The role of non-specific interactions in nuclear organization

The most important organelle in eukaryotic cells is the nucleus. Many processes occurring within the nucleus depend on spatial organization of the nucleus. The spatial organization of the eukaryotic nucleus derives from interactions between its constituents. Both specific interactions, for instance the interactions between a DNA binding protein and its target DNA sequence, and non-specific interactions occur. Non-specific interactions stem from physical encounters between molecules or particles, which can favour particular organizations, i.e. the ones that have the lowest entropy. The role of non-specific interactions in nuclear organization is so far not extensively studied. Here, we investigate the effects of non-specific interactions on nuclear organization, using molecular dynamics simulation techniques. Chromatin folding models can be implemented in these simulations as chains of monomers, which can form loops, branches or networks. Through a comparison of simulation results with experimental data, these models can be verified or falsified. We used MD simulations of models for Arabidopsis chromatin organisation to show that non-specific interactions can explain the in vivo localisation of nucleoli and chromocenters. Also, we quantitatively demonstrate that chromatin looping contributes to the formation of chromosome territories. Focussing on the forces driving nuclear organization in the rosette model, we derive effective interaction potentials for rosette-loop interactions. These potentials are weak, but nevertheless drive chromocenters and nucleoli to the nuclear periphery and away from each other. We also study the folding of a single human chromosome within its territory. The results of our simulations are analysed using a virtual confocal microscope algorithm which has the same limitations as a real confocal microscope. Thus we show that chromatin looping increases the volume occupied by a 10Mbp chromosomal sub-domain, but decreases the overlap between two neighbouring sub-domains. Our results furthermore show that the measured amount of overlap is highly dependent on both spatial resolution and signal detection threshold of the confocal microscope, and that in typical fluorescence in situ hybridisation experiments these two factors contribute to a gross underestimation of the real overlap. Zooming out to whole nucleus organization, we show that an interplay between interactions between heterochromatin and nuclear lamina generates a wide variety of nuclear organizations, with those occurring in nature requiring a fine balance between both interactions. The differences between chromosome folding in human and Arabidopsis can be explained through differences in genomic structure and chromosome loop formation, but the underlying mechanisms and forces that organize the nucleus are very similar. The insight how specific and non-specific forces cooperate to shape nuclear organization, is therefore the most important contribution of this thesis to scientific progress. <br/

Non-specific interactions are sufficient to explain the position of heterochromatic chromocenters and nucleoli in interphase nuclei

The organization of the eukaryote nucleus into functional compartments arises by self-organization both through specific protein–protein and protein–DNA interactions and non-specific interactions that lead to entropic effects, such as e.g. depletion attraction. While many specific interactions have so far been demonstrated, the contributions of non-specific interactions are still unclear. We used coarse-grained molecular dynamics simulations of previously published models for Arabidopsis thaliana chromatin organization to show that non-specific interactions can explain the in vivo localization of nucleoli and chromocenters. Also, we quantitatively demonstrate that chromatin looping contributes to the formation of chromosome territories. Our results are consistent with the previously published Rosette model for Arabidopsis chromatin organization and suggest that chromocenter-associated loops play a role in suppressing chromocenter clustering

Salinity control on Na incorporation into calcite tests of the planktonic foraminifera Trilobatus sacculifer – Evidence from culture experiments and surface sediments

The quantitative reconstruction of past seawater salinity has yet to be achieved and the search for a direct and independent salinity proxy is ongoing. Recent culture and field studies show a significant positive correlation of Na/Ca with salinity in benthic and planktonic foraminiferal calcite. For accurate paleoceanographic reconstructions, consistent and reliable calibrations are necessary, which are still missing. In order to assess the reliability of foraminiferal Na/Ca as a direct proxy for seawater salinity, this study presents electron microprobe Na/Ca data, measured on cultured specimens of Trilobatus sacculifer. The culture experiments were conducted over a wide salinity range of 26 to 45, while temperature was kept constant. To further understand potential controlling factors of Na incorporation, measurements were also performed on foraminifera cultured at various temperatures in the range of 19.5 °C to 29.5 °C under constant salinity conditions. Foraminiferal Na/Ca ratios positively correlate with seawater salinity (Na/Caforam = 0.97 + 0.115 ⋅ Salinity, R = 0.97, p < 0.005). Temperature on the other hand exhibits no statistically significant relationship with Na/Ca ratios indicating salinity to be the dominant factor controlling Na incorporation. The culturing results are corroborated by measurements on T. sacculifer from Caribbean and Gulf of Guinea surface sediments. In conclusion, planktonic foraminiferal Na/Ca can be applied as a reliable proxy for reconstructing sea surface salinities, albeit species-specific calibrations might be necessary

Risk factors for delayed presentation and referral of symptomatic cancer: Evidence for common cancers

Background:It has been suggested that the known poorer survival from cancer in the United Kingdom, compared with other European countries, can be attributed to more advanced cancer stage at presentation. There is, therefore, a need to understand the diagnostic process, and to ascertain the risk factors for increased time to presentation.Methods:We report the results from two worldwide systematic reviews of the literature on patient-mediated and practitioner-mediated delays, identifying the factors that may influence these.Results:Across cancer sites, non-recognition of symptom seriousness is the main patient-mediated factor resulting in increased time to presentation. There is strong evidence of an association between older age and patient delay for breast cancer, between lower socio-economic status and delay for upper gastrointestinal and urological cancers and between lower education level and delay for breast and colorectal cancers. Fear of cancer is a contributor to delayed presentation, while sanctioning of help seeking by others can be a powerful mediator of reduced time to presentation. For practitioner delay, ‘misdiagnosis’ occurring either through treating patients symptomatically or relating symptoms to a health problem other than cancer, was an important theme across cancer sites. For some cancers, this could also be linked to inadequate patient examination, use of inappropriate tests or failing to follow-up negative or inconclusive test results.Conclusion:Having sought help for potential cancer symptoms, it is therefore important that practitioners recognise these symptoms, and examine, investigate and refer appropriately. © 2009 Cancer Research UK All rights reserved

Interventions to Promote Cancer Awareness and Early Presentation: Systematic Review

Low cancer awareness contributes to delay in presentation for cancer symptoms and may lead to delay in cancer diagnosis. The aim of this study was to review the evidence for the effectiveness of interventions to raise cancer awareness and promote early presentation in cancer to inform policy and future research. We searched bibliographic databases and reference lists for randomised controlled trials of interventions delivered to individuals, and controlled or uncontrolled studies of interventions delivered to communities. We found some evidence that interventions delivered to individuals modestly increase cancer awareness in the short term and insufficient evidence that they promote early presentation. We found limited evidence that public education campaigns reduce stage at presentation of breast cancer, malignant melanoma and retinoblastoma

Coupled calcium and inorganic carbon uptake suggested by magnesium and sulfur incorporation in foraminiferal calcite

Shell chemistry of foraminiferal carbonate proves to be useful in reconstructing past ocean conditions. A new addition to the proxy toolbox is the ratio of sulfur (S) to calcium (Ca) in foraminiferal shells, reflecting the ratio of SO42- to CO32- in seawater. When comparing species, the amount of SO42- incorporated, and therefore the S∕Ca of the shell, increases with increasing magnesium (Mg) content. The uptake of SO42- in foraminiferal calcite is likely connected to carbon uptake, while the incorporation of Mg is more likely related to Ca uptake since this element substitutes for Ca in the crystal lattice. The relation between S and Mg incorporation in foraminiferal calcite therefore offers the opportunity to investigate the timing of processes involved in Ca and carbon uptake. To understand how foraminiferal S∕Ca is related to Mg∕Ca, we analyzed the concentration and within-shell distribution of S∕Ca of three benthic species with different shell chemistry: Ammonia tepida, Bulimina marginata and Amphistegina lessonii. Furthermore, we investigated the link between Mg∕Ca and S∕Ca across species and the potential influence of temperature on foraminiferal S∕Ca. We observed that S∕Ca is positively correlated with Mg∕Ca on a microscale within specimens, as well as between and within species. In contrast, when shell Mg∕Ca increases with temperature, foraminiferal S∕Ca values remain similar. We evaluate our findings in the light of previously proposed biomineralization models and abiological processes involved during calcite precipitation. Although all kinds of processes, including crystal lattice distortion and element speciation at the site of calcification, may contribute to changes in either the amount of S or Mg that is ultimately incorporated in foraminiferal calcite, these processes do not explain the covariation between Mg∕Ca and S∕Ca values within specimens and between species. We observe that groups of foraminifera with different calcification pathways, e.g., hyaline versus porcelaneous species, show characteristic values for S∕Ca and Mg∕Ca, which might be linked to a different calcium and carbon uptake mechanism in porcelaneous and hyaline foraminifera. Whereas Mg incorporation might be controlled by Ca dilution at the site of calcification due to Ca pumping, S is linked to carbonate ion concentration via proton pumping. The fact that we observe a covariation of S and Mg within specimens and between species suggests that proton pumping and Ca pumping are intrinsically coupled across multiple scales.</p

Anticipated help-seeking for cancer symptoms before and after the coronavirus pandemic: results from the Onco-barometer population survey in Spain

Background: The patient interval-the time patients wait before consulting their physician after noticing cancer symptoms-contributes to diagnostic delays. We compared anticipated help-seeking times for cancer symptoms and perceived barriers to help-seeking before and after the coronavirus pandemic. Methods: Two waves (pre-Coronavirus: February 2020, N = 3269; and post-Coronavirus: August 2020, N = 1500) of the Spanish Onco-barometer population survey were compared. The international ABC instrument was administered. Pre-post comparisons were performed using multiple logistic and Poisson regression models. Results: There was a consistent and significant increase in anticipated times to help-seeking for 12 of 13 cancer symptoms, with the largest increases for breast changes (OR = 1.54, 95% CI 1.22-1-96) and unexplained bleeding (OR = 1.50, 1.26-1.79). Respondents were more likely to report barriers to help-seeking in the post wave, most notably worry about what the doctor may find (OR = 1.58, 1.35-1.84) and worry about wasting the doctor's time (OR = 1.48, 1.25-1.74). Women and older individuals were the most affected. Conclusions: Participants reported longer waiting times to help-seeking for cancer symptoms after the pandemic. There is an urgent need for public interventions encouraging people to consult their physicians with symptoms suggestive of cancer and counteracting the main barriers perceived during the pandemic situation

The prevalence of physical, sexual and mental abuse among adolescents and the association with BMI status

<p>Abstract</p> <p>Background</p> <p>Studies among adults show an association between abuse and Body Mass Index (BMI) status. When an aberrant BMI status as a consequence of abuse is already prevalent in adolescence, early detection and treatment of abuse might prevent these adolescents from developing serious weight problems and other long-term social, emotional and physical problems in adulthood. Therefore, this study investigated the prevalence of physical, sexual and mental abuse among adolescents and examined the association of these abuse subtypes with BMI status.</p> <p>Methods</p> <p>In total, data of 51,856 secondary school students aged 13–16 who had completed a questionnaire on health, well-being and lifestyle were used. BMI was classified into four categories, underweight, normal weight, overweight and obesity. Adolescents reported if they had ever been physically, sexually or mentally abused. Crude and adjusted General Estimation Equation (GEE) analyses were performed to investigate the association between abuse subtypes and BMI status. Analyses were adjusted for ethnicity and parental communication, and stratified for gender and educational level.</p> <p>Results</p> <p>Eighteen percent of the adolescents reported mental abuse, 7% reported sexual abuse, and 6% reported physical abuse. For underweight, overweight and obese adolescents these percentages were 17%, 25%, and 44%; 7%, 8%, and 16%; and 6%, 8%, 18% respectively. For the entire population, all these subtypes of abuse were associated with being overweight and obese (OR=3.67, 1.79 and 1.50) and all but sexual abuse were associated with underweight (OR=1.21 and 1.12). Stratified analyses showed that physical and sexual abuse were significantly associated with obesity among boys (OR=1.77 and 2.49) and among vocational school students (OR=1.60 and 1.69), and with underweight among girls (OR=1.26 and 0.83).</p> <p>Conclusion</p> <p>Mental abuse was reported by almost half of the obese adolescents and associated with underweight, overweight and obesity. Longitudinal analyses are recommended to explore the causality of and the mechanisms explaining this association between abuse and overweight.</p

Lack of association between polymorphisms of the IL18R1 and IL18RAP genes and cardiovascular risk: the MORGAM Project

<p>Abstract</p> <p>Background</p> <p>Interleukin-18 is a pro-inflammatory cytokine suspected to be associated with atherosclerosis and its complications. We had previously shown that one single nucleotide polymorphism (SNP) of the <it>IL18 </it>gene was associated with cardiovascular disease (CVD) through an interaction with smoking. As a further step for elucidating the contribution of the IL-18 pathway to the etiology of CVD, we here investigated the association between the genetic variability of two IL-18 receptor genes, <it>IL18R1 </it>and <it>IL18RAP</it>, with the risk of developing CVD.</p> <p>Methods</p> <p>Eleven tagging SNPs, 5 in <it>IL18R1 </it>and 6 in <it>IL18RAP</it>, characterizing the haplotypic variability of the corresponding genes; were genotyped in 5 European prospective CVD cohorts including 1416 cases and 1772 non-cases, as part of the MORGAM project. Both single-locus and haplotypes analyses were carried out to investigate the association of these SNPs with CVD.</p> <p>Results</p> <p>We did not find any significant differences in allele, genotype and haplotype frequencies between cases and non-cases for either of the two genes. Moreover, the search for interactions between SNPs located in different genes, including 5 <it>IL18 </it>SNPs previously studied in the MORGAM project, and between SNPs and environmental factors remained unfruitful.</p> <p>Conclusion</p> <p>Our analysis suggests that the variability of <it>IL18R1 </it>and <it>IL18RAP </it>genes are unlikely to contribute to modulate the risk of CVD.</p