Showing papers by "Ludwig Maximilian University of Munich published in 2007"

Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.

Abstract: The distinct protein aggregates that are found in Alzheimer's, Parkinson's, Huntington's and prion diseases seem to cause these disorders. Small intermediates - soluble oligomers - in the aggregation process can confer synaptic dysfunction, whereas large, insoluble deposits might function as reservoirs of the bioactive oligomers. These emerging concepts are exemplified by Alzheimer's disease, in which amyloid beta-protein oligomers adversely affect synaptic structure and plasticity. Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.

Bias in random forest variable importance measures: Illustrations, sources and a solution

Abstract: Variable importance measures for random forests have been receiving increased attention as a means of variable selection in many classification tasks in bioinformatics and related scientific fields, for instance to select a subset of genetic markers relevant for the prediction of a certain disease. We show that random forest variable importance measures are a sensible means for variable selection in many applications, but are not reliable in situations where potential predictor variables vary in their scale of measurement or their number of categories. This is particularly important in genomics and computational biology, where predictors often include variables of different types, for example when predictors include both sequence data and continuous variables such as folding energy, or when amino acid sequence data show different numbers of categories. Simulation studies are presented illustrating that, when random forest variable importance measures are used with data of varying types, the results are misleading because suboptimal predictor variables may be artificially preferred in variable selection. The two mechanisms underlying this deficiency are biased variable selection in the individual classification trees used to build the random forest on one hand, and effects induced by bootstrap sampling with replacement on the other hand. We propose to employ an alternative implementation of random forests, that provides unbiased variable selection in the individual classification trees. When this method is applied using subsampling without replacement, the resulting variable importance measures can be used reliably for variable selection even in situations where the potential predictor variables vary in their scale of measurement or their number of categories. The usage of both random forest algorithms and their variable importance measures in the R system for statistical computing is illustrated and documented thoroughly in an application re-analyzing data from a study on RNA editing. Therefore the suggested method can be applied straightforwardly by scientists in bioinformatics research.

Evolution of genes and genomes on the Drosophila phylogeny.

Abstract: Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

The international classification for functioning, disability and health. A challenge and a need for rheumatology.

Abstract: The rheumatologic community is in a leading position for the development of International Classification of Functioning, Disability and Health (ICF) Core Sets and the research into the validity and application of the ICF We can be proud of this achievement, but not all of us are aware of this new development What is the ICF? Rheumatologic conditions have major impact on patients Apart from symptoms such as pain, stiffness, and fatigue, patients are limited in activities and restricted in participation in society [2] When unable to continue paid work, for example, there are important consequences for the patients, their families, but also for society A major goal of the management of rheumatic diseases is to maintain or restore functioning This contributes to the well-being of the patients, their families, and other caregivers It is clear that maintaining function requires more than control of disease activity By using the ICF, which was developed by the World Health Organization (WHO), we can obtain information on all three areas that are important for global functioning: body functions and structures, activities (actions by an individual), and participation (involvement in life situations) [3] The ICF is one of the three reference classification systems that were proposed and developed by the WHO and belong to the Family of International Classifications The main aim of the classification systems is to improve integration of health information The International Classification of Diagnosis (ICD) is well known and widely applied [4] The ICF was developed from the older International Classification of Impairments, Disabilities, and Handicaps (ICIDH) and accepted in 2001 [3] It is increasingly recognized as an important classification in clinical medicine, outcome research, and healthcare organization The International Classification of Health Interventions (ICHI) is proposed as the newest member of the family, and its development has just started [1] The WHO aims to implement effectively the ICF worldwide and formulated strategic directions in which the three following are the most relevant: (1) The ICF has to become the framework to classify function, (2) easy-to-use ICF linked instruments should be developed to assess functional outcome as well as effectiveness of interventions, and (3) the level and quality of implementation of the ICF should be improved to increase quality and comparability Clin Rheumatol (2007) 26:1803–1808 DOI 101007/s10067-007-0623-0

Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma

Abstract: Rates of childhood asthma diagnosis are rising: 6% of children in the United States are sufferers. Both genetic and environmental factors are clearly important. To discover more about the genetic element, Moffatt et al. looked for genes linked to asthma in a genome-wide association scan. More than a third of children with asthma of onset below the age of seven showed variations in expression of the ORMDL3 gene on chromosome 17. Similar genes are found in yeast and other primitive organisms, suggesting that they may be components of an ancient and conserved immune mechanism. Variations in expression of the gene ORMDL3 were found to be associated with development of childhood asthma, suggesting this gene should be examined in more patient groups. Asthma is caused by a combination of poorly understood genetic and environmental factors1,2. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum3. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

Material differentiation by dual energy CT: initial experience

Abstract: The aim of this study was to assess the feasibility of a differentiation of iodine from other materials and of different body tissues using dual energy CT. Ten patients were scanned on a SOMATOM Definition Dual Source CT (DSCT; Siemens, Forchheim, Germany) system in dual energy mode at tube voltages of 140 and 80 kVp and a ratio of 1:3 between tube currents. Weighted CT Dose Index ranged between 7 and 8 mGy, remaining markedly below reference dose values for the respective body regions. Image post-processing with three-material decomposition was applied to differentiate iodine or collagen from other tissue. The results showed that a differentiation and depiction of contrast material distribution is possible in the brain, the lung, the liver and the kidneys with or without the underlying tissue of the organ. In angiographies, bone structures can be removed from the dataset to ease the evaluation of the vessels. The differentiation of collagen makes it possible to depict tendons and ligaments. Dual energy CT offers a more specific tissue characterization in CT and can improve the assessment of vascular disease. Further studies are required to draw conclusions on the diagnostic value of the individual applications.

Translocation of proteins into mitochondria.

Abstract: About 10% to 15% of the nuclear genes of eukaryotic organisms encode mitochondrial proteins. These proteins are synthesized in the cytosol and recognized by receptors on the surface of mitochondria. Translocases in the outer and inner membrane of mitochondria mediate the import and intramitochondrial sorting of these proteins; ATP and the membrane potential are used as energy sources. Chaperones and auxilliary factors assist in the folding and assembly of mitochondrial proteins into their native, three-dimensional structures. This review summarizes the present knowledge on the import and sorting of mitochondrial precursor proteins, with a special emphasis on unresolved questions and topics of current research.

Venous thromboembolism (VTE) in Europe - The number of VTE events and associated morbidity and mortality

Abstract: Venous thromboembolism (VTE) is often asymptomatic, mis-diagnosed, and unrecognized at death, and there is a lack of routine postmortem examinations. These factors are thought to result in marked underestimates ofVTE incidence. The objective of our study was to estimate the total burden of VTE within the European Union (EU) per annum. An epidemiological model was constructed to estimate the number of community- and hospital-acquired incidents and recurrent cases (attack rate) of nonfatal VTE and VTE-related deaths, as well as incident and prevalent cases of post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary hypertension (PH) occurring in the EU per annum. Individual models were developed for six EU countries. The models were populated with data from published literature and, where necessary, expert opinions. The findings were tested using probabilistic sensitivity analyses. The estimated total number of symptomaticVTE events (range based on probabilistic sensitivity analysis) per annum within the six EU countries was 465,715 (404,664-538,189) cases of deep-vein thrombosis, 295,982 (242,450-360,363) cases of pulmonary embolism (PE), and 370,012 (300,193-483,108) VTE-related deaths. Of these deaths, an estimated 27,473 (7%) were diagnosed as being antemortem; 126,145 (34%) were sudden fatal PE, and 217,394 (59%) followed undiagnosed PE. Almost three-quarters of all VTE-related deaths were from hospital-acquired VTE. VTE is a major health problem in the EU, with over one million VTE events or deaths per annum in the six countries examined. Given the availability of effective VTE prophylaxis, many of these events and deaths could have been prevented. These results have important implications for the allocation of healthcare resources.

Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer: A Validation Study of the CellSearch System

Abstract: Purpose: The CellSearch system (Veridex, Warren, NJ) is designed to enrich and enumerate circulating tumor cells (CTCs) from peripheral blood. Here, we validated the analytic performance of this system for clinical use in patients with metastatic breast cancer. Experimental Design: This prospective multicenter study conducted at three independent laboratories involved samples from 92 patients with metastatic breast cancer. Intra- and inter-assay variability using controls containing defined numbers of cells (average, 50 and 1,000, respectively), cell stability based on varying storage and shipment conditions, recovery precision from samples spiked with 4 to 12 tumor cells, inter-instrument variability, and positivity of samples from metastatic breast cancer patients were tested. Results: Intra- and inter-assay precision for two sites were high: All eight positive controls analyzed in the same run and >95% of the run to run control values ( n = 299) were within the specified ranges. Recovery rate of spiked samples averaged between 80% and 82%. CTCs were detected in ∼70% of metastatic breast cancer patients. CTC values of identical samples processed either immediately after blood drawing or after storage for 24, 48, or 72 h at room temperature or at 4°C did not differ significantly. Shipment of samples had no influence on CTC values. When analyzing identical samples in different centers, inter-instrument accordance was high. Conclusions: The CellSearch system enables the reliable detection of CTCs in blood and is suitable for the routine assessment of metastatic breast cancer patients in the clinical laboratory. Blood samples should be shipped at room temperature and CTC counts are stable for at least 72 h.

MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment

Abstract: The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G αi- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition. © 2007 Nature Publishing Group.

Entanglement-based quantum communication over 144km

Abstract: Quantum entanglement is the main resource to endow the field of quantum information processing with powers that exceed those of classical communication and computation. In view of applications such as quantum cryptography or quantum teleportation, extension of quantum-entanglement-based protocols to global distances is of considerable practical interest. Here we experimentally demonstrate entanglement-based quantum key distribution over 144 km. One photon is measured locally at the Canary Island of La Palma, whereas the other is sent over an optical free-space link to Tenerife, where the Optical Ground Station of the European Space Agency acts as the receiver. This exceeds previous free-space experiments by more than an order of magnitude in distance, and is an essential step towards future satellite-based quantum communication and experimental tests on quantum physics in space.

Quantum Theory of Cavity-Assisted Sideband Cooling of Mechanical Motion

Abstract: We present a quantum-mechanical theory of the cooling of a cantilever coupled via radiation pressure to an illuminated optical cavity. Applying the quantum noise approach to the fluctuations of the radiation pressure force, we derive the optomechanical cooling rate and the minimum achievable phonon number. We find that reaching the quantum limit of arbitrarily small phonon numbers requires going into the good-cavity (resolved phonon sideband) regime where the cavity linewidth is much smaller than the mechanical frequency and the corresponding cavity detuning. This is in contrast to the common assumption that the mechanical frequency and the cavity detuning should be comparable to the cavity damping.

Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration

Abstract: The aim of this study was to improve the neuropathologic recognition and provide criteria for the pathological diagnosis in the neurodegenerative diseases grouped as frontotemporal lobar degeneration (FTLD); revised criteria are proposed. Recent advances in molecular genetics, biochemistry, and neuropathology of FTLD prompted the Midwest Consortium for Frontotemporal Lobar Degeneration and experts at other centers to review and revise the existing neuropathologic diagnostic criteria for FTLD. The proposed criteria for FTLD are based on existing criteria, which include the tauopathies [FTLD with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, sporadic multiple system tauopathy with dementia, argyrophilic grain disease, neurofibrillary tangle dementia, and FTD with microtubule-associated tau (MAPT) gene mutation, also called FTD with parkinsonism linked to chromosome 17 (FTDP-17)]. The proposed criteria take into account new disease entities and include the novel molecular pathology, TDP-43 proteinopathy, now recognized to be the most frequent histological finding in FTLD. TDP-43 is a major component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). Molecular genetic studies of familial cases of FTLD-U have shown that mutations in the progranulin (PGRN) gene are a major genetic cause of FTLD-U. Mutations in valosin-containing protein (VCP) gene are present in rare familial forms of FTD, and some families with FTD and/or MND have been linked to chromosome 9p, and both are types of FTLD-U. Thus, familial TDP-43 proteinopathy is associated with defects in multiple genes, and molecular genetics is required in these cases to correctly identify the causative gene defect. In addition to genetic heterogeneity amongst the TDP-43 proteinopathies, there is also neuropathologic heterogeneity and there is a close relationship between genotype and FTLD-U subtype. In addition to these recent significant advances in the neuropathology of FTLD-U, novel FTLD entities have been further characterized, including neuronal intermediate filament inclusion disease. The proposed criteria incorporate up-to-date neuropathology of FTLD in the light of recent immunohistochemical, biochemical, and genetic advances. These criteria will be of value to the practicing neuropathologist and provide a foundation for clinical, clinico-pathologic, mechanistic studies and in vivo models of pathogenesis of FTLD.

Selective changes of resting-state networks in individuals at risk for Alzheimer's disease

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder that prominently affects cerebral connectivity. Assessing the functional connectivity at rest, recent functional MRI (fMRI) studies reported on the existence of resting-state networks (RSNs). RSNs are characterized by spatially coherent, spontaneous fluctuations in the blood oxygen level-dependent signal and are made up of regional patterns commonly involved in functions such as sensory, attention, or default mode processing. In AD, the default mode network (DMN) is affected by reduced functional connectivity and atrophy. In this work, we analyzed functional and structural MRI data from healthy elderly (n = 16) and patients with amnestic mild cognitive impairment (aMCI) (n = 24), a syndrome of high risk for developing AD. Two questions were addressed: (i) Are any RSNs altered in aMCI? (ii) Do changes in functional connectivity relate to possible structural changes? Independent component analysis of resting-state fMRI data identified eight spatially consistent RSNs. Only selected areas of the DMN and the executive attention network demonstrated reduced network-related activity in the patient group. Voxel-based morphometry revealed atrophy in both medial temporal lobes (MTL) of the patients. The functional connectivity between both hippocampi in the MTLs and the posterior cingulate of the DMN was present in healthy controls but absent in patients. We conclude that in individuals at risk for AD, a specific subset of RSNs is altered, likely representing effects of ongoing early neurodegeneration. We interpret our finding as a proof of principle, demonstrating that functional brain disorders can be characterized by functional-disconnectivity profiles of RSNs.

The Control-Value Theory of Achievement Emotions: An Integrative Approach to Emotions in Education

Abstract: Publisher Summary This chapter presents an overview of the assumptions and corollaries of the control-value theory of achievement emotions, as well as some of its implications for educational practice. The control-value theory provides a theoretical framework making it possible to integrate constructs and assumptions from a variety of theoretical approaches to emotions in education and to achievement emotions more generally. Empirically, many facets of the theory have consistently been corroborated in qualitative and quantitative investigations. However, the assumptions provided by the theory on how to design emotionally sound learning environments for students, and occupational environments for teachers, have yet to be tested in empirical intervention studies. There is evidence that educational interventions can reduce students' test anxiety. The control-value theory implies that shaping educational environments in adequate ways can help to change achievement emotions other than anxiety as well. Future research should systematically explore measures to help both students and teachers to develop adaptive achievement emotions, prevent maladaptive emotions, and use their emotions in productive and healthy ways.

Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations

Abstract: Objective Amyotrophic lateral sclerosis (ALS) is a common, fatal motor neuron disorder with no effective treatment. Approximately 10% of cases are familial ALS (FALS), and the most common genetic abnormality is superoxide dismutase-1 (SOD1) mutations. Most ALS research in the past decade has focused on the neurotoxicity of mutant SOD1, and this knowledge has directed therapeutic strategies. We recently identified TDP-43 as the major pathological protein in sporadic ALS. In this study, we investigated TDP-43 in a larger series of ALS cases (n = 111), including familial cases with and without SOD1 mutations. Methods Ubiquitin and TDP-43 immunohistochemistry was performed on postmortem tissue from sporadic ALS (n = 59), ALS with SOD1 mutations (n = 15), SOD-1–negative FALS (n = 11), and ALS with dementia (n = 26). Biochemical analysis was performed on representative cases from each group. Results All cases of sporadic ALS, ALS with dementia, and SOD1-negative FALS had neuronal and glial inclusions that were immunoreactive for both ubiquitin and TDP-43. Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43. Biochemical analysis of postmortem tissue from sporadic ALS and SOD1-negative FALS demonstrated pathological forms of TDP-43 that were absent in cases with SOD1 mutations. Interpretation These findings implicate pathological TDP-43 in the pathogenesis of sporadic ALS. In contrast, the absence of pathological TDP-43 in cases with SOD1 mutations implies that motor neuron degeneration in these cases may result from a different mechanism, and that cases with SOD1 mutations may not be the familial counterpart of sporadic ALS. Ann Neurol 2007;61:427–434

Extraction, purification and analysis of histones.

Abstract: Histone proteins are the major protein components of chromatin, the physiologically relevant form of the genome (or epigenome) in all eukaryotic cells Chromatin is the substrate of many biological processes, such as gene regulation and transcription, replication, mitosis and apoptosis Since histones are extensively post-translationally modified, the identification of these covalent marks on canonical and variant histones is crucial for the understanding of their biological significance Many different biochemical techniques have been developed to purify and separate histone proteins Here, we present standard protocols for acid extraction and salt extraction of histones from chromatin; separation of extracted histones by reversed-phase HPLC; analysis of histones and their specific post-translational modification profiles by acid urea (AU) gel electrophoresis and the additional separation of non-canonical histone variants by triton AU(TAU) and 2D TAU electrophoresis; and immunoblotting of isolated histone proteins with modification-specific antibodies

Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition

Abstract: Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis; however, the underlying mechanisms are not well defined. To examine the role of hypoxia-inducible factor–1 (HIF-1), a key mediator of cellular adaptation to hypoxia, in the development of fibrosis in mice, we inactivated Hif-1α in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP–mediated gene targeting. We found that Hif-1α enhanced epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1α inhibited the development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and a reduction in the number of fibroblast-specific protein–1–expressing (FSP-1–expressing) interstitial cells. Furthermore, we demonstrate that increased renal HIF-1α expression is associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, we provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis by increasing expression of extracellular matrix–modifying factors and lysyl oxidase genes and by facilitating EMT.

Measurement of signal‐to‐noise ratios in MR images: Influence of multichannel coils, parallel imaging, and reconstruction filters

Abstract: Purpose To evaluate the validity of different approaches to determine the signal-to-noise ratio (SNR) in MRI experiments with multi-element surface coils, parallel imaging, and different reconstruction filters. Materials and Methods Four different approaches of SNR calculation were compared in phantom measurements and in vivo based on: 1) the pixel-by-pixel standard deviation (SD) in multiple repeated acquisitions; 2) the signal statistics in a difference image; and 3) and 4) the statistics in two separate regions of a single image employing either the mean value or the SD of background noise. Different receiver coil systems (with one and eight channels), acquisitions with and without parallel imaging, and five different reconstruction filters were compared. Results Averaged over all phantom measurements, the deviations from the reference value provided by the multiple-acquisitions method are 2.7% (SD 1.6%) for the difference method, 37.7% (25.9%) for the evaluation of the mean value of background noise, and 34.0% (38.1%) for the evaluation of the SD of background noise. Conclusion The conventionally determined SNR based on separate signal and noise regions in a single image will in general not agree with the true SNR measured in images after the application of certain reconstruction filters, multichannel reconstruction, or parallel imaging. J. Magn. Reson. Imaging 2007. © 2007 Wiley-Liss, Inc.

The evolution of sex-biased genes and sex-biased gene expression.

Abstract: Differences between males and females in the optimal phenotype that is favoured by selection can be resolved by the evolution of differential gene expression in the two sexes. Microarray experiments have shown that such sex-biased gene expression is widespread across organisms and genomes. Sex-biased genes show unusually rapid sequence evolution, are often labile in their pattern of expression, and are non-randomly distributed in the genome. Here we discuss the characteristics and expression of sex-biased genes, and the selective forces that shape this previously unappreciated source of phenotypic diversity. Sex-biased gene expression has implications beyond just evolutionary biology, including for medical genetics.

Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions

Abstract: The regulation of gene expression is mediated by interactions between chromatin and protein complexes. The importance of where and when these interactions take place in the nucleus is currently a subject of intense investigation. Increasing evidence indicates that gene activation or silencing is often associated with repositioning of the locus relative to nuclear compartments and other genomic loci. At the same time, however, structural constraints impose limits on chromatin mobility. Understanding how the dynamic nature of the positioning of genetic material in the nuclear space and the higher-order architecture of the nucleus are integrated is therefore essential to our overall understanding of gene regulation.

Unmasking melon by a complementary approach employing electron diffraction, solid-state NMR spectroscopy, and theoretical calculations: Structural characterization of a carbon nitride polymer

Abstract: Poly(aminoimino)heptazine, otherwise known as Liebig's melon, whose composition and structure has been subject to multitudinous speculations, was synthesized from melamine at 630 degrees C under the pressure of ammonia. Electron diffraction, solid-state NMR spectroscopy, and theoretical calculations revealed that the nanocrystalline material exhibits domains well-ordered in two dimensions, thereby allowing the structure solution in projection by electron diffraction. Melon ([C(6)N(7)(NH(2))(NH)](n), plane group p2 gg, a=16.7, b=12.4 A, gamma=90 degrees, Z=4), is composed of layers made up from infinite 1D chains of NH-bridged melem (C(6)N(7)(NH(2))(3)) monomers. The strands adopt a zigzag-type geometry and are tightly linked by hydrogen bonds to give a 2D planar array. The inter-layer distance was determined to be 3.2 A from X-ray powder diffraction. The presence of heptazine building blocks, as well as NH and NH(2) groups was confirmed by (13)C and (15)N solid-state NMR spectroscopy using (15)N-labeled melon. The degree of condensation of the heptazine core was further substantiated by a (15)N direct excitation measurement. Magnetization exchange observed between all (15)N nuclei using a fp-RFDR experiment, together with the CP-MAS data and elemental analysis, suggests that the sample is mainly homogeneous in terms of its basic composition and molecular building blocks. Semiempirical, force field, and DFT/plane wave calculations under periodic boundary conditions corroborate the structure model obtained by electron diffraction. The overall planarity of the layers is confirmed and a good agreement is obtained between the experimental and calculated NMR chemical shift parameters. The polymeric character and thermal stability of melon might render this polymer a pre-stage of g-C(3)N(4) and portend its use as a promising inert material for a variety of applications in materials and surface science.

Chitin induces accumulation in tissue of innate immune cells associated with allergy

Abstract: Allergic and parasitic worm immunity is characterized by infiltration of tissues with interleukin (IL)-4- and IL-13-expressing cells, including T-helper-2 cells, eosinophils and basophils. Tissue macrophages assume a distinct phenotype, designated alternatively activated macrophages. Relatively little is known about the factors that trigger these host responses. Chitin, a widespread environmental biopolymer of N-acetyl-beta-D-glucosamine, provides structural rigidity to fungi, crustaceans, helminths and insects. Here, we show that chitin induces the accumulation in tissue of IL-4-expressing innate immune cells, including eosinophils and basophils, when given to mice. Tissue infiltration was unaffected by the absence of Toll-like-receptor-mediated lipopolysaccharide recognition but did not occur if the injected chitin was pre-treated with the IL-4- and IL-13-inducible mammalian chitinase, AMCase, or if the chitin was injected into mice that overexpressed AMCase. Chitin mediated alternative macrophage activation in vivo and the production of leukotriene B(4), which was required for optimal immune cell recruitment. Chitin is a recognition element for tissue infiltration by innate cells implicated in allergic and helminth immunity and this process can be negatively regulated by a vertebrate chitinase.