Directed cell migration in the presence of obstacles

BACKGROUND: Chemotactic movement is a common feature of many cells and microscopic organisms. In vivo, chemotactic cells have to follow a chemotactic gradient and simultaneously avoid the numerous obstacles present in their migratory path towards the chemotactic source. It is not clear how cells detect and avoid obstacles, in particular whether they need a specialized biological mechanism to do so. RESULTS: We propose that cells can sense the presence of obstacles and avoid them because obstacles interfere with the chemical field. We build a model to test this hypothesis and find that this naturally enables efficient at-a-distance sensing to be achieved with no need for a specific and active obstacle-sensing mechanism. We find that (i) the efficiency of obstacle avoidance depends strongly on whether the chemotactic chemical reacts or remains unabsorbed at the obstacle surface. In particular, it is found that chemotactic cells generally avoid absorbing barriers much more easily than non-absorbing ones. (ii) The typically low noise in a cell's motion hinders the ability to avoid obstacles. We also derive an expression estimating the typical distance traveled by chemotactic cells in a 3D random distribution of obstacles before capture; this is a measure of the distance over which chemotaxis is viable as a means of directing cells from one point to another in vivo. CONCLUSION: Chemotactic cells, in many cases, can avoid obstacles by simply following the spatially perturbed chemical gradients around obstacles. It is thus unlikely that they have developed specialized mechanisms to cope with environments having low to moderate concentrations of obstacles

Climate change adaptation in European river basins

This paper contains an assessment and standardized comparative analysis of the current water management regimes in four case-studies in three European river basins: the Hungarian part of the Upper Tisza, the Ukrainian part of the Upper Tisza (also called Zacarpathian Tisza), Alentejo Region (including the Alqueva Reservoir) in the Lower Guadiana in Portugal, and Rivierenland in the Netherlands. The analysis comprises several regime elements considered to be important in adaptive and integrated water management: agency, awareness raising and education, type of governance and cooperation structures, information management and—exchange, policy development and—implementation, risk management, and finances and cost recovery. This comparative analysis has an explorative character intended to identify general patterns in adaptive and integrated water management and to determine its role in coping with the impacts of climate change on floods and droughts. The results show that there is a strong interdependence of the elements within a water management regime, and as such this interdependence is a stabilizing factor in current management regimes. For example, this research provides evidence that a lack of joint/participative knowledge is an important obstacle for cooperation, or vice versa. We argue that there is a two-way relationship between information management and collaboration. Moreover, this research suggests that bottom-up governance is not a straightforward solution to water management problems in large-scale, complex, multiple-use systems, such as river basins. Instead, all the regimes being analyzed are in a process of finding a balance between bottom-up and top–down governance. Finally, this research shows that in a basin where one type of extreme is dominant—like droughts in the Alentejo (Portugal) and floods in Rivierenland (Netherlands)—the potential impacts of other extremes are somehow ignored or not perceived with the urgency they might deserv

Single nucleotide polymorphisms (SNPs) in coding regions of canine dopamine- and serotonin-related genes

<p>Abstract</p> <p>Background</p> <p>Polymorphism in genes of regulating enzymes, transporters and receptors of the neurotransmitters of the central nervous system have been associated with altered behaviour, and single nucleotide polymorphisms (SNPs) represent the most frequent type of genetic variation. The serotonin and dopamine signalling systems have a central influence on different behavioural phenotypes, both of invertebrates and vertebrates, and this study was undertaken in order to explore genetic variation that may be associated with variation in behaviour.</p> <p>Results</p> <p>Single nucleotide polymorphisms in canine genes related to behaviour were identified by individually sequencing eight dogs (<it>Canis familiaris</it>) of different breeds. Eighteen genes from the dopamine and the serotonin systems were screened, revealing 34 SNPs distributed in 14 of the 18 selected genes. A total of 24,895 bp coding sequence was sequenced yielding an average frequency of one SNP per 732 bp (1/732). A total of 11 non-synonymous SNPs (nsSNPs), which may be involved in alteration of protein function, were detected. Of these 11 nsSNPs, six resulted in a substitution of amino acid residue with concomitant change in structural parameters.</p> <p>Conclusion</p> <p>We have identified a number of coding SNPs in behaviour-related genes, several of which change the amino acids of the proteins. Some of the canine SNPs exist in codons that are evolutionary conserved between five compared species, and predictions indicate that they may have a functional effect on the protein. The reported coding SNP frequency of the studied genes falls within the range of SNP frequencies reported earlier in the dog and other mammalian species. Novel SNPs are presented and the results show a significant genetic variation in expressed sequences in this group of genes. The results can contribute to an improved understanding of the genetics of behaviour.</p

Should Research Ethics Encourage the Production of Cost-Effective Interventions?

This project considers whether and how research ethics can contribute to the provision of cost-effective medical interventions. Clinical research ethics represents an underexplored context for the promotion of cost-effectiveness. In particular, although scholars have recently argued that research on less-expensive, less-effective interventions can be ethical, there has been little or no discussion of whether ethical considerations justify curtailing research on more expensive, more effective interventions. Yet considering cost-effectiveness at the research stage can help ensure that scarce resources such as tissue samples or limited subject popula- tions are employed where they do the most good; can support parallel efforts by providers and insurers to promote cost-effectiveness; and can ensure that research has social value and benefits subjects. I discuss and rebut potential objections to the consideration of cost-effectiveness in research, including the difficulty of predicting effectiveness and cost at the research stage, concerns about limitations in cost-effectiveness analysis, and worries about overly limiting researchers’ freedom. I then consider the advantages and disadvantages of having certain participants in the research enterprise, including IRBs, advisory committees, sponsors, investigators, and subjects, consider cost-effectiveness. The project concludes by qualifiedly endorsing the consideration of cost-effectiveness at the research stage. While incorporating cost-effectiveness considerations into the ethical evaluation of human subjects research will not on its own ensure that the health care system realizes cost-effectiveness goals, doing so nonetheless represents an important part of a broader effort to control rising medical costs

Mild hypothermia delays the development of stone heart from untreated sustained ventricular fibrillation - a cardiovascular magnetic resonance study

<p>Abstract</p> <p>Background</p> <p>'Stone heart' resulting from ischemic contracture of the myocardium, precludes successful resuscitation from ventricular fibrillation (VF). We hypothesized that mild hypothermia might slow the progression to stone heart.</p> <p>Methods</p> <p>Fourteen swine (27 ± 1 kg) were randomized to normothermia (group I; n = 6) or hypothermia groups (group II; n = 8). Mild hypothermia (34 ± 2°C) was induced with ice packs prior to VF induction. The LV and right ventricular (RV) cross-sectional areas were followed by cardiovascular magnetic resonance until the development of stone heart. A commercial 1.5T GE Signa NV-CV/i scanner was used. Complete anatomic coverage of the heart was acquired using a steady-state free precession (SSFP) pulse sequence gated at baseline prior to VF onset. Un-gated SSFP images were obtained serially after VF induction. The ventricular endocardium was manually traced and LV and RV volumes were calculated at each time point.</p> <p>Results</p> <p>In group I, the LV was dilated compared to baseline at 5 minutes after VF and this remained for 20 minutes. Stone heart, arbitrarily defined as LV volume <1/3 of baseline at the onset of VF, occurred at 29 ± 3 minutes. In group II, there was less early dilation of the LV (p < 0.05) and the development of stone heart was delayed to 52 ± 4 minutes after onset of VF (P < 0.001).</p> <p>Conclusions</p> <p>In this closed-chest swine model of prolonged untreated VF, hypothermia reduced the early LV dilatation and importantly, delayed the onset of stone heart thereby extending a known, morphologic limit of resuscitability.</p

Insights on the Evolution of Prolyl 3-Hydroxylation Sites from Comparative Analysis of Chicken and Xenopus Fibrillar Collagens

Recessive mutations that prevent 3-hydroxyproline formation in type I collagen have been shown to cause forms of osteogenesis imperfecta. In mammals, all A-clade collagen chains with a GPP sequence at the A1 site (P986), except α1(III), have 3Hyp at residue P986. Available avian, amphibian and reptilian type III collagen sequences from the genomic database (Ensembl) all differ in sequence motif from mammals at the A1 site. This suggests a potential evolutionary distinction in prolyl 3-hydroxylation between mammals and earlier vertebrates. Using peptide mass spectrometry, we confirmed that this 3Hyp site is fully occupied in α1(III) from an amphibian, Xenopus laevis, as it is in chicken. A thorough characterization of all predicted 3Hyp sites in collagen types I, II, III and V from chicken and xenopus revealed further differences in the pattern of occupancy of the A3 site (P707). In mammals only α2(I) and α2(V) chains had any 3Hyp at the A3 site, whereas in chicken all α-chains except α1(III) had A3 at least partially 3-hydroxylated. The A3 site was also partially 3-hydroxylated in xenopus α1(I). Minor differences in covalent cross-linking between chicken, xenopus and mammal type I and III collagens were also found as a potential index of evolving functional differences. The function of 3Hyp is still unknown but observed differences in site occupancy during vertebrate evolution are likely to give important clues

Genetic support for a quantitative trait nucleotide in the ABCG2 gene affecting milk composition of dairy cattle

<p>Abstract</p> <p>Background</p> <p>Our group has previously identified a quantitative trait locus (QTL) affecting fat and protein percentages on bovine chromosome 6, and refined the QTL position to a 420-kb interval containing six genes. Studies performed in other cattle populations have proposed polymorphisms in two different genes (<it>ABCG2 </it>and <it>OPN</it>) as the underlying functional QTL nucleotide. Due to these conflicting results, we have included these QTNs, together with a large collection of new SNPs produced from PCR sequencing, in a dense marker map spanning the QTL region, and reanalyzed the data using a combined linkage and linkage disequilibrium approach.</p> <p>Results</p> <p>Our results clearly exclude the <it>OPN </it>SNP (<it>OPN_3907</it>) as causal site for the QTL. Among 91 SNPs included in the study, the <it>ABCG2 </it>SNP (<it>ABCG2_49</it>) is clearly the best QTN candidate. The analyses revealed the presence of only one QTL for the percentage traits in the tested region. This QTL was completely removed by correcting the analysis for <it>ABCG2_49</it>. Concordance between the sires' marker genotypes and segregation status for the QTL was found for <it>ABCG2_49 </it>only. The C allele of <it>ABCG2_49 </it>is found in a marker haplotype that has an extremely negative effect on fat and protein percentages and positive effect on milk yield. Of the 91 SNPs, <it>ABCG2_49 </it>was the only marker in perfect linkage disequilibrium with the QTL.</p> <p>Conclusion</p> <p>Based on our results, OPN_3907 can be excluded as the polymorphism underlying the QTL. The results of this and other papers strongly suggest the [A/C] mutation in <it>ABCG2_49 </it>as the causal mutation, although the possibility that <it>ABCG2_49 </it>is only a marker in perfect LD with the true mutation can not be completely ruled out.</p

Galectins as immunoregulators during infectious processes: from microbial invasion to the resolution of the disease

Recent evidence has implicated galectins, a family of evolutionarily conserved carbohydrate-binding proteins, as regulators of immune cell homeostasis and host-pathogen interactions. Galectins operate at different levels of innate and adaptive immune responses, by modulating cell survival and cell activation or by influencing the Th1/Th2 cytokine balance. Furthermore, galectins may contribute to host-pathogen recognition and may serve as receptors for specific interactions of pathogens with their insect vectors. Here we will explore the influence of galectins in immunological processes relevant to microbial infection and will summarize exciting recent work related to the specific interactions between galectins and their glycoconjugate ligands as critical determinants of pathogen recognition. Understanding the role of galectin-sugar interactions during the course of microbial infections might contribute to defining novel targets for disease prevention and immune intervention.Fil: Rabinovich, Gabriel Adrián. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gruppi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentin

Statistical Modeling of Transcription Factor Binding Affinities Predicts Regulatory Interactions

Recent experimental and theoretical efforts have highlighted the fact that binding of transcription factors to DNA can be more accurately described by continuous measures of their binding affinities, rather than a discrete description in terms of binding sites. While the binding affinities can be predicted from a physical model, it is often desirable to know the distribution of binding affinities for specific sequence backgrounds. In this paper, we present a statistical approach to derive the exact distribution for sequence models with fixed GC content. We demonstrate that the affinity distribution of almost all known transcription factors can be effectively parametrized by a class of generalized extreme value distributions. Moreover, this parameterization also describes the affinity distribution for sequence backgrounds with variable GC content, such as human promoter sequences. Our approach is applicable to arbitrary sequences and all transcription factors with known binding preferences that can be described in terms of a motif matrix. The statistical treatment also provides a proper framework to directly compare transcription factors with very different affinity distributions. This is illustrated by our analysis of human promoters with known binding sites, for many of which we could identify the known regulators as those with the highest affinity. The combination of physical model and statistical normalization provides a quantitative measure which ranks transcription factors for a given sequence, and which can be compared directly with large-scale binding data. Its successful application to human promoter sequences serves as an encouraging example of how the method can be applied to other sequences