal learning are rare. Bats present a promising study system given their gregarious natures, small size, and the ability of some species to be maintained in captive colonies. We utilize the pale spear‐nosed bat (Phyllostomus discolor) and report advances in establishing this species as a tractable model for understanding vocal learning. We have taken an interdisciplinary approach, aiming to provide an integrated understanding across genomics (Part I), neurobiology (Part II), and transgenics (Part III). In Part I, we generated new, high‐quality genome annotations of coding genes and noncoding microRNAs to facilitate functional and evolutionary studies. In Part II, we traced connections between auditory‐related brain regions and reported neuroimaging to explore the structure of the brain and gene expression patterns to highlight brain regions. In Part III, we created the first successful transgenic bats by manipulating the expression of FoxP2, a speech‐related gene. These interdisciplinary approaches are facilitating a mechanistic and evolutionary understanding of mammalian vocal learning and can also contribute to other areas of investigation that utilize P. discolor or bats as study species. [ABSTRACT FROM AUTHOR]

Thymosin β4 (Tβ4) has been found to have several biological activities related to antiscarring and reduced fibrosis. For example, the anti-inflammatory properties of Tβ4 and its splice variant have been shown in the eye and skin. Moreover, Tβ4 treatment prevents profibrotic gene expression in cardiac and in hepatic cells in vitro and in vivo. In a recent study on scleroderma patients it was hypothesized that Tβ4 may exert a protective effect during human lung injury. In an ongoing study, we have explored the putative Tβ4 protective role in the lung context by utilizing a well-known in vivo model. We have observed significant protective effects of Tβ4 on bleomycin-induced lung damage, the main outcomes being the halting of the inflammatory process and a substantial reduction of histological evidence of lung injury. [ABSTRACT FROM AUTHOR]

After our 2002 report on the changes of gene expression in the brain from phencyclidine-treated mouse by using DNA microarray (Toyooka et al., Ann. N.Y. Acad. Sci. 965: 10-20), we decided to apply this DNA microarray method for the brain of the mouse treated with other drugs. We are now examining the effects of clozapine on the brain function. Clozapine is an atypical antipsychotic drug. Clozapine has affinity for neurotransmitter receptors, including D4 dopamine, serotonin, histamine, and adrenergic receptors. MacGibbon et al. (Mol. Brain Res. 23: 21-32) reported that clozapine and haloperidol produced a differential pattern of immediate early gene expression in rat caudate-putamen. Kobayashi et al. (Br. J. Pharmacol. 123: 421-426) have observed the effects of clozapine on the opioid receptors and G-protein- activated inwardly rectifying potassium channel of Xenopus oocytes. Thomas et al. (J. Neurochem. 76: 789-796) found that clozapine increases apolipoprotein D expression in the mouse brain. Therefore, we are going to apply this DNA microarray method to examine the effects of clozapine on mouse brain function. After we injected clozapine into mice for 20 days, we decapitated the mice. We then used the DNA microarray method to examine the gene expression of mouse brain. We found some changes in the mouse brain treated with clozapine. For example, the intensity of a potassium channel spot decreased, and that of a serotonin receptor spot increased. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) pathogenesis is mediated largely through the actions of proteolytic enzymes such as matrix metalloproteinase (MMP) 13. The transcriptional regulator CITED2, which suppresses the expression of MMP13 in chondrocytes, is induced by interleukin (IL)‐4 in T cells and macrophages, and by moderate mechanical loading in chondrocytes. We tested the hypothesis that CITED2 mediates cross‐talk between IL‐4 signaling and mechanical loading‐induced pathways that result in chondroprotection, at least in part, by downregulating MMP13. IL‐4 induced CITED2 gene expression in human chondrocytes in a dose‐ and time‐dependent manner through JAK/STAT signaling. Mechanical loading combined with IL‐4 resulted in additive effects on inducing CITED2 expression and downregulating of MMP13 in human chondrocytes in vitro. In vivo, IL‐4 gene knockout (KO) mice exhibited reduced basal levels of CITED2 expression in chondrocytes. While moderate treadmill running induced CITED2 expression and reduced MMP13 expression in wild‐type mice, these effects were blunted (for CITED2) or abolished (for MMP13) in chondrocytes of IL‐4 gene KO mice. Moreover, intra‐articular injections of mouse recombinant IL‐4 combined with regular cage activity mitigated post‐traumatic OA to a greater degree compared to immobilized mice treated with IL‐4 alone. These data suggest that using moderate loading to enhance IL‐4 may be a potential therapeutic strategy for chondroprotection in OA. [ABSTRACT FROM AUTHOR]

Abstract: A consequence of the assumptions of the infinitesimal model, one of the most important theoretical foundations of quantitative genetics, is that phenotypic traits are predicted to be most often normally distributed (so‐called Gaussian traits). But phenotypic traits, especially those interesting for evolutionary biology, might be shaped according to very diverse distributions. Here, I show how quantitative genetics tools have been extended to account for a wider diversity of phenotypic traits using first the threshold model and then more recently using generalized linear mixed models. I explore the assumptions behind these models and how they can be used to study the genetics of non‐Gaussian complex traits. I also comment on three recent methodological advances in quantitative genetics that widen our ability to study new kinds of traits: the use of “modular” hierarchical modeling (e.g., to study survival in the context of capture–recapture approaches for wild populations); the use of aster models to study a set of traits with conditional relationships (e.g., life‐history traits); and, finally, the study of high‐dimensional traits, such as gene expression. [ABSTRACT FROM AUTHOR]

Abstract: The genomic hypomethylation hypothesis of aging proposes that an overall decrease in global DNA methylation occurs with age, and it has been argued that the decrease in global DNA methylation could be an important factor in aging, resulting in the relaxation of gene expression regulation and abnormal gene expression. Since it was initially observed that DNA methylation decreased with age in 1974, 16 articles have been published describing the effect of age on global DNA methylation in various tissues from rodents and humans. We critically reviewed the publications on the effect of age on DNA methylation and the expression of the enzymes involved in DNA methylation to evaluate the validity of the hypomethylation hypothesis of aging. On the basis of the current scientific literature, we conclude that a decrease in the global methylation of the genome occurs in most if not all tissues/cells as an animal ages. However, age‐related changes in DNA methylation in specific regions or at specific sites in the genome occur even though the global DNA methylation does not change. [ABSTRACT FROM AUTHOR]

Adaptation to different host taxa is a key driver of insect diversification. Herbivorous insects are classic models for ecological and evolutionary research, but it is recent advances in sequencing, statistics, and molecular technologies that have cleared the way for investigations into the proximate genetic mechanisms underlying host shifts. In this review, we discuss how genome-scale data are revealing-at resolutions previously unimaginable-the genetic architecture of host-use traits, the causal loci underlying host shifts, and the predictability of host-use evolution. Collectively, these studies are providing novel insights into longstanding questions about host-use evolution. On the basis of this synthesis, we suggest that different host-use traits are likely to differ in their genetic architecture (number of causal loci and the nature of their genetic correlations) and genetic predictability (extent of gene or mutation reuse), indicating that any conclusions about the causes and consequences of host-use evolution will depend heavily on which host-use traits are investigated. To draw robust conclusions and identify general patterns in host-use evolution, we argue that investigation of diverse host-use traits and identification of causal genes and mutations should be the top priorities for future studies on the evolutionary genetics of host shifts. [ABSTRACT FROM AUTHOR]

Lateralizations of brain structure and motor behavior have been observed in humans as early as the first trimester of gestation, and are likely to arise from asymmetrical genetic-developmental programs, as in other animals. Studies of gene expression levels in postmortem tissue samples, comparing the left and right sides of the human cerebral cortex, have generally not revealed striking transcriptional differences between the hemispheres. This is likely due to lateralization of gene expression being subtle and quantitative. However, a recent re-analysis and meta-analysis of gene expression data from the adult superior temporal and auditory cortex found lateralization of transcription of genes involved in synaptic transmission and neuronal electrophysiology. Meanwhile, human subcortical mid-and hindbrain structures have not been well studied in relation to lateralization of gene activity, despite being potentially important developmental origins of asymmetry. Genetic polymorphisms with small effects on adult brain and behavioral asymmetries are beginning to be identified through studies of large datasets, but the core genetic mechanisms of lateralized human brain development remain unknown. Identifying subtly lateralized genetic networks in the brain will lead to a new understanding of how neuronal circuits on the left and right are differently fine-tuned to preferentially support particular cognitive and behavioral functions. [ABSTRACT FROM AUTHOR]

Depression is a heterogeneous disorder and, similar to other spectrum disorders, its manifestation varies by age of onset, severity, comorbidity, treatment responsiveness, and other factors. A laboratory blood test based on specific biomarkers for major depressive disorder (MDD) and its subgroups could increase diagnostic accuracy and expedite the initiation of treatment. We identified candidate blood biomarkers by examining genome-wide expression differences in the blood of animal models representing both the genetic and environmental/stress etiologies of depression. Human orthologs of the resulting transcript panel were tested in pilot studies. Transcript abundance of 11 blood markers differentiated adolescent subjects with early-onset MDD from adolescents with no disorder (ND). A set of partly overlapping transcripts distinguished adolescent patients who had comorbid anxiety disorders from those with only MDD. In adults, blood levels of nine transcripts discerned subjects with MDD from ND controls. Even though cognitive behavioral therapy (CBT) resulted in remission of some patients, the levels of three transcripts consistently signaled prior MDD status. A coexpression network of transcripts seems to predict responsiveness to CBT. Thus, our approach can be developed into clinically valid diagnostic panels of blood transcripts for different manifestations of MDD, potentially reducing diagnostic heterogeneity and advancing individualized treatment strategies. [ABSTRACT FROM AUTHOR]

Outdated gene definitions favored regions corresponding to mature messenger RNAs, in particular, the open reading frame. In eukaryotes, the intergenic space was widely regarded nonfunctional and devoid of RNA transcription. Original concepts were based on the assumption that RNA expression was restricted to known protein-coding genes and a few so-called structural RNA genes, such as ribosomal RNAs or transfer RNAs. With the discovery of introns and, more recently, sensitive techniques for monitoring genome-wide transcription, this view had to be substantially modified. Tiling microarrays and RNA deep sequencing revealed myriads of transcripts, which cover almost entire genomes. The tremendous complexity of non-protein-coding RNA transcription has to be integrated into novel gene definitions. Despite an ever-growing list of functional RNAs, questions concerning the mass of identified transcripts are under dispute. Here, we examined genome-wide transcription from various angles, including evolutionary considerations, and suggest, in analogy to novel alternative splice variants that do not persist, that the vast majority of transcripts represent raw material for potential, albeit rare, exaptation events. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) has been recognized as one of the major causes of morbidity and mortality in the United States; it is the third leading cause of deaths in the United States, with approximately 15 million Americans affected with COPD. Although exposure to cigarette smoke has been shown to be the main, if not the only, risk factor for COPD, the mechanisms underlying this association remain unclear. Most smokers do not develop COPD, suggesting that a combination of exposure and susceptibility (genetic background) is required. Several mechanisms contribute to the pathogenesis of COPD, such as influx of inflammatory cells into the lung, imbalance between proteolytic and antiproteolytic molecules, disruption of the balance between apoptosis and replenishment of structural cells in the lung, and disruption of oxidant/antioxidant balance. The scavenger receptor BI (SRB1) plays an important role in mediating the uptake of high-density lipoprotein (HDL)-derived cholesterol and cholesteryl ester in tissues. In addition to its role as the HDL receptor, SRB1 is also involved in pathogen recognition, identification of apoptotic cells, tissue antioxidant uptake (tocopherol and carotenoids), and lung surfactant composition, all factors involved in COPD pathogenesis. Therefore, it is possible that lung SRB1 levels are involved in the development of COPD. [ABSTRACT FROM AUTHOR]

Oxidative stress biomarkers are widely used in marine ecotoxicology. Environmental pollutants enhance intracellular formation of oxyradicals through several mechanisms, but complex oxidative interactions occur in response to chemical mixtures. Metabolism of individual classes of pollutants can be influenced by a sophisticated network of prooxidant relationships, reciprocal and cascade effects, changes of redox-sensitive signaling proteins, and transcription factors. Chemically mediated pathways can affect antioxidant responses at different levels, including pretranscriptional, transcriptional, protein, and catalytic functions; such mechanisms remain largely unexplored in marine organisms. Molecular responses of antioxidants are frequently not paralleled by expected biochemical changes or cellular effects, and caution is needed when interpreting the effects of environmental pollutants. Results on antioxidant variations can be influenced by mRNA stability and protein turnover, different timing for transcriptional and translational mechanisms, metabolic capability of tissues, posttranscriptional modifications of proteins, biphasic responses of antioxidant enzymes, and adaptation mechanisms to chronic pollution. [ABSTRACT FROM AUTHOR]

Inflammation is a central feature of stable chronic obstructive pulmonary disease (COPD) and involves both activation of structural cells of the airways and the lungs and the activation and/or recruitment of infiltrating inflammatory cells. This results in enhanced expression of many pro-inflammatory proteins and reduced expression of some anti-inflammatory mediators. An altered protein expression is generally associated with concomitant changes in gene expression profiles in a cell-specific manner. Increased understanding of the role of transcription factors and of the signaling pathways leading to their activation in stable COPD will provide new targets to enable the development of potential anti-inflammatory drugs. Several new compounds targeting these pathways and/or transcription factors are now in development for the treatment of stable COPD. Furthermore, glucocorticoids drugs already in clinical use act through their own transcription factor, the glucocorticoid receptor, to control the expression of inflammatory and anti-inflammatory genes. [ABSTRACT FROM AUTHOR]

Endogenous glucocorticoids are implicated in the development and resolution of inflammation. Until recently it was thought that these glucocorticoids arose primarily from the adrenal gland. However, it is now known that several cell types can generate active glucocorticoids within their cytoplasm through expression of the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. In a more limited range of cell types, glucocorticoids can be inactivated by the related 11β-HSD2 enzyme. Both enzymes are regulated by inflammation in various settings. In rheumatoid arthritis, 11β-HSD activity is present in the inflamed synovium and appears to influence articular and extraarticular disease processes. The generation of active glucocorticoids in the synovium is strongly linked to the level of inflammation. This local production of glucocorticoids is likely to have paracrine consequences and could underpin inflammation-associated bone loss. The role of 11β-HSD enzymes in the severity and persistence of inflammatory arthritis in a clinical setting is currently being explored. [ABSTRACT FROM AUTHOR]

Commercial probiotic strains for food or supplement use can be altered in different ways for a variety of purposes. Production conditions for the strain or final product may be changed to address probiotic yield, functionality, or stability. Final food products may be modified to improve flavor and other sensory properties, provide new product formats, or respond to market opportunities. Such changes can alter the expression of physiological traits owing to the live nature of probiotics. In addition, genetic approaches may be used to improve strain attributes. This review explores whether genetic or phenotypic changes, by accident or design, might affect the efficacy or safety of commercial probiotics. We highlight key issues important to determining the need to re-confirm efficacy or safety after strain improvement, process optimization, or product formulation changes. Research pinpointing the mechanisms of action for probiotic function and the development of assays to measure them are greatly needed to better understand if such changes have a substantive impact on probiotic efficacy. [ABSTRACT FROM AUTHOR]

Aire (autoimmune regulator) has a key role in the establishment of tolerance to autoantigens. Aire−/− mice present decreased thymic expression of AChR, significantly lower frequencies of regulatory T (Treg) cells, and higher expression of Th17 markers, compared to controls. We therefore predicted that Aire−/− mice would be more susceptible to induction of experimental autoimmune myasthenia gravis (EAMG). However, when EAMG was induced in young mice, Aire−/− mice presented a milder disease that wild-type (WT) controls. In contrast, when EAMG was induced in older mice, Aire−/− mice were more severely affected than WT mice. The relative resistance to EAMG in young Aire−/− mice correlated with increased numbers of Treg cells in their spleens compared to young controls. A similar age-related susceptibility was also observed when EAE was induced in Aire−/− mice, suggesting an age-related link among Aire, disease susceptibility, and peripheral Treg cells that may be a general feature of autoimmunity. [ABSTRACT FROM AUTHOR]

Thymosin β4 (Tβ4) is highly expressed in saliva of human newborns but not in adults. Here preliminary immunohistochemical analyses on different human tissues are reported. Immunoreactivity for Tβ4 in human salivary glands show high quantities of Tβ4 before birth, followed by downregulation of expression in adulthood. In contrast, Tβ4 is detected in tumors of salivary glands, suggesting that tumor cells might utilize fetal programs, including Tβ4 synthesis. Immunohistochemical analyses in the gastrointestinal tract showed strong reactivity for Tβ4 in enterocytes during development, but weak immunostaining in mature enterocytes. In colorectal cancer, the association of a high expression of Tβ4 with epithelial-mesenchymal transition was observed. On the basis of these data, the process of epithelial-mesenchymal transition could represent the unifying process that explains the role of Tβ4 during fetal development and in cancer progression. [ABSTRACT FROM AUTHOR]

Cripto has been known as an embryonic stem (ES)- or tumor-related soluble/cell membrane protein. In this study, we demonstrated that Cripto has a role as an important regulatory factor for hematopoietic stem cells (HSCs). Recombinant Cripto sustained the reconstitution ability of HSCs in vitro. Flow cytometry analysis uncovered that GRP78, one of the candidate receptors for Cripto, was expressed on a subset of HSCs and could distinguish dormant/myeloid-biased HSCs and active/lymphoid-biased HSCs. Cripto is expressed in hypoxic endosteal niche cells where GRP78+ HSCs mainly reside. Proteomics analysis revealed that Cripto-GRP78 binding stimulates glycolytic metabolism-related proteins and results in lower mitochondrial potential in HSCs. Furthermore, conditional knockout mice for HIF-1α, a master regulator of hypoxic responses, showed reduced Cripto expression and decreased GRP78+ HSCs in the endosteal niche area. Thus, Cripto-GRP78 is a novel HSC regulatory signal mainly working in the hypoxic niche. [ABSTRACT FROM AUTHOR]

Siglecs are expressed on most white blood cells of the immune system and are known to modulate the activity of cell signaling receptors via regulatory motifs in their cytoplasmic domains. This immunoglobulin subfamily of coreceptors recognize sialic acid containing glycans as ligands, which are found on glycoproteins and glycolipids of all mammalian cells. By virtue of their ability to recognize this common structural element, siglecs are increasingly recognized for their ability to help immune cells distinguish between self and nonself, and dampen autoimmune responses. [ABSTRACT FROM AUTHOR]

Sialic acids are a diverse family of monosaccharides widely expressed on all cell surfaces of vertebrates and so-called 'higher' invertebrates, and on certain bacteria that interact with vertebrates. This overview surveys examples of biological roles of sialic acids in immunity, with emphasis on an evolutionary perspective. Given the breadth of the subject, the treatment of individual topics is brief. Subjects discussed include biophysical effects regulation of factor H; modulation of leukocyte trafficking via selectins; Siglecs in immune cell activation; sialic acids as ligands for microbes; impact of microbial and endogenous sialidases on immune cell responses; pathogen molecular mimicry of host sialic acids; Siglec recognition of sialylated pathogens; bacteriophage recognition of microbial sialic acids; polysialic acid modulation of immune cells; sialic acids as pathogen decoys or biological masks; modulation of immunity by sialic acid O-acetylation; sialic acids as antigens and xeno-autoantigens; antisialoglycan antibodies in reproductive incompatibility; and sialic-acid-based blood groups. [ABSTRACT FROM AUTHOR]

Lymphocyte homing to the secondary lymphoid organs is pivotal for proper immune responses. Studies using sulfotransferase-deficient mice showed that 6-sulfo sialyl Lewis X (6-sulfo sLex), a major ligand for L-selectin that is expressed on the high endothelial venules (HEVs), plays critical roles in lymphocyte homing to the peripheral lymph nodes. More recent studies revealed that 6-sulfo sLex is essential for the homing of CD4+CD25− conventional T cells to the nasal-associated lymphoid tissues (NALT) and is involved in nasal allergy. Further studies revealed that the homing of the CD4+CD25+ regulatory T cells to the NALT is dependent not only on the L-selectin-sulfated glycan interaction but also on P-selectin glycoprotein ligand-1 and CD44. These findings suggest that different carbohydrate-dependent homing mechanisms are utilized for different lymphocyte subsets. Recent studies indicated that the L-selectin-sulfated glycan interaction is also important for lymphocyte homing in chronic inflammation. In this review, the functions of the sulfated glycans in lymphocyte homing in physiological and pathological conditions are discussed. [ABSTRACT FROM AUTHOR]

Regular moderate physical activity reduces the risk of several noncommunicable diseases. At the same time, evidence exists for oxidative stress resulting from acute and strenuous exercise by enhanced formation of reactive oxygen and nitrogen species, which may lead to oxidatively modified lipids, proteins, and possibly negative effects on DNA stability. The limited data on ultraendurance events such as an Ironman triathlon show no persistent DNA damage after the events. However, when considering the effects of endurance exercise comparable to a (half) marathon or a short triathlon distance, no clear conclusions could be drawn. In order to clarify which components of exercise participation, such as duration, intensity, frequency, or training status of the subjects, have an impact on DNA stability, more information is clearly needed that combines the measurement of DNA damage, gene expression, and DNA repair mechanisms before, during, and after exercise of differing intensities and durations. [ABSTRACT FROM AUTHOR]

Clinical and experimental studies in humans provide evidence that moderate physical activity significantly decreases artery oxidative damage to nuclear DNA, DNA-adducts related to age and dyslipedemia, and mitochondrial DNA damage. Maintenance of adequate mitochondrial function is crucial for preventing lipid accumulation and peroxidation occurring in atherosclerosis. Studies performed on human muscle biopsies analyzing gene expression in living humans reveal that physically active subjects improve the expression of genes involved in mitochondrial function and of related microRNAs. The attenuation of oxidative damage to nuclear and mitochondrial DNA by physical activity resulted in beneficial effects due to polymorphisms of glutathione S-transferases genes. Subjects bearing null GSTM1/T1 polymorphisms have poor life expectancy in the case of being sedentary, which was increased 2.6-fold in case they performed physical activity. These findings indicate that the preventive effect of physical activity undergoes interindividual variation affected by genetic polymorphisms. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are important mediators to induce pancreatitis. Serum levels of antioxidant enzymes and carotenoids including lycopene are lower in patients with pancreatitis than those of healthy subjects. The cholecystokinin (CCK) analog cerulein induces similar pathologic events as shown in human pancreatitis. Recent studies show that high doses of cerulein activate NF-κB and induce the expression of inflammatory cytokines, in pancreatic acinar cells, which is mediated by the activation of NADPH oxidase. Lycopene functions as a very potent antioxidant to suppress the induction of inflammatory cytokines, in pancreatic acinar cells stimulated with cerulein. In this review, the possible beneficial effect of lycopene on experimental pancreatitis shall be discussed based on its antioxidant activity. [ABSTRACT FROM AUTHOR]

To assess the role of the mitochondrial metabolic competence (MMC) in the development of age-related changes, we measured the levels of immunohistochemically stained (IH) mitochondrial- and nuclear-encoded subunits of cytochrome oxidase (COX II and COX IV, respectively) and compared these data with mRNA in situ hybridization (ISH) of the same subunits and with cytochemically evidenced COX activity in the temporal (TC) and frontal (FC) cortex of adult and late-adult monkeys. Quantitative cytochemistry of COX activity was performed by calculating the ratio (R) of the area of the cytochemical precipitate to the area of the respective organelle. Although ISH studies showed reduced gene expression of both subunits in FC of late-adult monkeys, no significant age-related difference was found either in TC or FC when considering the IH data. R was significantly increased in FC of late-adult animals, and a quartile distribution of the mitochondrial area showed that R is higher in the FC of older animals independent of the organelle size. The assessment of COX genetic and phenotypic parameters reliably reports on MMC because this enzyme is the terminal complex of the electron transport chain. Taken together, the present IH, ISH, and R findings suggest that, with advancing age, compensating mechanisms are activated to preserve the mitochondrial functional metabolic capacities. Although significant mitochondrial defects are currently reported to occur in Alzheimer's disease pathogenesis, our data document that MMC is actively involved in the physiological rearrangement of the age-related neuronal network and may provide substantial metabolic support for the energy demand of neuronal apoptosis. [ABSTRACT FROM AUTHOR]

Rocky Mountain spotted fever (RMSF) caused by Rickettsia rickettsii is a severe rickettsiosis that occurs in nearly every state of the continental USA. RMSF is endemic in Central and Southern America, with recent well-documented cases in Mexico, Costa Rica, Panama, Colombia, Brazil, and Argentina. RMSF is the most malignant among known rickettsioses causing severe multiorgan dysfunction and high case fatality rates, which can reach 73% in untreated cases. Variations in pathogenic biotypes of R. rickettsii isolates have been described, and potential correlations of these differences to various clinical manifestations of RMSF have been suggested. We have recently reported on a method of genetic comparison employing sequence differences in intergenic regions (IGR typing) in isolates of R. rickettsii of human, tick, and animal origin. The grouping obtained correlated well with 2 other genotyping systems we have developed, which target the presence and distribution of variable numbers of tandem repeats (TR) and insertion/deletion (INDEL) events. Twenty-five total genotypes of R. rickettsii in 4 primary groups could be distinguished: isolates from Montana, isolates associated with Rhipicephalus sanguineus ticks and human infections in Arizona, other isolates from the USA where Dermacentor variabilis is thought to be the primary vector, and the isolates primarily associated with Amblyomma ticks from Central and South America. In addition, isolate Hlp#2, which is often considered to be a nonpathogenic isolate of R. rickettsii and closely related serotype 364D, exhibited the most diversity from the other isolates compared, and they differ significantly from each other. Because complex interactions underlie the pathogenesis of R. rickettsii in vivo, it is difficult to define the causality of individual events that occur in infected vertebrate hosts and humans. Many microbial factors are likely to contribute to the varied ability of R. rickettsii to cause cellular injury; some of them may also contribute importantly to its virulence for vertebrate hosts and may be linked to the variable genetic markers we have identified. Since circulation of R. rickettsii in nature includes vertical transstadial and transovarial transmission within tick vectors and horizontal passages through vertebrate hosts, it is plausible that isolates of different virulence arose when they became isolated during adaptation to novel vertebrate and tick hosts. Characterization of the physiologically important changes in rickettsial gene expression that occur immediately after tick-to-human or tick-to-animal transitions may require development of new experimental systems. [ABSTRACT FROM AUTHOR]

Recent in vivo studies suggest a role for relaxin-3 in feeding and stress. To further elucidate the function of relaxin-3 in the central nervous system, we have employed a complementary approach, based on RNA interference, to modulate relaxin-3 expression. We have designed, constructed, and characterized three microRNAs (miRNAs) targeting different regions of the relaxin-3 transcript. These were tested to determine the amount of miRNA required to achieve the greatest knockdown and for their ability to reduce the expression of relaxin-3 in transfected HEK293Tcells. All miRNA constructs significantly reduced relaxin-3-induced cAMP responses; however, miR499 was most effective. This should be a useful tool for in vitro studies and central targeting of relaxin-3 in vivo using viral delivery systems. [ABSTRACT FROM AUTHOR]

Cellular processes are often carried out by intricate systems of interacting genes and proteins. Some of these systems are rather well studied and described in pathway databases, while the roles and functions of the majority of genes are poorly understood. A large compendium of public microarray data is available that covers a variety of conditions, samples, and tissues and provides a rich source for genome-scale information. We focus our study on the analysis of 35 curated biological pathways in the context of gene co-expression over a large variety of biological conditions. By defining a global co-expression similarity rank for each gene and pathway, we perform exhaustive leave-one-out computations to describe existing pathway memberships using other members of the corresponding pathway as reference. We demonstrate that while successful in recovering biological base processes such as metabolism and translation, the global correlation measure fails to detect gene memberships in signaling pathways where co-expression is less evident. Our results also show that pathway membership detection is more effective when using only a subset of corresponding pathway members as reference, supporting the existence of more tightly co-expressed subsets of genes within pathways. Our study assesses the predictive power of global gene expression correlation measures in reconstructing biological systems of various functions and specificity. The developed computational network has immediate applications in detecting dubious pathway members and predicting novel member candidates. [ABSTRACT FROM AUTHOR]

Thanks to the availability of high-throughput omics data, bioinformatics approaches are able to hypothesize thus-far undocumented genetic interactions. However, due to the amount of noise in these data, inferences based on a single data source are often unreliable. A popular approach to overcome this problem is to integrate different data sources. In this study, we describe DISTILLER, a novel framework for data integration that simultaneously analyzes microarray and motif information to find modules that consist of genes that are co-expressed in a subset of conditions, and their corresponding regulators. By applying our method on publicly available data, we evaluated the condition-specific transcriptional network of Escherichia coli. DISTILLER confirmed 62% of 736 interactions described in RegulonDB, and 278 novel interactions were predicted. [ABSTRACT FROM AUTHOR]