Regulation of arsenic trioxide-induced cellular responses by Mnk1 and Mnk2

Arsenic trioxide (As(2)O(3)) is a potent inducer of apoptosis of malignant cells in vitro and in vivo, but the precise mechanisms by which it mediates such effects are not well defined. We provide evidence that As(2)O(3) induces phosphorylation/activation of the MAPK signal-integrating kinases (Mnks) 1 and 2 in leukemia cell lines. Such activation is defective in cells with targeted disruption of the p38alpha MAPK gene, indicating that it requires upstream engagement of the p38 MAPK pathway. Studies using Mnk1(-/-) or Mnk2(-/-), or double Mnk1(-/-)Mnk2(-/-) knock-out cells, establish that activation of Mnk1 and Mnk2 by arsenic trioxide regulates downstream phosphorylation of the eukaryotic initiation factor 4E at Ser-209. Importantly, arsenic-induced apoptosis is enhanced in cells with targeted disruption of the Mnk1 and/or Mnk2 genes, suggesting that these kinases are activated in a negative-feedback regulatory manner, to control generation of arsenic trioxide responses. Consistent with this, pharmacological inhibition of Mnk activity enhances the suppressive effects of arsenic trioxide on primary leukemic progenitors from patients with acute leukemias. Taken together, these findings indicate an important role for Mnk kinases, acting as negative regulators for signals that control generation of arsenic trioxide-dependent apoptosis and antileukemic responses.     

ICOS costimulation expands Th2 immunity by augmenting migration of lymphocytes to draining lymph nodes

The T cell costimulatory molecule ICOS regulates Th2 effector function in allergic airway disease. Recently, several studies with ICOS(-/-) mice have also demonstrated a role for ICOS in Th2 differentiation. To determine the effects of ICOS on the early immune response, we investigated augmenting ICOS costimulation in a Th2-mediated immune response to Schistosoma mansoni Ags. We found that augmenting ICOS costimulation with B7RP-1-Fc increased the accumulation of T and B cells in the draining lymph nodes postimmunization. Interestingly, the increased numbers were due in part to increased migration of undivided Ag-specific TCR transgenic T cells and surprisingly B cells, as well as non-TCR transgenic T cells. B7RP-1-Fc also increased the levels of the chemokines CCL21 and CXCL13 in the draining lymph node, suggesting ICOS costimulation contributes to migration by direct or indirect effects on dendritic cells, stromal cells and high endothelial venules. Further, the effects of B7RP-1-Fc were not dependent on immunization. Our data support a model in which ICOS costimulation augments the pool of lymphocytes in the draining lymph nodes, leading to an increase in the frequency of potentially reactive T and B cells.     

HIV Infection and Awareness among Men Who Have Sex with Men–20 Cities,United States, 2008 and 2011

Over half of HIV infections in the United States occur among men who have sex with men (MSM). Awareness of infection is a necessary precursor to antiretroviral treatment and risk reduction among HIV-infected persons. We report data on prevalence and awareness of HIV infection among MSM in 2008 and 2011, using data from 20 cities participating in the 2008 and 2011 National HIV Behavioral Surveillance System (NHBS) among MSM. Venue-based, time-space sampling was used to recruit men for interview and HIV testing. We analyzed data for men who reported ≥1 male sex partner in the past 12 months. Participants who tested positive were considered to be aware of their infection if they reported a prior positive HIV test. We used multivariable analysis to examine differences between results from 2011 vs. 2008. HIV prevalence was 19% in 2008 and 18% in 2011 (p = 0.14). In both years, HIV prevalence was highest among older age groups, blacks, and men with lower education and income. In multivariable analysis, HIV prevalence did not change significantly from 2008 to 2011 overall (p = 0.51) or in any age or racial/ethnic category (p>0.15 in each category). Among those testing positive, a greater proportion was aware of their infection in 2011 (66%) than in 2008 (56%) (p<0.001). In both years, HIV awareness was higher for older age groups, whites, and men with higher education and income. In multivariable analysis, HIV awareness increased from 2008 to 2011 overall (p<0.001) and for all age and racial/ethnic categories (p<0.01 in each category). In both years, black MSM had the highest HIV prevalence and the lowest awareness among racial/ethnic groups. These findings suggest that HIV-positive MSM are increasingly aware of their infections.     

Sex ratio influences the motivational salience of facial attractiveness

The sex ratio of the local population influences mating-related behaviours in many species. Recent experiments show that male-biased sex ratios increase the amount of financial resources men will invest in potential mates, suggesting that sex ratios influence allocation of mating effort in humans. To investigate this issue further, we tested for effects of cues to the sex ratio of the local population on the motivational salience of attractiveness in own-sex and opposite-sex faces. We did this using an effort-based key-press task, in which the motivational salience of facial attractiveness was assessed in samples of faces in which the ratio of male to female images was manipulated. The motivational salience of attractive opposite-sex, but not own-sex, faces was greater in the own-sex-biased (high competition for mates) than in the opposite-sex-biased (low competition for mates) condition. Moreover, this effect was not modulated by participant sex. These results present new evidence that sex ratio influences human mating-related behaviours. They also present the first evidence that the perceived sex ratio of the local population may modulate allocation of mating effort in women, as well as men.     

Identification of Outer Membrane and Exoproteins of Carbapenem-Resistant Multilocus Sequence Type 258 Klebsiella pneumoniae

Carbapenem-resistant Klebsiella pneumoniae strains have emerged as a cause of life-threatening infections in susceptible individuals (e.g., transplant recipients and critically ill patients). Strains classified as multilocus sequence type (ST) 258 are among the most prominent causes of carbapenem-resistant K. pneumoniae infections worldwide, but the basis for the success of this lineage remains incompletely determined. To gain a more comprehensive view of the molecules potentially involved in the success of ST258, we used a proteomics approach to identify surface-associated and culture supernatant proteins produced by ST258. Protein samples were prepared from varied culture conditions in vitro, and were analyzed by a combination of two-dimensional electrophoresis and liquid chromatography followed by tandem mass spectrometry (LC-MS/MS). We identified a total of 193 proteins in outer membrane preparations from bacteria cultured in Luria-Bertani broth (LB) or RPMI 1640 tissue culture media (RPMI). Compared with LB, several iron-acquisition proteins, including IutA, HmuR, HmuS, CirA, FepA, FitA, FoxA, FhuD, and YfeX, were more highly expressed in RPMI. Of the 177 proteins identified in spent media, only the fimbrial subunit, MrkA, was predicted to be extracellular, a finding that suggests few proteins (or a limited quantity) are freely secreted by ST258. Notably, we discovered 203 proteins not reported in previous K. pneumoniae proteome studies. In silico modeling of proteins with unknown function revealed several proteins with beta-barrel transmembrane structures typical of porins, as well as possible host-interacting proteins. Taken together, these findings contribute several new targets for the mechanistic study of drug-resistance and pathogenesis by ST258 K. pneumoniae isolates.     

Morphological assessment of the Octopus vulgaris species complex evaluated in light of molecular‐based phylogenetic inferences

Cryptic species are common in the ocean, particularly among marine invertebrates such as octopuses. Delineating cryptic species is particularly problematic in octopus taxonomy where the plasticity recorded among taxonomic characters often results in low resolution at the species level. This study investigated the morphological relationships among seven phylogenetic clades (identified using cytochrome c oxidase subunit I) of the broadly distributed Octopus vulgaris species complex and close relatives. Morphological analyses in this study were successful in delimiting O. sinensis, Brazilian O. vulgaris and O. vulgaris sensu stricto, which was congruent with the molecular findings of this study. Analyses based on male morphology were successful in distinguishing 14 of 15 total pairwise comparisons and proved to be a more reliable indicator of species‐level relationships in comparison with female morphology. The majority of characters with the greatest discriminatory power were male sexual traits. Significant morphological differences were also recorded among sampling localities of conspecifics, with phenotype showing correlation with local environmental data. The findings of this study support the hypothesis that multiple O. vulgaris‐like species are currently being incorrectly treated under a single species name, O. vulgaris. Octopuses being exported globally under the name O. vulgaris are of extremely high fisheries market value and profile. Our findings have potentially significant implications for the naming and conservation of commercially harvested members of this species complex throughout their ranges.     

Biomimetic bone mechanotransduction modeling in neonatal rat femur organ cultures: structural verification of proof of concept

The goal of this work was to develop and validate a whole bone organ culture model to be utilized in biomimetic mechanotransduction research. Femurs harvested from 2-day-old neonatal rat pups were maintained in culture for 1 week post-harvest and assessed for growth and viability. For stimulation studies, femurs were physiologically stimulated for 350 cycles 24 h post-harvest then maintained in culture for 1 week at which time structural tests were conducted. Comparing 1 and 8 days in culture, bones grew significantly in size over the 7-day culture period. In addition, histology supported adequate diffusion and organ viability at 2 weeks in culture. For stimulation studies, 350 cycles of physiologic loading 24 h post-harvest resulted in increased bone strength over the 7-day culture period. In this work, structural proof of concept was established for the use of whole bone organ cultures as mechanotransduction models. Specifically, this work established that these cultures grow and remain viable in culture, are adequately nourished via diffusion and are capable of responding to a brief bout of mechanical stimulation with an increase in strength.