Citron Kinase, a RhoA Effector, Enhances HIV-1 Virion Production by Modulating Exocytosis

RhoGTPases play important roles in the regulation of protein transport and membrane recycling. Little is known, however, about how RhoGTPases affect HIV-1 virion production, which is dependent on the endosomal sorting pathway. We report that ectopic expression of citron kinase (citron-K), a RhoA effector, preferentially enhances HIV-1 virion production. Depletion of endogenous citron-K inhibits HIV-1 virion production. Citron-N, which lacks the kinase domain, also enhances HIV-1 virion production. The leucine zipper, Rho-binding and zinc finger domains of citron-N are necessary for the enhancement activity. Citron-K also enhances murine leukemia virion production and the HIV-1 late domain is not required for the citron-K-mediated enhancement. Ectopic expression of citron-K leads to the formation of cytoplasmic structures containing citron-K and HIV-1 Gag proteins. HIV-1 and citron-K cooperatively enhance acidic endosome and lysosome compartments. Finally, citron-K promotes exocytosis of microvesicles or exosomes that co-purify with HIV-1 virions. We conclude that citron-K enhances HIV-1 virion production by stimulating the endosomal compartments and exocytosis

Coal Home Heating and Environmental Tobacco Smoke in Relation to Lower Respiratory Illness in Czech Children, from Birth to 3 Years of Age

OBJECTIVE: The objective of this study was to evaluate how indoor pollution from tobacco and home heating may adversely affect respiratory health in young children. DESIGN: A birth cohort was followed longitudinally for 3 years to determine incidence of lower respiratory illness (LRI). PARTICIPANTS: A total of 452 children born 1994–1996 in two districts in the Czech Republic participated. EVALUATIONS: Indoor combustion exposures were home heating and cooking fuel, mother’s smoking during pregnancy, and other adult smokers in the household. Diagnoses of LRI (primarily acute bronchitis) from birth to 3 years of age were abstracted from pediatric records. Questionnaires completed at delivery and at 3-year follow-up provided covariate information. LRI incidence rates were modeled with generalized linear models adjusting for repeated measures and for numerous potential confounders. RESULTS: LRI diagnoses occurred more frequently in children from homes heated by coal [vs. other energy sources or distant furnaces; rate ratio (RR) = 1.45; 95% confidence interval (CI), 1.07–1.97]. Maternal prenatal smoking and other adult smokers also increased LRI rates (respectively: RR = 1.48; 95% CI, 1.10–2.01; and RR = 1.29; 95% CI, 1.01–1.65). Cooking fuels (primarily electricity, natural gas, or propane) were not associated with LRI incidence. For children never breast-fed, coal home heating and mother’s smoking conferred substantially greater risks: RR = 2.77 (95% CI, 1.45–5.27) and RR = 2.52 (95% CI, 1.31–4.85), respectively. CONCLUSIONS: Maternal smoking and coal home heating increased risk for LRI in the first 3 years of life, particularly in children not breast-fed. RELEVANCE: Few studies have described effects of coal heating fuel on children’s health in a Western country. Breast-feeding may attenuate adverse effects of prenatal and childhood exposures to combustion products

The effects of size changes on haptic object recognition

Two experiments examined the effects of size changes on haptic object recognition. In Experiment 1, participants named one of three exemplars (a standard-size-and-shape, different-size, or different-shape exemplar) of 36 categories of real, familiar objects. They then performed an old/new recognition task on the basis of object identity for the standard exemplars of all 36 objects. Half of the participants performed both blocks visually; the other half performed both blocks haptically. The participants were able to efficiently name unusually sized objects haptically, consistent with previous findings of good recognition of small-scale models of stimuli (Lawson, in press). However, performance was impaired for both visual and haptic old/new recognition when objects changed size or shape between blocks. In Experiment 2, participants performed a short-term haptic shapematching task using 3-D plastic models of familiar objects, and as in Experiment 1, a cost emerged for ignoring the irrelevant size change. Like its visual counterpart, haptic object recognition incurs a significant but modest cost for generalizing across size changes. © 2009 The Psychonomic Society, Inc

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Prime-boost immunization of rabbits with HIV-1 gp120 elicits potent neutralization activity against a primary viral isolate

<div><p>Development of a vaccine for HIV-1 requires a detailed understanding of the neutralizing antibody responses that can be experimentally elicited to difficult-to-neutralize primary isolates. Rabbits were immunized with the gp120 subunit of HIV-1 JR-CSF envelope (Env) using a DNA-prime protein-boost regimen. We analyzed five sera that showed potent autologous neutralizing activity (IC50s at ∼10³ to 10⁴ serum dilution) against pseudoviruses containing Env from the primary isolate JR-CSF but not from the related isolate JR-FL. Pseudoviruses were created by exchanging each variable and constant domain of JR-CSF gp120 with that of JR-FL or with mutations in putative N-glycosylation sites. The sera contained different neutralizing activities dependent on C3 and V5, C3 and V4, or V4 regions located on the glycan-rich outer domain of gp120. All sera showed enhanced neutralizing activity toward an Env variant that lacked a glycosylation site in V4. The JR-CSF gp120 epitopes recognized by the sera are generally distinct from those of several well characterized mAbs (targeting conserved sites on Env) or other type-specific responses (targeting V1, V2, or V3 variable regions). The activity of one serum requires specific glycans that are also important for 2G12 neutralization and this serum blocked the binding of 2G12 to gp120. Our findings show that different fine specificities can achieve potent neutralization of HIV-1, yet this strong activity does not result in improved breadth.</p> </div

Emerging Vaccine Technologies

Vaccination has proven to be an invaluable means of preventing infectious diseases by reducing both incidence of disease and mortality. However, vaccines have not been effectively developed for many diseases including HIV-1, hepatitis C virus (HCV), tuberculosis and malaria, among others. The emergence of new technologies with a growing understanding of host-pathogen interactions and immunity may lead to efficacious vaccines against pathogens, previously thought impossible

The C-Terminal Portion of the Hrs Protein Interacts with Tsg101 and Interferes with Human Immunodeficiency Virus Type 1 Gag Particle Production

The human immunodeficiency virus type 1 (HIV-1) Gag protein recruits Tsg101 to facilitate HIV-1 particle budding and release. In uninfected cells, the Hrs protein recruits the ESCRT-I complex to the endosome, also through an interaction with Tsg101, to promote the sorting of host proteins into endosomal vesicles and multivesicular bodies. Here, we show that the overexpression of the C-terminal fragment of Hrs (residues 391 to 777) or Hrs mutants lacking either the N-terminal FYVE domain (mutant dFYVE) or the PSAP (residues 348 to 351) motif (mutant ASAA) all efficiently inhibit HIV-1 Gag particle production. Expression of the dFYVE or ASAA mutants of Hrs had no effect on the release of Moloney murine leukemia virus. Coimmunoprecipitation analysis showed that the expression of Hrs mutant dFYVE or ASAA significantly reduced or abolished the HIV-1 Gag-Tsg101 interaction. Yeast-two hybrid assays were used to identify two new and independent Tsg101 binding sites, one in the Hrs coiled-coil domain and one in the proline/glutamic acid-rich domain. Scanning electron microscopy of HeLa cells expressing HIV-1 Gag and the Hrs ASAA mutant showed viral particles arrested in “lump-like” structures that remained attached to the cell surface. Together, these data indicate that fragments of Hrs containing the C-terminal portion of the protein can potently inhibit HIV-1 particle release by efficiently sequestering Tsg101 away from the Gag polyprotein

Training Curriculum: Responding to Sexual Abuse of Youth in Custody: Addressing the Needs of Boys, Girls, and Gender Nonconforming Youth - Notification of Curriculum Use (Facilitator’s Guide)

The enclosed Responding to Sexual Abuse of Youth in Custody: Addressing the Needs of Boys, Girls, and Gender Nonconforming Youth curriculum was developed by the Project on Addressing Prison Rape at American University, Washington College of Law as part of contract deliverables for the National PREA Resource Center (PRC), a cooperative agreement between the National Council on Crime and Delinquency (NCCD) and the Bureau of Justice Assistance (BJA). The Prison Rape Elimination Act (PREA) standards served as the basis for the curriculum’s content and development with the goal of the Responding to Sexual Abuse of Youth in Custody: Addressing the Needs of Boys, Girls, and Gender Nonconforming Youth curriculum being to satisfy specific PREA standard requirements. It is recommended that the Responding to Sexual Abuse of Youth in Custody: Addressing the Needs of Boys, Girls, and Gender Nonconforming Youth curriculum be reviewed in its entirety before choosing which modules to use. Any alterations to the original materials require either acknowledgement during their presentation or removal of the PRC and Project on Addressing Prison Rape logos. BJA is currently undergoing a comprehensive review of the enclosed curriculum for official approval, at which point the BJA logo may be added