bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasticity in the Visual System Is Correlated With a Change in Lifestyle of Solitarious and Gregarious Locusts
Authors: Matheson Thomas , Rogers Stephen M. , Krapp Holger G.
Published: January 2004

We demonstrate pronounced differences in the visual system of a polyphenic locust species that can change reversibly between two forms (phases), which vary in morphology and behavior. At low population densities, individuals of Schistocerca gregaria develop into the solitarious phase, are cryptic, and tend to avoid other locusts. At high densities, individuals develop instead into the swarm-forming gregarious phase. We analyzed in both phases the responses of an identified visual interneuron, the descending contralateral movement detector (DCMD), which responds to approaching objects. We demonstrate that habituation of DCMD is fivefold stronger in solitarious locusts. In both phases, the mean time of peak firing relative to the time to collision nevertheless occurs with a similar characteristic delay after an approaching object reaches a particular angular extent on the retina. Variation in the time of peak firing is greater in solitarious locusts, which have lower firing rates. Threshold angle and delay are therefore conserved despite changes in habituation or behavioral phase state. The different rates of habituation should contribute to different predator escape strategies or flight control for locusts living either in a swarm or as isolated individuals. For example, increased variability in the habituated responses of solitarious locusts should render their escape behaviors less predictable. Relative resistance to habituation in gregarious locusts should permit the continued responsiveness required to avoid colliding with other locusts in a swarm. These results will permit us to analyze neuronal plasticity in a model system with a well-defined and controllable behavioral context.
Transmitter Metabolism as a Mechanism of Synaptic Plasticity: A Modeling Study
Authors: Axmacher Nikolai , Stemmler Martin , Engel Dominique , Draguhn Andreas , Ritz Raphael
Published: January 2004

The nervous system adapts to experience by changes in synaptic strength. The mechanisms of synaptic plasticity include changes in the probability of transmitter release and in postsynaptic responsiveness. Experimental and neuropharmacological evidence points toward a third variable in synaptic efficacy: changes in presynaptic transmitter concentration. Several groups, including our own, have reported changes in the amplitude and frequency of postsynaptic (miniature) events indicating that alterations in transmitter content cause alterations in vesicular transmitter content and vesicle dynamics. It is, however, not a priori clear how transmitter metabolism will affect vesicular transmitter content and how this in turn will affect pre- and postsynaptic functions. We therefore have constructed a model of the presynaptic terminal incorporating vesicular transmitter loading and the presynaptic vesicle cycle. We hypothesize that the experimentally observed synaptic plasticity after changes in transmitter metabolism puts predictable restrictions on vesicle loading, cytoplasmic–vesicular transmitter concentration gradient, and on vesicular cycling or release. The results of our model depend on the specific mechanism linking presynaptic transmitter concentration to vesicular dynamics, that is, alteration of vesicle maturation or alteration of release. It also makes a difference whether differentially filled vesicles are detected and differentially processed within the terminal or whether vesicle filling acts back onto the terminal by presynaptic autoreceptors. Therefore, the model allows one to decide, at a given synapse, how transmitter metabolism is linked to presynaptic function and efficacy.
Activity of Neurons in Cortical Area MT During a Memory for Motion Task
Authors: Bisley James W. , Zaksas Daniel , Droll Jason A. , Pasternak Tatiana
Published: January 2004

We recorded the activity of middle temporal (MT) neurons in 2 monkeys while they compared the directions of motion in 2 sequentially presented random-dot stimuli, sample and test, and reported them as the same or different by pressing one of 2 buttons. We found that MT neurons were active not only in response to the sample and test stimuli but also during the 1,500-ms delay separating them. Most neurons showed a characteristic pattern of activity consisting of a small burst of firing early in the delay, followed by a period of suppression and a subsequent increase in firing rate immediately preceding the presentation of the test stimulus. In a third of the neurons, the activity early in the delay not only reflected the direction of the sample stimulus, but was also related to the range of local directions it contained. During the middle of the delay the majority of neurons were suppressed, consistent with a gating mechanism that could be used to ignore task-irrelevant stimuli. Late in the delay, most neurons showed an increase in response, probably in anticipation of the upcoming test. Throughout most of the delay there was a directional signal in the population of MT neurons, manifested by higher firing rates following the sample moving in the antipreferred direction. Whereas some of these effects may be related to sensory adaptation, others are more likely to represent a more active task-related process. These results support the hypothesis that MT neurons actively participate in the successful execution of all aspects of the task requiring processing and remembering visual motion.
Neuronal Activity in the Supplementary Motor Area of Monkeys Adapting to a New Dynamic Environment
Authors: Padoa-Schioppa Camillo , Li Chiang-Shan Ray , Bizzi Emilio
Published: January 2004

To execute visually guided reaching movements, the central nervous system (CNS) must transform a desired hand trajectory (kinematics) into appropriate muscle-related commands (dynamics). It has been suggested that the CNS might face this challenging computation by using internal forward models for the dynamics. Previous work in humans found that new internal models can be acquired through experience. In a series of studies in monkeys, we investigated how neurons in the motor areas of the frontal lobe reflect the movement dynamics and how their activity changes when monkeys learn a new internal model. Here we describe the results for the supplementary motor area (SMA-proper, or SMA). In the experiments, monkeys executed visually guided reaching movements and adapted to an external perturbing force field. The experimental design allowed dissociating the neuronal activity related to movement dynamics from that related to movement kinematics. It also allowed dissociating the changes related to motor learning from the activity related to motor performance (kinematics and dynamics). We show that neurons in SMA reflect the movement dynamics individually and as a population, and that their activity undergoes a variety of plastic changes when monkeys adapt to a new dynamic environment.
Temperature-Induced Reciprocal Activation of Hippocampal Field Activity
Authors: Karlsson Karl Æ. , Blumberg Mark S.
Published: January 2004

Hippocampal network activity oscillates between sustained rhythms (e.g., theta) and aperiodic population spikes (e.g., sharp waves, dentate spikes). Although temperature is known to modulate various aspects of rhythmic hippocampal activity, little is known regarding the influence of temperature on the incidence of population spikes. We recorded spontaneous hippocampal activity along the CA1-dentate gyrus axis using multisite silicon electrodes in urethanized infant rats (P2-P16) at brain temperatures of 37 and 27°C. Theta and gamma activity, as well as sharp waves, were detected at 37°C but not at 27°C. In contrast, dentate spikes were rare at 37°C but their incidence increased several-fold at 27°C (epileptiform activity also emerged at 27°C in the oldest pups). This surprising increase in the incidence of dentate spike activity in a cold brain represents the first such demonstration for a neuronal field pattern. In addition, these findings indicate that changes in brain temperature produce systems-level shifts in the balance among reciprocally interacting hippocampal components.
On Heat and Cells and Proteins
Authors: Katschinski Dörthe M.
Published: January 2004

Two principal forms of temperature-control strategies have evolved, i.e., poikilothermic and homeothermic life. Even in homeothermic animals, the temperature field of the body is not homogenous. These observed temperature differences can affect cellular function directly or via the expression of heat shock or cold shock proteins.
Proteoglycans and Brain Repair
Authors: Properzi Francesca , Fawcett James W.
Published: January 2004

Proteoglycans are complex molecules composed of long, unbranched sugar chains attached to a protein core. In the mammalian central nervous system, they are a major component of the extracellular matrix and of the cellular surface. After a central nervous system injury, their expression in the lesion area changes strongly and contributes to the inhibition of axon regrowth and brain repair.
Selectins Facilitate Carcinoma Metastasis and Heparin Can Prevent Them
Authors: Borsig Lubor
Published: January 2004

Selectins are cell adhesion molecules mediating attachment of leukocytes to activated endothelium as well as the adhesion reaction of tumors during malignancy. Heparin, which is known to attenuate metastasis, is a potent blocker of selectins. Here, the role of selectins in metastasis and the potential of heparin to modulate malignancy are discussed.
Why Do We Not All Have Proteinuria? An Update of Our Current Understanding of the Glomerular Barrier
Authors: Haraldsson Börje , Sörensson Jenny
Published: January 2004

The key question is not why some patients have proteinuria but rather why not all people have it. In the present review, we will present an update on the glomerular barrier after the recent breakthroughs in podocyte biology. In particular, we will discuss the role of the endothelium, which seems to be a neglected part of the glomerular membrane.
Hypothalamic and Midbrain Circuitry That Distinguishes Between Escapable and Inescapable Pain
Authors: Lumb Bridget M.
Published: January 2004

Characteristics of emotional, behavioral, and physiological responses to pain are determined to a large extent by the behavioral significance of the pain, in particular to the degree to which the pain can be escaped. This review presents evidence that these different patterns of response depend on the activation of distinct pathways within the brain.
The Physiological Regulation of Thirst and Fluid Intake
Authors: McKinley Michael J. , Johnson Alan Kim
Published: January 2004

Thirst is important for maintaining body fluid homeostasis and may arise from deficits in either intracellular or extracellular fluid volume. Neural signals arising from osmotic and hormonal influences on the lamina terminalis may be integrated within the brain, with afferent information relayed from intrathoracic baroreceptors via the hindbrain to generate thirst.
Quantitative trait loci for maximal exercise capacity phenotypes and their responses to training in the HERITAGE Family Study
Authors: Rico-Sanz J. , Rankinen T. , Rice T. , Leon A. S. , Skinner J. S. , Wilmore J. H. , Rao D. C. , Bouchard C.
Published: January 2004

The purpose of this study was to identify regions of the human genome linked to maximal oxygen uptake (V̇o2 max) and maximal power output (MPO), and their response to a standardized 20-wk endurance-training program in sedentary black and white subjects. A total of 509 polymorphic markers covering the 22 autosomes were used in the genome-wide linkage scan. Baseline phenotypes were adjusted for age, sex, and body mass, whereas the training responses were adjusted for age, sex, and the baseline values. Regression-based single- and multipoint linkage analyses were used. In the sedentary state, a total of 351 and 102 sibling pairs were available for whites and blacks, respectively, and 329 and 90 sibling pairs, respectively, for the training response phenotypes. Baseline V̇o2 maxshowed promising linkage ( P < 0.0023) with 11p15.1 (whites), and suggestive evidence of linkage (0.01 > P > 0.0023) was found on 1p31, 7q32, and 7q36 (blacks). Baseline MPO exhibited promising linkage on 10q23 and suggestive evidence of linkage on 13q33 and 18q11-q12 (whites). V̇o2 maxtraining response yielded promising linkages with markers on 1p31 (blacks) and suggestive on 4q27, 7q34, and 13q12 (whites) and on 16q22 and 20q13.1 (blacks). Training-induced changes in MPO showed promising linkages on 5q23 (whites) and suggestive on 1q21, 4p15.1, and 4p13 (whites) and on 1q22 and 13q11 (blacks). In conclusion, the strongest evidence of linkage was found on chromosomal regions 11p15 and 10q23 for V̇o2 maxand MPO in the sedentary state and on chromosomes 1p31 and 5q23 for their responsiveness to training. These chromosomal regions harbor several candidate genes that deserve further investigation.
Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter
Authors: Dangond Fernando , Hwang Daehee , Camelo Sandra , Pasinelli Piera , Frosch Matthew P. , Stephanopoulos Gregory , Stephanopoulos George , Brown Robert H. , Gullans Steven R.
Published: January 2004

Little is known about global gene expression patterns in the human neurodegenerative disease amyotrophic lateral sclerosis (ALS). To address this, we used high-density oligonucleotide microarray technology to compare expression levels of ∼6,800 genes in postmortem spinal cord gray matter obtained from individuals with ALS as well as normal individuals. Using Fisher discriminant analysis (FDA) and leave-one-out cross-validation (LOOCV), we discerned an ALS-specific signature. Moreover, it was possible to distinguish familial ALS (FALS) from sporadic ALS (SALS) gene expression profiles. Characterization of the specific genes significantly altered in ALS uncovered a pro-inflammatory terminal state. Moreover, we found alterations in genes involved in mitochondrial function, oxidative stress, excitotoxicity, apoptosis, cytoskeletal architecture, RNA transcription and translation, proteasomal function, and growth and signaling. It is apparent from this study that DNA microarray analysis and appropriate bioinformatics can reveal distinct phenotypic changes that underlie the terminal stages of neurodegeneration in ALS.
Metabolic and transcriptional patterns accompanying glutamine depletion and repletion in mouse hepatoma cells: a model for physiological regulatory networks
Authors: Wong Matthew S. , Raab R. Michael , Rigoutsos Isidore , Stephanopoulos Gregory N. , Kelleher Joanne K.
Published: January 2004

An important objective in postgenomic biology is to link gene expression to function by developing physiological networks that include data from the genomic and functional levels. Here, we develop a model for the analysis of time-dependent changes in metabolites, fluxes, and gene expression in a hepatic model system. The experimental framework chosen was modulation of extracellular glutamine in confluent cultures of mouse Hepa1-6 cells. The importance of glutamine has been demonstrated previously in mammalian cell culture by precipitating metabolic shifts with glutamine depletion and repletion. Our protocol removed glutamine from the medium for 24 h and returned it for a second 24 h. Flux assays of glycolysis, the tricarboxylic acid (TCA) cycle, and lipogenesis were used at specified intervals. All of these fluxes declined in the absence of glutamine and were restored when glutamine was repleted. Isotopomer spectral analysis identified glucose and glutamine as equal sources of lipogenic carbon. Metabolite measurements of organic acids and amino acids indicated that most metabolites changed in parallel with the fluxes. Experiments with actinomycin D indicated that de novo mRNA synthesis was required for observed flux changes during the depletion/repletion of glutamine. Analysis of gene expression data from DNA microarrays revealed that many more genes were anticorrelated with the glycolytic flux and glutamine level than were correlated with these indicators. In conclusion, this model may be useful as a prototype physiological regulatory network where gene expression profiles are analyzed in concert with changes in cell function.
Growth hormone-mediated alteration of fuel metabolism in the aged rat as determined from transcript profiles
Authors: Tollet-Egnell Petra , Parini Paolo , Ståhlberg Nina , Lönnstedt Ingrid , Lee Norman H. , Rudling Mats , Flores-Morales Amilcar , Norstedt Gunnar
Published: January 2004

Age-related changes in body composition and serum lipids resemble symptoms of adult-onset growth hormone (GH) deficiency. GH treatment has been shown to normalize these changes in both GH-deficient adult patients and elderly subjects. The aim of this study was to identify GH-responsive genes that might mediate positive effects of GH treatment on fuel metabolism and body composition. cDNA microarrays were used to analyze age- and GH-induced changes in gene expression patterns in male rats. Tissues analyzed were liver, adipose tissue, and skeletal muscle from animals on or off GH treatment. A value of 1.5 was chosen to denote differences (increased or decreased expression) in the level of mRNA expression. In the liver, 7.3% of the expressed genes were affected by age and 6.5% by GH. Similar values for the other tissues were 8.3% and 5.3% (fat), and 7.9% and 9.6% (muscle), respectively. Among the differentially expressed genes, we identified several that encode proteins involved in fuel metabolism. Old rats were shown to have induced expression of genes involved in hepatic glucose oxidation and lipid synthesis, whereas these pathways were reduced in adipose tissue. GH treatment induced the expression of genes for lipid oxidation in liver and for glucose oxidation in skeletal muscle. In adipose tissue, GH reduced the expression of genes involved in lipogenesis even further. Changes in transcript levels were reflected in serum in terms of altered lipid profiles. Serum levels of triglycerides, high-density lipoprotein (HDL) cholesterol, and total cholesterol were higher in the old animals than in the young and normalized by GH treatment.
Nutritional genomics: the next frontier in the postgenomic era
Authors: Kaput Jim , Rodriguez Raymond L.
Published: January 2004

The interface between the nutritional environment and cellular/genetic processes is being referred to as “nutrigenomics.” Nutrigenomics seeks to provide a molecular genetic understanding for how common dietary chemicals (i.e., nutrition) affect health by altering the expression and/or structure of an individual’s genetic makeup. The fundamental concepts of the field are that the progression from a healthy phenotype to a chronic disease phenotype must occur by changes in gene expression or by differences in activities of proteins and enzymes and that dietary chemicals directly or indirectly regulate the expression of genomic information. We present a conceptual basis and specific examples for this new branch of genomic research that focuses on the tenets of nutritional genomics: 1) common dietary chemicals act on the human genome, either directly or indirectly, to alter gene expression or structure; 2) under certain circumstances and in some individuals, diet can be a serious risk factor for a number of diseases; 3) some diet-regulated genes (and their normal, common variants) are likely to play a role in the onset, incidence, progression, and/or severity of chronic diseases; 4) the degree to which diet influences the balance between healthy and disease states may depend on an individual’s genetic makeup; and 5) dietary intervention based on knowledge of nutritional requirement, nutritional status, and genotype (i.e., “individualized nutrition”) can be used to prevent, mitigate, or cure chronic disease.
Microarray analysis of gene expression in blood neutrophils of parturient cows
Authors: Madsen Sally A. , Chang Ling-Chu , Hickey Mary-Clare , Rosa Guilherme J. M. , Coussens Paul M. , Burton Jeanne L.
Published: January 2004

It is well documented that blood neutrophils from parturient dairy cows do not perform as well as neutrophils from nonparturient cows in laboratory assays of adhesion, migration, or phagocytosis-induced respiratory burst. However, little is known about the possible molecular basis for parturition-induced changes in neutrophils. cDNA microarray analysis was used in the current study to explore parturition-induced changes in gene expression profiles in bovine blood neutrophils. Total RNA from isolated blood neutrophils of four parturient Holstein cows was obtained before, during, and after parturition, reverse transcribed into cDNA, and sequentially labeled with Cy3 or Cy5 dyes prior to paired hybridizations to 1,056 member bovine total leukocyte (BOTL-3) microarrays in a loop design. Resulting gene expression data were LOWESS normalized by array and analyzed using a mixed model approach. Results showed that expression profiles for 302 BOTL-3 genes were influenced by parturition. BLASTn analysis and preliminary clustering of affected genes by biological function indicated that the largest proportion (14%) of changed genes encode proteins critical to regulation of apoptosis. Independent confirmation of altered expression for 16 of these genes was achieved using quantitative real-time RT-PCR (Q-RT-PCR). A predominantly survival phenotype inferred from the microarray and Q-RT-PCR results was substantiated by monitoring apoptosis status of blood neutrophils from castrated male cattle cultured in the presence of sera from parturient cows. Thus our combined gene expression and apoptosis phenotyping results suggest that bovine parturition may induce prolonged survival in normally short-lived blood neutrophils.
Altered mRNA abundance of ASB15 and four other genes in skeletal muscle following administration of β-adrenergic receptor agonists
Authors: McDaneld Tara G. , Hancock Deana L. , Moody Diane E.
Published: January 2004

β-Adrenergic receptor agonists (BA) stimulate skeletal muscle growth. However, downstream signaling pathways that facilitate this effect remain poorly defined. Objectives of this study were to identify genes differentially expressed after administration of a novel BA and to evaluate the expression of one of those genes in additional models of skeletal muscle growth. Differentially expressed gene fragments were identified through differential display of skeletal muscle biopsies from five steers 24 h after administration of the BA. Five gene fragments designated DD53, DD143, DD163, DD209, and DD214 were identified. Tissue distribution of these genes was evaluated by RT-PCR. While DD53, DD163, DD209, and DD214 were expressed across tissues, DD143 mRNA expression was most abundant in skeletal muscle. DD143, later identified as bovine ASB15, was evaluated in rats following administration of anabolic compounds. Thirteen 7-wk-old female rats were randomly assigned to each of four treatment groups including: control, clenbuterol, trenbolone acetate (TBA), and growth hormone (GH). Changes in rat Asb-15 mRNA were measured at 30 min, 12 h, and 24 h following intraperitoneal injections of each compound. Clenbuterol treatment decreased Asb-15 mRNA in skeletal muscle at 12 and 24 h ( P < 0.01) and also decreased mRNA in lung at 12 h ( P < 0.05). TBA and GH treatments did not alter Asb-15 mRNA in any of the tissues evaluated ( P > 0.10). These results are the first to associate an Asb gene family member with muscle growth or BA administration and suggest a potential role for ASB15 in β-agonist-induced skeletal muscle hypertrophy.
Influence of diet and genetics on hypertension and renal disease in Dahl salt-sensitive rats
Authors: Mattson David L. , Kunert Mary Pat , Kaldunski Mary L. , Greene Andrew S. , Roman Richard J. , Jacob Howard J. , Cowley Allen W.
Published: January 2004

Experiments examined the influence of diet and genetics on hypertension and renal disease in inbred Dahl salt-sensitive (SS/Mcw) rats and consomic rats in which chromosomes 16 (SS.BN16) or 18 (SS.BN18) of the normotensive Brown Norway rat were inserted into the genetic background of the SS/Mcw. Dahl SS/Mcw breeders and offspring were randomly placed on a purified AIN-76A diet or a grain-based diet, and male offspring were screened for cardiovascular and renal phenotypes following 3 wk on a 4.0% NaCl diet. High-salt arterial blood pressure (162 ± 5 mmHg, n = 10), urinary protein excretion (147 ± 16 mg/day, n = 14), and albumin excretion (72 ± 9 mg/day, n = 14) were significantly elevated in the Dahl SS/Mcw maintained on the purified diet compared with rats fed the grain-based diet. Rats fed the purified diet also exhibited significantly more renal glomerular and tubular damage than rats fed the grain diet. Moreover, feeding the purified diet to the parents led to a significant increase in blood pressure in the offspring, regardless of offspring diet. Similar dietary effects were observed in SS.BN16 and SS.BN18 rats. In rats fed the purified diet, substitution of chromosomes 16 or 18 led to a significant decrease in arterial blood pressure, albumin excretion, and protein excretion compared with the SS/Mcw. Chromosomal substitution did not, however, affect albumin or protein excretion in the consomic rats compared with the SS/Mcw when the rats were maintained on the grain diet. These data demonstrate a significant influence of diet composition on salt-induced hypertension and renal disease in the Dahl SS/Mcw rat.
Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins
Authors: Wright Jerry M. , Zeitlin Pamela L. , Cebotaru Liudmila , Guggino Sandra E. , Guggino William B.
Published: January 2004

Most individuals with cystic fibrosis (CF) carry one or two mutations that result in a maturation defect of the full-length CFTR protein. The ΔF508 mutation results in a mutant protein that is degraded by the proteosome instead of progressing to the apical membrane where it functions as a cAMP-regulated chloride channel. 4-Phenylbutyrate (PBA) modulates heat-shock protein expression and promotes trafficking of ΔF508, thus permitting maturation and membrane insertion. The goal of this study was to gain insight into the genetic mechanism of PBA action through a large-scale analysis of gene expression. The Affymetrix genome-spanning U133 microarray set was used to compare mRNA expression levels in untreated IB3-1 cell line cultures with cultures treated with 1 mM PBA for 12 and 24 h. The most notable changes in mRNA levels were transient elevations in heat-shock proteins. The majority of genes downregulated throughout the application period were functionally associated with control of gene expression. Another set of genes increased in expression starting at 24 h, suggesting these are downstream effects of altered gene expression initiated by PBA. More than one-third of the genes in this late expressing set were identified as having potential significance in understanding the pathology of CF. Our results demonstrate the usefulness of gene expression profile analysis in understanding the consequences of PBA treatment and provide insights in how this drug exerts its effect on the trafficking of CFTR.
A survey of genetic and epigenetic variation affecting human gene expression
Authors: Pastinen Tomi , Sladek Robert , Gurd Scott , Sammak Alya’a , Ge Bing , Lepage Pierre , Lavergne Karine , Villeneuve Amelie , Gaudin Tiffany , Brändström Helena , Beck Allon , Verner Andrei , Kingsley Jade , Harmsen Eef , Labuda Damian , Morgan Kenneth , Vohl Marie-Claude , Naumova Anna K. , Sinnett Daniel , Hudson Thomas J.
Published: January 2004

The identification of human sequence polymorphisms that regulate gene expression is key to understanding human genetic diseases. We report a survey of human genes that demonstrate allelic differences in gene expression, reflecting the presence of putative allele-specific cis-acting factors of either genetic or epigenetic nature. The expression of allelic transcripts in heterozygous samples is assessed directly by relative quantitation of intragenic marker alleles in messenger or heteronuclear RNA derived from cells or tissues. This survey used 193 single-nucleotide polymorphisms (SNPs) from 129 genes expressed in lymphoblastoid cell lines, to identify 23 genes (18%) with common allele-specific transcripts whose expression deviated from the expected equimolar ratio. A subset of these deviations, or “allelic imbalances,” can be observed in multiple samples derived from reference CEPH (“Centre d’Etude du Polymorphisme Humain”) pedigrees and demonstrate a spectrum of patterns of transmission, including cosegregation of allelic skewing across generations compatible with Mendelian inheritance as well as random monoallelic expression for three genes ( IL1A, HTR2A, and FGB). Additional studies for BTN3A2 provide evidence of SNPs and haplotypes in complete linkage disequilibrium with high- and low-expressing transcripts. The pipeline described herein offers tools for efficient identification and characterization of allelic expression allowing identification of regulatory sequence variants as well as epigenetic variation affecting human gene expression.
Developmental changes in the fetal pig transcriptome
Authors: Wesolowski Stephanie R. , Raney Nancy E. , Ernst Catherine W.
Published: January 2004

Growth and development of pig fetuses is dependent on the coordinated expression of multiple genes. Between 21 and 45 days of gestation, fetuses experience increasing growth rates that can result in uterine crowding and increased mortality. We used differential display reverse transcription-PCR (DDRT-PCR) to identify differentially expressed genes in pig fetuses at 21, 35, and 45 days of gestation. Pig cDNAs were identified with homologies to CD3 γ-subunit, collagen type XIV α1, complement component C6, craniofacial developmental protein 1, crystallin-γE, DNA binding protein B, ε-globin, formin binding protein 2, ribosomal protein L23, small acidic protein, secreted frizzled related protein 2, titin, vitamin D binding protein, and two hypothetical protein products. Two novel expressed sequence tags (ESTs) were also identified. Expression patterns were confirmed for eight genes, and spatiotemporal expression of three genes was evaluated. We identified novel transcriptome changes in fetal pigs during a period of rapid growth. These changes involved genes with a spectrum of proposed functions, including musculoskeletal growth, immune system function, and cellular regulation. This information can ultimately be used to enhance production efficiency through improved pig growth and survival.
Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button
Authors: CEULEMANS HUGO , BOLLEN MATHIEU
Published: January 2004

Ceulemans, Hugo, and Mathieu Bollen. Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button. Physiol Rev 84: 1–39, 2004; 10.1152/physrev.00013.2003.—The protein serine/threonine phosphatase protein phosphatase-1 (PP1) is a ubiquitous eukaryotic enzyme that regulates a variety of cellular processes through the dephosphorylation of dozens of substrates. This multifunctionality of PP1 relies on its association with a host of function-specific targetting and substrate-specifying proteins. In this review we discuss how PP1 affects the biochemistry and physiology of eukaryotic cells. The picture of PP1 that emerges from this analysis is that of a “green” enzyme that promotes the rational use of energy, the recycling of protein factors, and a reversal of the cell to a basal and/or energy-conserving state. Thus PP1 promotes a shift to the more energy-efficient fuels when nutrients are abundant and stimulates the storage of energy in the form of glycogen. PP1 also enables the relaxation of actomyosin fibers, the return to basal patterns of protein synthesis, and the recycling of transcription and splicing factors. In addition, PP1 plays a key role in the recovery from stress but promotes apoptosis when cells are damaged beyond repair. Furthermore, PP1 downregulates ion pumps and transporters in various tissues and ion channels that are involved in the excitation of neurons. Finally, PP1 promotes the exit from mitosis and maintains cells in the G1or G2phases of the cell cycle.
Long-Term Potentiation and Memory
Authors: LYNCH M. A.
Published: January 2004

Lynch, MA. Long-Term Potentiation and Memory. Physiol Rev 84: 87–136, 2004; 10.1152/physrev.00014.2003.—One of the most significant challenges in neuroscience is to identify the cellular and molecular processes that underlie learning and memory formation. The past decade has seen remarkable progress in understanding changes that accompany certain forms of acquisition and recall, particularly those forms which require activation of afferent pathways in the hippocampus. This progress can be attributed to a number of factors including well-characterized animal models, well-defined probes for analysis of cell signaling events and changes in gene transcription, and technology which has allowed gene knockout and overexpression in cells and animals. Of the several animal models used in identifying the changes which accompany plasticity in synaptic connections, long-term potentiation (LTP) has received most attention, and although it is not yet clear whether the changes that underlie maintenance of LTP also underlie memory consolidation, significant advances have been made in understanding cell signaling events that contribute to this form of synaptic plasticity. In this review, emphasis is focused on analysis of changes that occur after learning, especially spatial learning, and LTP and the value of assessing these changes in parallel is discussed. The effect of different stressors on spatial learning/memory and LTP is emphasized, and the review concludes with a brief analysis of the contribution of studies, in which transgenic animals were used, to the literature on memory/learning and LTP.
Brown Adipose Tissue: Function and Physiological Significance
Authors: CANNON BARBARA , NEDERGAARD JAN
Published: January 2004

Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.
Neuroendocrine Control of Body Fluid Metabolism
Authors: ANTUNES-RODRIGUES JOSÉ , DE CASTRO MARGARET , ELIAS LUCILA L. K. , VALENÇA MARCELO M. , McCANN SAMUEL M.
Published: January 2004

Antunes-Rodrigues, José, Margaret de Castro, Lucila L. K. Elias, Marcelo M. Valença, and Samuel M. McCann. Neuroendocrine Control of Body Fluid Metabolism. Physiol Rev 84: 169–208, 2004; 10.1152/physrev.00017.2003.—Mammals control the volume and osmolality of their body fluids from stimuli that arise from both the intracellular and extracellular fluid compartments. These stimuli are sensed by two kinds of receptors: osmoreceptor-Na+receptors and volume or pressure receptors. This information is conveyed to specific areas of the central nervous system responsible for an integrated response, which depends on the integrity of the anteroventral region of the third ventricle, e.g., organum vasculosum of the lamina terminalis, median preoptic nucleus, and subfornical organ. The hypothalamo-neurohypophysial system plays a fundamental role in the maintenance of body fluid homeostasis by secreting vasopressin and oxytocin in response to osmotic and nonosmotic stimuli. Since the discovery of the atrial natriuretic peptide (ANP), a large number of publications have demonstrated that this peptide provides a potent defense mechanism against volume overload in mammals, including humans. ANP is mostly localized in the heart, but ANP and its receptor are also found in hypothalamic and brain stem areas involved in bodyfluid volume and blood pressure regulation. Blood volume expansion acts not only directly on the heart, by stretch of atrial myocytes to increase the release of ANP, but also on the brain ANPergic neurons through afferent inputs from baroreceptors. Angiotensin II also plays an important role in the regulation of body fluids, being a potent inducer of thirst and, in general, antagonizes the actions of ANP. This review emphasizes the role played by brain ANP and its interaction with neurohypophysial hormones in the control of body fluid homeostasis.
Cellular and Molecular Regulation of Muscle Regeneration
Authors: CHARGÉ SOPHIE B. P. , RUDNICKI MICHAEL A.
Published: January 2004

Chargé, Sophie B. P., and Michael A. Rudnicki. Cellular and Molecular Regulation of Muscle Regeneration. Physiol Rev 84: 209–238, 2004; 10.1152/physrev.00019.2003.—Under normal circumstances, mammalian adult skeletal muscle is a stable tissue with very little turnover of nuclei. However, upon injury, skeletal muscle has the remarkable ability to initiate a rapid and extensive repair process preventing the loss of muscle mass. Skeletal muscle repair is a highly synchronized process involving the activation of various cellular responses. The initial phase of muscle repair is characterized by necrosis of the damaged tissue and activation of an inflammatory response. This phase is rapidly followed by activation of myogenic cells to proliferate, differentiate, and fuse leading to new myofiber formation and reconstitution of a functional contractile apparatus. Activation of adult muscle satellite cells is a key element in this process. Muscle satellite cell activation resembles embryonic myogenesis in several ways including the de novo induction of the myogenic regulatory factors. Signaling factors released during the regenerating process have been identified, but their functions remain to be fully defined. In addition, recent evidence supports the possible contribution of adult stem cells in the muscle regeneration process. In particular, bone marrow-derived and muscle-derived stem cells contribute to new myofiber formation and to the satellite cell pool after injury.
ConusVenoms: A Rich Source of Novel Ion Channel-Targeted Peptides
Authors: TERLAU HEINRICH , OLIVERA BALDOMERO M.
Published: January 2004

Terlau, Heinrich, and Baldomero M. Olivera. Conus Venoms: A Rich Source of Novel Ion Channel-Targeted Peptides. Physiol Rev 84: 41–68, 2004; 10.1152/physrev.00020.2003.—The cone snails (genus Conus) are venomous marine molluscs that use small, structured peptide toxins (conotoxins) for prey capture, defense, and competitor deterrence. Each of the 500 Conus can express ∼100 different conotoxins, with little overlap between species. An overwhelming majority of these peptides are probably targeted selectively to a specific ion channel. Because conotoxins discriminate between closely related subtypes of ion channels, they are widely used as pharmacological agents in ion channel research, and several have direct diagnostic and therapeutic potential. Large conotoxin families can comprise hundreds or thousands of different peptides; most families have a corresponding ion channel family target (i.e., ω-conotoxins and Ca channels, α-conotoxins and nicotinic receptors). Different conotoxin families may have different ligand binding sites on the same ion channel target (i.e., μ-conotoxins and δ-conotoxins to sites 1 and 6 of Na channels, respectively). The individual peptides in a conotoxin family are typically each selectively targeted to a diverse set of different molecular isoforms within the same ion channel family. This review focuses on the targeting specificity of conotoxins and their differential binding to different states of an ion channel.
Localized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A
Authors: TASKÉN KJETIL , AANDAHL EINAR MARTIN
Published: January 2004

Taskén, Kjetil, and Einar Martin Aandahl. Localized Effects of cAMP Mediated by Distinct Routes of Protein Kinase A. Physiol Rev 84: 137–167, 2004; 10.1152/physrev.00021.2003.—More than 20% of the human genome encodes proteins involved in transmembrane and intracellular signaling pathways. The cAMP-protein kinase A (PKA) pathway is one of the most common and versatile signal pathways in eukaryotic cells and is involved in regulation of cellular functions in almost all tissues in mammals. Various extracellular signals converge on this signal pathway through ligand binding to G protein-coupled receptors, and the cAMP-PKA pathway is therefore tightly regulated at several levels to maintain specificity in the multitude of signal inputs. Ligand-induced changes in cAMP concentration vary in duration, amplitude, and extension into the cell, and cAMP microdomains are shaped by adenylyl cyclases that form cAMP as well as phosphodiesterases that degrade cAMP. Different PKA isozymes with distinct biochemical properties and cell-specific expression contribute to cell and organ specificity. A kinase anchoring proteins (AKAPs) target PKA to specific substrates and distinct subcellular compartments providing spatial and temporal specificity for mediation of biological effects channeled through the cAMP-PKA pathway. AKAPs also serve as scaffolding proteins that assemble PKA together with signal terminators such as phosphatases and cAMP-specific phosphodiesterases as well as components of other signaling pathways into multiprotein signaling complexes that serve as crossroads for different paths of cell signaling. Targeting of PKA and integration of a wide repertoire of proteins involved in signal transduction into complex signal networks further increase the specificity required for the precise regulation of numerous cellular and physiological processes.
Hyperinsulinism in Infancy: From Basic Science to Clinical Disease
Authors: DUNNE MARK J. , COSGROVE KAREN E. , SHEPHERD RUTH M. , AYNSLEY-GREEN ALBERT , LINDLEY KEITH J.
Published: January 2004

Dunne, Mark J., Karen E. Cosgrove, Ruth M. Shepherd, Albert Aynsley-Green, and Keith J. Lindley. Hyperinsulinism in Infancy: From Basic Science to Clinical Disease. Physiol Rev 84: 239–275, 2004; 10.1152/physrev.00022.2003.—Ion channelopathies have now been described in many well-characterized cell types including neurons, myocytes, epithelial cells, and endocrine cells. However, in only a few cases has the relationship between altered ion channel function, cell biology, and clinical disease been defined. Hyperinsulinism in infancy (HI) is a rare, potentially lethal condition of the newborn and early childhood. The causes of HI are varied and numerous, but in almost all cases they share a common target protein, the ATP-sensitive K+channel. From gene defects in ion channel subunits to defects in β-cell metabolism and anaplerosis, this review describes the relationship between pathogenesis and clinical medicine. Until recently, HI was generally considered an orphan disease, but as parallel defects in ion channels, enzymes, and metabolic pathways also give rise to diabetes and impaired insulin release, the HI paradigm has wider implications for more common disorders of the endocrine pancreas and the molecular physiology of ion transport.
Inherited Arrhythmogenic Diseases
Authors: Priori Silvia G.
Published: February 2004

Twelve years after the identification of the molecular bases of the long-QT syndrome, it is now possible to express some considerations on the impact that genetic findings have had in the understanding of inherited arrhythmogenic diseases. Along with the excitement for the emerging data on genotype/phenotype correlation and for the development of the first recommendations for gene-specific management of patients, it is also important to acknowledge the unexpected complexity that has emerged. The focus of this article is to analyze the elusive aspects of the relationship between genetic defects and clinical manifestations and to propose some research directions that may provide the needed answers to move forward in the understanding of the genetics of heart rhythm abnormalities.
Is “China Fear” Warranted? Perspectives from Japan's Trade and Investment Relationships with China
Authors: Abe Shigeyuki
Published: February 2004

A fear of China's economic growth, particularly with regard to its recent evolution into the “factory of the world,” is often expressed in the Japanese mass media. This paper reviews the development of trade and investment relations between Japan and China and examines the validity of this “China fear,” pointing out the ways in which China continues to lag behind Japan on many economic fronts and describing strategies that Japan could use to improve its performance. Japanese firms need to focus on producing more specialized high-tech products. At the same time, to cope with competition from China, they must take more drastic measures to keep costs down in the production of low-tech products. Some Japanese enterprises have already initiated new approaches in management, production, and distribution. The views of three of Japan's leading economists are critically reviewed, with a focus on how Japanese firms might draw profitable lessons from China's situation, improve their joint ventures with Chinese firms, and benefit from China's large market by concentrating more on local conditions.
Causal association between cannabis and psychosis: examination of the evidence
Authors: Arseneault Louise , Cannon Mary , Witton John , Murray Robin M.
Published: January 2004

Background

Controversy remains as to whether cannabis acts as a causal risk factor for schizophrenia or other functional psychotic illnesses.

Aims

To examine critically the evidence that cannabis causes psychosis using established criteria of causality.

Method

We identified five studies that included a well-defined sample drawn from population-based registers or cohorts and used prospective measures of cannabis use and adult psychosis.

Results

On an individual level, cannabis use confers an overall twofold increase in the relative risk for later schizophrenia. At the population level, elimination of cannabis use would reduce the incidence of schizophrenia by approximately 8%, assuming a causal relationship. Cannabis use appears to be neither a sufficient nor a necessary cause for psychosis. It is a component cause, part of a complex constellation of factors leading to psychosis.

Conclusions

Cases of psychotic disorder could be prevented by discouraging cannabis use among vulnerable youths. Research is needed to understand the mechanisms by which cannabis causes psychosis.