Verification of predicted alternatively spliced Wnt genes reveals two new splice variants (CTNNB1 and LRP5) and altered Axin-1 expression during tumour progression

BACKGROUND: Splicing processes might play a major role in carcinogenesis and tumour progression. The Wnt pathway is of crucial relevance for cancer progression. Therefore we focussed on the Wnt/β-catenin signalling pathway in order to validate the expression of sequences predicted as alternatively spliced by bioinformatic methods. Splice variants of its key molecules were selected, which may be critical components for the understanding of colorectal tumour progression and may have the potential to act as biological markers. For some of the Wnt pathway genes the existence of splice variants was either proposed (e.g. β-Catenin and CTNNB1) or described only in non-colon tissues (e.g. GSK3β) or hitherto not published (e.g. LRP5). RESULTS: Both splice variants – normal and alternative form – of all selected Wnt pathway components were found to be expressed in cell lines as well as in samples derived from tumour, normal and healthy tissues. All splice positions corresponded totally with the bioinformatical prediction as shown by sequencing. Two hitherto not described alternative splice forms (CTNNB1 and LRP5) were detected. Although the underlying EST data used for the bioinformatic analysis suggested a tumour-specific expression neither a qualitative nor a significant quantitative difference between the expression in tumour and healthy tissues was detected. Axin-1 expression was reduced in later stages and in samples from carcinomas forming distant metastases. CONCLUSION: We were first to describe that splice forms of crucial genes of the Wnt-pathway are expressed in human colorectal tissue. Newly described splicefoms were found for β-Catenin, LRP5, GSK3β, Axin-1 and CtBP1. However, the predicted cancer specificity suggested by the origin of the underlying ESTs was neither qualitatively nor significant quantitatively confirmed. That let us to conclude that EST sequence data can give adequate hints for the existence of alternative splicing in tumour tissues. That no difference in the expression of these splice forms between cancerous tissues and normal mucosa was found, may indicate that the existence of different splice forms is of less significance for cancer formation as suggested by the available EST data. The currently available EST source is still insufficient to clearly deduce colon cancer specificity. More EST data from colon (tumour and healthy) is required to make reliable predictions

Systems analysis of iron metabolism: the network of iron pools and fluxes

<p>Abstract</p> <p>Background</p> <p>Every cell of the mammalian organism needs iron as trace element in numerous oxido-reductive processes as well as for transport and storage of oxygen. The very versatility of ionic iron makes it a toxic entity which can catalyze the production of radicals that damage vital membranous and macromolecular assemblies in the cell. The mammalian organism maintains therefore a complex regulatory network of iron uptake, excretion and intra-body distribution. Intracellular regulation in different cell types is intertwined with a global hormonal signalling structure. Iron deficiency as well as excess of iron are frequent and serious human disorders. They can affect every cell, but also the organism as a whole.</p> <p>Results</p> <p>Here, we present a kinematic model of the dynamic system of iron pools and fluxes. It is based on ferrokinetic data and chemical measurements in C57BL6 wild-type mice maintained on iron-deficient, iron-adequate, or iron-loaded diet. The tracer iron levels in major tissues and organs (16 compartment) were followed for 28 days. The evaluation resulted in a whole-body model of fractional clearance rates. The analysis permits calculation of absolute flux rates in the steady-state, of iron distribution into different organs, of tracer-accessible pool sizes and of residence times of iron in the different compartments in response to three states of iron-repletion induced by the dietary regime.</p> <p>Conclusions</p> <p>This mathematical model presents a comprehensive physiological picture of mice under three different diets with varying iron contents. The quantitative results reflect systemic properties of iron metabolism: dynamic closedness, hierarchy of time scales, switch-over response and dynamics of iron storage in parenchymal organs.</p> <p>Therefore, we could assess which parameters will change under dietary perturbations and study in quantitative terms when those changes take place.</p

Solid State Fluorination on the Minute Scale: Synthesis of WO₃₋ₓFx with Photocatalytic Activity

Solid state reactions are notoriously slow, because the rate‐limiting step is diffusion of atoms or ions through reactant, intermediate, and product crystalline phases. This requires days or even weeks of high temperature treatment, consuming large amounts of energy. Metal oxides are particularly difficult to react, because they have high melting points. The study reports a high‐speed solid state fluorination of WO₃ with Teflon to the oxyfluorides WO₃₋ₓFx on a minute (<10 min) scale by spark plasma sintering, a technique that is used typically for a high‐speed consolidation of powders. Automated electron diffraction analysis reveals an orthorhombic ReO₃‐type structure of WO₃₋ₓFx with F atom disorder as demonstrated by ¹⁹F magic angle spinning nuclear magnetic resonance spectroscopy. The potential of this new approach is demonstrated by the following results. i) Mixed‐ valent tungsten oxide fluorides WO₃₋ₓFx with high F content (0 < x < 0.65) are obtained as metastable products in copious amounts within minutes. ii) The spark plasma sintering technique yields WO₃₋ₓFx nanoparticles with high photocatalytic activity, whereas the corresponding bulk phases obtained by conventional solid‐state (ampoule) reactions have no photocatalytic activity. iii) The catalytic activity is caused by the microstructure originating from the processing by spark plasma sintering

Association of early life stress and cognitive performance in patients with schizophrenia and healthy controls

As core symptoms of schizophrenia, cognitive deficits contribute substantially to poor outcomes. Early life stress (ELS) can negatively affect cognition in patients with schizophrenia and healthy controls, but the exact nature of the mediating factors is unclear. Therefore, we investigated how ELS, education, and symptom burden are related to cognitive performance. The sample comprised 215 patients with schizophrenia (age, 42.9 ± 12.0 years; 66.0 % male) and 197 healthy controls (age, 38.5 ± 16.4 years; 39.3 % male) from the PsyCourse Study. ELS was assessed with the Childhood Trauma Screener (CTS). We used analyses of covariance and correlation analyses to investigate the association of total ELS load and ELS subtypes with cognitive performance. ELS was reported by 52.1 % of patients and 24.9 % of controls. Independent of ELS, cognitive performance on neuropsychological tests was lower in patients than controls (p < 0.001). ELS load was more closely associated with neurocognitive deficits (cognitive composite score) in controls (r = −0.305, p < 0.001) than in patients (r = −0.163, p = 0.033). Moreover, the higher the ELS load, the more cognitive deficits were found in controls (r = −0.200, p = 0.006), while in patients, this correlation was not significant after adjusting for PANSS. ELS load was more strongly associated with cognitive deficits in healthy controls than in patients. In patients, disease-related positive and negative symptoms may mask the effects of ELS-related cognitive deficits. ELS subtypes were associated with impairments in various cognitive domains. Cognitive deficits appear to be mediated through higher symptom burden and lower educational level

A genome-wide association study of the longitudinal course of executive functions

Executive functions are metacognitive capabilities that control and coordinate mental processes. In the transdiagnostic PsyCourse Study, comprising patients of the affective-to-psychotic spectrum and controls, we investigated the genetic basis of the time course of two core executive subfunctions: set-shifting (Trail Making Test, part B (TMT-B)) and updating (Verbal Digit Span backwards) in 1338 genotyped individuals. Time course was assessed with four measurement points, each 6 months apart. Compared to the initial assessment, executive performance improved across diagnostic groups. We performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with performance change over time by testing for SNP-by-time interactions using linear mixed models. We identified nine genome-wide significant SNPs for TMT-B in strong linkage disequilibrium with each other on chromosome 5. These were associated with decreased performance on the continuous TMT-B score across time. Variant rs150547358 had the lowest P value = 7.2 × 10(−10) with effect estimate beta = 1.16 (95% c.i.: 1.11, 1.22). Implementing data of the FOR2107 consortium (1795 individuals), we replicated these findings for the SNP rs150547358 (P value = 0.015), analyzing the difference of the two available measurement points two years apart. In the replication study, rs150547358 exhibited a similar effect estimate beta = 0.85 (95% c.i.: 0.74, 0.97). Our study demonstrates that longitudinally measured phenotypes have the potential to unmask novel associations, adding time as a dimension to the effects of genomics

The number of tree species on Earth

One of the most fundamental questions in ecology is how many species inhabit the Earth. However, due to massive logistical and financial challenges and taxonomic difficulties connected to the species concept definition, the global numbers of species, including those of important and well-studied life forms such as trees, still remain largely unknown. Here, based on global ground-sourced data, we estimate the total tree species richness at global, continental, and biome levels. Our results indicate that there are ∼73,000 tree species globally, among which ∼9,000 tree species are yet to be discovered. Roughly 40% of undiscovered tree species are in South America. Moreover, almost one-third of all tree species to be discovered may be rare, with very low populations and limited spatial distribution (likely in remote tropical lowlands and mountains). These findings highlight the vulnerability of global forest biodiversity to anthropogenic changes in land use and climate, which disproportionately threaten rare species and thus, global tree richness.Additional co-authors: Junho Lee, Jun Zhu, Jinyun Fang, Douglass F. Jacobs, Bryan Pijanowski, Arindam Banerjee, Robert A. Giaquinto, Giorgio Alberti, Angelica Maria Almeyda Zambrano, Esteban Alvarez-Davila, Alejandro Araujo-Murakami, Valerio Avitabile, Gerardo A. Aymard, Radomir Balazy, Chris Baraloto, Jorcely G. Barroso, Meredith L. Bastian, Philippe Birnbaum, Robert Bitariho, Jan Bogaert, Frans Bongers, Olivier Bouriaud, Pedro H. S. Brancalion, Francis Q. Brearley, Eben North Broadbent, Filippo Bussotti, Wendeson Castro da Silva, Ricardo Gomes César, Goran Češljar, Víctor Chama Moscoso, Han Y. H. Chen, Emil Cienciala, Connie J. Clark, David A. Coomes, Selvadurai Dayanandan, Mathieu Decuyper, Laura E. Dee, Jhon Del Aguila Pasquel, Géraldine Derroire, Marie Noel Kamdem Djuikouo, Tran Van Do, Jiri Dolezal, Ilija Đ. Đorđević, Julien Engel, Tom M. Fayle, Ted R. Feldpausch, Jonas K. Fridman, David J. Harris, Andreas Hemp, Geerten Hengeveld, Bruno Herault, Martin Herold, Thomas Ibanez, Andrzej M. Jagodzinski, Bogdan Jaroszewicz, Vivian Kvist Johannsen, Tommaso Jucker, Ahto Kangur, Victor N. Karminov, Kuswata Kartawinata, Deborah K. Kennard, Sebastian Kepfer-Rojas, Gunnar Keppel, Mohammed Latif Khan, Pramod Kumar Khare, Timothy J. Kileen, Hyun Seok Kim, Henn Korjus, Amit Kumar, Ashwani Kumar, Diana Laarmann, Nicolas Labrière, Mait Lang, Simon L. Lewis, Natalia Lukina, Brian S. Maitner, Yadvinder Malhi, Andrew R. Marshall, Olga V. Martynenko, Abel L. Monteagudo Mendoza, Petr V. Ontikov, Edgar Ortiz-Malavasi, Nadir C. Pallqui Camacho, Alain Paquette, Minjee Park, Narayanaswamy Parthasarathy, Pablo Luis Peri, Pascal Petronelli, Sebastian Pfautsch, Oliver L. Phillips, Nicolas Picard, Daniel Piotto, Lourens Poorter, John R. Poulsen, Hans Pretzsch, Hirma Ramírez-Angulo, Zorayda Restrepo Correa, Mirco Rodeghiero, Rocío Del Pilar Rojas Gonzáles, Samir G. Rolim, Francesco Rovero, Ervan Rutishauser, Purabi Saikia, Christian Salas-Eljatib, Dmitry Schepaschenko, Michael Scherer-Lorenzen, Vladimír Šebeň, Marcos Silveira, Ferry Slik, Bonaventure Sonké, Alexandre F. Souza, Krzysztof Jan Stereńczak, Miroslav Svoboda, Hermann Taedoumg, Nadja Tchebakova, John Terborgh, Elena Tikhonova, Armando Torres-Lezama, Fons van der Plas, Rodolfo Vásquez, Helder Viana, Alexander C. Vibrans, Emilio Vilanova, Vincent A. Vos, Hua-Feng Wang, Bertil Westerlund, Lee J. T. White, Susan K. Wiser, Tomasz Zawiła-Niedźwiecki, Lise Zemagho, Zhi-Xin Zhu, Irié C. Zo-Bi, and Jingjing Lian

The number of tree species on Earth

One of the most fundamental questions in ecology is how many species inhabit the Earth. However, due to massive logistical and financial challenges and taxonomic difficulties connected to the species concept definition, the global numbers of species, including those of important and well-studied life forms such as trees, still remain largely unknown. Here, based on global ground sourced data, we estimate the total tree species richness at global, continental, and biome levels. Our results indicate that there are ∼73,000 tree species globally, among which ∼9,000 tree species are yet to be discovered. Roughly 40% of undiscovered tree species are in South America. Moreover, almost one-third of all tree species to be discovered may be rare, with very low populations and limited spatial distribution (likely in remote tropical lowlands and mountains). These findings highlight the vulnerability of global forest biodiversity to anthropogenic changes in land use and climate, which disproportionately threaten rare species and thus, global tree richness. Please note an (erratum/corrigendum) for this article is available via https://www.pnas.org/doi/10.1073/pnas.220278411

Computational Lipidology: Predicting Lipoprotein Density Profiles in Human Blood Plasma

Monitoring cholesterol levels is strongly recommended to identify patients at risk for myocardial infarction. However, clinical markers beyond “bad” and “good” cholesterol are needed to precisely predict individual lipid disorders. Our work contributes to this aim by bringing together experiment and theory. We developed a novel computer-based model of the human plasma lipoprotein metabolism in order to simulate the blood lipid levels in high resolution. Instead of focusing on a few conventionally used predefined lipoprotein density classes (LDL, HDL), we consider the entire protein and lipid composition spectrum of individual lipoprotein complexes. Subsequently, their distribution over density (which equals the lipoprotein profile) is calculated. As our main results, we (i) successfully reproduced clinically measured lipoprotein profiles of healthy subjects; (ii) assigned lipoproteins to narrow density classes, named high-resolution density sub-fractions (hrDS), revealing heterogeneous lipoprotein distributions within the major lipoprotein classes; and (iii) present model-based predictions of changes in the lipoprotein distribution elicited by disorders in underlying molecular processes. In its present state, the model offers a platform for many future applications aimed at understanding the reasons for inter-individual variability, identifying new sub-fractions of potential clinical relevance and a patient-oriented diagnosis of the potential molecular causes for individual dyslipidemia