Genome-wide linkage analysis of malaria infection intensity and mild disease

Although balancing selection with the sickle-cell trait and other red blood cell disorders has emphasized the interaction between malaria and human genetics, no systematic approach has so far been undertaken towards a comprehensive search for human genome variants influencing malaria. By screening 2,551 families in rural Ghana, West Africa, 108 nuclear families were identified who were exposed to hyperendemic malaria transmission and were homozygous wild-type for the established malaria resistance factors of hemoglobin (Hb)S, HbC, alpha⁺ thalassemia, and glucose-6-phosphate-dehydrogenase deficiency. Of these families, 392 siblings aged 0.5–11 y were characterized for malaria susceptibility by closely monitoring parasite counts, malaria fever episodes, and anemia over 8 mo. An autosome-wide linkage analysis based on 10,000 single-nucleotide polymorphisms was conducted in 68 selected families including 241 siblings forming 330 sib pairs. Several regions were identified which showed evidence for linkage to the parasitological and clinical phenotypes studied, among them a prominent signal on Chromosome 10p15 obtained with malaria fever episodes (asymptotic z score = 4.37, empirical p-value = 4.0 × 10⁻⁵, locus-specific heritability of 37.7%; 95% confidence interval, 15.7%–59.7%). The identification of genetic variants underlying the linkage signals may reveal as yet unrecognized pathways influencing human resistance to malaria.     

E-cadherin as a reliable cell surface marker for the identification of liver specific stem cells

Oval cells are liver-specific bipotent stem cells which accumulate in injured liver when proliferation of mature hepatocytes and/or cholangiocytes is impaired. They represent an intermediary cell type with phenotypical characteristics of both, hepatocytes and cholangiocytes. Oval cells express specific cell surface proteins allowing their identification in situ. Most of these cell surface proteins, however, are recognized by antibodies in mouse liver tissue that are not commercially available or work only on frozen sections. We show herein the unequivocal identification of oval cells in paraffin-embedded mouse liver samples based on strong E-cadherin expression different from that of hepatocytes and bile duct cells. By comparing the pattern of E-cadherin expression with that of both, A6-antigen and CD44, we suggest a tight control of E-cadherin expression depending on the differentiation stage of the progenitor cells. In human cirrhotic liver samples E-cadherin expression was found as a common feature of both, typical and atypical reactions, and, thus, can also serve as an indication of the progenitor cell compartment activation.     

Primary desminopathies

Mutations of the human desmin gene on chromosome 2q35 cause a familial or sporadic form of skeletal myopathy frequently associated with cardiac abnormalities. Skeletal and cardiac muscle from patients with primary desminopathies characteristically display cytoplasmic accumulation of desmin-immunoreactive material and myofibrillar changes. However, desmin-positive protein aggregates in conjunction with myofibrillar abnormalities are also the morphological hallmark of the large group of secondary desminopathies (synonyms: myofibrillar myopathies, desmin-related myopathies), which comprise sporadic and familial neuromuscular conditions of considerable clinical and genetic heterogeneity. Here, we will give an overview on the functional role of desmin in striated muscle as well as the main clinical, myopathological, genetic and patho-physiological aspects of primary desminopathies. Furthermore, we will discuss recent genetic and biochemical advances in distinguishing primary from secondary desminopathies.     

Biosonar-inspired technology: goals, challenges and insights

Bioinspired engineering based on biosonar systems in nature is reviewed and discussed in terms of the merits of different approaches and their results: biosonar systems are attractive technological paragons because of their capabilities, built-in task-specific knowledge, intelligent system integration and diversity. Insights from the diverse set of sensing tasks solved by bats are relevant to a wide range of application areas such as sonar, biomedical ultrasound, non-destructive testing, sensors for autonomous systems and wireless communication. Challenges in the design of bioinspired sonar systems are posed by transducer performance, actuation for sensor mobility, design, actuation and integration of beamforming baffle shapes, echo encoding for signal processing, estimation algorithms and their implementations, as well as system integration and feedback control. The discussed examples of experimental systems have capabilities that include localization and tracking using binaural and multiple-band hearing as well as self-generated dynamic cues, classification of small deterministic and large random targets, beamforming with bioinspired baffle shapes, neuromorphic spike processing, artifact rejection in sonar maps and passing range estimation. In future research, bioinspired engineering could capitalize on some of its strengths to serve as a model system for basic automation methodologies for the bioinspired engineering process.     

"Negative vaccination" by specific CD4 T cell tolerisation enhances virus-specific protective antibody responses

Background

Cooperation of CD4⁺ T helper cells with specific B cells is crucial for protective vaccination against pathogens by inducing long-lived neutralizing antibody responses. During infection with persistence-prone viruses, prolonged virus replication correlates with low neutralizing antibody responses. We recently described that a viral mutant of lymphocytic choriomeningitis virus (LCMV), which lacks a T helper epitope, counterintuitively induced an enhanced protective antibody response. Likewise, partial depletion of the CD4⁺ T cell compartment by using anti-CD4 antibodies enhanced protective antibodies.

Principal Findings

Here we have developed a protocol to selectively reduce the CD4⁺ T cell response against viral CD4⁺ T cell epitopes. We demonstrate that in vivo treatment with LCMV-derived MHC-II peptides induced non-responsiveness of specific CD4⁺ T cells without affecting CD4⁺ T cell reactivity towards other antigens. This was associated with accelerated virus-specific neutralizing IgG-antibody responses. In contrast to a complete absence of CD4⁺ T cell help, tolerisation did not impair CD8⁺ T cell responses.

Conclusions

This result reveals a novel “negative vaccination” strategy where specific CD4⁺ T cell unresponsiveness may be used to enhance the delayed protective antibody responses in chronic virus infections.     

Identification and classification of hubs in brain networks

Brain regions in the mammalian cerebral cortex are linked by a complex network of fiber bundles. These inter-regional networks have previously been analyzed in terms of their node degree, structural motif, path length and clustering coefficient distributions. In this paper we focus on the identification and classification of hub regions, which are thought to play pivotal roles in the coordination of information flow. We identify hubs and characterize their network contributions by examining motif fingerprints and centrality indices for all regions within the cerebral cortices of both the cat and the macaque. Motif fingerprints capture the statistics of local connection patterns, while measures of centrality identify regions that lie on many of the shortest paths between parts of the network. Within both cat and macaque networks, we find that a combination of degree, motif participation, betweenness centrality and closeness centrality allows for reliable identification of hub regions, many of which have previously been functionally classified as polysensory or multimodal. We then classify hubs as either provincial (intra-cluster) hubs or connector (inter-cluster) hubs, and proceed to show that lesioning hubs of each type from the network produces opposite effects on the small-world index. Our study presents an approach to the identification and classification of putative hub regions in brain networks on the basis of multiple network attributes and charts potential links between the structural embedding of such regions and their functional roles.     

Abnormal lens morphogenesis and ectopic lens formation in the absence of beta-catenin function

beta-Catenin plays a key role in cadherin-mediated cell adhesion as well as in canonical Wnt signaling. To study the role of beta-catenin during eye development, we used conditional Cre/loxP system in mouse to inactivate beta-catenin in developing lens and retina. Inactivation of beta-catenin does not suppress lens fate, but instead results in abnormal morphogenesis of the lens. Using BAT-gal reporter mice, we show that beta-catenin-mediated Wnt signaling is notably absent from lens and neuroretina throughout eye development. The observed defect is therefore likely due to the cytoskeletal role of beta-catenin, and is accompanied by impaired epithelial cell adhesion. In contrast, inactivation of beta-catenin in the nasal ectoderm, an area with active Wnt signaling, results in formation of crystallin-positive ectopic lentoid bodies. These data suggest that, outside of the normal lens, beta-catenin functions as a coactivator of canonical Wnt signaling to suppress lens fate.     

Enhancing the functionality of biobased polyester coating resins through modification with citric acid

Citric acid (CA) was evaluated as a functionality-enhancing monomer in biobased polyesters suitable for coating applications. Model reactions of CA with several primary and secondary alcohols and diols, including the 1,4:3,6-dianhydrohexitols, revealed that titanium(IV) n-butoxide catalyzed esterification reactions involving these compounds proceed at relatively low temperatures, often via anhydride intermediates. Interestingly, the facile anhydride formation from CA at temperatures around CA's melting temperature ( T m = 153 degrees C) proved to be crucial in modifying sterically hindered secondary hydroxyl end groups. OH-functional polyesters were reacted with CA in the melt between 150 and 165 degrees C, yielding slightly branched carboxylic acid functional materials with strongly enhanced functionality. The acid/epoxy curing reaction of the acid-functional polymers was simulated with a monofunctional glycidyl ether. Finally, the CA-modified polyesters were applied as coatings, using conventional cross-linking agents. The formulations showed rapid curing, resulting in chemically and mechanically stable coatings. These results demonstrate that citric acid can be applied in a new way, making use of its anhydride formation to functionalize OH-functional polyesters, which is an important new step toward fully biobased coating systems.     

Inverse inkjet printed gold micro electrodes for the structured deposition of epithelial cells and fibrin

The micro structured deposition of vital cells is an important challenge in tissue engineering, biosensor technology, and in all research dealing with cell-cell and cell-substrate contacts. Hence, an inkjet printing technology has been developed to manufacture Au-based micro electrodes by sputter coating inversely printed polyester-foils. These electrodes feature minimal structure sizes of 35 microm and consist of an anode and a cathode part. They were used with fibrinogenic epithelial cell suspensions to deposit human keratinocytes (HaCaT), mouse fibroblasts (L-929) and the protein fibrin by applying DC voltage. Subsequently cells were electrophoretically attracted to the anode, following exactly its shape, while the insoluble fibrin was simultaneously precipitated due to the electrically mediated polymerization of the soluble fibrinogen molecule. Furthermore, it was demonstrated that this technique is suitable to co-deposit both cell types in a layered fashion. The lower voltage boundary for successful deposition was set at approximately 0.8 V needed for the conversion of fibrinogen into fibrin, while the upper voltage boundary was set at approximately 1.85 V, when commencing electrolysis inhibited the deposition of vital cells. Subsequent to the anodic cell-fibrin deposition, cells were cultivated for up to 4 days and then characterized by FDA+EB staining, methyl violet staining, MNF staining and SEM. The conversion from fibrinogen into fibrin was studied using ATR/FTIR.     

Induced Shift in Ecosystem Productivity? Extensive Scale Effects of Abundant Large Herbivores

Abundant large herbivores can strongly alter vegetation composition, shifting the ecosystem into a lasting state of changed productivity. Previous studies of the effects of abundant reindeer on alpine and arctic vegetation have yielded equivocal results, probably due to differing environmental contexts. To overcome context dependency we devised a large-scale survey in the region of Finnmark, northern Norway, possessing some of the most densely stocked reindeer herds in the world. The effects of reindeer abundance on summer pasture vegetation were assessed by employing a quasi-experimental design, including site fertility as a potential modifier of the reindeer–vegetation interaction. The study design comprised ten pairs of neighboring management districts (encompassing 18,003 km²), where over the two last decades a high-density district on average had reindeer densities more than twice as high and calf weights consistently lower than the low-density district. The abundance of different plant functional groups, ranging from those having facilitating to retarding effects on ecosystem productivity, were quantified by the point intercept method on plots selected according to a hierarchical, stratified random sampling design. Species with strong retarding effects on ecosystem productivity (for example, ericoids) were by far the most abundant. However, we found no consistent effects of reindeer density on their abundance. The most consistent differences between high- and low-density districts were found in plant functional groups with facilitating to neutral effects on ecosystem productivity. In particular, the abundance of N-facilitators, large dicotyledons and grasses were substantially reduced in the high-density districts. However, this reduction was restricted to fertile sites. Thus, reindeer when present at high densities have homogenized the biomass of palatable plants across environmental productivity gradients according to predictions from exploitation ecosystem models. Such reduction of plants with facilitating to neutral effects on ecosystem productivity indicates a reduced state of ecosystem productivity in high-density districts. Electronic supplementary material: The online version of this article (doi:) contains supplementary material, which is available to authorized users.