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Functional Link (functional + link)
Selected AbstractsYOU CAN'T KEEP A GOOD PARASITE DOWN: EVOLUTION OF A MALE-KILLER SUPPRESSOR UNCOVERS CYTOPLASMIC INCOMPATIBILITYEVOLUTION, Issue 5 2008Emily A. Hornett Maternally inherited parasites are known to impose a wide variety of reproductive manipulations upon their host. These often produce strong selection on the host to suppress the parasite, resulting in a reduction in the frequency of the parasite. However, in the butterfly Hypolimnas bolina, infected with a Wolbachia bacterium, field data demonstrate that suppression of the male-killing phenotype does not depress parasite frequency. Here we test and verify one hypothesis to explain this apparent paradox,Wolbachia induces a second phenotype, Cytoplasmic Incompatibility (CI), in populations where host suppression has evolved. We further demonstrate that the capacity to induce CI has not evolved de novo, but instead is instantaneously expressed upon the survival of infected males. The significance of these results is threefold: (1) multiple phenotypes can provide Wolbachia with the means to maintain itself in a host following suppression of a single manipulative phenotype; (2) the ability to induce CI can remain hidden in systems in which male-killing is observed, just as the ability to induce male-killing may be obscured in strains exhibiting CI; (3) the evolutionary maintenance of CI in a system in which it is not expressed suggests a functional link with male-killing or other traits under selection. [source] AATYK1A phosphorylation by Cdk5 regulates the recycling endosome pathwayGENES TO CELLS, Issue 7 2010Tetsuya Takano Trafficking of recycling endosomes (REs) is regulated by the small GTPase, Rab11A; however, the regulatory mechanism remains elusive. Apoptosis-associated tyrosine kinase 1A (AATYK1A) is a Ser/Thr kinase expressed highly in brain. We have recently shown that AATYK1A localizes to Rab11A-positive RE and is phosphorylated at Ser34 by cyclin-dependent kinase 5 (Cdk5). Here, we have investigated a role of AATYK1A and its phosphorylation in recycling endosomal trafficking using Chinese hamster ovary-K1 (CHO-K1) cells. AATYK1A localizes predominantly to Rab11A-positive pericentrosomal endocytic recycling compartment (ERC). Phosphorylation at Ser34 of AATYK1A disrupts its accumulation in the pericentrosomal ERC. Consistently, phosphorylation-mimic mutant (AATYK1A-S34D) did not accumulate in the ERC and additionally attenuated ERC formation. ERC formation suppression can be reversed by constitutively active Rab11A-Q70L, suggesting a functional link between AATYK1A phosphorylation and Rab11A activity. Although no direct interaction between AATYK1A and Rab11A could be detected, the exchange of guanine nucleotides bound to Rab11A was significantly reduced in the presence of the phosphorylation-mimic AATYK1A-S34D. Together, our results reveal a regulatory role for AATYK1A in the formation of pericentrosomal ERC. They furthermore indicate that Cdk5 can disrupt ERC formation via Ser34 phosphorylation of AATYK1A. Finally, our data suggest a mechanism by which AATYK1A signaling couples Cdk5 to Rab11A activity. [source] RBP2 is an MRG15 complex component and down-regulates intragenic histone H3 lysine 4 methylationGENES TO CELLS, Issue 6 2007Tomohiro Hayakawa MRG15 is a conserved chromodomain protein that associates with histone deacetylases (HDACs) and Tip60-containing histone acetyltransferase (HAT) complexes. Here we further characterize MRG15-containing complexes and show a functional link between MRG15 and histone H3K4 demethylase activity in mammalian cells. MRG15 was predominantly localized to discrete nuclear subdomains enriched for Ser2 -phosphorylated RNA polymerase II, suggesting it is involved specifically with active transcription. Protein analysis of the MRG15-containing complexes led to the identification of RBP2, a JmjC domain-containing protein. Remarkably, over-expression of RBP2 greatly reduced the H3K4 methylation in culture human cells in vivo, and recombinant RBP2 efficiently removed H3K4 methylation of histone tails in vitro. Knockdown of RBP2 resulted in increased H3K4 methylation levels within transcribed regions of active genes. Our findings demonstrate that RBP2 associated with MRG15 complex to maintain reduced H3K4 methylation at transcribed regions, which may ensure the transcriptional elongation state. [source] miR-20b modulates VEGF expression by targeting HIF-1, and STAT3 in MCF-7 breast cancer cells,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2010Sandra Cascio MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of different genes, including genes involved in cancer progression. A functional link between hypoxia, a key feature of the tumor microenvironment, and miRNA expression has been documented. We investigated whether and how miR-20b can regulate the expression of vascular endothelial growth factor (VEGF) in MCF-7 breast cancer cells under normoxic and hypoxia-mimicking conditions (CoCl2 exposure). Using immunoblotting, ELISA, and quantitative real-time PCR, we demonstrated that miR-20b decreased VEGF protein levels at 4 and 24,h following CoCl2 treatment, and VEGF mRNA at 4,h of treatment. In addition, miR-20b reduced VEGF protein expression in untreated cells. Next, we investigated the molecular mechanism by which pre-miR-20b can affect VEGF transcription, focusing on hypoxia inducible factor 1 (HIF-1) and signal transducer and activator of transcription 3 (STAT3), transcriptional inducers of VEGF and putative targets of miR-20b. Downregulation of VEGF mRNA by miR-20b under a 4,h of CoCl2 treatment was associated with reduced levels of nuclear HIF-1, subunit and STAT3. Chromatin immunoprecipitation (ChIP) assays revealed that HIF-1,, but not STAT3, was recruited to the VEGF promoter following the 4,h of CoCl2 treatment. This effect was inhibited by transfection of cells with pre-miR-20b. In addition, using siRNA knockdown, we demonstrated that the presence of STAT3 is necessary for CoCl2 -mediated HIF-1, nuclear accumulation and recruitment on VEGF promoter. In summary, this report demonstrates, for the first time, that the VEGF expression in breast cancer cells is mediated by HIF-1 and STAT3 in a miR-20b-dependent manner. J. Cell. Physiol. 224:242,249, 2010 © 2010 Wiley-Liss, Inc. [source] MRI diffusion tensor tracking of a new amygdalo-fusiform and hippocampo-fusiform pathway system in humansJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 6 2009Charles D. Smith MD Abstract Purpose To use MRI diffusion-tensor tracking (DTT) to test for the presence of unknown neuronal fiber pathways interconnecting the mid-fusiform cortex and anteromedial temporal lobe in humans. Such pathways are hypothesized to exist because these regions coactivate in functional MRI (fMRI) studies of emotion-valued faces and words, suggesting a functional link that could be mediated by neuronal connections. Materials and Methods A total of 15 normal human subjects were studied using unbiased DTT approaches designed for probing unknown pathways, including whole-brain seeding and large pathway-selection volumes. Several quality-control steps verified the results. Results Parallel amygdalo-fusiform and hippocampo-fusiform pathways were found in all subjects. The pathways begin/end at the mid-fusiform gyrus above the lateral occipitotemporal sulcus bilaterally. The superior pathway ends/begins at the superolateral amygdala. The inferior pathway crosses medially and ends/begins at the hippocampal head. The pathways are left-lateralized, with consistently larger cross-sectional area, higher anisotropy, and lower minimum eigenvalue (D-min) on the left, where D-min assesses intrinsic cross-fiber diffusivity independent of curvature. Conclusion A previously-undescribed pathway system interconnecting the mid-fusiform region with the amygdala/hippocampus has been revealed. This pathway system may be important for recognition, memory consolidation, and emotional modulation of face, object, and lexical information, which may be disrupted in conditions such as Alzheimer's disease. J. Magn. Reson. Imaging 2009. © 2009 Wiley-Liss, Inc. [source] Selective enhancement of the activity of C-terminally truncated, but not intact, acetylcholinesteraseJOURNAL OF NEUROCHEMISTRY, Issue 1 2008Martina Zimmermann Abstract Acetylcholinesterase (AChE) is one of the fastest enzymes approaching the catalytic limit of enzyme activity. The enzyme is involved in the terminal breakdown of the neurotransmitter acetylcholine, but non-enzymatic roles have also been described for the entire AChE molecule and its isolated C-terminal sequences. These non-cholinergic functions have been attributed to both the developmental and degenerative situation: the major form of AChE present in these conditions is monomeric. Moreover, AChE has been shown to lose its typical characteristic of substrate inhibition in both development and degeneration. This study characterizes a form of AChE truncated after amino acid 548 (T548-AChE), whose truncation site is homologue to that of a physiological form of T-AChE detected in fetal bovine serum that has lost its C-terminal moiety supposedly due to proteolytic cleavage. Peptide sequences covered by this C-terminal sequence have been shown to be crucially involved in both developmental and degenerative mechanisms in vitro. Numerous studies have addressed the structure,function relationship of the AChE C-terminus with T548-AChE representing one of the most frequently studied forms of truncated AChE. In this study, we provide new insight into the understanding of the functional characteristics that T548-AChE acquires in solution: T548-AChE is incubated with agents of varying net charge and molecular weight. Together with kinetic studies and an analysis of different molecular forms and aggregation states of T548-AChE, we show that the enzymatic activity of T548-AChE, an enzyme verging at its catalytic limit is, nonetheless, apparently enhanced by up to 800%. We demonstrate, first, how the activity of T548-AChE can be enhanced through agents that contain highly positive charged moieties. Moreover, the un-competitive mechanism of activity enhancement most likely involves the peripheral anionic site of AChE that is reflected in delayed substrate inhibition being observed for activity enhanced T548-AChE. The data provides evidence towards a mechanistic and functional link between the form of AChE unique to both development and degeneration and a C-terminal peptide of T-AChE acting under those conditions. [source] Individualized and time-variant model for the functional link between thermoregulation and sleep onsetJOURNAL OF SLEEP RESEARCH, Issue 2 2006STIJN QUANTEN Summary This study makes use of control system model identification techniques to examine the relationship between thermoregulation and sleep regulation. Specifically, data-based mechanistic (DBM) modelling is used to formulate and experimentally test the hypothesis, put forth by Gilbert et al. [Sleep Med. Rev.8 (2004) 81], that there exists a connection between distal heat loss and sleepiness. Six healthy sleepers each spent three nights and the following day in the sleep laboratory: an adaptation, a cognitive arousal and a neutral testing day. In the cognitive arousal condition, a visit of a television camera crew took place and subjects were asked to be interviewed. During each of the three 25-min driving simulator tasks per day, the distal-to-proximal gradient and the electroencephalogram are recorded. It is observed from these experimental data that there exists a feedback connection between thermoregulation and sleep. In addition to providing experimental evidence in support of the Gilbert et al. (2004) hypothesis, the authors propose that the nature of the feedback connection is determined by the nature of sleep/wake state (i.e. NREM sleep versus unwanted sleepiness in active subjects). Besides this, an individualized and time-variant model for the linkage between thermoregulation and sleep onset is presented. This compact model feeds on real-time data regarding distal heat loss and sleepiness and contains a physically meaningful parameter that delivers an individual- and time-depending quantification of a well known biological features in the field of thermoregulation: the thermoregulatory error signal Thypo(t),Tset(t). A validation of these physical/biological features emphasizes the reliability and power of DBM in describing individual differences related to the sleep process. [source] Systemin-dependent salinity tolerance in tomato: evidence of specific convergence of abiotic and biotic stress responsesPHYSIOLOGIA PLANTARUM, Issue 1 2010Francesco Orsini Plants have evolved complex mechanisms to perceive environmental cues and develop appropriate and coordinated responses to abiotic and biotic stresses. Considerable progress has been made towards a better understanding of the molecular mechanisms of plant response to a single stress. However, the existence of cross-tolerance to different stressors has proved to have great relevance in the control and regulation of organismal adaptation. Evidence for the involvement of the signal peptide systemin and jasmonic acid in wound-induced salt stress adaptation in tomato has been provided. To further unravel the functional link between plant responses to salt stress and mechanical damage, transgenic tomato (Lycopersicon esculentum Mill.) plants constitutively expressing the prosystemin cDNA have been exposed to a moderate salt stress. Prosystemin over-expression caused a reduction in stomatal conductance. However, in response to salt stress, prosystemin transgenic plants maintained a higher stomatal conductance compared with the wild-type control. Leaf concentrations of abscissic acid (ABA) and proline were lower in stressed transgenic plants compared with their wild-type control, implying that either the former perceived a less stressful environment or they adapted more efficiently to it. Consistently, under salt stress, transgenic plants produced a higher biomass, indicating that a constitutive activation of wound responses is advantageous in saline environment. Comparative gene expression profiling of stress-induced genes suggested that the partial stomatal closure was not mediated by ABA and/or components of the ABA signal transduction pathway. Possible cross-talks between genes involved in wounding and osmotic stress adaptation pathways in tomato are discussed. [source] Brief communication: Forelimb compliance in arboreal and terrestrial opossumsAMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 1 2010Daniel Schmitt Abstract Primates display high forelimb compliance (increased elbow joint yield) compared to most other mammals. Forelimb compliance, which is especially marked among arboreal primates, moderates vertical oscillations of the body and peak vertical forces and may represent a basal adaptation of primates for locomotion on thin, flexible branches. However, Larney and Larson (Am J Phys Anthropol 125 [2004] 42,50) reported that marsupials have forelimb compliance comparable to or greater than that of most primates, but did not distinguish between arboreal and terrestrial marsupials. If forelimb compliance is functionally linked to locomotion on thin branches, then elbow yield should be highest in marsupials relying on arboreal substrates more often. To test this hypothesis, we compared forelimb compliance between two didelphid marsupials, Caluromys philander (an arboreal opossum relying heavily on thin branches) and Monodelphis domestica (an opossum that spends most of its time on the ground). Animals were videorecorded while walking on a runway or a horizontal 7-mm pole. Caluromys showed higher elbow yield (greater changes in degrees of elbow flexion) on both substrates, similar to that reported for arboreal primates. Monodelphis was characterized by lower elbow yield that was intermediate between the values reported by Larney and Larson (Am J Phys Anthropol 125 [2004] 42,50) for more terrestrial primates and rodents. This finding adds evidence to a model suggesting a functional link between arboreality,particularly locomotion on thin, flexible branches,and forelimb compliance. These data add another convergent trait between arboreal primates, Caluromys, and other arboreal marsupials and support the argument that all primates evolved from a common ancestor that was a fine-branch arborealist. Am J Phys Anthropol, 2010. © 2009 Wiley-Liss, Inc. [source] Programmed cell death-10 enhances proliferation and protects malignant T cells from apoptosisAPMIS, Issue 10 2010BRITT LAUENBORG Lauenborg B, Kopp K, Krejsgaard T, Eriksen KW, Geisler C, Dabelsteen S, Gniadecki R, Zhang Q, Wasik MA, Woetmann A, Odum N. Programmed cell death-10 enhances proliferation and protects malignant T cells from apoptosis. APMIS 2010; 118: 719,28. The programmed cell death-10 (PDCD10; also known as cerebral cavernous malformation-3 or CCM3) gene encodes an evolutionarily conserved protein associated with cell apoptosis. Mutations in PDCD10 result in cerebral cavernous malformations, an important cause of cerebral hemorrhage. PDCD10 is associated with serine/threonine kinases and phosphatases and modulates the extracellular signal-regulated kinase pathway suggesting a role in the regulation of cellular growth. Here we provide evidence of a constitutive expression of PDCD10 in malignant T cells and cell lines from peripheral blood of cutaneous T-cell lymphoma (Sezary syndrome) patients. PDCD10 is associated with protein phosphatase-2A, a regulator of mitogenesis and apoptosis in malignant T cells. Inhibition of oncogenic signal pathways [Jak3, Notch1, and nuclear factor-,B (NF-,B)] partly inhibits the constitutive PDCD10 expression, whereas an activator of Jak3 and NF-,B, interleukin-2 (IL-2), enhances PDCD10 expression. Functional data show that PDCD10 depletion by small interfering RNA induces apoptosis and decreases proliferation of the sensitive cells. To our knowledge, these data provide the first functional link between PDCD10 and cancer. [source] Genetic connections of the actin cytoskeleton and beyond,BIOESSAYS, Issue 5 2007Piergiorgio Percipalle Actin is a key protein in numerous cellular functions. One recent study has identified a large set of genes, associated with the actin cytoskeleton, which could be grouped into a wide spectrum of cytoplasmic and nuclear functions, such as protein biosynthesis and gene transcription.1 Deletions of many of the identified genes affected cellular actin organization,1 suggesting a functional link between different actin fractions probably regulated through changes in actin dynamics. The data are very exciting; speculations on the crosstalk between cytoplasmic and nuclear actin fractions in different cellular contexts may help placing the results in perspective to further understand how actin-mediated signalling affects cellular functions, such as gene expression. BioEssays 29:407,411, 2007. © 2007 Wiley Periodicals, Inc. [source] Emerging pharmacology and physiology of neuromedin U and the structurally related peptide neuromedin SBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009JD Mitchell Neuromedin U (NMU) has been paired with the G-protein-coupled receptors (GPRs) NMU1 (formely designated as the orphan GPR66 or FM-3) and NMU2 (FM-4 or hTGR-1). Recently, a structurally related peptide, neuromedin S (NMS), which shares an amidated C-terminal heptapeptide motif, has been identified in both rat and human, and has been proposed as a second ligand for these receptors. Messenger RNA encoding NMU receptor subtypes shows differential expression: NMU1 is predominantly expressed in peripheral tissues, particularly the gastrointestinal tract, whereas NMU2 is abundant within the brain and spinal cord. NMU peptide parallels receptor distribution with highest expression in the gastrointestinal tract and specific structures within the brain, reflecting its major role in the regulation of energy balance. The NMU knockout mouse has an obese phenotype and, in agreement, the Arg165Trp amino acid variant of NMU-25 in humans, which is functionally inactive, co-segregated with childhood-onset obesity. Emerging physiological roles for NMU include vasoconstriction mediated predominantly via NMU1 with nociception and bone remodelling via NMU2. The NMU system has also been implicated in the pathogenesis of septic shock and cancers including bladder carcinoma and acute myeloid leukaemia. Intriguingly, NMS is more potent at NMU2 receptors in vivo where it has similar central actions in suppression of feeding and regulation of circadian rhythms to NMU. Taken together with its vascular actions, NMU may be a functional link between energy balance and the cardiovascular system and may provide a future target for therapies directed against the disorders that comprise metabolic syndrome. [source] Nitric oxide evaluation in upper and lower respiratory tracts in nasal polyposisCLINICAL & EXPERIMENTAL ALLERGY, Issue 7 2008C. Delclaux Summary Background A decrease in nasal nitric oxide (NO) and an increase in exhaled NO have been demonstrated in patients with nasal polyposis (NP). Objectives The aims were to evaluate the flux of NO from the three compartments of the respiratory tract, namely, upper nasal, lower conducting and distal airways, and to search for relationships between NO parameters and indexes of upper and lower disease activity (bronchial reactivity and obstruction). The effect of medical treatment of polyposis was also evaluated. Methods Seventy patients with polyposis were recruited. At baseline, pulmonary function tests (spirometry, plethysmography, bronchomotor response to deep inspiration using forced oscillation measurement of resistance of respiratory system, methacholine challenge, multiple flow rates of exhaled NO and nasal NO measurements) were performed together with an assessment of polyposis [clinical, endoscopic and computed tomography (CT) scores]. Results Statistical relationships were demonstrated between nasal NO flux and severity scores (clinical: ,=,0.31, P=0.015; endoscopic: ,=,0.57, P<0.0001; CT: ,=,0.46, P=0.0005), and between alveolar NO concentration and distal airflow limitation (FEF25,75, ,=,0.32, P=0.011). Thirty-six patients were assessed after 11 [7,13] (median [interquartile]) months of medical treatment, demonstrating an improvement in clinical and endoscopic scores, an increase in nasal NO flux, a decrease in NO flux from conducting airways, an improvement in the mild airflow limitation (forced expiratory volume in 1 s, FEF25,75, even in non-asthmatic patients) and a decrease in the bronchoconstrictor effect of deep inspiration. Conclusions The medical treatment of NP improves both airway reactivity and obstruction, whatever the presence of asthma, suggesting a functional link between upper and lower airway functions. [source] A Metabolic Mechanism For Cardiac K+ Channel RemodellingCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2002George J Rozanski SUMMARY 1. Electrical remodelling of the ventricle is a common pathogenic feature of cardiovascular disease states that lead to heart failure. Experimental data suggest this change in electrophysiological phenotype is largely due to downregulation of K+ channels involved in repolarization of the action potential. 2. Voltage-clamp studies of the transient outward current (Ito) in diabetic cardiomyopathy support a metabolic mechanism for K+ channel downregulation. In particular, Ito density is significantly increased in diabetic rat isolated ventricular myocytes treated in vitro with insulin or agents that activate pyruvate dehydrogenase. Recent data suggest this mechanism is not limited to diabetic conditions, because metabolic stimuli that upregulate Ito in diabetic rat myocytes act similarly in non- diabetic models of heart failure. 3. Depressed Ito channel activity is also reversed by experimental conditions that increase myocyte levels of reduced glutathione, indicating that oxidative stress is involved in electrical remodelling. Moreover, upregulation of Ito density by activators of glucose utilization is blocked by inhibitors of glutathione metabolism, supporting the premise that there is a functional link between glucose utilization and the glutathione system. 4. Electrophysiological studies of diabetic and non-diabetic disease conditions affecting the heart suggest Ito channels are regulated by a redox-sensitive mechanism, where glucose utilization plays an essential role in maintaining a normally reduced state of the myocyte. This hypothesis has implications for clinical approaches aimed at reversing pathogenic electrical remodelling in a variety of cardiovascular disease states. [source] Daily Meal Timing is Not Necessary for Resetting the Main Circadian Clock by Calorie RestrictionJOURNAL OF NEUROENDOCRINOLOGY, Issue 2 2008J. Mendoza In rodents, entrainment and/or resetting by feeding of the central circadian clock, the suprachiasmatic nucleus (SCN), is more efficient when food cues arise from a timed calorie restriction. Because timed calorie restriction is associated with a single meal each day at the same time, its resetting properties on the SCN possibly depend on a combination of meal time-giving cues and hypocaloric conditions per se. To exclude any effect of daily meal timing in resetting by calorie restriction, the present study employed a model of ultradian feeding schedules, divided into six meals with different durations of food access (6 × 8-min versus 6 × 12-min meal schedule) every 4 h over the 24-h cycle. The effects of such an ultradian calorie restriction were evaluated on the rhythms of wheel-running activity (WRA) and body temperature (Tb) in rats. The results indicate that daily/circadian rhythms of WRA and Tb were shifted by a hypocaloric feeding distributed in six ultradian short meals (i.e. 6 × 8-min meal schedule), showing both phase advances and delays. The magnitude of phase shifts was positively correlated with body weight loss and level of day-time behavioural activity. By contrast, rats fed daily with six ultradian meals long enough (i.e. 6 × 12-min meal schedule) to prevent body weight loss, showed only small, if any, phase shifts in WRA and Tb rhythms. The results obtained reveal the potency of calorie restriction to reset the SCN clock without synchronisation to daily meal timing, highlighting functional links between metabolism, calorie restriction and the circadian timing system. [source] | |||||||||||||