Discovery of a small-molecule inhibitor of the TRIP8b–HCN interaction with efficacy in neurons

Major depressive disorder is a critical public health problem with a lifetime prevalence of nearly 17% in the United States. One potential therapeutic target is the interaction between hyperpolarization-activated cyclic nucleotide–gated (HCN) channels and an auxiliary subunit of the channel named tetratricopeptide repeat–containing Rab8b-interacting protein (TRIP8b). HCN channels regulate neuronal excitability in the mammalian hippocampus, and recent work has established that antagonizing HCN function rescues cognitive impairment caused by chronic stress. Here, we utilize a high-throughput virtual screen to find small molecules capable of disrupting the TRIP8b–HCN interaction. We found that the hit compound NUCC-0200590 disrupts the TRIP8b–HCN interaction in vitro and in vivo. These results provide a compelling strategy for developing new small molecules capable of disrupting the TRIP8b–HCN interaction.     

A covariotide model explains apparent phylogenetic structure of oxygenic photosynthetic lineages

The aims of the work were (1) to develop statistical tests to identify whether substitution takes place under a covariotide model in sequences used for phylogenetic inference and (2) to determine the influence of covariotide substitution on phylogenetic trees inferred for photosynthetic and other organisms. (Covariotide and covarion models are ones in which sites that are variable in some parts of the underlying tree are invariable in others and vice versa.) Two tests were developed. The first was a contingency test, and the second was an inequality test comparing the expected number of variable sites in two groups with the observed number. Application of these tests to 16S rDNA and tufA sequences from a range of nonphotosynthetic prokaryotes and oxygenic photosynthetic prokaryotes and eukaryotes suggests the occurrence of a covariotide mechanism. The degree of support for partitioning of taxa in reconstructed trees involving these organisms was determined in the presence or absence of sites showing particular substitution patterns. This analysis showed that the support for splits between (1) photosynthetic eukaryotes and prokaryotes and (2) photosynthetic and nonphotosynthetic organisms could be accounted for by patterns arising from covariotide substitution. We show that the additional problem of compositional bias in sequence data needs to be considered in the context of patterns of covariotide/covarion substitution. We argue that while covariotide or covarion substitution may give rise to phylogenetically informative patterns in sequence data, this may not always be so.      

The effect of a combined high-intensity strength and speed training program on the running and jumping ability of soccer players

The purpose of this study was to investigate the effect of a combined heavy-resistance and running-speed training program performed in the same training session on strength, running velocity (RV), and vertical-jump performance (VJ) of soccer players. Thirty-five individuals were divided into 3 groups. The first group (n = 12, COM group) performed a combined resistance and speed training program at the same training session, and the second one (n = 11, STR group) performed the same resistance training without speed training. The third group was the control group (n = 12, CON group). Three jump tests were used for the evaluation of vertical jump performance: squat jump, countermovement jump, and drop jump. The 30-m dash and 1 repetition maximum (1RM) tests were used for running speed and strength evaluation, respectively. After training, both experimental groups significantly improved their 1RM of all tested exercises. Furthermore, the COM group performed significantly better than the STR and the CON groups in the 30-m dash, squat jump, and countermovement jump. It is concluded that the combined resistance and running-speed program provides better results than the conventional resistance training, regarding the power performance of soccer players.     

Using ontologies to describe mouse phenotypes

The mouse is an important model of human genetic disease. Describing phenotypes of mutant mice in a standard, structured manner that will facilitate data mining is a major challenge for bioinformatics. Here we describe a novel, compositional approach to this problem which combines core ontologies from a variety of sources. This produces a framework with greater flexibility, power and economy than previous approaches. We discuss some of the issues this approach raises.     

Immunoassay and antibody microarray analysis of the HUPO Plasma Proteome Project reference specimens: systematic variation between sample types and calibration of mass spectrometry data

Four different immunoassay and antibody microarray methods performed at four different sites were used to measure the levels of a broad range of proteins (N = 323 assays; 39, 88, 168, and 28 assays at the respective sites; 237 unique analytes) in the human serum and plasma reference specimens distributed by the Plasma Proteome Project (PPP) of the HUPO. The methods provided a means to (1) assess the level of systematic variation in protein abundances associated with blood preparation methods (serum, citrate-anticoagulated-plasma, EDTA-anticoagulated-plasma, or heparin-anticoagulated-plasma) and (2) evaluate the dependence on concentration of MS-based protein identifications from data sets using the HUPO specimens. Some proteins, particularly cytokines, had highly variable concentrations between the different sample preparations, suggesting specific effects of certain anticoagulants on the stability or availability of these proteins. The linkage of antibody-based measurements from 66 different analytes with the combined MS/MS data from 18 different laboratories showed that protein detection and the quality of MS data increased with analyte concentration. The conclusions from these initial analyses are that the optimal blood preparation method is variable between analytes and that the discovery of blood proteins by MS can be extended to concentrations below the ng/mL range under certain circumstances. Continued developments in antibody-based methods will further advance the scientific goals of the PPP.     

Ovarian response to hCG injections during the prepubertal period in three breeds of sheep with different ovulation rates and litter sizes

A positive correlation was reported between ovulation (OR) rate in response to hCG in prepubertal ewe lambs and adult ewes. The finding suggested that the response to hCG may be used to select prepubertal ewe lambs for prolificacy. We studied plasma FSH concentrations and ovarian response to hCG injection during the prepubertal period in breeds with high (Chios), medium (Florina) and low (Karagouniki) OR and litter sizes (LS). The results showed that Chios ewe lambs presented a higher profile of plasma FSH during the 3rd to 7th wk of age when compared to the breeds with medium (Florina) and low (Karagouniki) OR and LS. The ovarian response to hCG showed that the Chios ewe lambs responded earlier, by exhibiting ovulation at 6 wks and more effectively, by demonstrating a higher OR than the other two breeds. There was no correlation among plasma FSH concentrations during prepubertal age (3rd to 7th wk), ovulation rate after hCG injection, or litter size at first and second lambing for all breeds. Therefore we concluded that the plasma FSH concentrations and/or the ovarian response to hCG injection during the prepubertal period is not a suitable criterion for early selection for litter size in the adult ewe of these breeds.     

Olfactory sensitivity in tsetse flies: a daily rhythm

The diurnal tsetse Glossina morsitans morsitans bites especially in early morning and late afternoon; around midday feeding is at a low. In laboratory apparatus that measures the amount of locomotion under constant conditions over the photophase, the flies display a similar patterning of activity levels. The profile of daily rhythms for G. morsitans reported in the literature includes a number of motor and sensory motor systems that fluctuate cophasically. Lacking is a study on the patterning of the senses' response levels. In this paper we present the first instance of a daily modulation in the sense of smell. We stimulated the antennae with concentration series of host-derived odours and measured the spiking rate of cells at different times during the photophase. The concentration-response curves suggest that the sensitivity of antennal olfactory cells flows in parallel with the other daily rhythms. This was also reflected in electroantennograms (EAGs). The electroantennography was extended to G. fuscipes fuscipes, whose level of spontaneous locomotor activity--instead of following a U- shaped pattern--rises gradually over the photophase. Again, the EAGs appeared to parallel the species' locomotor activity. What we believe happens is that the organism tones down the sensitivity of its odour receptors during periods of anticipated inactivity for reasons of economy.      

Algorithm of OMA for large-scale orthology inference

Since the publication of our article (Roth, Gonnet, and Dessimoz: BMC Bioinformatics 2008 9: 518), we have noticed several errors, which we correct in the following.