Broad HIV-1 neutralization mediated by CD4-binding site antibodies

We have identified several patient sera showing potent and broad HIV-1 neutralization. Using antibody adsorption and elution from selected gp120 variants, the neutralizing specificities of the two most broadly reactive sera were mapped to the primary receptor CD4-binding region of HIV-1 gp120. Novel antibodies to the CD4-binding site are elicited in some HIV-1-infected individuals, and new approaches to present this conserved region of gp120 to the immune system may result in improved vaccine immunogens.     

6,7-dihydroxyisoquinoline-3-carboxylic acids are potent inhibitors on the binding of insulin-like growth factor (IGF) to IGF-binding proteins: optimization of the 1-position benzoyl side chain

A series of 1-benzoyl isoquinolines, based on compound 1, was synthesized and evaluated for their ability to displace IGF-I from its complex with IGF-binding protein-3. Successful modifications of 1 included the replacement of the 3,4-dihydroxybenzoyl group with a substituted benzyl group. These alternations culminated in the discovery of compounds such as 7o which had excellent in vitro potency (K(i)=9.4 nM) but with one less of the labile catechol functionality of 1.     

The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt

In the search for neuroprotective factors in Huntington's disease, we found that insulin growth factor 1 via activation of the serine/threonine kinase Akt/PKB is able to inhibit neuronal death specifically induced by mutant huntingtin containing an expanded polyglutamine stretch. The IGF-1/Akt pathway has a dual effect on huntingtin-induced toxicity, since activation of this pathway also results in a decrease in the formation of intranuclear inclusions of mutant huntingtin. We demonstrate that huntingtin is a substrate of Akt and that phosphorylation of huntingtin by Akt is crucial to mediate the neuroprotective effects of IGF-1. Finally, we show that Akt is altered in Huntington's disease patients. Taken together, these results support a potential role of the Akt pathway in Huntington's disease.     

Electrophysiological and morphological properties of neurons in layer 5 of the rat postrhinal cortex

The postrhinal (POR) cortex of the rat is homologous to the parahippocampal cortex of the primate based on connections and other criteria. POR provides the major visual and visuospatial input to the hippocampal formation, both directly to CA1 and indirectly through connections with the medial entorhinal cortex. Although the cortical and hippocampal connections of the POR cortex are well described, the physiology of POR neurons has not been studied. Here, we examined theelectrical and morphological characteristics of layer 5 neurons from POR cortex of 14- to 16-day-old rats using an in vitro slice preparation. Neurons were subjectively classified as regular-spiking (RS), fast-spiking (FS), or low-threshold spiking (LTS) based on their electrophysiological properties and similarities with neurons in other regions of neocortex. Cells stained with biocytin included pyramidal cells and interneurons with bitufted or multipolar dendritic patterns. Similarity analysis using only physiological data yielded three clusters that corresponded to FS, LTS, and RS classes. The cluster corresponding to the FS class was composed entirely of multipolar nonpyramidal cells, and the cluster corresponding to the RS class was composed entirely of pyramidal cells. The third cluster, corresponding to the LTS class, was heterogeneous and included both multipolar and bitufted dendritic arbors as well as one pyramidal cell. We did not observe any intrinsically bursting pyramidal cells, which is similar to entorhinal cortex but unlike perirhinal cortex. We conclude that POR includes at least two major classes of neocortical inhibitory interneurons, but has a functionally restricted cohort of pyramidal cells. ? 2012 Wiley Periodicals, Inc.     

Allee effects may slow the spread of parasites in a coastal marine ecosystem

Allee effects are thought to mediate the dynamics of population colonization, particularly for invasive species. However, Allee effects acting on parasites have rarely been considered in the analogous process of infectious disease establishment and spread. We studied the colonization of uninfected wild juvenile Pacific salmon populations by ectoparasitic salmon lice (Lepeophtheirus salmonis) over a 4-year period. In a data set of 68,376 fish, we observed 85 occurrences of precopular pair formation among 1,259 preadult female and 613 adult male lice. The probability of pair formation was dependent on the local abundance of lice, but this mate limitation is likely offset somewhat by mate-searching dispersal of males among host fish. A mathematical model of macroparasite population dynamics that incorporates the empirical results suggests a high likelihood of a demographic Allee effect, which can cause the colonizing parasite populations to die out. These results may provide the first empirical evidence for Allee effects in a macroparasite. Furthermore, the data give a rare detailed view of Allee effects in colonization dynamics and suggest that Allee effects may dampen the spread of parasites in a coastal marine ecosystem.     

A predictive model for respiratory syncytial virus (RSV) hospitalisation of premature infants born at 33–35 weeks of gestational age,based on data from the Spanish FLIP study

Background

The aim of this study, conducted in Europe, was to develop a validated risk factor based model to predict RSV-related hospitalisation in premature infants born 33–35 weeks'' gestational age (GA).

Methods

The predictive model was developed using risk factors captured in the Spanish FLIP dataset, a case-control study of 183 premature infants born between 33–35 weeks'' GA who were hospitalised with RSV, and 371 age-matched controls. The model was validated internally by 100-fold bootstrapping. Discriminant function analysis was used to analyse combinations of risk factors to predict RSV hospitalisation. Successive models were chosen that had the highest probability for discriminating between hospitalised and non-hospitalised infants. Receiver operating characteristic (ROC) curves were plotted.

Results

An initial 15 variable model was produced with a discriminant function of 72% and an area under the ROC curve of 0.795. A step-wise reduction exercise, alongside recalculations of some variables, produced a final model consisting of 7 variables: birth ± 10 weeks of start of season, birth weight, breast feeding for ≤ 2 months, siblings ≥ 2 years, family members with atopy, family members with wheeze, and gender. The discrimination of this model was 71% and the area under the ROC curve was 0.791. At the 0.75 sensitivity intercept, the false positive fraction was 0.33. The 100-fold bootstrapping resulted in a mean discriminant function of 72% (standard deviation: 2.18) and a median area under the ROC curve of 0.785 (range: 0.768–0.790), indicating a good internal validation. The calculated NNT for intervention to treat all at risk patients with a 75% level of protection was 11.7 (95% confidence interval: 9.5–13.6).

Conclusion

A robust model based on seven risk factors was developed, which is able to predict which premature infants born between 33–35 weeks'' GA are at highest risk of hospitalisation from RSV. The model could be used to optimise prophylaxis with palivizumab across Europe.     

Effects of exogenous interleukin-1β on primary sporocysts of Schistosoma mansoni (Trematoda) incubated with plasma and hemocytes from schistosome-susceptible and resistant Biomphalaria glabrata (Gastropoda)

Abstract. The cytokine interleukin-1β (IL-1β) mediates interactions of immune and inflammatory cells in mammals. Previous reports also have linked plasma (cell-free hemolymph) levels of IL-1β in the snail Biomphalaria glabrata to resistance against Schistosoma mansoni . In the present study, fluorescent probes were used to study larval schistosome and snail hemocyte viability during in vitro encounters. Hemolymph (plasma and hemocytes) from schistosome-susceptible (M-line) and resistant (13–16-R1) B. glabrata was added to sporocysts of S. mansoni and the viability of hemocytes and parasites was assessed. Next, IL-1β was added to sporocyst-hemolymph samples, the viability of sporocysts and hemocytes determined and then compared to control assays. The number of live sporocysts present after incubation for 1 h with hemolymph from M-line snails was significantly greater than the number seen when hemolymph from 13–16-R1 snails was tested. Nearly all sporocysts survived the 1 h incubation with M-line hemolymph, and most of the hemocytes attached to sporocysts were dead. In contrast, nearly all sporocysts were dead when hemolymph from 13–16-R1 snails was tested, and most attached hemocytes were alive. Addition of IL-1β to M-line hemolymph resulted in a dramatic increase in sporocyst death. Addition of IL-1β to 13–16-R1 hemolymph produced a small but significant increase in the rate of sporocyst death. These results indicate that the concentration of IL-1β present in hemolymph from B. glabrata is directly related to the ability of this snail to kill S. mansoni sporocysts in vitro.