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.     

The effect of membrane preparation and cellular maturation on human erythrocyte adenylate cyclase

We found that adenylate cyclase activity of human erythrocytes is potentially labile during isolation of their plasmalemma. Addition of 1 mM EGTA to solution used to remove hemoglobin from lysed cells protected activity. Human erythrocyte adenylate cyclase is minimally activated by catecholamines, in the absence or presence of exogenous guanyl nucleotide, but substantially by 5′-guanylyl imidodiphosphate or sodium fluoride and concentration-dependently by Mg²⁺ or Mn²⁺. Basal catalytic activity is an age-dependent component of the human erythrocyte; 5′-guanylyl imidodiphosphate- or fluoride-activated activities decline with cellular maturation proportionally to the decrease in basal activity.     

Genetic perspectives on forager‐farmer interaction in the Luangwa Valley of Zambia

The transformation from a foraging way of life to a reliance on domesticated plants and animals often led to the expansion of agropastoralist populations at the expense of hunter‐gatherers (HGs). In Africa, one of these expansions involved the Niger‐Congo Bantu‐speaking populations that started to spread southwards from Cameroon/Nigeria ～4,000 years ago, bringing agricultural technologies. Genetic studies have shown different degrees of gene flow (sometimes involving sex‐biased migrations) between Bantu agriculturalists and HGs. Although these studies have covered many parts of sub‐Saharan Africa, the central part (e.g. Zambia) was not yet studied, and the interactions between immigrating food‐producers and local HGs are still unclear. Archeological evidence from the Luangwa Valley of Zambia suggests a long period of coexistence (～1,700 years) of early food‐producers and HGs. To investigate if this apparent coexistence was accompanied by genetic admixture, we analyzed the mtDNA control region, Y chromosomal unique event polymorphisms, and 12 associated Y‐ short tandem repeats in two food‐producing groups (Bisa and Kunda) that live today in the Luangwa Valley, and compared these data with available published data on African HGs. Our results suggest that both the Bisa and Kunda experienced at most low levels of admixture with HGs, and these levels do not differ between the maternal and paternal lineages. Coalescent simulations indicate that the genetic data best fit a demographic scenario with a long divergence (62,500 years) and little or no gene flow between the ancestors of the Bisa/Kunda and existing HGs. This scenario contrasts with the archaeological evidence for a long period of coexistence between the two different communities in the Luangwa Valley, and suggests a process of sociocultural boundary maintenance may have characterized their interaction. Am J Phys Anthropol 2010. © 2009 Wiley‐Liss, Inc.     

Quantitative proteomics analysis of phosphorylated proteins in the hippocampus of Alzheimer's disease subjects

Phosphorylation on tyrosine, threonine and serine residues represents one of the most important post-translational modifications and is a key regulator of cellular signaling of multiple biological processes that require a strict control by protein kinases and protein phosphatases. Abnormal protein phosphorylation has been associated with several human diseases including Alzheimer's disease (AD). One of the characteristic hallmarks of AD is the presence of neurofibrillary tangles, composed of microtubule-associated, abnormally hyperphosphorylated tau protein. However, several others proteins showed altered phosphorylation levels in AD suggesting that deregulated phosphorylation may contribute to AD pathogenesis. Phosphoproteomics has recently gained attention as a valuable approach to analyze protein phosphorylation, both in a quantitative and a qualitative way. We used the fluorescent phosphospecific Pro-Q Diamond dye to identify proteins that showed alterations in their overall phosphorylation in the hippocampus of AD vs. control (CTR) subjects. Significant changes were found for 17 proteins involved in crucial neuronal process such as energy metabolism or signal transduction. These phosphoproteome data may provide new clues to better understand molecular pathways that are deregulated in the pathogenesis and progression of AD.     

A class of pyrrole derivatives endowed with analgesic/anti-inflammatory activity

We report the synthesis and bio-pharmacological evaluation of a class of pyrrole derivatives featuring a small appendage fragment (carbaldehyde, oxime, nitrile) on the central core. Compound 1c proved to be extremely effective in vivo, showing an interesting anti-nociceptic profile that is comparable to reference compounds already marketed, hence representing a great stimulus for a further improvement of this class of molecules.     

Quantitative evaluation of rigid and elastic registrations for abdominal perfusion imaging with X-ray computed tomography

ObjectivesDynamic X-ray computed tomography with contrast agent injection allows quantifying the tumor response to an antiangiogenic treatment. For hepatic tumors, it is crucial to correct for respiratory movements to ensure a good quantification of perfusion parameters.Material and MethodsTwo registration models were tested on eight dynamic exams: 1) rigid model and 2) elastic model based on Free Form Deformation. Each exam included about 50 volumes acquired under free-breathing conditions. The registration methods were quantitatively and automatically evaluated by defining a global score. This score was based on a Dice index and measured the superimposition rate between corresponding bony structures of different frames of the temporal exam.ResultsBefore registration, the mean value of the score was 0.78. After rigid registration, these values were globally lower with an average of 0.73. After elastic registration, a mean score of 0.90 was reached which was much higher than before registration.ConclusionThis automatic evaluation showed its interest for controlling the quality of dynamic CT registrations. It also helped proving that elastic methods are much more efficient than rigid methods for registering abdominal dynamic volumes, when considering the whole field of view.     

Moderate Warming in Microcosm Experiment Does Not Affect Microbial Communities in Temperate Vineyard Soils

Changes in the soil microbial community structure can lead to dramatic changes in the soil ecosystem. Temperature, which is projected to increase with climate change, is commonly assumed to affect microbial communities, but its effects on agricultural soils are not fully understood. We collected soil samples from six vineyards characterised by a difference of about 2 °C in daily soil temperature over the year and simulated in a microcosm experiment different temperature regimes over a period of 1 year: seasonal fluctuations in soil temperature based on the average daily soil temperature measured in the field; soil temperature warming (2 °C above the normal seasonal temperatures); and constant temperatures normally registered in these temperate soils in winter (3 °C) and in summer (20 °C). Changes in the soil bacterial and fungal community structures were analysed by automated ribosomal intergenic spacer analysis (ARISA). We did not find any effect of warming on soil bacterial and fungal communities, while stable temperatures affected the fungal more than the bacterial communities, although this effect was soil dependent. The soil bacterial community exhibited soil-dependent seasonal fluctuations, while the fungal community was mainly stable. Each soil harbours different microbial communities that respond differently to seasonal temperature fluctuations; therefore, any generalization regarding the effect of climate change on soil communities should be made carefully.     

When correlation implies causation in multisensory integration

Inferring which signals have a common underlying cause, and hence should be integrated, represents a primary challenge for a perceptual system dealing with multiple sensory inputs [1-3]. This challenge is often referred to as the correspondence problem or causal inference. Previous research has demonstrated that spatiotemporal cues, along with prior knowledge, are exploited by the human brain to solve this problem [4-9]. Here we explore the role of correlation between the fine temporal structure of auditory and visual signals in causal inference. Specifically, we investigated whether correlated signals are inferred to originate from the same distal event and hence are integrated optimally [10]. In a localization task with visual, auditory, and combined audiovisual targets, the improvement in precision for combined relative to unimodal targets was statistically optimal only when audiovisual signals were correlated. This result demonstrates that humans use the similarity in the temporal structure of multisensory signals to solve the correspondence problem, hence inferring causation from correlation.     

Interaction of mildronate with the mitochondrial carnitine/acylcarnitine transport protein

The interaction of mildronate [3-(2,2,2-trimethylhydrazine) propionate] with the purified mitochondrial carnitine/acylcarnitine transporter reconstituted in liposomes has been studied. Mildronate, externally added to the proteoliposomes, strongly inhibited the carnitine/carnitine antiport catalyzed by the reconstituted transporter with an IC(50) of 560 muM. A kinetic analysis revealed that the inhibition is completely competitive, that is, mildronate interacts with the substrate-binding site. The half-saturation constant of the transporter for external mildronate (K(i)) is 530 muM. Carnitine/mildronate antiport has been measured as [(3)H]carnitine uptake into proteoliposomes containing internal mildronate or as [(3)H]carnitine efflux from proteoliposomes in the presence of external mildronate, indicating that mildronate is transported by the carnitine/acylcarnitine transporter and that the inhibition observed was due to the transport of mildronate in the place of carnitine. The intraliposomal half-saturation constant for mildronate transport (K(m)) has been determined. Its value, 18 mM, is much higher than the external half-saturation constant (K(i)) in agreement with the asymmetric properties of the transporter. In vivo, the antiport reaction between cytosolic (administered) mildronate and matrix carnitine may cause intramitochondrial carnitine depletion. This effect, together with the inhibition of the physiological transport, will lead to impairment of fatty acid utilization.