Apelin, the natural ligand of the orphan seven-transmembrane receptor APJ, inhibits human immunodeficiency virus type 1 entry

In addition to the CCR5 and CXCR4 chemokine receptors, a subset of primary human immunodeficiency virus type 1 (HIV-1) isolates can also use the seven-transmembrane-domain receptor APJ as a coreceptor. A previously identified ligand of APJ, apelin, specifically inhibited the entry of primary T-tropic and dualtropic HIV-1 isolates from different clades into cells expressing CD4 and APJ. Analysis of apelin analogues demonstrated that potent and specific antiviral activity was retained by a 13-residue, arginine-rich peptide. Antiviral potency was influenced by the integrity of methionine 75, which contributes to APJ-binding affinity, and by the retention of apelin residues 63 to 65. These studies demonstrate the ability of a small peptide ligand to block the function of APJ as an HIV-1 coreceptor, identify apelin sequences important for the inhibition, and provide new reagents for the investigation of the significance of APJ to HIV-1 infection and pathogenesis.     

Neural network schemes for detecting rare events in human genomic DNA

MOTIVATION: Many problems in molecular biology as well as other areas involve detection of rare events in unbalanced data. We develop two sample stratification schemes in conjunction with neural networks for rare event detection in such databases. Sample stratification is a technique for making each class in a sample have equal influence on decision making. The first scheme proposed stratifies a sample by adding up the weighted sum of the derivatives during the backward pass of training. The second scheme proposed uses a technique of modified bootstrap aggregating. After training neural networks with multiple sets of bootstrapped examples of the rare event classes and subsampled examples of common event classes, multiple voting for classification is performed. RESULTS: These two schemes make rare event classes have a better chance of being included in the sample used for training neural networks and thus improve the classification accuracy for rare event detection. The experimental performance of the two schemes using two sets of human DNA sequences as well as another set of Gaussian data indicates that proposed schemes have the potential of significantly improving accuracy of neural networks to recognize rare events.     

Differential effects of substrate-analogue inhibitors on nitric oxide synthase dimerization

Cigarette smoking has been linked to almost all major types of cancer. Emerging evidence suggests that smoking initiates transformed cell growth and migration by disrupting cell-cell interactions in the polarized mucosal epithelium. Together with other adherens junction proteins, p120-catenin (p120ctn) maintains cell-cell adhesion through its direct interaction with E-cadherin (E-cad). Mislocalization and/or loss of p120ctn have been reported in all lung cancer subtypes and are related to poor prognosis. Here, we showed that p120ctn modulates smoke-induced cell migration via the EGFR/Src-P pathway. Chemical blockade of EGFR/Src signaling inhibited smoke-induced activation of cofilin (an actin severing protein) and promoted cell migration in the presence of p120ctn but had little effect on blocking migration in the absence of p120ctn. These data suggested that smoke-induced cell migration was mediated via an EGFR/Src-dependent signaling pathway in cells that expressed p120ctn, but upon loss of p120ctn, migration continued to occur via an alternative, EGFR/Src-independent pathway. Thus, gradual loss of membrane p120ctn with lung cancer progression may contribute to reduced effectiveness of conventional chemotherapies, such as those directed against EGFR.     

Temporal polyethism in Korean yellowjacket foragers,Vespula koreensis (Hymenoptera,Vespidae)

We examined the foraging behavior of the Korean yellowjacket, Vespula koreensis, to determine whether this species displays temporal polyethism. Using video-recordings of the entrances of artificial nest boxes installed in the field, we investigated the association between the tasks performed by workers and age. We identified three foraging tasks (pulp, nectar and prey foraging). Pulp foraging was performed by younger foragers, while nectar and prey foraging were performed by older foragers. We measured the foraging time (time spent outside of the nest during a single foraging bout) and the weight of the materials that foragers brought into the nest for each task to estimate the cost of the task. Pulp foraging was less costly than nectar or prey foraging by both measures. Taken together, the results suggest that yellowjacket foragers tend to perform low-cost task in their early foraging days and high-cost task later. Our results add to a growing literature showing temporal polyethism in social insects.     

An antibody recognizing the apical domain of human transferrin receptor 1 efficiently inhibits the entry of all new world hemorrhagic Fever arenaviruses

Five New World (NW) arenaviruses cause human hemorrhagic fevers. Four of these arenaviruses are known to enter cells by binding human transferrin receptor 1 (hTfR1). Here we show that the fifth arenavirus, Chapare virus, similarly uses hTfR1. We also identify an anti-hTfR1 antibody, ch128.1, which efficiently inhibits entry mediated by the glycoproteins of all five viruses, as well as replication of infectious Junín virus. Our data indicate that all NW hemorrhagic fever arenaviruses utilize a common hTfR1 apical-domain epitope and suggest that therapeutic agents targeting this epitope, including ch128.1 itself, can be broadly effective in treating South American hemorrhagic fevers.     

The GAP between axon pruning and repulsion

How cells orchestrate their behavior during collective migration is a long-standing question. Using magnetic tweezers to apply mechanical stimuli to Xenopus mesendoderm cells, Weber et al. (2012) now reveal, in this issue of Developmental Cell, a cadherin-mediated mechanosensitive response that promotes cell polarization and movement persistence during the collective mesendoderm migration in gastrulation.     

Fine tuning of vesicle assembly and properties using dual hydrophilic triblock copolypeptides

The design, synthesis, and self-assembly of the first dual hydrophilic triblock copolypeptide vesicles, R(H)(m)E(n)L(o) and K(P)(m)R(H)(n)L(o), is reported. Variation of the two distinct hydrophilic domains is used to tune cellular interactions without disrupting the self-assembled structure. The aqueous self-assemblies of these triblock copolypeptides in water are characterized using microscopy and DLS. Cell culture studies are used to evaluate cytotoxicity as well as intracellular uptake of the vesicles. The ability of polypeptides to incorporate ordered chain conformations that direct self-assembly, combined with the facile preparation of functional, multiblock copolypeptide sequences of defined lengths, allow the design of vesicles attractive for development as drug carriers.     

Overexpression of 3β-hydroxysteroid dehydrogenases/C-4 decarboxylases causes growth defects possibly due to abnormal auxin transport in arabidopsis

Sterols play crucial roles as membrane components and precursors of steroid hormones (e.g., brassinosteroids, BR). Within membranes, sterols regulate membrane permeability and fluidity by interacting with other lipids and proteins. Sterols are frequently enriched in detergent-insoluble membranes (DIMs), which organize molecules involved in specialized signaling processes, including auxin transporters. To be fully functional, the two methyl groups at the C-4 position of cycloartenol, a precursor of plant sterols, must be removed by bifunctional 3β-hydroxysteroid dehydrogenases/C-4 decarboxylases (3βHSD/D). To understand the role of 3βHSD/D in Arabidopsis development, we analyzed the phenotypes of knock-out mutants and overexpression lines of two 3βHSD/D genes (At1g47290 and At2g26260). Neither single nor double knock-out mutants displayed a noticeable phenotype; however, overexpression consistently resulted in plants with wrinkled leaves and short inflorescence internodes. Interestingly, the internode growth defects were opportunistic; even within a plant, some stems were more severely affected than others. Endogenous levels of BRs were not altered in the overexpression lines, suggesting that the growth defect is not primarily due to a flaw in BR biosynthesis. To determine if overexpression of the sterol biosynthetic genes affects the functions of membrane-localized auxin transporters, we subjected plants to the auxin efflux carrier inhibitor, 1-N-naphthylphthalamic acid (NPA). Where-as the gravity vectors of wild-type roots became randomly scattered in response to NPA treatment, those of the overexpression lines continued to grow in the direction of gravity. Overexpression of the two Arabidopsis 3βHSD/D genes thus appears to affect auxin transporter activity, possibly by altering sterol composition in the membranes.