Explore the vast range of titles available.

There is increasing evidence from genetic, biochemical, pharmacological, neuroimaging and post-mortem studies that immunological dysregulation plays a crucial role in the pathogenesis of psychoses. The involvement of microglia in schizophrenia and bipolar disorder (BD) has remained controversial, however, since results from various post-mortem studies are still inconclusive. Here, we analyzed the estimated density of microglia of age-matched individuals with schizophrenia (n = 17), BD (n = 13), and non-psychiatric control subjects (n = 17) in the anterior midcingulate cortex (aMCC), a brain area putatively involved in the pathogenesis of psychoses, using ionized calcium binding adaptor molecule 1 (Iba1)—immunohistochemistry. The microglial cells displayed a homogenously distributed Iba1—staining pattern in the aMCC with slightly varying activation states in all three groups. The estimated microglial densities did not differ significantly between individuals with schizophrenia, BD and control subjects. Remarkably, when both hemispheres were investigated separately within the three groups, the density was significantly lateralized towards the right aMCC in schizophrenia (p = 0.01) and—even more evident—in BD subjects (p = 0.008). This left–right lateralization was not observed in the control group (p = 0.52). Of note, microglial density was significantly lower in BD individuals who did not commit suicide compared with BD individuals who died from suicide (p = 0.002). This difference was not observed between individuals with BD who committed suicide and controls. The results, tentatively interpreted, suggest a hitherto unknown increased lateralization of microglial density to the right hemisphere in both psychiatric groups. If confirmed in independent samples, lateralization should be considered in all post-mortem studies on microglia. Density differences between suicide and non-suicide individuals needs further elucidation.

Summary The obligate intracellular pathogen Coxiella burnetii replicates in a large phagolysosomal‐like vacuole. Currently, both host and bacterial factors required for creating this replicative parasitophorous C. burnetii‐containing vacuole (PV) are poorly defined. Here, we assessed the contributions of the most abundant proteins of the lysosomal membrane, LAMP‐1 and LAMP‐2, to the establishment and maintenance of the PV. Whereas these proteins were not critical for uptake of C. burnetii, they influenced the intracellular replication of C. burnetii. In LAMP‐1/2 double‐deficient fibroblasts as well as in LAMP‐1/2 knock‐down cells, C. burnetii establishes a significantly smaller, yet faster maturing vacuole, which harboured more bacteria. The accelerated maturation of PVs in LAMP double‐deficient fibroblasts, which was partially or fully reversed by ectopic expression of LAMP‐1 or LAMP‐2, respectively, was characterized by an increased fusion rate with endosomes, lysosomes and bead‐containing phagosomes, but not by different fusion kinetics with autophagy vesicles. These findings establish that LAMP proteins are critical for the maturation delay of PVs. Unexpectedly, neither the creation of the spacious vacuole nor the delay in maturation was found to be prerequisites for the intracellular replication of C. burnetii.

Homospermidine synthase (HSS), the first pathway-specific enzyme of pyrrolizidine alkaloid biosynthesis, is known to have its origin in the duplication of a gene encoding deoxyhypusine synthase. To study the processes that followed this gene duplication event and gave rise to HSS, we identified sequences encoding HSS and deoxyhypusine synthase from various species of the Convolvulaceae. We show that HSS evolved only once in this lineage. This duplication event was followed by several losses of a functional gene copy attributable to gene loss or pseudogenization. Statistical analyses of sequence data suggest that, in those lineages in which the gene copy was successfully recruited as HSS, the gene duplication event was followed by phases of various selection pressures, including purifying selection, relaxed functional constraints, and possibly positive Darwinian selection. Site-specific mutagenesis experiments have confirmed that the substitution of sites predicted to be under positive Darwinian selection is sufficient to convert a deoxyhypusine synthase into a HSS. In addition, analyses of transcript levels have shown that HSS and deoxyhypusine synthase have also diverged with respect to their regulation. The impact of protein—protein interaction on the evolution of HSS is discussed with respect to current models of enzyme evolution.

Background/Aims/MethodsLocalization of mutant Huntingtin (mHtt) aggregates is extensively investigated in animal models, but has remained a challenge in human Huntington´s disease (HD). Its distribution is of paramount interest as novel therapeutic approaches focus on lowering or preventing mHtt expression. In human HD brains aggregates occur more numerous in cortical than subcortical areas. Subcellular localization is still poorly understood. To provide a base for further targeted imaging and molecular studies, we investigated the density of aggregates in many cortices including previously unexamined areas by peroxidase immunohistochemistry. Cortices with abundant aggregates were further analyzed by confocal and super resolution fluorescence microscopy.Results/OutcomeIn all HD brains investigated most aggregates were localized in frontal lobe areas. Notably, the highest density was detected in ventral orbitofrontal cortices which are associated with emotion-related processing in the limbic cortex-basal ganglia-loop. Aggregates were patch-like distributed mainly in layer 5 and 6, all of different size, which correlated with the CAG-length. When comparing the anterior cingulate cortex receiving input from orbitofrontal cortices with the postcingulate cortex with input from parietal cortex, aggregates were more abundant in the anterior cingulate, confirming the high density in emotion-associated areas. Subcellular analyses of neurons detected most aggregates in cytoplasm, dendrites and axons, fewer in nuclei. Astrocytes and microglia presented with smaller aggregates, localized in all cell compartments.ConclusionThe present study shows that emotion-related forebrain cortices play a crucial role in mHtt aggregate distribution and are therefore recommended for further investigations on aggregates and to elucidate emotional dysfunction of the disease.

The indusium griseum (IG) is a cortical structure overlying the corpus callosum along its anterior–posterior extent. It has been classified either as a vestige of the hippocampus or as an extension of the dentate gyrus via the fasciola cinerea, but its attribution to a specific hippocampal subregion is still under debate. To specify the identity of IG neurons more precisely, we investigated the spatiotemporal expression of calbindin, secretagogin, Necab2, PCP4, and Prox1 in the postnatal mouse IG, fasciola cinerea, and hippocampus. We identified the calcium-binding protein Necab2 as a first reliable marker for the IG and fasciola cinerea throughout postnatal development into adulthood. In contrast, calbindin, secretagogin, and PCP4 were expressed each with a different individual time course during maturation, and at no time point, IG or fasciola cinerea principal neurons expressed Prox1, a transcription factor known to define dentate granule cell fate. Concordantly, in a transgenic mouse line expressing enhanced green fluorescent protein (eGFP) in dentate granule cells, neurons of IG and fasciola cinerea were eGFP-negative. Our findings preclude that IG neurons represent dentate granule cells, as earlier hypothesized, and strongly support the view that the IG is an own hippocampal subfield composed of a distinct neuronal population.

Two major global challenges related to agriculture are climate change and the unbalanced nitrogen cycle. For both, national and international reduction targets have been defined to catalyse policy support for more sustainable farming systems. Miscanthus cultivation in water protection areas has been proposed as a contribution to achieving these targets. However, a thorough understanding of the underlying system dynamics at various spatial levels is required before recommendations for policy development can be provided. In this study, a model framework was established to provide economic and environmental indicator results at regional and sub‐regional levels. It presents a consequential Life Cycle Assessment coupled with an agro‐economic supply model (Economic Farm Emission Model) that simulates crop and livestock production, and an agricultural hydrology model (DAISY) that assesses effects on the nitrogen cycle. The framework is applied to Baden‐Württemberg, a federal state in southwest Germany with eight agro‐ecological regions. Scenarios investigating the differences between mandatory and voluntary miscanthus cultivation were also explored. While the results show the high potential of miscanthus cultivation for the reduction of greenhouse gas emissions (−16% to −724%), the potential to reduce nitrate leaching (−4% to −44%) is compromised in some sub‐regions and scenarios (+4% to +13%) by substantial effects on the crop rotation. Furthermore, the cultivation of miscanthus reduces gross margins in most sub‐regions (−0.1% to −9.6%) and decreases domestic food production (−1% to −50%). However, in regions with low livestock density and high yields, miscanthus cultivation can maintain or increase farmers' income (0.1%–5.8%) and improve environmental protection. The study shows that the heterogeneity of arable land requires a flexible promotion programme for miscanthus. Voluntary cultivation schemes were identified as most suitable to capture sub‐regional differences. Policies should address the demand for miscanthus, for example, support the development of regional value chains, including farmers, water suppliers and the biobased industry. Miscanthus cultivation in water protection areas has been proposed as a contribution to achieving sustainability targets in the European farming sector. To investigate underlying system dynamics, a model framework (Life Cycle Assessment, Economic Farm Emission Model and agricultural hydrology model) was established to provide indicator results at regional and sub‐regional levels for Baden‐Württemberg. While the results show high potential of miscanthus cultivation for the reduction of greenhouse gas emissions and (in most cases) of nitrate leaching, the gross margins were reduced in most sub‐regions and the domestic food production in all sub‐regions. The study shows that the heterogeneity of arable land requires a flexible promotion programme for miscanthus.

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and commonly used induction immunochemotherapies include the anti-CD20 antibody rituximab. However, efficacy data for rituximab regarding overall survival (OS) in first line MCL therapy remain conflicting.We report long-term outcomes of a pooled trials analysis comparing Cyclophosphamide, Doxorubicine, Vincristine, Prednisone (CHOP) to R-CHOP in MCL to confirm efficacy on failure free survival (FFS) and OS in relevant subgroups. Untreated, adult MCL patients of two prospective trials assigned to CHOP or R-CHOP were included. Primary endpoints were FFS and OS, secondary endpoints included duration of response (DOR), secondary malignancies and OS after relapse. Between 1996 and 2003, 385 MCL patients were assigned to CHOP (201) or R-CHOP (184). After a median follow-up of 13.4 years, the addition of Rituximab significantly improved FFS (1.36 vs. 2.07 years, HR 0.62 (0.50–0.77)), OS (4.84 vs. 5.81 years, HR 0.78 (0.61–0.99)) and DOR (1.48 vs. 2.08 years, HR 0.67 (0.53–0.86)). Furthermore, Rituximab improved survival across different MCL risk groups. In a post-hoc analysis of OS after relapse comparing patients receiving chemotherapy with / without rituximab, rituximab maintained efficacy with a median OS of 3.10 vs. 2.11 years (HR 0.70, 0.54–0.91). The rate of secondary malignancies was 0.5 and 3.9% for hematological and 7 and 8% for non-hematological malignancies for CHOP and R-CHOP patients, respectively. We present mature results of a pooled MCL cohort, demonstrating prolonged FFS, OS and DOR for the combined immuno-chemotherapy, confirming the standard of care in first line treatment.

The expansion of the bioeconomy sector will increase the competition for agricultural land regarding biomass production. Furthermore, the particular path of the expansion of the bioeconomy is associated with great uncertainty due to the early stage of technology development and its dependency on political framework conditions. Economic models are suitable tools to identify trade‐offs in agricultural production and address the high uncertainty of the bioeconomy expansion. We present results from the farm model Economic Farm Emission Model of four bioeconomy scenarios in order to evaluate impacts and trade‐offs of different potential bioeconomy developments and the corresponding uncertainty at regional and farm level in Baden‐Wuerttemberg, Germany. The demand‐side effects of the bioeconomy scenarios are based on downscaling European Union level results of a separate model linkage between an agricultural sector and an energy sector model. The general model results show that the expanded use of agricultural land for the bioeconomy sector, especially for the cultivation of perennial biomass crops (PBC), reduces biomass production for established value chains, especially for food and feed. The results also show differences between regions and farm types in Baden‐Wuerttemberg. Fertile arable regions and arable farms profit more from the expanded use of biomass in the bioeconomy than farms that focus on cattle farming. Latter farms use the arable land to produce feed for the cattle, whereas arable farms can expand feedstock production for new value chains. Additionally, less intensive production systems like extensive grassland suffer from economic losses, whereas the competition in fertile regions further increases. Hence, if the extensive production systems are to be preserved, appropriate subsidies must be provided. This emphasizes the relevance of downscaling aggregated model results to higher spatial resolution, even as far as to the decision maker (farm), to identify possible contradicting effects of the bioeconomy as well as policy implications. The expansion of the bioeconomy sector will increase the competition for agricultural land regarding biomass production that will cause various trade‐offs. This study presents an integrated model framework, which is able to assess European Union bioeconomy scenario impacts on the state Baden‐Wuerttemberg in Germany. Four bioeconomy scenarios are simulated in a soft‐model linkage, in which the Economic Farm Emission Model is used for downscaling national results to the regional and farm level. The results show regions with less intensive production systems such as suckler cows suffer economic losses due to decreasing profitability, whereas the competition in fertile regions further increases.