Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene,is associated with schizophrenia

Prior evidence has supported the existence of multiple susceptibility genes for schizophrenia. Multipoint linkage analysis of the 270 Irish high-density pedigrees that we have studied, as well as results from several other samples, suggest that at least one such gene is located in region 6p24-21. In the present study, family-based association analysis of 36 simple sequence-length-polymorphism markers and of 17 SNP markers implicated two regions, separated by approximately 7 Mb. The first region, and the focus of this report, is 6p22.3. In this region, single-nucleotide polymorphisms within the 140-kb gene DTNBP1 (dystrobrevin-binding protein 1, or dysbindin) are strongly associated with schizophrenia. Uncorrected, empirical P values produced by the program TRANSMIT were significant (P<.01) for a number of individual SNP markers, and most remained significant when the data were restricted to include only one affected offspring per nuclear family per extended pedigree; multiple three-marker haplotypes were highly significant (P=.008-.0001) under the restricted conditions. The pattern of linkage disequilibrium is consistent with the presence of more than one susceptibility allele, but this important issue is unresolved. The number of markers tested in the adjacent genes, all of which are negative, is not sufficient to rule out the possibility that the dysbindin gene is not the actual susceptibility gene, but this possibility appears to be very unlikely. We conclude that further investigation of dysbindin is warranted.     

Disruption of neurogenesis by amyloid beta-peptide,and perturbed neural progenitor cell homeostasis,in models of Alzheimer's disease

Neurogenesis occurs in the adult mammalian brain and may play roles in learning and memory processes and recovery from injury, suggesting that abnormalities in neural progenitor cells (NPC) might contribute to the pathogenesis of disorders of learning and memory in humans. The objectives of this study were to determine whether NPC proliferation, survival and neuronal differentiation are impaired in a transgenic mouse model of Alzheimer's disease (AD), and to determine the effects of the pathogenic form of amyloid beta-peptide (Abeta) on the survival and neuronal differentiation of cultured NPC. The proliferation and survival of NPC in the dentate gyrus of the hippocampus was reduced in mice transgenic for a mutated form of amyloid precursor protein that causes early onset familial AD. Abeta impaired the proliferation and neuronal differentiation of cultured human and rodent NPC, and promoted apoptosis of neuron-restricted NPC by a mechanism involving dysregulation of cellular calcium homeostasis and the activation of calpains and caspases. Adverse effects of Abeta on NPC may contribute to the depletion of neurons and cognitive impairment in AD.     

Properties of triple helices formed by parallel-stranded hairpins containing 8-aminopurines

Parallel-stranded hairpins with a polypyrimidine sequence linked to a complementary purine carrying 8-aminopurines such as 8-aminoadenine, 8-aminoguanine and 8-aminohypoxanthine bind polypyrimidine sequences complementary (in an antiparallel sense) to the purine part by a triple helix. The relative stabilities of triplexes were assessed by UV-absorption melting experiments as a function of pH and salt concentration. Hairpins carrying 8-aminopurines give very stable triple helical structures even at neutral pH, as confirmed by gel-shift experiments, circular dichroism and nuclear magnetic resonance spectroscopy. The modified hairpins may be redesigned to cope with small interruptions in the polypyrimidine target sequence.     

Resolution of parallel and antiparallel oligonucleotide triple helices formation and melting processes by multivariate curve resolution

A procedure is described for the complete resolution of concentration profiles of oligonucleotide triplexes as a function of pH and temperature. The pH and temperature ranges at which triplexes are present and the relative concentrations of all the species involved in acid-base and conformational equilibria are successfully estimated from Multivariate Curve Resolution analysis of UV absorbance spectra recorded along acid-base titrations and melting experiments of single stranded, hairpin and their mixtures. The dependence of formation constants upon pH was successfully estimated. The hairpin h26 (5'-GAAGGAGGAGA-TTTT-TCTCCTCCTTC-3'), and the single stranded oligonucleotides s11CT (5'-CTTCCTCCTCT-3'), s11AG (5'-AGAGGAGGAAG-3') and s11TG (5'-TGTGGTGGTTG-3') were synthesized and their protonation and conformational equilibria were studied in detail. The procedure was shown to be especially useful for the study of triplexes with a low hypochromism upon formation.     

Chickens fed with biomass of the red microalga Porphyridium sp. have reduced blood cholesterol level and modified fatty acid composition in egg yolk

The biomass of the red alga Porphyridium sp.constitutes a unique combination of soluble sulfatedpolysaccharide that accounts for about 70% of thealgal dry weight, and various polyunsaturatedfatty acids (PUFA) such as arachidonic andeicosapentaenoic acid (AA, 20:4 6 and EPA,20:5 3). In view of earlier results in ourlaboratory showing a reduction in serum cholesteroland triglyceride levels in rodents fed with red algalbiomass, we set out to examine the influence of algalbiomass as a feed additive on the metabolism ofchickens, with an emphasis on blood and eggcholesterol levels. For that purpose, lyophilizedalgal biomass was fed to 12–13, 30-week-old, WhiteLeghorn chickens for 10 days at a proportion of 5% or10% of the standard chicken diet. Twelve chickensfed with unsupplemented diet served as the control. No differences in body weight, egg number, and eggweight were found between the algal-fed chickens (atboth concentrations) and the control. However,chickens fed with algal biomass consumed 10% lessfood for both groups, and their serum cholesterollevels were significantly lower (by 11% and 28% forthe groups fed with 5% and 10% supplement,respectively) as compared with the respective valuesof the control group. Egg yolk of chickens fed withalgae tended to have reduced cholesterol levels (by10%) and increased linoleic acid and arachidonic acidlevels (by 29% and 24%, respectively). In addition,the color of the egg yolk was darker as a result ofthe higher carotenoid levels (2.4 fold higher) forchickens that fed with 5% supplement. Theseresults encourage the development of an improvedchicken feed having dietary fibers and polyunsaturatedfatty acids.     

Designing Cell-Targeted Therapeutic Proteins Reveals the Interplay between Domain Connectivity and Cell Binding

The therapeutic efficacy of cytokines is often hampered by severe side effects due to their undesired binding to healthy cells. One strategy for overcoming this obstacle is to tether cytokines to antibodies or antibody fragments for targeted cell delivery. However, how to modulate the geometric configuration and relative binding affinity of the two domains for optimal activity remains an outstanding question. As a result, many antibody-cytokine complexes do not achieve the desired level of cell-targeted binding and activity. Here, we address these design issues by developing a computational model to simulate the dynamics and binding kinetics of natural and engineered fusion proteins such as antibody-cytokine complexes. To verify the model, we developed a modular system in which an antibody fragment and a cytokine are conjugated via a DNA linker that allows for programmable linker geometry and protein spatial configuration. By assembling and testing several anti-CD20 antibody fragment-interferon α complexes, we showed that varying the linker length and cytokine binding affinity controlled the magnitude of cell-targeted signaling activation in a manner that agreed with the model predictions, which were expressed as dose-signaling response curves. The simulation results also revealed that there is a range of cytokine binding affinities that would achieve optimal therapeutic efficacy. This rapid prototyping platform will facilitate the rational design of antibody-cytokine complexes for improved therapeutic outcomes.     

UNCovering the molecular machinery of dependence receptor signaling

Dependence receptors send opposite signals in the presence or absence of ligand, but the underlying mechanisms have been elusive. In this issue of Molecular Cell, Guenebeaud et al. (2010) elucidate the molecular signaling machinery of the dependence receptor UNC5B.     

Coding "what" and "when" in the Archer fish retina

Traditionally, the information content of the neural response is quantified using statistics of the responses relative to stimulus onset time with the assumption that the brain uses onset time to infer stimulus identity. However, stimulus onset time must also be estimated by the brain, making the utility of such an approach questionable. How can stimulus onset be estimated from the neural responses with sufficient accuracy to ensure reliable stimulus identification? We address this question using the framework of colour coding by the archer fish retinal ganglion cell. We found that stimulus identity, “what”, can be estimated from the responses of best single cells with an accuracy comparable to that of the animal''s psychophysical estimation. However, to extract this information, an accurate estimation of stimulus onset is essential. We show that stimulus onset time, “when”, can be estimated using a linear-nonlinear readout mechanism that requires the response of a population of 100 cells. Thus, stimulus onset time can be estimated using a relatively simple readout. However, large nerve cell populations are required to achieve sufficient accuracy.

Authors Summary

In our interaction with the environment we are flooded with a stream of numerous objects and events. Our brain needs to understand the nature of these complex and rich stimuli in order to react. Research has shown ways in which a ‘what’ stimulus was presented can be encoded by the neural responses. However, to understand ‘what was the nature of the stimulus’ the brain needs to know ‘when’ the stimulus was presented. Here, we investigated how the onset of visual stimulus can be signalled by the retina to higher brain regions. We used archer fish as a framework to test the notion that the answer to the question of ‘when’ something has been presented lies within the larger cell population, whereas the answer to the question of ‘what’ has been presented may be found at the single-neuron level. The utility of the archer fish as model animal stems from its remarkable ability to shoot down insects settling on the foliage above the water level, and its ability to distinguish between artificial targets. Thus, the archer fish can provide the fish equivalent of a monkey or a human that can report psychophysical decisions.