Microglial activation arises after aggregation of phosphorylated-tau in a neuron-specific P301S tauopathy mouse model

Alzheimer's disease, progressive supranuclear palsy and frontotemporal dementia are characterized by neuronal expression of aberrant tau protein, tau hyperphosphorylation (pTAU), tau aggregation and neurofibrillary tangle formation sequentially culminating into neuronal cell death, a process termed tauopathy. Our aim was to address at which tauopathy stage neuroinflammation starts and to study the related microglial phenotype. We used Thy1-hTau.P301S (PS) mice expressing human tau with a P301S mutation specifically in neurons. Significant levels of cortical pTAU were present from 2 months onwards. Dystrophic morphological complexity of cortical microglia arose after pTAU accumulation concomitant with increased microglial lysosomal volumes and a significant loss of homeostatic marker Tmem119. Interestingly, we detected increases in neuronal pTAU and postsynaptic structures in the lysosomes of PS microglia. Moreover, the overall cortical postsynaptic density was decreased in 6-month-old PS mice. Together, our results indicate that microglia adopt a pTAU-associated phenotype, and are morphologically and functionally distinct from wild-type microglia after neuronal pTAU accumulation has initiated

Genome-wide transcriptomic responses of the seagrasses Zostera marina and Nanozostera noltii under a simulated heatwave confirm functional types

Genome-wide transcription analysis between related species occurring in overlapping ranges can provide insights into the molecular basis underlying different ecological niches. The co-occurring seagrass species, Zostera marina and Nanozostera noltii, are found in marine coastal environments throughout the northern hemisphere. Z. marina is often dominant in subtidal environments and subjected to fewer temperature extremes compared to the predominately intertidal and more stress-tolerant N. noltii. We exposed plants of both species to a realistic heat wave scenario in a common-stress-garden experiment. Using RNA-seq (~ 7 million reads/library), four Z. marina and four N. noltii libraries were compared representing northern (Denmark) and southern (Italy) locations within the co-occurring range of the species' European distribution. A total of 8977 expressed genes were identified, of which 78 were directly related to heat stress. As predicted, both species were negatively affected by the heat wave, but showed markedly different molecular responses. In Z. marina the heat response was similar across locations in response to the heatwave at 26 °C, with a complex response in functions related to protein folding, synthesis of ribosomal chloroplast proteins, proteins involved in cell wall modification and heat shock proteins (HSPs). In N. noltii the heat response markedly differed between locations, while HSP genes were not induced in either population. Our results suggest that as coastal seawater temperatures increase, Z. marina will disappear along its southern most ranges, whereas N. noltii will continue to move north. As a consequence, sub- and intertidal habitat partitioning may weaken in more northern regions because the higher thermal tolerance of N. noltii provides a competitive advantage in both habitats. Although previous studies have focused on HSPs, the present study clearly demonstrates that a broader examination of stress related genes is necessary

Genomic analysis of natural intra-specific hybrids among Ethiopian isolates of Leishmania donovani.

Parasites of the genus Leishmania (Kinetoplastida: Trypanosomatidae) cause widespread and devastating human diseases. Visceral leishmaniasis due to Leishmania donovani is endemic in Ethiopia where it has also been responsible for major epidemics. The presence of hybrid genotypes has been widely reported in surveys of natural populations, genetic variation reported in a number of Leishmania species, and the extant capacity for genetic exchange demonstrated in laboratory experiments. However, patterns of recombination and the evolutionary history of admixture that produced these hybrid populations remain unclear. Here, we use whole-genome sequence data to investigate Ethiopian L. donovani isolates previously characterized as hybrids by microsatellite and multi-locus sequencing. To date there is only one previous study on a natural population of Leishmania hybrids based on whole-genome sequences. We propose that these hybrids originate from recombination between two different lineages of Ethiopian L. donovani occurring in the same region. Patterns of inheritance are more complex than previously reported with multiple, apparently independent, origins from similar parents that include backcrossing with parental types. Analysis indicates that hybrids are representative of at least three different histories. Furthermore, isolates were highly polysomic at the level of chromosomes with differences between parasites recovered from a recrudescent infection from a previously treated individual. The results demonstrate that recombination is a significant feature of natural populations and contributes to the growing body of data that shows how recombination, and gene flow, shape natural populations of Leishmania

Identifying core features of adaptive metabolic mechanisms for chronic heat stress attenuation contributing to systems robustness

The contribution of metabolism to heat stress may play a significant role in defining robustness and recovery of systems; either by providing the energy and metabolites required for cellular homeostasis, or through the generation of protective osmolytes. However, the mechanisms by which heat stress attenuation could be adapted through metabolic processes as a stabilizing strategy against thermal stress are still largely unclear. We address this issue through metabolomic and transcriptomic profiles for populations along a thermal cline where two seagrass species, Zostera marina and Zostera noltii, were found in close proximity. Significant changes captured by these profile comparisons could be detected, with a larger response magnitude observed in northern populations to heat stress. Sucrose, fructose, and myo-inositol were identified to be the most responsive of the 29 analyzed organic metabolites. Many key enzymes in the Calvin cycle, glycolysis and pentose phosphate pathways also showed significant differential expression. The reported comparison suggests that adaptive mechanisms are involved through metabolic pathways to dampen the impacts of heat stress, and interactions between the metabolome and proteome should be further investigated in systems biology to understand robust design features against abiotic stress

Targeting human prostate cancer with In-111-labeled D2B IgG, F(ab ')(2) and Fab fragments in nude mice with PSMA-expressing xenografts

D2B is a new monoclonal antibody directed against an extracellular domain of prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer. The potential of D2B IgG, and F(ab)(2) and Fab fragments of this antibody for targeting prostate cancer was determined in mice bearing subcutaneous prostate cancer xenografts. The optimal time point for imaging was determined in biodistribution and microSPECT imaging studies with In-111-D2B IgG, In-111-capromab pendetide, In-111-D2B F(ab)(2) and In-111-D2B Fab fragments in mice with PSMA-expressing LNCaP and PSMA-negative PC3 tumors at several time points after injection. All In-111-labeled antibody formats specifically accumulated in the LNCaP tumors, with highest uptake of In-111-D2B IgG and In-111-capromab pendetide at 168h p.i. (94.8 +/- 19.2% injected dose per gram (ID/g) and 16.7 +/- 2.2% ID/g, respectively), whereas uptake of In-111-D2B F(ab)(2) and In-111-D2B Fab fragments peaked at 24h p.i. (12.1 +/- 3.0% ID/g and 15.1 +/- 2.9% ID/g, respectively). Maximum LNCaP tumor-to-blood ratios were 13.0 +/- 2.3 (168h p.i.), 6.2 +/- 0.7 (24h p.i.), 23.0 +/- 4.0 (24h p.i.) and 4.5 +/- 0.6 (168h p.i.) for In-111-D2B IgG, In-111-F(ab)(2), In-111-Fab and In-111-capromab pendetide, respectively. LNCaP tumors were clearly visualized with microSPECT with all antibody formats. This study demonstrates the feasibility of D2B IgG, F(ab)(2) and Fab fragments for targeting PSMA-expressing prostate cancer xenografts. Copyright (c) 2014 John Wiley & Sons, Ltd

Comprehensive transcriptome analysis of the highly complex Pisum sativum genome using next generation sequencing

<p>Abstract</p> <p>Background</p> <p>The garden pea, <it>Pisum sativum</it>, is among the best-investigated legume plants and of significant agro-commercial relevance. <it>Pisum sativum </it>has a large and complex genome and accordingly few comprehensive genomic resources exist.</p> <p>Results</p> <p>We analyzed the pea transcriptome at the highest possible amount of accuracy by current technology. We used next generation sequencing with the Roche/454 platform and evaluated and compared a variety of approaches, including diverse tissue libraries, normalization, alternative sequencing technologies, saturation estimation and diverse assembly strategies. We generated libraries from flowers, leaves, cotyledons, epi- and hypocotyl, and etiolated and light treated etiolated seedlings, comprising a total of 450 megabases. Libraries were assembled into 324,428 unigenes in a first pass assembly.</p> <p>A second pass assembly reduced the amount to 81,449 unigenes but caused a significant number of chimeras. Analyses of the assemblies identified the assembly step as a major possibility for improvement. By recording frequencies of Arabidopsis orthologs hit by randomly drawn reads and fitting parameters of the saturation curve we concluded that sequencing was exhaustive. For leaf libraries we found normalization allows partial recovery of expression strength aside the desired effect of increased coverage. Based on theoretical and biological considerations we concluded that the sequence reads in the database tagged the vast majority of transcripts in the aerial tissues. A pathway representation analysis showed the merits of sampling multiple aerial tissues to increase the number of tagged genes. All results have been made available as a fully annotated database in fasta format.</p> <p>Conclusions</p> <p>We conclude that the approach taken resulted in a high quality - dataset which serves well as a first comprehensive reference set for the model legume pea. We suggest future deep sequencing transcriptome projects of species lacking a genomics backbone will need to concentrate mainly on resolving the issues of redundancy and paralogy during transcriptome assembly.</p

Rationale and study design of the prospective, longitudinal, observational cohort study “rISk strAtification in end-stage renal disease” (ISAR) study

Background: The ISAR study is a prospective, longitudinal, observational cohort study to improve the cardiovascular risk stratification in endstage renal disease (ESRD). The major goal is to characterize the cardiovascular phenotype of the study subjects, namely alterations in micro-and macrocirculation and to determine autonomic function. Methods/design: We intend to recruit 500 prevalent dialysis patients in 17 centers in Munich and the surrounding area. Baseline examinations include: (1) biochemistry, (2) 24-h Holter Electrocardiography (ECG) recordings, (3) 24-h ambulatory blood pressure measurement (ABPM), (4) 24 h pulse wave analysis (PWA) and pulse wave velocity (PWV), (5) retinal vessel analysis (RVA) and (6) neurocognitive testing. After 24 months biochemistry and determination of single PWA, single PWV and neurocognitive testing are repeated. Patients will be followed up to 6 years for (1) hospitalizations, (2) cardiovascular and (3) non-cardiovascular events and (4) cardiovascular and (5) all-cause mortality. Discussion/conclusion: We aim to create a complex dataset to answer questions about the insufficiently understood pathophysiology leading to excessively high cardiovascular and non-cardiovascular mortality in dialysis patients. Finally we hope to improve cardiovascular risk stratification in comparison to the use of classical and non-classical (dialysis-associated) risk factors and other models of risk stratification in ESRD patients by building a multivariable Cox-Regression model using a combination of the parameters measured in the study

Flexibilität in der Verteidigung mariner Makroalgen gegen Fraß: der Einfluss der Größe des Fraßdrucks auf die Induktion einer Verteidigung

Fraßbefall kann sehr intensiv sein und einen starken Einfluss auf die Strukturierung mariner Küustenökosysteme ausüben. Marine Makroalgen haben unterschiedliche Strategien entwickelt sich vor zu großem, durch Fraßfeinde verursachten Schaden zu schützen. Eine Möglichkeit ist die Induktion einer chemischen oder morphologischen Verteidigung. Es gibt mehrere Hypothesen über die Vorteile einer Verteidigungsinduktion im Gegensatzsatz zu einer konstitutiven (d.h. fortwährend anwesenden) Verteidigung. Eine geht davon aus, dass das Bereitstellen einer Verteidigung Kosten für die Pflanze verursacht. Es verschafft der Pflanze somit einen Fitnessvorteil, wenn sie in der Lage ist ihre Ressourcen bei nicht oder nur schwach vorhandenem Fraßdruck anderweitig zu nutzen. In diesem Zusammenhang stellt sich die Frage, inwieweit die Verteidigungsinduktion flexibel auf unterschiedlich starken Fraßdruck reagieren kann. In dieser Studie wurden fünf verschiedene Braunalgen (Carpophyllum flexuosum, Carpophyllum maschalocarpum, Carpophyllum plumosum, Cystophora torulosa und Cystophora retroflexa), heimisch an der Nordost-Küste Neuseelands, auf ihre Fähigkeit zur Verteidigungsinduktion als Antwort auf Fraßbefall durch die Isopodenart Batedotea elongata getestet. Algenstücke wurden über einen Zeitraum von 15 Tagen in Anwesenheit von Fraßfeinden (Behandlung) und in deren Abwesenheit (Kontrolle) gehältert. Die Probenentnahme erfolgte von Tag 1 des Experiments beginnend an jedem dritten Tag. Die Induktion einer Verteidigung, wurde über die Konsumptionsraten des Weidegängers B. elongata in Zwei-Wege-Fraßversuchen mit zuvor stimuliertem und nicht-stimuliertem, lebendem Algenmaterial festgestellt. Für C. flexuosum, die einzige Algenart, die die Induktion einer Verteidigung zeigte, wurde ein solches Induktionsexperiment für drei verschiedene Herbivorendichten wiederholt. Zwei-Wege-Fraßversuche wurden mit lebendem Algenmaterial und zusätzlich für einige Tage mit Futterpellets aus homogenisiertem Algenmaterial durchgeführt. Die Ergebnisse zeigen eine geringere Konsumption an zuvor stimuliertem Algenmaterial in lebendem wie auch in homogenisiertem Zustand. Dieser Efekt trat bei jeder Herbivorendichte nur an einem Tag im Zeitraum von 15 Tagen auf. In den Fraßversuchen mit lebendem Algenmaterial wurden Kontrollalgen der beiden niedrigeren Herbivorendichten an Tag 15 bevorzugt. Diese Präferenz war bei der höchsten Herbivorendichte bereits drei Tage früher vorhanden. Ein Unterschied in der Stärke der Verteidigung in den Algen, die unterschiedlichen Herbivorendichten ausgesetzt waren, konnte nicht festgestellt werden. Aufgrund dieser Ergebnisse ist es möglich, dass eine induzierte Verteidigung bei anhaltendem Fraßdruck als kurzzeitig anwesender Impuls auftritt. Dieser wird bei größerem Fraßbefall schneller induziert, ohne dass die Stärke des Impulses beeinflusst wird

A way straight-forward for Leishmania genetics

Genetic exchange between Leishmania parasites was demonstrated in sandflies over 10 years ago. Louradour et al. have shown in vitro hybridization of two Leishmania tropica isolates, with the potential to remove a major roadblock to using forward genetics in Leishmania, understanding Leishmania reproductive biology, and analyzing gene flow in natural populations

Data from: Uncovering the genetic signature of quantitative trait evolution with replicated time series data

The genetic architecture of adaptation in natural populations has not yet been resolved: it is not clear to what extent the spread of beneficial mutations (selective sweeps) or the response of many quantitative trait loci drive adaptation to environmental changes. Although much attention has been given to the genomic footprint of selective sweeps, the importance of selection on quantitative traits is still not well studied, as the associated genomic signature is extremely difficult to detect. We propose ‘Evolve and Resequence’ as a promising tool, to study polygenic adaptation of quantitative traits in evolving populations. Simulating replicated time series data we show that adaptation to a new intermediate trait optimum has three characteristic phases that are reflected on the genomic level: (1) directional frequency changes towards the new trait optimum, (2) plateauing of allele frequencies when the new trait optimum has been reached and (3) subsequent divergence between replicated trajectories ultimately leading to the loss or fixation of alleles while the trait value does not change. We explore these 3 phase characteristics for relevant population genetic parameters to provide expectations for various experimental evolution designs. Remarkably, over a broad range of parameters the trajectories of selected alleles display a pattern across replicates, which differs both from neutrality and directional selection. We conclude that replicated time series data from experimental evolution studies provide a promising framework to study polygenic adaptation from whole-genome population genetics data