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Mechanistic Explanation (mechanistic + explanation)
Selected AbstractsSphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti-inflammatory phenotypeINTERNATIONAL JOURNAL OF CANCER, Issue 9 2009Andreas Weigert Abstract A challenging task of the immune system is to fight cancer cells. However, a variety of human cancers educate immune cells to become tumor supportive. This is exemplified for tumor-associated macrophages (TAMs), which are polarized towards an anti-inflammatory and cancer promoting phenotype. Mechanistic explanations, how cancer cells influence the macrophage phenotype are urgently needed to address potential anti-cancer strategies along this line. One potential immune modulating compound, sphingosine-1-phosphate (S1P), was recently highlighted in both tumor growth and immune modulation. Using a xenograft model in nude mice, we demonstrate a supportive role of sphingosine kinase 2 (SphK2), one of the S1P-producing enzymes for tumor progression. The growth of SphK2-deficient MCF-7 breast tumor xenografts was markedly delayed when compared with controls. Infiltration of macrophages in SphK2-deficient and control tumors was comparable. However, TAMs from SphK2-deficient tumors displayed a pronounced anti-tumor phenotype, showing an increased expression of pro-inflammatory markers/mediators such as NO, TNF-,, IL-12 and MHCII and a low expression of anti-inflammatory IL-10 and CD206. These data suggest a role for S1P, generated by SphK2, in early tumor development by affecting macrophage polarization. © 2009 UICC [source] Snap-off of a liquid drop immersed in another liquid flowing through a constricted capillaryAICHE JOURNAL, Issue 8 2009T. J. Peña Abstract Emulsions are encountered at different stages of oil production processes, often impacting many aspects of oilfield operations. Emulsions may form as oil and water come in contact inside the reservoir rock, valves, pumps, and other equipments. Snap-off is a possible mechanism to explain emulsion formation in two-phase flow in porous media. Quartz capillary tubes with a constriction (pore neck) served to analyze snap-off of long ("infinite") oil droplets as a function of capillary number and oil-water viscosity ratio. The flow of large oil drops through the constriction and the drop break-up process were visualized using an optical microscope. Snap-off occurrence was mapped as a function of flow parameters. High oil viscosity suppresses the breakup process, whereas snap-up was always observed at low dispersed-phase viscosity. At moderate viscosity oil/water ratio, snap-off was observed only at low capillary number. Mechanistic explanations based on competing forces in the liquid phases were proposed. © 2009 American Institute of Chemical Engineers AIChE J, 2009 [source] Review article: nuclear receptors and liver disease , current understanding and new therapeutic implicationsALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2009D. A. H. ELFAKI Aliment Pharmacol Ther,30, 816,825 Summary Background, The important role of nuclear receptors and their contribution to liver function in both physiological and pathological conditions has come to attention in recent years and has advanced our understanding of several liver diseases. These findings led to the introduction of targeting nuclear receptors as treatment strategies for various liver diseases. Aims, To review the new insights brought by the study of nuclear receptors to our understanding of the molecular basis of various liver diseases, and to summarize some of the recent studies that evaluated the efficacy of targeting nuclear receptor as a new approach in treating liver diseases. Methods, Review of articles, using PubMed and article references. Results, Nuclear receptor ligands in patients with liver diseases have been associated with a variety of toxicities. Some clinical results have not met the expectations predicted from animal experiments. Mechanistic explanations at the molecular level are needed for preventing toxicity and improving outcomes from nuclear receptor ligands. Conclusion, The use of various nuclear receptor ligands in liver diseases is a promising approach that can benefit many patients suffering from these devastating diseases. However, we are far from a full understanding of the molecular mechanisms by which these receptors work. [source] Abundance , occupancy relationships in macrofauna on exposed sandy beaches: patterns and mechanismsECOGRAPHY, Issue 5 2004Matthew T. Frost We studied the relationship between abundance and extent of occupancy of 158 species of macrofauna inhabiting 66 sandy beaches around the coast of Great Britain. We also used these data to test the predictions of two hypotheses proposed to explain positive abundance-occupancy relationships. We found a strong positive relationship between abundance and extent of occupancy; this pattern was apparent in taxonomic subsets of organisms which have contrasting reproductive and dispersal traits such as planktotrophic/lecithotrophic development in the plankton vs brood development under parental care. Moreover, the abundance-occupancy relationships in these taxonomic subsets had statistically indistinguishable slopes, and elevation. We propose that this lends support to the notion that differences in population structure such as the tendency to form metapopulations may not be primary determinants of the abundance-occupancy pattern in these taxa as proposed by the rescue/metapopulation hypothesis. To test the predictions of the niche-breadth hypothesis we derived values describing the range of sediment grain-sizes exploited by members of two taxonomic subgroups: amphipods and bivalves. We found a weak, statistically non-significant relationship between this niche-breadth measure and occupancy in bivalves which have been shown to respond to grain-size in previous studies, however this was negated after correction for possible artefacts of sampling effort. All other relationships between abundance or occupancy and grain-size range were non-significant. The consistency of the demonstrated abundance-occupancy relationship with those demonstrated in other studies of primarily terrestrial fauna indicates some shared mechanistic explanation, but our data fail to provide support for the two mechanistic hypotheses investigated. [source] Does habitat use explain large scale species richness patterns of aquatic beetles in Europe?ECOGRAPHY, Issue 2 2003Ignacio Ribera Regularities in species richness are widely observed but controversy continues over its mechanistic explanation. Because richness patterns are usually a compound measure derived from taxonomically diverse species with different ecological requirements, these analyses may confound diverse causes of species numbers. Here we investigate species richness in the aquatic beetle fauna of Europe, separating major taxonomic groups and two major ecological types, species occurring in standing and running water bodies. We collated species distributions for 800+ species of water beetles in 15 regions across western Europe. Species number in any of these regions was related to three variables: total area size, geographic connectedness of the area, and latitude. Pooled species numbers were accurately predicted, but correlations were different for species associated with either running or standing water. The former were mostly correlated with latitude, while the latter were only correlated with the measure of connectedness or with area size. These differences were generally also observed in each of the four phylogenetically independent lineages of aquatic Coleoptera when analysed separately. We propose that effects of habitat, in this case possibly mediated by different long term persistence of running and standing water bodies, impose constraints at the population or local level which, if effective over larger temporal and spatial scales, determine global patterns of species richness. [source] Are there general mechanisms of animal home range behaviour?ECOLOGY LETTERS, Issue 6 2008A review, prospects for future research Abstract Home range behaviour is a common pattern of space use, having fundamental consequences for ecological processes. However, a general mechanistic explanation is still lacking. Research is split into three separate areas of inquiry , movement models based on random walks, individual-based models based on optimal foraging theory, and a statistical modelling approach , which have developed without much productive contact. Here we review recent advances in modelling home range behaviour, focusing particularly on the problem of identifying mechanisms that lead to the emergence of stable home ranges from unbounded movement paths. We discuss the issue of spatiotemporal scale, which is rarely considered in modelling studies, as well as highlighting the need to consider more closely the dynamical nature of home ranges. Recent methodological and theoretical advances may soon lead to a unified approach, however, conceptually unifying our understanding of linkages among home range behaviour and ecological or evolutionary processes. [source] Antioxidants, showy males and sperm qualityECOLOGY LETTERS, Issue 5 2001Jonathan D. Blount The fertility of males sometimes correlates with their ornamental display, but we do not have a mechanistic explanation to universally link these traits. We suggest that both sperm quality (fertility; integrity of DNA), and the substrates responsible for male ornamentation, may be vulnerable to free radical attack, which can be mitigated by antioxidants. Support for these ideas is at present weak, and requires validation in ecological contexts. We hypothesize that a link between ornamentation and sperm quality could arise if antioxidants are in limited supply, and the showiest males may be preferred because they are most likely to be fertile, or to provide sperm with undamaged genotypes that could give rise to fit offspring. [source] Dose-dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by TopiramateEPILEPSIA, Issue 12 2003Srikanth C. Nallani Summary:,Purpose: In clinical studies, topiramate (TPM) was shown to cause a dose-dependent increase in the clearance of ethinyl estradiol. We hypothesized that this interaction results from induction of hepatic cytochrome P450 (CYP) 3A4 by TPM. Accordingly, we investigated whether TPM induces CYP3A4 in primary human hepatocytes and activates the human pregnane X receptor (hPXR), a nuclear receptor that serves as a regulator of CYP3A4 transcription. Methods: Human hepatocytes were treated for 72 h with TPM (10, 25, 50, 100, 250, and 500 ,M) and known inducers, phenobarbital (PB; 2 mM), and rifampicin (10 ,M). The rate of testosterone 6,-hydroxylation by hepatocytes served as a marker for CYP3A4 activity. The CYP3A4-specific protein and mRNA levels were determined by using Western and Northern blot analyses, respectively. The hPXR activation was assessed with cell-based reporter gene assay. Results: Compared with controls, TPM (50,500 ,M),treated hepatocytes exhibited a considerable increase in the CYP3A4 activity (1. 6- to 8.2-fold), protein levels (4.6- to 17.3-fold), and mRNA levels (1.9- to 13.3-fold). Comparatively, rifampicin (10 ,M) effected 14.5-, 25.3-, and a 20.3-fold increase in CYP3A4 activity, immunoreactive protein levels, and mRNA levels, respectively. TPM (50,500 ,M) caused 1.3- to 3-fold activation of the hPXR, whereas rifampicin (10 ,M) caused a 6-fold activation. Conclusions: The observed induction of CYP3A4 by TPM, especially at the higher concentrations, provides a potential mechanistic explanation of the reported increase in the ethinyl estradiol clearance by TPM. It also is suggestive of other potential interactions when high-dose TPM therapy is used. [source] Bacterivorous grazers facilitate organic matter decomposition: a stoichiometric modeling approachFEMS MICROBIOLOGY ECOLOGY, Issue 2 2009Hao Wang Abstract There is widespread empirical evidence that protist grazing on bacteria reduces bacterial abundances but increases bacteria-mediated decomposition of organic matter. This paradox has been noted repeatedly in the microbiology literature but lacks a generally accepted mechanistic explanation. To explain this paradox quantitatively, we develop a bacteria-grazer model of organic matter decomposition that incorporates protozoa-driven nutrient recycling and stoichiometry. Unlike previous efforts, the current model includes explicit limitation, via Liebig's law of minimum, by two possible factors, nutrient and carbon densities, as well as their relative ratios in bacteria and grazers. Our model shows two principal results: (1) when the environment is carbon limiting, organic matter can always be decomposed completely, regardless of the presence/absence of grazers; (2) when the environment is nutrient (such as nitrogen) limiting, it is possible for organic matter to be completely decomposed in the presence, but not absence, of grazers. Grazers facilitate decomposition by releasing nutrients back into the environment, which would otherwise be limiting, while preying upon bacteria. Model analysis reveals that facilitation of organic matter decomposition by grazers is positively related to the stoichiometric difference between bacteria and grazers. In addition, we predict the existence of an optimal density range of introduced grazers, which maximally facilitate the decomposition of organic matter in a fixed time period. This optimal range reflects a trade-off between grazer-induced nutrient recycling and grazer-induced mortality of bacteria. [source] Life history correlates of oxidative damage in a free-living mammal populationFUNCTIONAL ECOLOGY, Issue 4 2009Daniel H. Nussey Summary 1Reactive oxygen species, produced as a by-product of normal metabolism, can cause intracellular damage and negatively impact on cell function. Such oxidative damage has been proposed as an evolutionarily important cost of growth and reproduction and as a mechanistic explanation for organismal senescence, although few tests of these ideas have occurred outside the laboratory. 2Here, we examined correlations between a measure of phospholipid oxidative damage in plasma samples and age, growth rates, parasite burden and investment in reproduction in a population of wild Soay sheep on St. Kilda, Scotland. 3We found that, amongst females of different ages, lambs had significantly elevated levels of oxidative damage compared to all other age classes and there was no evidence of increasing damage with age amongst adult sheep. 4Amongst lambs, levels of oxidative damage increased significantly with increasing growth rates over the first 4 months of life. Neither mean damage nor the effect of growth rate on damage differed between male and female lambs. 5Amongst adult female sheep, there was no evidence that body mass, current parasite burden or metrics of recent and past reproductive effort significantly predicted oxidative damage levels. 6This study is the first to examine age variation in an assay of oxidative damage and correlations between oxidative damage, growth and reproduction in a wild mammal. Our results suggest strong links between early conditions and oxidative damage in lambs, but also serve to highlight the limitations of cross-sectional data for studies examining associations between oxidative stress, ageing and life history in free-living populations. [source] Nest attentiveness and egg temperature do not explain the variation in incubation periods in tropical birdsFUNCTIONAL ECOLOGY, Issue 4 2004B. I. TIELEMAN Summary 1The wide range in incubation periods among bird species has puzzled biologists for decades, because an extended egg-phase increases time-dependent mortality of the eggs. 2We investigated a recently proposed mechanistic explanation inspired by life-history theory, suggesting that adults may increase their own survival by reducing nest attentiveness, the percentage of daytime spent incubating eggs, in exchange for reduced offspring (egg) survival due to a longer incubation period. Incubation behaviour and egg temperatures (Tegg) of 14 bird species in the humid lowland tropics were studied to test the hypothesis that lower nest attentiveness and reduced Tegg cause longer incubation periods. 3Increased nest attentiveness correlated with higher average Tegg. However, neither nest attentiveness nor average Tegg was associated with the length of the incubation period. Longer off-bouts resulted in lower Tegg, but neither number of off-bouts nor off-bout length was associated with incubation period. In addition, we reanalysed a previously published negative association between Tegg and incubation period based on literature data from temperate passerine birds using a larger data set and found no significant correlation. 4In conclusion, our results do not support the hypothesis that longer incubation periods are caused by reduced nest attentiveness and corresponding lower Tegg. [source] Synergistic induction of cyclin D1 in oligodendrocyte progenitor cells by IGF-I and FGF-2 requires differential stimulation of multiple signaling pathwaysGLIA, Issue 10 2007Terra J. Frederick Abstract D-type cyclins are direct targets of extracellular signals and critical regulators of G1 progression. Our previous data demonstrated that IGF-I and FGF-2 synergize to enhance cyclin D1 expression, cyclin E/cdk2 complex activation, and S-phase entry in OP cells. Here, we provide a mechanistic explanation for how two growth factor signaling pathways converge on a major cell cycle regulator. IGF-I and FGF-2 differentially activate signaling pathways to coordinately promote cyclin D1 expression. We show that the p44/p42 MAPK signaling pathway is essential for FGF-2 induction of cyclin D1 mRNA. In contrast, blocking the PI3-Kinase pathway results in loss of IGF-I/FGF-2 synergistic induction of cyclin D1 protein levels. Moreover, the presence of IGF-I significantly enhances nuclear localization of cyclin D1, which also requires PI3K signaling. GSK-3,, a downstream target of the PI3K/Akt pathway, is phosphorylated in the presence of IGF-I in OPs. Consistent with a known role for GSK-3, in cyclin D1 degradation, we show that proteasome inhibition in OPs exposed to FGF-2 increased cyclin D1 levels, equivalent to levels seen in IGF-I/FGF-2 treated cells. Thus, we provide a model for cyclin D1 coordinate regulation where FGF-2 stimulation of the MAPK pathway promotes cyclin D1 mRNA expression while IGF-I activation of the PI3K pathway inhibits proteasome degradation of cyclin D1 and enhances nuclear localization of cyclin D1. © 2007 Wiley-Liss, Inc. [source] Climate change affects colonization dynamics in a metacommunity of three Daphnia speciesGLOBAL CHANGE BIOLOGY, Issue 6 2008FLORIAN ALTERMATT Abstract Climate change is expected to alter the range and abundance of many species by influencing habitat qualities. For species living in fragmented populations, not only the quality of the present patches but also access to new habitat patches may be affected. Here, we show that colonization in a metacommunity can be directly influenced by weather changes, and that these observed weather changes are consistent with global climate change models. Using a long-term dataset from a rock pool metacommunity of the three species Daphnia magna, Daphnia longispina and Daphnia pulex with 507 monitored habitat patches, we correlated a four-fold increase in colonization rate with warmer, drier weather for the period from 1982 to 2006. The higher colonization rate after warm and dry summers led to an increase in metacommunity dynamics over time. A mechanistic explanation for the increased colonization rate is that the resting stages have a higher exposure to animal and wind dispersal in desiccated rock pools. Although colonization rates reacted in the same direction in all three species, there were significant species-specific effects that resulted in an overall change in the metacommunity composition. Increased local instability and colonization dynamics may even lead to higher global stability of the metacommunity. Thus, whereas climate change has been reported to cause a unidirectional change in species range for many other species, it changes the dynamics and composition of an entire community in this metacommunity, with winners and losers difficult to predict. [source] Neutral loss of amino acid residues from protonated peptides in collision-induced dissociation generates N- or C-terminal sequence ladders,JOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 11 2003Mogjiborahman Salek Abstract The widespread occurrence of the neutral loss of one to six amino acid residues as neutral fragments from doubly protonated tryptic peptides is documented for 23 peptides with individual sequences. Neutral loss of amino acids from the N-terminus of doubly charged tryptic peptides results in doubly charged y-ions, forming a ladder-like series with the ions [M + 2H]2+ = ymax2+, ymax , 12+, ymax , 22+, etc. An internal residue such as histidine, proline, lysine or arginine appears to favor this type of fragmentation, although it was sometimes also observed for peptides without this structure. For doubly protonated non-tryptic peptides with one of these residues at or near the N-terminus, we observed neutral loss from the C-terminus, resulting in a doubly charged b-type ion ladder. The analyses were performed by Q-TOF tandem mass spectrometry, facilitating the recognition of neutral loss ladders by their 2+ charge state and the conversion of the observed mass differences into reliable sequence information. It is shown that the neutral loss of amino acid residues requires low collision offset values, a simple mechanistic explanation based on established fragmentation rules is proposed and the utility of this neutral loss fragmentation pathway as an additional source for dependable peptide sequence information is documented. Copyright © 2003 John Wiley & Sons, Ltd. [source] Timing of Thyroid Hormone Action in the Developing Brain: Clinical Observations and Experimental FindingsJOURNAL OF NEUROENDOCRINOLOGY, Issue 10 2004R. T. Zoeller Abstract The original concept of the critical period of thyroid hormone (TH) action on brain development was proposed to identify the postnatal period during which TH supplement must be provided to a child with congenital hypothyroidism to prevent mental retardation. As neuropsychological tools have become more sensitive, it has become apparent that even mild TH insufficiency in humans can produce measurable deficits in very specific neuropsychological functions, and that the specific consequences of TH deficiency depends on the precise developmental timing of the deficiency. Models of maternal hypothyroidism, hypothyroxinaemia and congential hyperthyroidism have provided these insights. If the TH deficiency occurs early in pregnancy, the offspring display problems in visual attention, visual processing (i.e. acuity and strabismus) and gross motor skills. If it occurs later in pregnancy, children are at additional risk of subnormal visual (i.e. contrast sensitivity) and visuospatial skills, as well as slower response speeds and fine motor deficits. Finally, if TH insufficiency occurs after birth, language and memory skills are most predominantly affected. Although the experimental literature lags behind clinical studies in providing a mechanistic explanation for each of these observations, recent studies confirm that the specific action of TH on brain development depends upon developmental timing, and studies informing us about molecular mechanisms of TH action are generating hypotheses concerning possible mechanisms to account for these pleiotropic actions. [source] Syntactic Priming Effects in Comprehension: A Critical ReviewLINGUISTICS & LANGUAGE COMPASS (ELECTRONIC), Issue 10 2010Kristen M. Tooley Syntactic priming occurs when processing of a target sentence is facilitated following processing of a prime sentence that has the same syntactic structure (Bock, 1986 Cognitive Psychology, 18. 355,387). Syntactic priming has been widely investigated in production (Bock, 1986 Cognitive Psychology, 18. 355,387; Bock and Griffin, 2000 General. 129(2). 177,192; Cleland and Pickering, 2003. Journal of Memory and Language, 49. 214,230; Cleland and Pickering 2006. Journal of Memory and Language, 54. 185,198; Pickering and Branigan, 1998. Journal of Memory and Language, 39. 633,651; and others), but only relatively recently in comprehension (Arai et al. 2007. Cognitive Psychology, 54(3). 218,250; Ledoux et al., 2007. Psychological Science. 18(2). 135,143; and others). This article reviews the current literature on syntactic priming in comprehension and contrasts these findings to those in production. Critically, syntactic priming effects in comprehension are observed more often when prime and target sentences share a content word, whereas in production, these effects are often observed when there are no shared content words between the primes and targets. Possible explanations for the differing degrees of lexical dependency between syntactic priming effects in production and in comprehension are posed and include differences in task paradigms and stimuli, differences in time course and syntactic processing between the two modalities, and mechanistic differences. Implications from the reviewed literature are then considered in attempts at determining the most likely mechanistic explanation for syntactic priming effects in both comprehension and production. A residual activation account (Pickering and Branigan, 1998. Journal of Memory and Language, 39. 633,651), an implicit learning account (Bock and Griffin, 2000 General. 129(2). 177,192; Chang et al. 2006. Psychological Review, 113(2). 234,272), and a dual mechanism account (Tooley, 2009. Is Syntactic Priming in Sentence Comprehension Really Just Implicit Learning? Paper presented to the 22nd Annual CUNY Conference on Human Sentence Processing, Davis, March 26,28) are outlined. The dual mechanism account may prove more consistent with a wider range of the reviewed research findings. [source] Gas-phase ion chemistry of Glu/Met systems,RAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 1 2002H. Wincel A combined chemical ionisation and tandem mass spectrometry (MS/MS) approach has been used for investigation of the gas-phase ion chemistry of systems containing the amino acids Glu and Met, and the dipeptides ,-Glu-Met and Met-Glu. The metastable fragmentation of the protonated dimer, (Glu)2H+, reveals an intracluster reaction leading to the elimination of the Glu residue. The main features of the ion-molecule reactions observed in the systems containing Glu and Glu,+,Met can be described in terms of sequential adduct formation. The results obtained for the thermal dehydration of Glu were used to rationalise the formation of the proton-bound structures (Glu,,,H2O)···H+··· (Glu,,,H2O) and (Glu,,,H2O)3·H+. The adduct ions, [(Glu,,,H2O),+,H,+,Glu]+ and [(Glu,,,H2O),+ H,+,Met]+, and further association products were also observed. The results lead to a reconsideration of the structural aspects proposed earlier for these species in the sense that they suggest that the systems correspond to a mixture of isomeric covalent and proton-bound structures. The thermal effects on the decomposition of the neutral (,-Glu-Met) and its protonated form, (,-Glu-Met)H+, at m/z 279 were investigated, and dramatic changes in the MI spectra of the m/z 279 ion with temperature were found. A mechanistic explanation for the observed evolution of higher mass ion peaks in the mass spectra is developed. Copyright © 2001 John Wiley & Sons, Ltd. [source] Phosphate metabolite concentrations and ATP hydrolysis potential in normal and ischaemic heartsTHE JOURNAL OF PHYSIOLOGY, Issue 17 2008Fan Wu To understand how cardiac ATP and CrP remain stable with changes in work rate , a phenomenon that has eluded mechanistic explanation for decades , data from 31phosphate-magnetic resonance spectroscopy (31P-MRS) are analysed to estimate cytoplasmic and mitochondrial phosphate metabolite concentrations in the normal state, during high cardiac workstates, during acute ischaemia and reactive hyperaemic recovery. Analysis is based on simulating distributed heterogeneous oxygen transport in the myocardium integrated with a detailed model of cardiac energy metabolism. The model predicts that baseline myocardial free inorganic phosphate (Pi) concentration in the canine myocyte cytoplasm , a variable not accessible to direct non-invasive measurement , is approximately 0.29 mm and increases to 2.3 mm near maximal cardiac oxygen consumption. During acute ischaemia (from ligation of the left anterior descending artery) Pi increases to approximately 3.1 mm and ATP consumption in the ischaemic tissue is reduced quickly to less than half its baseline value before the creatine phosphate (CrP) pool is 18% depleted. It is determined from these experiments that the maximal rate of oxygen consumption of the heart is an emergent property and is limited not simply by the maximal rate of ATP synthesis, but by the maximal rate at which ATP can be synthesized at a potential at which it can be utilized. The critical free energy of ATP hydrolysis for cardiac contraction that is consistent with these findings is approximately ,63.5 kJ mol,1. Based on theoretical findings, we hypothesize that inorganic phosphate is both the primary feedback signal for stimulating oxidative phosphorylation in vivo and also the most significant product of ATP hydrolysis in limiting the capacity of the heart to hydrolyse ATP in vivo. Due to the lack of precise quantification of Piin vivo, these hypotheses and associated model predictions remain to be carefully tested experimentally. [source] BAFF Is Increased in Renal Transplant Patients Following Treatment with AlemtuzumabAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009D. Bloom Alemtuzumab is a monoclonal antibody that depletes T and B cells and is used as induction therapy for renal transplant recipients. Without long-term calcineurin inhibitor (CNI) therapy, alemtuzumab-treated patients have a propensity to develop alloantibody and may undergo antibody-mediated rejection (AMR). In pursuit of a mechanistic explanation, we analyzed peripheral B cells and serum of these patients for BAFF (Blys) and BAFF-R, factors known to be integral for B-cell activation, survival, and homeostasis. Serum BAFF levels of 22/24 alemtuzumab-treated patients were above normal range, with average levels of 1967 pg/mL compared to 775 pg/mL in healthy controls (p = 0.006). BAFF remained elevated 2 years posttransplant in 78% of these patients. BAFF-R on CD19+ B cells was significantly downregulated, suggesting ligand/receptor engagement. BAFF mRNA expression was increased 2,7-fold in CD14+ cells of depleted patients, possibly linking monocytes to the BAFF dysregulation. Addition of recombinant BAFF to mixed lymphocyte cultures increased B-cell activation to alloantigen, as measured by CD25 and CD69 coexpression on CD19+ cells. Of note, addition of sirolimus (SRL) augmented BAFF-enhanced B-cell activation whereas CNIs blocked it. These data suggest associations between BAFF/BAFF-R and AMR in alemtuzumab-treated patients. [source] Infection of human mucosal tissue by Pseudomonas aeruginosa requires sequential and mutually dependent virulence factors and a novel pilus-associated adhesinCELLULAR MICROBIOLOGY, Issue 8 2010Ryan W. Heiniger Summary Tissue damage predisposes humans to life-threatening disseminating infection by the opportunistic pathogen Pseudomonas aeruginosa. Bacterial adherence to host tissue is a critical first step in this infection process. It is well established that P. aeruginosa attachment to host cells involves type IV pili (TFP), which are retractile surface fibres. The molecular details of attachment and the identity of the bacterial adhesin and host receptor remain controversial. Using a mucosal epithelium model system derived from primary human tissue, we show that the pilus-associated protein PilY1 is required for bacterial adherence. We establish that P. aeruginosa preferentially binds to exposed basolateral host cell surfaces, providing a mechanistic explanation for opportunistic infection of damaged tissue. Further, we demonstrate that invasion and fulminant infection of intact host tissue requires the coordinated and mutually dependent action of multiple bacterial factors, including pilus fibre retraction and the host cell intoxication system, termed type III secretion. Our findings offer new and important insights into the complex interactions between a pathogen and its human host and provide compelling evidence that PilY1 serves as the principal P. aeruginosa adhesin for human tissue and that it specifically recognizes a host receptor localized or enriched on basolateral epithelial cell surfaces. [source] Biotic ligand model of the acute toxicity of metals.ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2001Abstract The biotic ligand model (BLM) was developed to explain and predict the effects of water chemistry on the acute toxicity of metals to aquatic organisms. The biotic ligand is defined as a specific receptor within an organism where metal complexation leads to acute toxicity. The BLM is designed to predict metal interactions at the biotic ligand within the context of aqueous metal speciation and competitive binding of protective cations such as calcium. Toxicity is defined as accumulation of metal at the biotic ligand at or above a critical threshold concentration. This modeling framework provides mechanistic explanations for the observed effects of aqueous ligands, such as natural organic matter, and water hardness on metal toxicity. In this paper, the development of a copper version of the BLM is described. The calibrated model is then used to calculate LC50 (the lethal concentration for 50% of test organisms) and is evaluated by comparison with published toxicity data sets for freshwater fish (fathead minnow, Pimephales promelas) and Daphnia. [source] DNA binding properties of human DNA polymerase ,: implications for fidelity and polymerase switching of translesion synthesisGENES TO CELLS, Issue 12 2004Rika Kusumoto The human XPV (xeroderma pigmentosum variant) gene is responsible for the cancer,prone xeroderma pigmentosum syndrome and encodes DNA polymerase , (pol ,), which catalyses efficient translesion synthesis past cis -syn cyclobutane thymine dimers (TT dimers) and other lesions. The fidelity of DNA synthesis by pol , on undamaged templates is extremely low, suggesting that pol , activity must be restricted to damaged sites on DNA. Little is known, however, about how the activity of pol , is targeted and restricted to damaged DNA. Here we show that pol , binds template/primer DNAs regardless of the presence of TT dimers. Rather, enhanced binding to template/primer DNAs containing TT dimers is only observed when the 3,-end of the primer is an adenosine residue situated opposite the lesion. When two nucleotides have been incorporated into the primer beyond the TT dimer position, the pol ,-template/primer DNA complex is destabilized, allowing DNA synthesis by DNA polymerases , or , to resume. Our study provides mechanistic explanations for polymerase switching at TT dimer sites. [source] The modulatory effects of lipopolysaccharide-stimulated B cells on differential T-cell polarizationIMMUNOLOGY, Issue 2 2008Hui Xu Summary Lipopolysaccharide (LPS) is a major component of environmental microbial products. Studies have defined the LPS dose as a critical determining factor in driving differential T-cell polarization but the direct effects of LPS on individual antigen-presenting cells is unknown. Here, we investigated the effects of LPS doses on naive B cells and the subsequent modulatory effects of these LPS-activated B cells on T-cell polarization. The LPS was able to induce a proliferative response starting at a dose of 100 ng/ml and was capable of enhancing antigen internalization at a dose of 1 ,g/ml in naive B cells. Following LPS stimulation, up-regulation of the surface markers CD40, CD86, I-Ad, immunoglobulin M, CD54 and interleukin-10 production, accompanied by down-regulation of CD5 and CD184 (CXCR4) were observed in a LPS dose-dependent manner. Low doses (< 10 ng/ml) of LPS-activated B cells drove T helper type 2 polarization whereas high doses (> 0·1 ,g/ml) of LPS-activated B cells resulted in T regulatory type 1 cell polarization. In conclusion, LPS-activated B cells acquire differential modulatory effects on T-cell polarization. Such modulatory effects of B cells are dependent on the stimulation with LPS in a dose-dependent manner. These observations may provide one of the mechanistic explanations for the influence of environmental microbes on the development of allergic diseases. [source] From molecules to ecosystems through dynamic energy budget modelsJOURNAL OF ANIMAL ECOLOGY, Issue 6 2000R. M. Nisbet Summary 1. Dynamic energy budget (DEB) models describe how individuals acquire and utilize energy, and can serve as a link between different levels of biological organization. 2. We describe the formulation and testing of DEB models, and show how the dynamics of individual organisms link to molecular processes, to population dynamics, and (more tenuously) to ecosystem dynamics. 3. DEB models offer mechanistic explanations of body-size scaling relationships. 4. DEB models constitute powerful tools for applications in toxicology and biotechnology. 5. Challenging questions arise when linking DEB models with evolutionary theory. [source] Trade-offs between direct and indirect defences of lima bean (Phaseolus lunatus)JOURNAL OF ECOLOGY, Issue 5 2008Daniel J. Ballhorn Summary 1Plant defence theory predicts trade-offs among defence traits as a result of resource limitation or pleiotropic effects. Although theoretically widely accepted, empirical demonstrations of such trade-offs are surprisingly scarce and mechanistic explanations are usually lacking. 2We quantified cyanogenesis (the release of hydrogen cyanide (HCN)) as a direct defence and the emission of volatile organic compounds (VOCs) as an indirect defence against herbivores. To elucidate whether the trade-offs occur at the genetic or phenotypic level we investigated cultivated and wild-type accessions of lima bean (Fabaceae: Phaseolus lunatus L.) and compared different leaf developmental stages. Genetic relationships among the accessions were studied using amplified fragment length polymorphism (AFLP) analysis. 3Cyanogenesis and the release of VOCs differed significantly among the accessions and were negatively correlated: high cyanogenic accessions released low amounts of VOCs and vice versa. The same remained true for the ontogenetic stages, since primary leaves of all accessions hardly ever produced HCN at all, yet regularly showed high release rates of VOCs. 4Low and high cyanogenic accessions of lima bean formed distinct clades in an AFLP-based dendrogram, while wild-types and cultivars did not separate. The first pattern indicates that the underlying defensive syndromes are genetically conserved, while the latter is likely to be caused by a multiple origin of cultivated lima beans or an extensive gene flow among cultivated and wild plants. 5Synthesis. Trade-offs between cynogenesis and VOC release were obvious both between accessions and at the ontogenetic level, and thus cannot be explained by pleiotropy. We contend that allocation restrictions and/or adaptations to different enemy pressures are most likely to explain why lima bean can invest into cyanogenesis or VOCs, but not both. [source] Reasoning across ontologically distinct levels: Students' understandings of molecular geneticsJOURNAL OF RESEARCH IN SCIENCE TEACHING, Issue 7 2007Ravit Golan Duncan Abstract In this article we apply a novel analytical framework to explore students' difficulties in understanding molecular genetics,a domain that is particularly challenging to learn. Our analytical framework posits that reasoning in molecular genetics entails mapping across ontologically distinct levels,an information level containing the genetic information, and a physical level containing hierarchically organized biophysical entities such as proteins, cells, tissues, etc. This mapping requires an understanding of what the genetic information specifies, and how the physical entities in the system mediate the effects of this information. We therefore examined, through interview and written assessments, 10th grade students' understandings of molecular genetics phenomena to uncover the conceptual obstacles involved in reasoning across these ontologically distinct levels. We found that students' described the genetic instructions as containing information about both the structure and function of biological entities across multiple organization levels; a view that is far less constrained than the scientific understandings of the genetic information. In addition, students were often unaware of the different functions of proteins, their relationship to genes, and the role proteins have in mediating the effects of the genetic information. Students' ideas about genes and proteins hindered their ability to reason across the ontologically distinct levels of genetic phenomena, and to provide causal mechanistic explanations of how the genetic information brings about effects of a physical nature. © 2007 Wiley Periodicals, Inc. J Res Sci Teach 44: 938,959, 2007 [source] The molecular basis of factor V and VIII procofactor activationJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2009R. M. CAMIRE Summary., Activation of precursor proteins by specific and limited proteolysis is a hallmark of the hemostatic process. The homologous coagulation factors (F)V and FVIII circulate in an inactive, quiescent state in blood. In this so-called procofactor state, these proteins have little, if any procoagulant activity and do not participate to any significant degree in their respective macromolecular enzymatic complexes. Thrombin is considered a key physiological activator, cleaving select peptide bonds in FV and FVIII which ultimately leads to appropriate structural changes that impart cofactor function. As the active cofactors (FVa and FVIIIa) have an enormous impact on thrombin and FXa generation, maintaining FV and FVIII as inactive procofactors undoubtedly plays an important regulatory role that has likely evolved to maintain normal hemostasis. Over the past three decades there has been widespread interest in studying the proteolytic events that lead to the activation of these proteins. While a great deal has been learned, mechanistic explanations as to how bond cleavage facilitates conversion to the active cofactor species remain incompletely understood. However, recent advances have been made detailing how thrombin recognizes FV and FVIII and also how the FV B-domain plays a dominant role in maintaining the procofactor state. Here we review our current understanding of the molecular process of procofactor activation with a particular emphasis on FV. [source] Vogt-Koyanagi-Harada disease associated with interferon alpha-2b/ribavirin combination therapyJOURNAL OF VIRAL HEPATITIS, Issue 6 2003D. L. Sylvestre Summary. The complex immunological effects of interferon and ribavirin therapy (IFN/R) in hepatitis C virus (HCV) may also exacerbate or trigger the de novo development of autoimmunity. We report the first case of IFN/R therapy associated with Vogt-Koyanagi-Harada disease, a T-cell-mediated autoimmune response to melanocytes. This condition, which has characteristic ocular, neurological and integumentary findings, elicits a systemic prodrome that may mimic side-effect profile and delay of IFN or mask its recognition. We discuss this disease in the context of the known immunomodulatory effects of IFN-alpha and ribavirin and suggest potential mechanistic explanations for the association. [source] Evolutionary adaptation to high altitude: A view from in utero,AMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 5 2009Colleen Glyde Julian A primary focus within biological anthropology has been to elucidate the processes of evolutionary adaptation. Frisancho helped to move anthropology towards more mechanistic explanations of human adaptation by drawing attention to the importance of the functional relevance of human variation. Using the natural laboratory of high altitude, he and others asked whether the unique physiology of indigenous high-altitude residents was the result of acclimatization, developmental plasticity, and/or genetic adaptation in response to the high-altitude environment. We approach the question of human adaptation to high altitude from a somewhat unique vantage point; namely, by examining physiological characteristics,pregnancy and pregnancy outcome,which are closely associated with reproductive fitness. Here we review the potent example of high-altitude native population's resistance to hypoxia-associated reductions in birth weight, which is often associated with higher infant morbidity and mortality at high altitude. With the exception of two recent publications, these comparative birth weight studies have utilized surnames, self-identification, and/or linguistic characteristics to assess ancestry, and none have linked ,advantageous' phenotypes to specific genetic variations. Recent advancements in genetic and statistical tools have enabled us to assess individual ancestry with higher resolution, identify the genetic basis of complex phenotypes and to infer the effect of natural selection on specific gene regions. Using these technologies our studies are now directed to determine the genetic variations that underlie the mechanisms by which high-altitude ancestry protects fetal growth and, in turn, to further our understanding of evolutionary processes involved in human adaptation to high altitude. Am. J. Hum. Biol., 2009. © 2009 Wiley-Liss, Inc. [source] A proteome analysis of the dorsolateral prefrontal cortex in human alcoholic patientsPROTEOMICS - CLINICAL APPLICATIONS, Issue 1 2007Kimberley Alexander-Kaufman Abstract Alcoholic patients commonly experience cognitive decline. It is postulated that cognitive dysfunction is caused by an alcohol-induced region-selective brain damage, particularly to the prefrontal region, and grey and white matter may be affected differently. We used a proteomics-based approach to compare protein expression profiles of the dorsolateral prefrontal cortex (Brodmann area 9 (BA9)) from human alcoholic and healthy control brains. Changes in the relative expression of 110 protein 'spots' were identified in the BA9 grey matter, of which 54 were identified as 44 different proteins. In our recent article, 60 protein spots were differentially expressed in the BA9 white matter and 18 of these were identified (Alexander-Kaufman, K., James, G., Sheedy, D., Harper, C., Matsumoto, I., Mol. Psychiatry 2006, 11, 56-65). Additional BA9 white matter proteins are identified here and discussed in conjunction to our grey matter results. Thiamine-dependent enzymes transketolase and pyruvate dehydrogenase (E1, ubunit) were among the proteins identified. To our knowledge, this is the first time a disruption in thiamine-dependent enzymes has been demonstrated in the brains of ,neurologically uncomplicated' alcoholics. By identifying protein expression changes in prefrontal grey and white matter separately, hypotheses may draw upon more mechanistic explanations as to how alcoholism causes the structural alterations associated with alcohol-related brain damage and cognitive dysfunction. [source] | |||||||||||||||||||||||||||||||