The rockefeller university

A vaccine that elicits broadly neutralizing antibodies (bNAbs) against HIV-1 is likely to be protective, but this has not been achieved. To explore immunization regimens that might elicit bNAbs, we produced and immunized mice expressing the predicted germline PGT121, a bNAb specific for the V3-loop and surrounding glycans on the HIV-1 spike. Priming with an epitope-modified immunogen designed to activate germline antibody-expressing B cells, followed by ELISA-guided boosting with a sequence of directional immunogens, native-like trimers with decreasing epitope modification, elicited heterologous tier-2-neutralizing responses. In contrast, repeated immunization with the priming immunogen did not. Antibody cloning confirmed elicitation of high levels of somatic mutation and tier-2-neutralizing antibodies resembling the authentic human bNAb. Our data establish that sequential immunization with specifically designed immunogens can induce high levels of somatic mutation and shepherd antibody maturation to produce bNAbs from their inferred germline precursors.

Critical periods are temporary windows of heightened neural plasticity early in development. For example, fear memories in juvenile rodents are subject to erasure following extinction training, while after closure of this critical period, extinction training only temporarily and weakly suppresses fear memories. Persistence of fear memories is important for survival, but the inability to effectively adapt to the trauma is a characteristic of post-traumatic stress disorder (PTSD). We examined whether Nogo Receptor 1 (NgR1) regulates the plasticity associated with fear extinction. The loss of NgR1 function in adulthood eliminates spontaneous fear recovery and fear renewal, with a restoration of fear reacquisition rate equal to that of naive mice; thus, mimicking the phenotype observed in juvenile rodents. Regional gene disruption demonstrates that NgR1 expression is required in both the basolateral amygdala (BLA) and infralimbic (IL) cortex to prevent fear erasure. NgR1 expression by parvalbumin expressing interneurons is essential for limiting extinction-dependent plasticity. NgR1 gene deletion enhances anatomical changes of inhibitory synapse markers after extinction training. Thus, NgR1 robustly inhibits elimination of fear expression in the adult brain and could serve as a therapeutic target for anxiety disorders, such as PTSD.

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent -offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP - induced osteoblast differentiation (p<10(-20)). SMAD6 mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.

Background: Centromeres are essential for accurate chromosome segregation, yet sequence conservation is low even among closely related species. Centromere drive predicts rapid turnover because some centromeric sequences may compete better than others during female meiosis. In addition to sequence composition, longer centromeres may have a transmission advantage. Results: We report the first observations of extremely long centromeres, covering on average 34 % of the chromosomes, in the red imported fire ant Solenopsis invicta. By comparison, cytological examination of Solenopsis geminata revealed typical small centromeric constrictions. Bioinformatics and molecular analyses identified CenSol, the major centromeric satellite DNA repeat. We found that CenSol sequences are very similar between the two species but the CenSol copy number in S. invicta is much greater than that in S. geminata. In addition, centromere expansion in S. invicta is not correlated with the duplication of CenH3. Comparative analyses revealed that several closely related fire ant species also possess long centromeres. Conclusions: Our results are consistent with a model of simple runaway centromere expansion due to centromere drive. We suggest expanded centromeres may be more prevalent in hymenopteran insects, which use haplodiploid sex determination, than previously considered.

In Texas, Arizona, and New Mexico, colonias refer to unincorporated rural settlements along the U.S. Mexico border. Colonias lack governance and public services normally provided by local government (Ward, 1999). Residents typically rely on well water or hauled water stored in above-ground containers. This study attempted to quantify and compare water-related perceptions and practices of colonia residents. No significant differences were observed between colonia residents using well water versus hauled-stored water for water quality perceptions and water use practices. Most, however, had negative perceptions of their water supply; a majority perceived daily water supplies as not potable. Significant paradoxical discrepancies between perceptions and practice were identified. This study adds to a small but growing literature on subjective dimensions of quality of life indicators for colonia residents. Additional studies are needed to quantify the type and level of health risks posed by compromised water supplies for this vulnerable population. Understanding differences in perceptions and practices associated with water sources could help to identify which subpopulations of colonia residents are in greatest need of water infrastructure or remediation.

The liver is essential for the synthesis of plasma proteins and integration of lipid metabolism. While the role of transcriptional networks in these processes is increasingly understood, less is known about post-transcriptional control of gene expression by RNA-binding proteins (RBPs). Here, we show that the RBP vigilin is upregulated in livers of obese mice and in patients with fatty liver disease. By using in vivo, biochemical and genomic approaches, we demonstrate that vigilin controls very-low-density lipoprotein (VLDL) secretion through the modulation of apolipoproteinB/Apob mRNA translation. Crosslinking studies reveal that vigilin binds to CU-rich regions in the mRNA coding sequence of Apob and other proatherogenic secreted proteins, including apolipoproteinC-III/Apoc3 and fibronectin/Fn1. Consequently, hepatic vigilin knockdown decreases VLDL/low-density lipoprotein (LDL) levels and formation of atherosclerotic plaques in Ldlr(-/-) mice. These studies uncover a role for vigilin as a key regulator of hepatic Apob translation and demonstrate the therapeutic potential of inhibiting vigilin for cardiovascular diseases.

Objectives We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals. Methods This study was a within-participant, double-blind, placebo-controlled inpatient human laboratory evaluation of 65 nontreatment-seeking, cocaine-dependent [ Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)] individuals aged 18-55 years. Participants received both placebo (saline, IV) and cocaine (40 mg, IV), and subjective responses were assessed 15 min before receiving an infusion and at 5 min intervals for the subsequent 20 min. The rs1048101 variant of the alpha(1A)-adrenoceptor (ADRA1A) gene was genotyped and it was evaluated whether the Cys to Arg substitution at codon 347 in exon 2 (Cys347Arg) moderated the magnitude of the subjective effects produced by cocaine. Results Thirty (46%) participants were found to have the major allele CC genotype and 35 (44%) carried at least one minor T-allele of rs1048101 (TT or TC genotype). Individuals with the CC genotype showed greater responses for 'desire' (P < 0.0001),'high' (P < 0.0001),'any drug effect' (P < 0.0001), 'like cocaine' (P < 0.0001), and 'likely to use cocaine if given access' (P < 0.05) with experiment-wise significance. Conclusion This study indicates that the ADRA1A genotype could be used to identify individuals for whom acute cocaine exposure may be more rewarding and by inference may result in greater difficulty in establishing and/or maintaining abstinence from cocaine. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

The parasitic protozoa Trypanosome brucei and Plasmodium falciparum are lethal human parasites that have developed elegant strategies of immune evasion by antigenic variation. Despite the vast evolutionary distance between the two taxa, both parasites employ strict monoallelic expression of their membrane proteins, variant surface glycoproteins in Trypanosomes and the var, rif and stevor genes in Plasmodium, in order to evade their host's immune system. Additionally, both telomeric location and epigenetic controls are prominent features of these membrane proteins. As such, telomeres, chromatin structure and nuclear organization all contribute to control of gene expression and immune evasion. Here, we discuss the importance of epigenetics and sub-nuclear context for the survival of these disease-causing parasites. (C) 2016 Elsevier B.V. All rights reserved.