Males Prefer Small Females in a Dichotomous Choice Test in the Poeciliid Fish Heterandria formosa

Male choice is expected to evolve when females differ in quality, even if male investment in each mating is low. The family Poeciliidae is an example of fishes in which males show little parental investment as they only provide sperm. Up until now, a preference for large females has been found in all species studied. Here we show that unexpectedly, males of the least killifish (Heterandria formosa) prefer to interact with small instead of large females in a dichotomous male choice test, even though large females are more fecund. During a free‐swimming choice experiment, males did not discriminate between females based on their size. We suggest that this unique preference for small females, or the lack of preference for large females, results from strong first male sperm precedence in this species. Smaller females are younger and therefore more likely to be virgin, which probably makes them more profitable mates for males. When presented with a virgin and a mated female of similar size, males showed no preference for either type. This suggests that males do not use pheromone cues to assess female mating status but that they are likely to use female size as a proxy for it.     

The incidence of hip, forearm, humeral, ankle, and vertebral fragility fractures in Italy: results from a 3-year multicenter study

Introduction

We aimed to assess the incidence and hospitalization rate of hip and "minor" fragility fractures in the Italian population.

Methods

We carried out a 3-year survey at 10 major Italian emergency departments to evaluate the hospitalization rate of hip, forearm, humeral, ankle, and vertebral fragility fractures in people 45 years or older between 2004 and 2006, both men and women. These data were compared with those recorded in the national hospitalizations database (SDO) to assess the overall incidence of fragility fractures occurring at hip and other sites, including also those events not resulting in hospital admissions.

Results

We observed 29,017 fractures across 3 years, with hospitalization rates of 93.0% for hip fractures, 36.3% for humeral fractures, 31.3% for ankle fractures, 22.6% for forearm/wrist fractures, and 27.6% for clinical vertebral fractures. According to the analyses performed with the Italian hospitalization database in year 2006, we estimated an annual incidence of 87,000 hip, 48,000 humeral, 36,000 ankle, 85,000 wrist, and 155,000 vertebral fragility fractures in people aged 45 years or older (thus resulting in almost 410,000 new fractures per year). Clinical vertebral fractures were recorded in 47,000 events per year.

Conclusions

The burden of fragility fractures in the Italian population is very high and calls for effective preventive strategies.     

A minimal model for multiple epidemics and immunity spreading

Pathogens and parasites are ubiquitous in the living world, being limited only by availability of suitable hosts. The ability to transmit a particular disease depends on competing infections as well as on the status of host immunity. Multiple diseases compete for the same resource and their fate is coupled to each other. Such couplings have many facets, for example cross-immunization between related influenza strains, mutual inhibition by killing the host, or possible even a mutual catalytic effect if host immunity is impaired. We here introduce a minimal model for an unlimited number of unrelated pathogens whose interaction is simplified to simple mutual exclusion. The model incorporates an ongoing development of host immunity to past diseases, while leaving the system open for emergence of new diseases. The model exhibits a rich dynamical behavior with interacting infection waves, leaving broad trails of immunization in the host population. This obtained immunization pattern depends only on the system size and on the mutation rate that initiates new diseases.     

Transferrin Receptor 2 Is Frequently and Highly Expressed in Glioblastomas

Under physiological conditions, transferrin receptor 2 (TfR2) is expressed in the liver and its balance is related to the cell cycle rather than to intracellular iron levels. We recently showed that TfR2 is highly expressed in glioblastoma cell lines. Here, we demonstrate that, in these cells, TfR2 appears to localize in lipid rafts, induces extracellular signal-regulated kinase 1/2 phosphorylation after transferrin binding, and contributes to cell proliferation, as shown by RNA silencing experiments. In vitro hypoxic conditions induce a significant TfR2 up-regulation, suggesting a role in tumor angiogenesis. As assessed by immunohistochemistry, the level of TfR2 expression in astrocytic tumors is related to histologic grade, with the highest expression observed in glioblastomas. The level of TfR2 expression represents a favorable prognostic factor, which is associated with the higher sensitivity to temozolomide of TfR2-positive tumor cells in vitro. The endothelial cells of glioblastoma vasculature also stain for TfR2, whereas those of the normal brain vessels do not. Importantly, TfR2 is expressed by the subpopulation of glioblastoma cells with properties of cancer-initiating cells. TfR2-positive glioblastoma cells retain their TfR2 expression on xenografting in immunodeficient mice. In conclusion, our observations demonstrate that TfR2 is a neoantigen for astrocytomas that seems attractive for developing target therapies.     

Efficacy and safety of rabeprazole, amoxicillin, and gatifloxacin after treatment failure of initial Helicobacter pylori eradication

OBJECTIVES: To evaluate the efficacy of a 7-day regimen of gatifloxacin (400 mg daily), amoxicillin (1 g twice a day), and rabeprazole (20 mg twice a day) in the secondary eradication of Helicobacter pylori infection. METHODS: Eligible patients with persistent infection following one or more conventional clarithromycin-containing triple therapies were enrolled in this open-label trial. Eradication of infection was documented by (14)C-urea breath test a minimum of 4 weeks after therapy and 2 weeks off any acid suppressive therapy. Culture of H. pylori and in vitro susceptibility testing to amoxicillin, clarithromycin, and gatifloxacin was done in cases of failed eradication. RESULTS: A total of 45 patients (22 females:23 males; mean age 44.5 +/- 13 years) were enrolled. Eradication occurred in 38 patients [both per-protocol (PP) and intention-to-treat analysis: 84.4%; 95% CI: 74-95%]. No significant adverse effects were reported. In vitro susceptibility testing showed no secondary resistance to gatifloxacin or amoxicillin in any of the seven nonresponders. Smoking, age, and sex were not predictors of potential eradication failure. CONCLUSIONS: A 7-day regimen of gatifloxacin, rabeprazole, and amoxicillin is effective after failed eradication therapy for H. pylori and does not appear to result in secondary resistance. This combination is simple, well tolerated, and may lead to higher compliance and lower costs.     

Statistical properties of neutral evolution

Neutral evolution is the simplest model of molecular evolution and thus it is most amenable to a comprehensive theoretical investigation. In this paper, we characterize the statistical properties of neutral evolution of proteins under the requirement that the native state remains thermodynamically stable, and compare them to the ones of Kimura's model of neutral evolution. Our study is based on the Structurally Constrained Neutral (SCN) model which we recently proposed. We show that, in the SCN model, the substitution rate decreases as longer time intervals are considered. Fluctuations from one branch of the evolutionary tree to another are strong, leading to a non-Poissonian statistics for the substitution process. Such strong fluctuations are in part due to the fact that neutral substitution rates for individual residues are strongly correlated for most residue pairs. Interestingly, structurally conserved residues, characterized by a much below average substitution rate, are also much less correlated to other residues and evolve in a much more regular way. Our results can improve methods aimed at distinguishing between neutral and adaptive substitutions as well as methods for computing the expected number of substitutions occurred since the divergence of two protein sequences. In particular, we compute the minimal sequence similarity below which no information about the evolutionary divergence of the compared sequences can be obtained.     

Connectivity of Neutral Networks,Overdispersion, and Structural Conservation in Protein Evolution

Abstract Protein structures are much more conserved than sequences during evolution. Based on this observation, we investigate the consequences of structural conservation on protein evolution. We study seven of the most studied protein folds, determining that an extended neutral network in sequence space is associated with each of them. Within our model, neutral evolution leads to a non-Poissonian substitution process, due to the broad distribution of connectivities in neutral networks. The observation that the substitution process has non-Poissonian statistics has been used to argue against the original Kimura neutral theory, while our model shows that this is a generic property of neutral evolution with structural conservation. Our model also predicts that the substitution rate can strongly fluctuate from one branch to another of the evolutionary tree. The average sequence similarity within a neutral network is close to the threshold of randomness, as observed for families of sequences sharing the same fold. Nevertheless, some positions are more difficult to mutate than others. We compare such structurally conserved positions to positions conserved in protein evolution, suggesting that our model can be a valuable tool to distinguish structural from functional conservation in databases of protein families. These results indicate that a synergy between database analysis and structurally based computational studies can increase our understanding of protein evolution.     

Association of the X-linked lymphoproliferative disease gene product SAP/SH2D1A with 2B4, a natural killer cell-activating molecule, is dependent on phosphoinositide 3-kinase

Natural killer (NK) cells express an activating receptor, 2B4, that enhances cellular cytotoxicity. Upon NK cell activation by ligation of 2B4, the intracellular domain of 2B4 associates with the X-linked lymphoproliferative disease (XLP) gene product, signaling lymphocytic activation molecule-associated protein/SH2D1A (SAP/SH2D1A). Defective intracellular association of 2B4 with mutated SAP/SH2D1A is likely to underlie the defects in cytotoxicity observed in NK cells from patients with XLP. We report here a role for phosphoinositide 3-kinase (PI3K) in the recruitment and association of SAP/SH2D1A to 2B4 in human NK cells. The activation of normal NK cells by ligation of 2B4 leads to the phosphorylation of 2B4, recruitment of SAP/SH2D1A, and association of the p85 regulatory subunit of PI3K. The inhibition of PI3K enzymatic activity with either wortmannin or LY294002 prior to 2B4 ligation does not alter the association of 2B4 with the p85 subunit but prevents the recruitment of SAP/SH2D1A to 2B4. In addition, PI3K inhibitors significantly diminish the cytotoxic function of primary NK cells. This observed inhibition of cytotoxicity, present in normal NK cells, was less apparent or absent in NK cells derived from a patient with XLP. These data indicate that the cytotoxicity of activated NK cells is mediated by the association of 2B4 and SAP/SH2D1A, and that this association is dependent upon the activity of PI3K.     

Structure--activity relationships among novel phenoxybenzamine-related beta-chloroethylamines

A series of beta-chloroethylamines 5--18, structurally related to the irreversible alpha(1)-adrenoceptor antagonist phenoxybenzamine [PB, N-benzyl-N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)amine hydrochloride, 1] and the competitive antagonist WB4101 [N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N-[2-(2,6-dimethoxyphenoxy)ethyl]amine hydrochloride, 2], were synthesized and evaluated for their activity at alpha-adrenoceptors of the epididymal and the prostatic portion of young CD rat vas deferens. All compounds displayed irreversible antagonist activity. Most of them showed similar antagonism at both alpha(1)- and alpha(2)-adrenoceptors, whereas compounds 13 and 18, lacking substituents on both the phenoxy group and the oxyamino carbon chain, displayed a moderate alpha(1)-adrenoceptor selectivity (10--35 times), which was comparable to that of PB. Compounds 14 and 15, belonging to the benzyl series and bearing, respectively, a 2-ethoxyphenoxy and a 2-i-propoxyphenoxy moiety, were the most potent alpha(1)-adrenoceptor antagonists with an affinity value similar to that of PB (pIC(50) values of 7.17 and 7.06 versus 7.27). Interestingly, several compounds were able to distinguish two alpha(1)-adrenoceptor subtypes in the epididymal tissue, as revealed by the discontinuity of their inhibition curves. A mean ratio of 24:76 for these alpha(1)-adrenoceptors was determined from compounds 8--10, 12, and 15--17. Furthermore, compounds 9, 10, 12, 16a, and 16b showed higher affinity towards the minor population of receptors, whereas compounds 8, 15, and 17 preferentially inhibited the major population of alpha(1)-adrenoceptors. In addition, selected pharmacological experiments demonstrated the complementary antagonism of the two series of compounds and their different, preferential affinity for one of the two alpha(1)-adrenoceptor subtypes. In conclusion, we found beta-chloroethylamines that demonstrate a multiplicity of alpha(1)-adrenoceptors in the epididymal portion of young CD rat vas deferens and, as a consequence, they are possible useful tools for alpha(1)-adrenoceptor characterization.