bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative trait loci with opposing blood pressure effects demonstrating epistasis on Dahl rat chromosome 3
Authors: Palijan Ana , Dutil Julie , Deng Alan Y.
Published: March 2015

Our previous linkage studies indicated that there might be a blood pressure (BP) quantitative trait locus (QTL) on chromosome 3 (Chr 3) contrasting between the Dahl salt-sensitive (S) strain and the Lewis (LEW) strain. To prove and then to narrow down the segment containing this QTL, five congenic strains have been generated by replacing various segments of the S rats with the homologous segments of the LEW rats. They are designated as S.L1, S.L2, S.L3, S.L4, and S.L5, respectively. S.L2, S.L3, S.L4, and S.L5 are substrains of S.L1, i.e., they contain substitutions of smaller sections within the large fragment defined by S.L1. The construction of these congenic strains was facilitated by a genome-wide marker screening process. BPs of the rats were measured by telemetry. S.L2 and S.L3 shared a fragment of Chr 3 in common and both showed a BP-lowering effect, indicating the existence of “−BP” QTL alleles from LEW compared with S. In contrast, S.L4 involves a section with no overlap with either S.L2 or S.L3, and S.L4 showed a BP significantly higher than that of S rats, indicating the presence of “+BP” QTL alleles from LEW compared with S. Interestingly, the combined effect of the −BP QTL and +BP QTL alleles was “−” in S.L1, implying that the “−” QTL is epistatic to “+” QTL.
Physiological genomics of Escherichia coli protein families
Authors: Liang Ping , Labedan Bernard , Riley Monica
Published: March 2015

The well-researched Escherichia coli genome offers the opportunity to explore the value of using protein families within a single organism to enrich functional annotation procedures and to study mechanisms of protein evolution. Having identified multimodular proteins resulting from gene fusion, and treated each module as a separate protein, nonoverlapping sequence-similar families in E. coli could be assembled. Of 3,902 proteins of length 100 residues or more, 2,415 clustered into 609 protein families. The relatedness of function among members of each family was dissected in detail. Data on paralogous protein families provides valuable information in attributing putative function to unknown genes, supplementing existing function annotation. Enzymes, transporters, and regulators represent the three major types of proteins in E. coli. They are shown to have distinctive patterns in gene duplication and divergence and gene fusion, suggesting that details of protein evolution have been different for genes in these categories. Data for the complete list of paralogous protein families and updated functional annotation for E. coli K-12 are accessible in GenProtEC ( http://genprotec.mbl.edu ).
Development and testing of a high-density cDNA microarray resource for cattle
Authors: Suchyta Steven P. , Sipkovsky Sue , Kruska Rachael , Jeffers Abra , McNulty Amanda , Coussens Matthew J. , Tempelman Robert J. , Halgren Robert G. , Saama Peter M. , Bauman Dale E. , Boisclair Yves R. , Burton Jeanne L. , Collier Robert J. , DePeters Edward J. , Ferris Theodore A. , Lucy Matthew C. , McGuire Mark A. , Medrano Juan F. , Overton Thomas R. , Smith Timothy P. , Smith George W. , Sonstegard Tad S. , Spain James N. , Spiers Donald E. , Yao Jianbo , Coussens Paul M.
Published: March 2015

A cDNA microarray resource has been developed with the goal of providing integrated functional genomics resources for cattle. The National Bovine Functional Genomics Consortium’s (NBFGC) expressed sequence tag (EST) collection was established in 2001 to develop resources for functional genomics research. The NBFGC EST collection and microarray contains 18,263 unique transcripts, derived from many different tissue types and various physiologically important states within these tissues. The NBFGC microarray has been tested for false-positive rates using self-self hybridizations and was shown to yield robust results in test microarray experiments. A web-accessible database has been established to provide pertinent data related to NBFGC clones, including sequence data, BLAST results, and ontology information. The NBFGC microarray represents the largest cDNA microarray for a livestock species prepared to date and should prove to be a valuable tool in studying genome-wide gene expression in cattle.
Disease genes and intracellular protein networks
Authors: Bortoluzzi S. , Romualdi C. , Bisognin A. , Danieli G. A.
Published: March 2015

By a computational approach we reconstructed genomic transcriptional profiles of 19 different adult human tissues, based on information on activity of 27,924 genes obtained from unbiased UniGene cDNA libraries. In each considered tissue, a small number of genes resulted highly expressed or “tissue specific.” Distribution of gene expression levels in a tissue appears to follow a power law, thus suggesting a correspondence between transcriptional profile and “scale-free” topology of protein networks. The expression of 737 genes involved in Mendelian diseases was analyzed, compared with a large reference set of known human genes. Disease genes resulted significantly more expressed than expected. The possible correspondence of their products to important nodes of intracellular protein network is suggested. Auto-organization of the protein network, its stability in time in the differentiated state, and relationships with the degree of genetic variability at genome level are discussed.
IDEG6: a web tool for detection of differentially expressed genes in multiple tag sampling experiments
Authors: Romualdi Chiara , Bortoluzzi Stefania , d’Alessi Fabio , Danieli Gian Antonio
Published: March 2015

Here we present a novel web tool for the statistical analysis of gene expression data in multiple tag sampling experiments. Differentially expressed genes are detected by using six different test statistics. Result tables, linked to the GenBank, UniGene, or LocusLink database, can be browsed or searched in different ways. Software is freely available at the site: http://telethon.bio.unipd.it/bioinfo/IDEG6_form/ , together with additional information on statistical methodologies.
Programmed cell death takes flight: genetic and genomic approaches to gene discovery inDrosophila
Authors: Gorski S. , Marra M.
Published: March 2015

Programmed cell death (PCD) is an essential and wide-spread physiological process that results in the elimination of cells. Genes required to carry out this process have been identified, and many of these remain the subjects of intense investigation. Here, we describe PCD, its functions, and some of the consequences when it goes awry. We review PCD in the model system, the fruit fly, Drosophila melanogaster, with a particular emphasis on cell death gene discovery resulting from both genetics and genomics-based approaches.
Changes in urinary bladder cytokine mRNA and protein after cyclophosphamide-induced cystitis
Authors: Malley Susan E. , Vizzard Margaret A.
Published: March 2015

Cyclophosphamide (CYP)-induced cystitis alters micturition function and produces reorganization of the micturition reflex. This reorganization may involve cytokine expression in the urinary bladder. These studies have determined candidate cytokines in the bladder that may contribute to the reorganization process. An RNase protection assay was used to measure changes in rat bladder cytokine mRNA [interferon-γ (IFN)-γ, interleukin-1α/β (IL-1α/β), IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, and tumor necrosis factor-α/β (TNF-α/β)] after acute (4 h), intermediate (48 h), or chronic (10 day) cystitis. The correlation between bladder cytokine mRNA and protein expression was also determined by immunoassay. Although at each time point after cystitis significant changes in bladder cytokine mRNA were observed, the magnitude differed (acute > intermediate > chronic). Acute cystitis demonstrated the most robust changes ( P ≤ 0.005; IL-1β, 330-fold increase; IL-2, 20-fold increase; IL-4, 8-fold increase; IL-6, 80-fold increase) in cytokine mRNA expression and TNF-α or TNF-β mRNA were only increased (2–10-fold) after acute cystitis. More modest increases in cytokine mRNA expression were observed after 48-h or 10-day cystitis. Cytokine protein expression generally paralleled that of mRNA. Increased cytokine expression after CYP-induced cystitis, alone or in combination with other inflammatory mediators or growth factors, may contribute to altered lower urinary tract function after cystitis.
A common human SCN5A polymorphism modifies expression of an arrhythmia causing mutation
Authors: Ye Bin , Valdivia Carmen R. , Ackerman Michael J. , Makielski Jonathan C.
Published: March 2015

SCN5A encodes the α-subunit of the ion channel that carries Na current in human heart. From a human cardiac cDNA library we recloned SCN5A. The new clone hH1b differed from existing clones hH1 in four and from hH1a in three positions. The common polymorphism H558R was uniquely present in hH1b. Voltage clamp study showed minor but potentially important kinetic differences between hH1b and the other clones. More dramatically, when the LQT3 mutation M1766L was introduced into the different clones, Na current was markedly reduced in the hH1 and hH1a backgrounds, whereas in hH1b the Na current was not reduced. Immunocytochemistry experiments showed a trafficking defect for M1766L Na channels in hH1 and hH1a but not in hH1b. The double-mutation M1766L/H558R in the hH1a background restored normal trafficking and current including persistent late current, suggesting the disease phenotype was the result of a “double hit” that included the common polymorphism, H558R. These results show that the choice of background clone must be carefully considered in mutagenesis studies. This also represents an example of intragenic complementation, the first for such a large protein.
Comparison of different labeling methods for two-channel high-density microarray experiments
Authors: Manduchi Elisabetta , Scearce L. Marie , Brestelli John E. , Grant Gregory R. , Kaestner Klaus H. , Stoeckert Christian J.
Published: March 2015

In this report we evaluate three methods for labeling nucleic acids to be hybridized to a cDNA microarray: direct labeling, indirect amino-allyl labeling, and the dendrimer labeling method (Genisphere). The dendrimer method requires the smallest quantity of sample, 2.5 μg of total RNA compared with 20 μg with the direct or indirect methods. Therefore, we wanted to know whether the performance of the dendrimer method is comparable to the other methods, or whether significant information is lost. Performance can be considered in terms of sensitivity, dynamic range, and reproducibility of the quantitative signals for gene intensity. We compared the three labeling methods by generating three sets of eight self-to-self hybridizations using the same total RNA sample in all cases (“replicate study”). In our analysis, we controlled for the effects of print-tip and background subtraction biases. We also performed a smaller study, namely, a dilution series study with five dilution points per labeling method, to evaluate one aspect of predictive ability. From the replicate study, the dendrimer method appeared to perform as well, and often better, with respect to reproducibility and ability to detect expression. However, in the dilution series study, this method was outperformed by the other two in terms of predictive ability and did not perform very well. These findings are helping to guide our decisions on what labeling method to use for subsequent studies, based on the purpose of a specific study and its limitations in terms of available material.
Age-related changes in the transcriptional profile of mouse RPE/choroid
Authors: Ida Hisashi , Boylan Sharon A. , Weigel Andrea L. , Hjelmeland Leonard M.
Published: March 2015

To evaluate the age-related changes in gene expression occurring in the complex of retinal pigmented epithelium, Bruch’s membrane, and choroid (RPE/choroid), we examined the gene expression profiles of young adult (2 mo) and old (24 mo) male C57BL/6 mice. cDNA probe sets from individual animals were synthesized using total RNA isolated from the RPE/choroid of each animal. Probes were amplified using the Clontech SMART system, radioactively labeled, and hybridized to two different Clontech Atlas mouse cDNA arrays. From each age group, three independent triplicates were hybridized to the arrays. Statistical analyses were performed using the Significance Analysis of Microarrays program (SAM version 1.13; Stanford University). Selected array results were confirmed by semi-quantitative RT-PCR analysis. Of 2,340 genes represented on the arrays, ∼60% were expressed in young and/or old mouse RPE/choroid. A moderate fraction (12%) of all expressed genes exhibited a statistically significant change in expression with age. Of these 150 genes, all but two, HMG14 and carboxypeptidase E, were upregulated with age. Many of these upregulated genes can be grouped into several broad functional categories: immune response, proteases and protease inhibitors, stress response, and neovascularization. RT-PCR results from six of six genes examined confirmed the differential change in expression with age of these genes. Our study provides likely candidate genes to further study their role in the development of age-related macular degeneration and other aging diseases affecting the RPE/choroid.
Gene expression profile of zebrafish exposed to hypoxia during development
Authors: Ton Christopher , Stamatiou Dimitri , Liew Choong-Chin
Published: March 2015

Understanding how vertebrates respond to hypoxia can have important clinical implications. Fish have evolved the ability to survive long exposure to low oxygen levels. However, little is known about the specific changes in gene expression that result from hypoxia. In this study we used a zebrafish cDNA microarray to examine the expression of >4,500 genes in zebrafish embryos exposed to 24 h of hypoxia during development. We tested the hypotheses that hypoxia changes gene expression profile of the zebrafish embryos and that these changes can be reverted by reexposure to a normoxic (20.8% O2) environment. Our data were consistent with both of these hypotheses: indicating that zebrafish embryos undergo adaptive changes in gene expression in response to hypoxia. Our study provides a striking genetic portrait of the zebrafish embryos’ adaptive responses to hypoxic stress and demonstrates the utility of the microarray technology as a tool for analyzing complex developmental processes in the zebrafish.
Efficient large-scale production and concentration of HIV-1-based lentiviral vectors for use in vivo
Authors: Coleman Jason E. , Huentelman Matthew J. , Kasparov Sergey , Metcalfe Beverly L. , Paton Julian F. R. , Katovich Michael J. , Semple-Rowland Susan L. , Raizada Mohan K.
Published: March 2015

The aim of this study was to develop an efficient method for packaging and concentrating lentiviral vectors that consistently yields high-titer virus on a scale suitable for in vivo applications. Transient cotransfection of 293T packaging cells with DNA plasmids encoding lentiviral vector components was optimized using SuperFect, an activated dendrimer-based transfection reagent. The use of SuperFect allowed reproducible and efficient production of high-titer lentiviral vector at concentrations greater than 1 × 107transducing units per ml (TU/ml) and required less than one-third of the total amount of DNA used in traditional calcium phosphate transfection methods. Viral titers were further increased using a novel concentration protocol that yielded an average final titer of 1.4 × 1010TU/ml. Lentiviruses produced using these methods exhibited efficient transduction of central nervous system and peripheral tissues in vivo. The method is reproducible and can be scaled up to facilitate the use of these vectors in animal studies.
Genetic component of sensorimotor capacity in rats
Authors: Koch Lauren Gerard , Britton Steven L.
Published: March 2015

Creation of generalized genetic models for low and high sensorimotor capacity would be important tools for resolution of this complex trait. As proof-of-principle we estimated phenotypic variation and narrow-sense heritability (h2) of sensorimotor capacity in 19 families of genetically heterogeneous N:NIH rats and in 11 strains of inbred rats. Sensorimotor capacity was defined as the time a rat remained on an accelerating rotorod. N:NIH rats recorded variation in rotorod scores that ranged from 3- to 7-fold. The value of h2, estimated from offspring-parent regression across one generation, was 0.68 for females and 0.74 for males in N:NIH rats. In inbred rats, h2 was estimated by partitioning phenotypic variation into additive genetic and environmental components and averaged 0.39 in females and 0.48 in males. These results demonstrate a heritable component to sensorimotor capacity sufficient for success in developing contrasting genetic models by divergent artificial selection in rats.
Neurokinin 1 receptors and neprilysin modulation of mouse bladder gene regulation
Authors: Dozmorov Igor , Saban Marcia R. , Gerard Norma P. , Lu Bao , Nguyen Ngoc-Bich , Centola Michael , Saban Ricardo
Published: March 2015

Neurokinin 1 (NK1) receptors play a fundamental role in neurogenic inflammation. We sought to determine the mechanisms downstream from NK1receptor (NK1R) activation using cDNA arrays and a novel statistical method to analyze gene expression. We used female NK1R−/−and wild-type (WT) mice that were sensitized actively by intraperitoneal injections of dinitrophenol 4 (DNP4)-human serum albumin. Cystitis was induced by intravesical instillation of antigen of DNP4-ovalbumin, and control mice were challenged with saline. At 1, 4, and 24 h after instillation, bladders were removed for 1) RNA extraction ( n = 3), 2) replicate of RNA extraction ( n = 3), and 3) morphological analysis ( n = 6). For cDNA array experiments, three bladders from each group were homogenized, and total RNA was obtained. DNase-treated RNA was reverse-transcribed to cDNA, labeled with [α-32P]dATP and hybridized to Atlas Mouse 1.2 Arrays (Clontech). After calculating the mean and SD for background spots, each experimental value was assigned a normalized score S using the formula S′ = ( S − Av)/SD, where S′ is the original pixel value, and Av and SD are the mean and standard deviation of background spots, respectively. Only genes that expressed 3 SD values above background were used. Hypervariable genes were sorted by cluster analysis. Matrices of correlation coefficients were calculated and represented in a connectivity mosaic. As results, we found that in WT mice the most prominent gene cluster had neprilysin in a central position and positively correlated to a group of activator protein-1 (AP-1)-responsive genes, including laminin-α3, tissue plasminogen activator 11, fos-B, and TNF-β. In WT mice, antigen-induced bladder inflammation led to a downregulation in neprilysin expression. In contrast, NK1R−/−mice failed to mount an inflammatory reaction and presented neprilysin negatively correlated with the same genes described in WT. In conclusion, this work indicates an overriding participation of NK1R and neprilysin in bladder inflammation, provides a working model for the involvement of AP-1 transcription factor, and evokes testable hypotheses regarding the role of NK1R and neprilysin in inflammation.
Thesldmutation is specific for sublingual salivary mucous cells and disrupts apomucin gene expression
Authors: Fallon M. A. , Latchney L. R. , Hand A. R. , Johar A. , Denny P. A. , Georgel P. T. , Denny P. C. , Culp D. J.
Published: March 2015

NFS/N- sld mice harbor a spontaneous autosomal recessive mutation, sld (sublingual gland differentiation arrest) and histologically display attenuated mucous cell expression in sublingual glands (Hayashi et al. Am J Pathol 132: 187–191, 1988). Because altered serous demilune cell expression is unknown, we determined the phenotypic expression of this cell type in mutants. Moreover, we evaluated whether absence of glycoconjugate staining in 3-day-old mutant glands is related to disruption in apomucin gene expression and/or to posttranslational glycosylation events. Serous cell differentiation is unaffected, determined morphologically and by serous cell marker expression (PSP, parotid secretory protein; and Dcpp, demilune cell and parotid protein). Conversely, apical granules in “atypical” exocrine cells of mutant glands are PSP and mucin negative, but contain abundant SMGD (mucous granule marker). Age-related appearance of mucous cells is associated with expression of apomucin gene products, whereas SMGD expression is unaltered. “Atypical” cells thus appear specified to a mucous cell fate but do not synthesize mucin glycoproteins unless selectively induced postnatally, indicating the sld mutation disrupts apomucin transcriptional regulation and/or decreases apomucin mRNA stability.
Fidelity and enhanced sensitivity of differential transcription profiles following linear amplification of nanogram amounts of endothelial mRNA
Authors: Polacek Denise C. , Passerini Anthony G. , Shi Congzhu , Francesco Nadeene M. , Manduchi Elisabetta , Grant Gregory R. , Powell Steven , Bischof Helen , Winkler Hans , Stoeckert Christian J. , Davies Peter F.
Published: March 2015

Although mRNA amplification is necessary for microarray analyses from limited amounts of cells and tissues, the accuracy of transcription profiles following amplification has not been well characterized. We tested the fidelity of differential gene expression following linear amplification by T7-mediated transcription in a well-established in vitro model of cytokine [tumor necrosis factor α (TNFα)]-stimulated human endothelial cells using filter arrays of 13,824 human cDNAs. Transcriptional profiles generated from amplified antisense RNA (aRNA) (from 100 ng total RNA, ∼1 ng mRNA) were compared with profiles generated from unamplified RNA originating from the same homogeneous pool. Amplification accurately identified TNFα-induced differential expression in 94% of the genes detected using unamplified samples. Furthermore, an additional 1,150 genes were identified as putatively differentially expressed using amplified RNA which remained undetected using unamplified RNA. Of genes sampled from this set, 67% were validated by quantitative real-time PCR as truly differentially expressed. Thus, in addition to demonstrating fidelity in gene expression relative to unamplified samples, linear amplification results in improved sensitivity of detection and enhances the discovery potential of high-throughput screening by microarrays.
Identification of new genes differentially expressed in coronary artery disease by expression profiling
Authors: Archacki Stephen R. , Angheloiu George , Tian Xiao-Li , Tan Fen Lai , DiPaola Nick , Shen Gong-Qing , Moravec Christine , Ellis Stephen , Topol Eric J. , Wang Qing
Published: March 2015

Genetic factors increase the risk to coronary artery disease (CAD). To date, a limited number of genes that potentially contribute to development of CAD have been identified. In this study, we have performed large-scale gene expression analysis of ∼12,000 human genes in nine severely atherosclerotic and six nonatherosclerotic human coronary arteries using oligonucleotide microarrays. Fifty-six genes showed differential expression in atherosclerotic coronary artery tissues; expression of 55 genes was increased in atherosclerotic coronary arteries, whereas only one gene, GST, encoding a reducing agent, showed downregulated expression. The expression data of selected genes were validated by quantitative RT-PCR analysis as well as immunostaining. The associations of 49 genes with CAD appear to be novel, and they include genes encoding ICAM-2, PIM-2, ECGF1, fusin, B cell activator ( BL34, GOS8), Rho GTPase activating protein-4, retinoic acid receptor responder, β2-arrestin, membrane aminopeptidase, cathepsins K and H, MIR-7, TNF-α-induced protein 2 (B94), and flavocytochrome 558. In conclusion, we have identified 56 genes whose expression is associated with CAD, and 49 of them may represent new genes linked to CAD.
The Amygdaloid Complex: Anatomy and Physiology
Authors: SAH P. , FABER E. S. L. , LOPEZ DE ARMENTIA M. , POWER J.
Published: March 2015

Sah, P., E. S. L. Faber, M. Lopez de Armentia, and J. Power. The Amygdaloid Complex: Anatomy and Physiology. Physiol Rev 83: 803–834, 2003; 10.1152/physrev.00002.2003.—A converging body of literature over the last 50 years has implicated the amygdala in assigning emotional significance or value to sensory information. In particular, the amygdala has been shown to be an essential component of the circuitry underlying fear-related responses. Disorders in the processing of fear-related information are likely to be the underlying cause of some anxiety disorders in humans such as posttraumatic stress. The amygdaloid complex is a group of more than 10 nuclei that are located in the midtemporal lobe. These nuclei can be distinguished both on cytoarchitectonic and connectional grounds. Anatomical tract tracing studies have shown that these nuclei have extensive intranuclear and internuclear connections. The afferent and efferent connections of the amygdala have also been mapped in detail, showing that the amygdaloid complex has extensive connections with cortical and subcortical regions. Analysis of fear conditioning in rats has suggested that long-term synaptic plasticity of inputs to the amygdala underlies the acquisition and perhaps storage of the fear memory. In agreement with this proposal, synaptic plasticity has been demonstrated at synapses in the amygdala in both in vitro and in vivo studies. In this review, we examine the anatomical and physiological substrates proposed to underlie amygdala function.
Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions
Authors: SÁEZ JUAN C. , BERTHOUD VIVIANA M. , BRAÑES MARÍA C. , MARTÍNEZ AGUSTÍN D. , BEYER ERIC C.
Published: March 2015

Sáez, Juan C., Viviana M. Berthoud, María C. Brañes, Agustín D. Martínez, and Eric C. Beyer. Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions. Physiol Rev 83: 1359-1400, 2003; 10.1152/physrev.00007.2003.—Members of the connexin gene family are integral membrane proteins that form hexamers called connexons. Most cells express two or more connexins. Open connexons found at the nonjunctional plasma membrane connect the cell interior with the extracellular milieu. They have been implicated in physiological functions including paracrine intercellular signaling and in induction of cell death under pathological conditions. Gap junction channels are formed by docking of two connexons and are found at cell-cell appositions. Gap junction channels are responsible for direct intercellular transfer of ions and small molecules including propagation of inositol trisphosphate-dependent calcium waves. They are involved in coordinating the electrical and metabolic responses of heterogeneous cells. New approaches have expanded our knowledge of channel structure and connexin biochemistry (e.g., protein trafficking/assembly, phosphorylation, and interactions with other connexins or other proteins). The physiological role of gap junctions in several tissues has been elucidated by the discovery of mutant connexins associated with genetic diseases and by the generation of mice with targeted ablation of specific connexin genes. The observed phenotypes range from specific tissue dysfunction to embryonic lethality.
Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology
Authors: YELLON DEREK M. , DOWNEY JAMES M.
Published: March 2015

Yellon, Derek M., and James M. Downey. Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology. Physiol Rev 83: 1113-1151, 2003; 10.1152/physrev.00009.2003.—The phenomenon of ischemic preconditioning, in which a period of sublethal ischemia can profoundly protect the cell from infarction during a subsequent ischemic insult, has been responsible for an enormous amount of research over the last 15 years. Ischemic preconditioning is associated with two forms of protection: a classical form lasting ∼2 h after the preconditioning ischemia followed a day later by a second window of protection lasting ∼3 days. Both types of preconditioning share similarities in that the preconditioning ischemia provokes the release of several autacoids that trigger protection by occupying cell surface receptors. Receptor occupancy activates complex signaling cascades which during the lethal ischemia converge on one or more end-effectors to mediate the protection. The end-effectors so far have eluded identification, although a number have been proposed. A range of different pharmacological agents that activate the signaling cascades at the various levels can mimic ischemic preconditioning leading to the hope that specific therapeutic agents can be designed to exploit the profound protection seen with ischemic preconditioning. This review examines, in detail, the complex mechanisms associated with both forms of preconditioning as well as discusses the possibility to exploit this phenomenon in the clinical setting. As our understanding of the mechanisms associated with preconditioning are unravelled, we believe we can look forward to the development of new therapeutic agents with novel mechanisms of action that can supplement current treatment options for patients threatened with acute myocardial infarction.
Transport-Mediated Synapses in the Retina
Authors: Schwartz E. A.
Published: March 2015

Most synapses rely on regulated exocytosis for determining the concentration of transmitter in the synaptic cleft. However, this mechanism may not be universal. Several synapses in the retina appear to use a synaptic machinery in which transmitter transporters play an essential role. Two types of transport-mediated synapses have been proposed. These synapses have been best observed in horizontal cells and cones of nonmammalian retinas. Horizontal cells use a transporter to mediate a bidirectional shuttle, whose balance point is set by ion concentrations and voltage. Nonmammalian cones combine exocytosis and the activity of a transporter. Because exocytosis is voltage independent over most of a cone's physiological voltage range, a voltage-dependent transporter determines the concentration of transmitter in the synaptic cleft. These two synapses may be models for transport-mediated synapses that operate in other parts of the brain.
Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels
Authors: Perez-Reyes Edward
Published: March 2015

T-type Ca2+channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+entry via T-type channels can directly regulate intracellular Ca2+concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+channels, and Na+channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.
Blood Glucose Dynamics and Control of Meal Initiation: A Pattern Detection and Recognition Theory
Authors: Campfield L. Arthur , Smith Françoise J.
Published: March 2015

A new framework for understanding the control of feeding behavior, with special emphasis on the evolution of hunger, the initiation of feeding, and its dependence on patterns of blood glucose, is the subject of this review. A perspective on the current status and future directions of this search for a more complete understanding of the regulation of feeding behavior in laboratory rats and humans is presented including theoretical and experimental components. First, a historical perspective on the role of blood glucose in the control of feeding is presented. Next, the theoretical approaches that have been applied to the control of feeding and had a strong influence on experimental feeding research are summarized. This is followed by a statement and overview of a current theory that has emerged from studies of the role of transient declines in blood glucose in the control of meal initiation. The current working hypothesis that transient declines in blood glucose are endogenous metabolic patterns that are detected and recognized by the central nervous system and are mapped into meal initiation in rats and are correlated with meal requests in humans are then presented. Then, the experimental studies on meal initiation and its dependence on patterns of blood glucose, first in rats and then in humans, are reviewed in detail. Finally, the future directions of the work, limitations, and the implications for the understanding of the control of feeding behavior and the regulation of energy balance are discussed.
Voltage-Gated Proton Channels and Other Proton Transfer Pathways
Authors: Decoursey Thomas E.
Published: March 2015

Proton channels exist in a wide variety of membrane proteins where they transport protons rapidly and efficiently. Usually the proton pathway is formed mainly by water molecules present in the protein, but its function is regulated by titratable groups on critical amino acid residues in the pathway. All proton channels conduct protons by a hydrogen-bonded chain mechanism in which the proton hops from one water or titratable group to the next. Voltage-gated proton channels represent a specific subset of proton channels that have voltage- and time-dependent gating like other ion channels. However, they differ from most ion channels in their extraordinarily high selectivity, tiny conductance, strong temperature and deuterium isotope effects on conductance and gating kinetics, and insensitivity to block by steric occlusion. Gating of H+channels is regulated tightly by pH and voltage, ensuring that they open only when the electrochemical gradient is outward. Thus they function to extrude acid from cells. H+channels are expressed in many cells. During the respiratory burst in phagocytes, H+current compensates for electron extrusion by NADPH oxidase. Most evidence indicates that the H+channel is not part of the NADPH oxidase complex, but rather is a distinct and as yet unidentified molecule.
The Calpain System
Authors: GOLL DARREL E. , THOMPSON VALERY F. , LI HONGQI , WEI WEI , CONG JINYANG
Published: March 2015

Goll, Darrel E., Valery F. Thompson, Hongqi Li, Wei Wei, and Jinyang Cong. The Calpain System. Physiol Rev 83: 731–801, 2003; 10.1152/physrev.00029.2002.—The calpain system originally comprised three molecules: two Ca2+-dependent proteases, μ-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both μ- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55–65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six “domains” in the 80-kDa subunit: 1) a 19-amino acid NH2-terminal sequence; 2) and 3) two domains that constitute the active site, IIa and IIb; 4) domain III; 5) an 18-amino acid extended sequence linking domain III to domain IV; and 6) domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of μ- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.
Interaction of Mycoplasmas With Host Cells
Authors: Rottem Shlomo
Published: March 2015

-The mycoplasmas form a large group of prokaryotic microorganisms with over 190 species distinguished from ordinary bacteria by their small size, minute genome, and total lack of a cell wall. Owing to their limited biosynthetic capabilities, most mycoplasmas are parasites exhibiting strict host and tissue specificities. The aim of this review is to collate present knowledge on the strategies employed by mycoplasmas while interacting with their host eukaryotic cells. Prominant among these strategies is the adherence of mycoplasma to host cells, identifying the mycoplasmal adhesins as well as the mammalian membrane receptors; the invasion of mycoplasmas into host cells including studies on the role of mycoplasmal surface molecules and signaling mechanisms in the invasion; the fusion of mycoplasmas with host cells, a novel process that raises intriguing questions of how microinjection of mycoplasma components into eukaryotic cells subvert and damage the host cells. The observations of diverse interactions of mycoplasmas with cells of the immune system and their immunomodulatory effects and the discovery of genetic systems that enable mycoplasmas to rapidly change their surface antigenic composition have been important developments in mycoplasma research over the past decade, showing that mycoplasmas possess an impressive capability of maintaining a dynamic surface architecture that is antigenically and functionally versatile, contributing to the capability of the mycoplasmas to adapt to a large range of habitats and cause diseases that are often chronic in nature.
Integrative Physiology and Functional Genomics of Epithelial Function in a Genetic Model Organism
Authors: DOW JULIAN A. T. , DAVIES SHIREEN A.
Published: March 2015

Dow, Julian A. T, and Shireen A. Davies. Integrative Physiology and Functional Genomics of Epithelial Function in a Genetic Model Organism. Physiol Rev 83: 687–729, 2003; 10.1152/physrev.00035.2002.—Classically, biologists try to understand their complex systems by simplifying them to a level where the problem is tractable, typically moving from whole animal and organ-level biology to the immensely powerful “cellular” and “molecular” approaches. However, the limitations of this reductionist approach are becoming apparent, leading to calls for a new, “integrative” physiology. Rather than use the term as a rallying cry for classical organismal physiology, we have defined it as the study of how gene products integrate into the function of whole tissues and intact organisms. From this viewpoint, the convergence between integrative physiology and functional genomics becomes clear; both seek to understand gene function in an organismal context, and both draw heavily on transgenics and genetics in genetic models to achieve their goal. This convergence between historically divergent fields provides powerful leverage to those physiologists who can phrase their research questions in a particular way. In particular, the use of appropriate genetic model organisms provides a wealth of technologies (of which microarrays and knock-outs are but two) that allow a new precision in physiological analysis. We illustrate this approach with an epithelial model system, the Malpighian (renal) tubule of Drosophila melanogaster. With the use of the beautiful genetic tools and extensive genomic resources characteristic of this genetic model, it has been possible to gain unique insights into the structure, function, and control of epithelia.
Efficient Resource Scheduling by Exploiting Relay Cache for Cellular Networks
Authors: He Chun , Cui Haixia , Feng Gang
Published: March 2015

In relay-enhanced cellular systems, throughput of User Equipment (UE) is constrained by the bottleneck of the two-hop link, backhaul link (or the first hop link), and access link (the second hop link). To maximize the throughput, resource allocation should be coordinated between these two hops. A common resource scheduling algorithm, Adaptive Distributed Proportional Fair, only ensures that the throughput of the first hop is greater than or equal to that of the second hop. But it cannot guarantee a good balance of the throughput and fairness between the two hops. In this paper, we propose a Two-Hop Balanced Distributed Scheduling (TBS) algorithm by exploiting relay cache for non-real-time data traffic. The evolved Node Basestation (eNB) adaptively adjusts the number of Resource Blocks (RBs) allocated to the backhaul link and direct links based on the cache information of relays. Each relay allocates RBs for relay UEs based on the size of the relay UE’s Transport Block. We also design a relay UE’s ACK feedback mechanism to update the data at relay cache. Simulation results show that the proposed TBS can effectively improve resource utilization and achieve a good trade-off between system throughput and fairness by balancing the throughput of backhaul and access link.
Enhancement of the Acrolein-Induced Production of Reactive Oxygen Species and Lung Injury by GADD34
Authors: Sun Yang , Ito Sachiko , Nishio Naomi , Tanaka Yuriko , Chen Nana , Liu Lintao , Isobe Ken-ichi
Published: March 2015

Chronic obstructive pulmonary disease (COPD) is characterized by lung destruction and inflammation. As a major compound of cigarette smoke, acrolein plays a critical role in the induction of respiratory diseases. GADD34 is known as a growth arrest and DNA damage-related gene, which can be overexpressed in adverse environmental conditions. Here we investigated the effects of GADD34 on acrolein-induced lung injury. The intranasal exposure of acrolein induced the expression of GADD34, developing the pulmonary damage with inflammation and increase of reactive oxygen species (ROS). Conversely, the integrality of pulmonary structure was preserved and the generation of ROS was reduced in GADD34-knockout mice. Acrolein-induced phosphorylation of eIF2αin GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress. These data indicate that GADD34 participates in the development of acrolein-induced lung injury.
An Open-Label Uncontrolled, Multicenter Study for the Evaluation of the Efficacy and Safety of the Dermal Filler Princess VOLUME in the Treatment of Nasolabial Folds
Authors: Kopera Daisy , Palatin Michael , Bartsch Rolf , Bartsch Katrin , O’Rourke Maria , Höller Sonja , Baumgartner Renate R. , Prinz Martin
Published: March 2015

The dermal filler Princess VOLUME is a highly cross-linked, viscoelastic hyaluronic acid injectable gel implant used for aesthetic treatment. To evaluate the efficacy and safety of Princess VOLUME in the treatment of nasolabial folds, an open-label uncontrolled, multicenter study was conducted. Forty-eight subjects were recruited who had moderate to deep wrinkles, according to the Modified Fitzpatrick Wrinkle Scale (MFWS). Subjects received Princess VOLUME in both nasolabial folds at Day 0. Nasolabial fold severity was evaluated at 30, 90, 180, and 270 days after treatment, using the MFWS and the Global Aesthetic Improvement Scale (GAIS). Adverse events and treatment site reactions were recorded. Among the 48 subjects, 93.8% were female with a median age of 52 years. There were significant improvements(P<0.0001)in the MFWS scores at 30, 180, and 270 days after treatment compared with those at baseline, with a mean decrease of 1.484 (±0.408), 1.309 (±0.373), and 1.223 (±0.401), respectively; hence the primary endpoint was achieved and clinical efficacy demonstrated. Princess VOLUME was well tolerated, and most adverse events were injection site reactions of mild to moderate severity. Subject satisfaction (97.9%), subject recommendation of the treatment (93.6%), and investigators GAIS scores (97.9% improvement) were high.
Combined Epidermal Growth Factor Receptor and Beclin1 Autophagic Protein Expression Analysis Identifies Different Clinical Presentations, Responses to Chemo- and Radiotherapy, and Prognosis in Glioblastoma
Authors: Tini Paolo , Belmonte Giuseppe , Toscano Marzia , Miracco Clelia , Palumbo Silvia , Pastina Pierpaolo , Battaglia Giuseppe , Nardone Valerio , Butorano Marie Aimée Gloria Munezero , Masucci Armando , Cerase Alfonso , Pirtoli Luigi
Published: March 2015

Dysregulated EGFR in glioblastoma may inactivate the key autophagy protein Beclin1. Each of high EGFR and low Beclin1 protein expression, independently, has been associated with tumor progression and poor prognosis. High (H) compared to low (L) expression of EGFR and Beclin1 is here correlated with main clinical data in 117 patients after chemo- and radiotherapy. H-EGFR correlated with low Karnofsky performance and worse neurological performance status, higher incidence of synchronous multifocality, poor radiological evidence of response, shorter progression disease-free (PDFS), and overall survival (OS). H-Beclin1 cases showed better Karnofsky performance status, higher incidence of objective response, longer PDFS, and OS. A mutual strengthening effect emerges in correlative power of stratified L-EGFR and H-Beclin1 expression with incidence of radiological response after treatment, unifocal disease, and better prognosis, thus identifying an even longer OS group (30 months median OS compared to 18 months in L-EGFR, 15 months in H-Beclin1, and 11 months in all GBs) (P=0.0001). Combined L-EGFR + H-Beclin1 expression may represent a biomarker in identifying relatively favorable clinical presentations and prognosis, thus envisaging possible EGFR/Beclin1-targeted therapies.
A Low-Dose Combination of Fluvastatin and Valsartan: A New “Drug” and a New Approach for Decreasing the Arterial Age
Authors: Janić Miodrag , Lunder Mojca , Šabovič Mišo
Published: March 2015

We have developed a new “drug” and approach that appear to be effective in reducing arterial age. This “drug” represents a low, subtherapeutic dose of statin and sartan and particularly their low-dose combination. The improvement of arterial wall characteristics, also reflecting in a decrease of arterial age, was achieved after a short period of treatment (one month) with the above-mentioned drugs. In addition, we have also implemented a new, innovative therapeutic approach, consisting of intermittent (cyclic) treatment—alternating short “treatment” periods and much longer “rest” periods (when the beneficial effects are still present but gradually decline). This new “drug” and approach both merit further investigation in order to confirm their antiaging efficacy.