Authors: Ghazizadeh A, Griggs W, Hikosaka O
Journal: Front Neurosci. 2016 Aug 19;10:378. doi: 10.3389/fnins.2016.00378. eCollection 2016.
Among many objects around us, some are more salient than others (i.e., attract our attention automatically). Some objects may be inherently salient (e.g., brighter), while others may become salient by virtue of their ecological relevance through experience. However, the role of ecological experience in automatic attention has not been studied systematically. To address this question, we let subjects (macaque monkeys) view a large number of complex objects (>300), each experienced repeatedly (>5 days) with rewarding, aversive or no outcome association (mere-perceptual exposure). Test of salience was done on separate days using free viewing with no outcome. We found that gaze was biased among the objects from the outset, affecting saccades to objects or fixations within objects. When the outcome was rewarding, gaze preference was stronger (i.e., positive) for objects with larger or equal but uncertain rewards. The effects of aversive outcomes were variable. Gaze preference was positive for some outcome associations (e.g., airpuff), but negative for others (e.g., time-out), possibly due to differences in threat levels. Finally, novel objects attracted gaze, but mere perceptual exposure of objects reduced their salience (learned negative salience). Our results show that, in primates, object salience is strongly influenced by previous ecological experience and is supported by a large memory capacity. Owing to such high capacity for learned salience, the ability to rapidly choose important objects can grow during the entire life to promote biological fitness.
Authors: Shin HY, Willi M, Yoo KH, Zeng X, Wang C, Metser G, Hennighausen L
Journal: Nat Genet. 2016 Aug;48(8):904-11. doi: 10.1038/ng.3606. Epub 2016 Jul 4.
Super-enhancers comprise dense transcription factor platforms highly enriched for active chromatin marks. A paucity of functional data led us to investigate the role of super-enhancers in the mammary gland, an organ characterized by exceptional gene regulatory dynamics during pregnancy. ChIP-seq analysis for the master regulator STAT5A, the glucocorticoid receptor, H3K27ac and MED1 identified 440 mammary-specific super-enhancers, half of which were associated with genes activated during pregnancy. We interrogated the Wap super-enhancer, generating mice carrying mutations in STAT5-binding sites within its constituent enhancers. Individually, the most distal site displayed the greatest enhancer activity. However, combinatorial mutation analysis showed that the 1,000-fold induction in gene expression during pregnancy relied on all enhancers. Disabling the binding sites of STAT5, NFIB and ELF5 in the proximal enhancer incapacitated the entire super-enhancer. Altogether, these data suggest a temporal and functional enhancer hierarchy. The identification of mammary-specific super-enhancers and the mechanistic exploration of the Wap locus provide insights into the regulation of cell-type-specific expression of hormone-sensing genes.
Authors: Parr CL, Magnus MC, Karlstad Ø, Haugen M, Refsum H, Ueland PM, McCann A, Nafstad P, Håberg SE, Nystad W, London SJ.
Journal: Am J Respir Crit Care Med. 2016 Aug 12.
RATIONALE: A potential adverse effect of high folate intake during pregnancy on children's asthma development remains controversial.
OBJECTIVES: To prospectively investigate folate intake from both food and supplements during pregnancy and asthma at age seven years when the diagnosis is more reliable than at preschool age.
METHODS: This study included eligible children born 2002-2006 from the Norwegian Mother and Child Cohort Study, a population-based pregnancy cohort, linked to the Norwegian Prescription Database. Current asthma at age seven was defined by asthma medications dispensed at least twice in the year (1,901 cases, n=39,846) or by maternal questionnaire report (1,624 cases, n=28,872). Maternal folate intake was assessed with a food frequency questionnaire validated against plasma folate. We used log-binomial and multinomial regression to calculate adjusted relative risks with 95% confidence intervals.
MEASUREMENTS AND MAIN RESULTS: Risk of asthma was increased in the highest vs. lowest quintile of total folate intake with an adjusted relative risk of 1.23 (95% confidence interval 1.06 to 1.44) that was similar for maternally reported asthma. Mothers in the highest quintile had a relatively high intake of food folate (median 308, interquartile range 241-366 μg/day) and nearly all took at least 400 μg/day of supplemental folic acid (median 500, interquartile range 400-600).
CONCLUSIONS: In this large prospective population based cohort with essentially complete follow-up, pregnant women taking supplemental folic-acid at or above the recommended dose, combined with a diet rich in folate, reach a total folate intake level that may slightly increase risk of asthma in children.
Authors: Hussain S, Ji Z, Taylor AJ, DeGraff LM, George M, Tucker CJ, Chang CH, Li R, Bonner JC, Garantziotis S
Journal: ACS Nano. 2016 Aug 23;10(8):7675-88. doi: 10.1021/acsnano.6b03013.
Commercialization of multiwalled carbon nanotubes (MWCNT)-based applications has been hampered by concerns regarding their lung toxicity potential. Hyaluronic acid (HA) is a ubiquitously found polysaccharide, which is anti-inflammatory in its native high molecular weight form. HA-functionalized smart MWCNTs have shown promise as tumor-targeting drug delivery agents and can enhance bone repair and regeneration. However, it is unclear whether HA functionalization could reduce the pulmonary toxicity potential of MWCNTs. Using in vivo and in vitro approaches, we investigated the effectiveness of MWCNT functionalization with HA in increasing nanotube biocompatibility and reducing lung inflammatory and fibrotic effects. We utilized three-dimensional cultures of differentiated primary human bronchial epithelia to translate findings from rodent assays to humans. We found that HA functionalization increased stability and dispersion of MWCNTs and reduced postexposure lung inflammation, fibrosis, and mucus cell metaplasia compared with nonfunctionalized MWCNTs. Cocultures of fully differentiated bronchial epithelial cells (cultivated at air-liquid interface) and human lung fibroblasts (submerged) displayed significant reduction in injury, oxidative stress, as well as pro-inflammatory gene and protein expression after exposure to HA-functionalized MWCNTs compared with MWCNTs alone. In contrast, neither type of nanotubes stimulated cytokine production in primary human alveolar macrophages. In aggregate, our results demonstrate the effectiveness of HA functionalization as a safer design approach to eliminate MWCNT-induced lung injury and suggest that HA functionalization works by reducing MWCNT-induced epithelial injury.
Authors: Boritz EA, Darko S, Swaszek L, Wolf G, Wells D, Wu X, Henry AR, Laboune F, Hu J, Ambrozak D, Hughes MS, Hoh R, Casazza JP, Vostal A, Bunis D, Nganou-Makamdop K, Lee JS, Migueles SA, Koup RA, Connors M, Moir S, Schacker T, Maldarelli F, Hughes SH, Deeks SG, Douek DC
Journal: Cell. 2016 Jul 20. pii: S0092-8674(16)30810-8. doi: 10.1016/j.cell.2016.06.039.
Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity.
Authors: Liu S, Liu J, Ma Q, Cao L, Fattah RJ, Yu Z, Bugge TH, Finkel T, Leppla SH
Journal: Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):E4079-87. doi: 10.1073/pnas.1600982113.
Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors.
Authors: Ding H, Smith RG, Poleg-Polsky A, Diamond JS, Briggman KL
Journal: Nature. 2016 Jul 7;535(7610):105-10.
Directionally tuned signalling in starburst amacrine cell (SAC) dendrites lies at the heart of the circuit that detects the direction of moving stimuli in the mammalian retina. The relative contributions of intrinsic cellular properties and network connectivity to SAC direction selectivity remain unclear. Here we present a detailed connectomic reconstruction of SAC circuitry in mouse retina and describe two previously unknown features of synapse distributions along SAC dendrites: input and output synapses are segregated, with inputs restricted to proximal dendrites; and the distribution of inhibitory inputs is fundamentally different from that observed in rabbit retina. An anatomically constrained SAC network model suggests that SAC–SAC wiring differences between mouse and rabbit retina underlie distinct contributions of synaptic inhibition to velocity and contrast tuning and receptive field structure. In particular, the model indicates that mouse connectivity enables SACs to encode lower linear velocities that account for smaller eye diameter, thereby conserving angular velocity tuning. These predictions are confirmed with calcium imaging of mouse SAC dendrites responding to directional stimuli.
Authors: Joyce MG, Wheatley AK, Thomas PV, Chuang GY, Soto C, Bailer RT, Druz A, Georgiev IS, Gillespie RA, Kanekiyo M, Kong WP, Leung K, Narpala SN, Prabhakaran MS, Yang ES, Zhang B, Zhang Y, Asokan M, Boyington JC, Bylund T, Darko S, Lees CR, Ransier A, Shen CH, Wang L, Whittle JR, Wu X, Yassine HM, Santos C, Matsuoka Y, Tsybovsky Y, Baxa U; NISC Comparative Sequencing Program, Mullikin JC, Subbarao K, Douek DC, Graham BS, Koup RA, Ledgerwood JE, Roederer M, Shapiro L, Kwong PD, Mascola JR, McDermott AB
Journal: Cell. 2016 Jul 20. pii: S0092-8674(16)30851-0. doi: 10.1016/j.cell.2016.06.043.
Antibodies capable of neutralizing divergent influenza A viruses could form the basis of a universal vaccine. Here, from subjects enrolled in an H5N1 DNA/MIV-prime-boost influenza vaccine trial, we sorted hemagglutinin cross-reactive memory B cells and identified three antibody classes, each capable of neutralizing diverse subtypes of group 1 and group 2 influenza A viruses. Co-crystal structures with hemagglutinin revealed that each class utilized characteristic germline genes and convergent sequence motifs to recognize overlapping epitopes in the hemagglutinin stem. All six analyzed subjects had sequences from at least one multidonor class, and-in half the subjects-multidonor-class sequences were recovered from >40% of cross-reactive B cells. By contrast, these multidonor-class sequences were rare in published antibody datasets. Vaccination with a divergent hemagglutinin can thus increase the frequency of B cells encoding broad influenza A-neutralizing antibodies. We propose the sequence signature-quantified prevalence of these B cells as a metric to guide universal influenza A immunization strategies.
Authors: Planchart A, Mattingly CJ, Allen D, Ceger P, Casey W, Hinton D, Kanungo J, Kullman SW, Tal T, Bondesson M, Burgess SM, Sullivan C, Kim C, Behl M, Padilla S, Reif DM, Tanguay RL, Hamm J
Journal: ALTEX. 2016 Jun 21. doi: 10.14573/altex.1601281.
Small freshwater fish models, especially zebrafish,offer advantages over traditional rodent models, including low maintenance and husbandry costs, high fecundity, genetic diversity, physiology similar to that of traditional biomedical models, and reduced animal welfare concerns. The Collaborative Workshop on Aquatic Models and 21st Century Toxicology was held at North Carolina State University on May 5-6, 2014, in Raleigh, North Carolina, USA. Participants discussed the ways in which small fish are being used as models to screen toxicants and understand mechanisms of toxicity. Workshop participants agreed that the lack of standardized protocols is an impediment to broader acceptance of these models, whereas development of standardized protocols, validation, and subsequent regulatory acceptance would facilitate greater usage. Given the advantages and increasing application of small fish models, there was widespread interest in follow-up workshops to review and discuss developments in their use. In this article, we summarize the recommendations formulated by workshop participants to enhance the utility of small fish species in toxicology studies, as well as many of the advances in the field of toxicology that resulted from using small fish species, including advances in developmental toxicology, cardiovascular toxicology, neurotoxicology, and immunotoxicology. We alsoreview many emerging issues that will benefit from using small fish species, especially zebrafish, and new technologies that will enable using these organisms to yield results unprecedented in their information content to better understand how toxicants affect development and health.
Authors: Liu R, Young MT, Chen JC, Kaufman JD, Chen H
Journal: Environ Health Perspect. 2016 Jun 10.
BACKGROUND: Few epidemiologic studies have evaluated the effects of air pollution on risk of Parkinson's disease (PD).
OBJECTIVE: We investigated the associations of long-term residential concentrations of ambient particulate matter (PM) less than 10µm in diameter (PM10), less than 2.5µm in diameter (PM2.5), and nitrogen dioxide (NO2) in relation to PD risk.
METHODS: Our nested case-control analysis included 1,556 self-reported physician-diagnosed PD cases identified between 1995-2006 and 3,313 controls frequency matched on age, sex, and race. We geocoded home addresses reported in 1995-1996 and estimated the average ambient concentrations of PM10, PM2.5 and NO2 using a national fine-scale geo-statistical model incorporating roadway information and other geographic covariates. Air pollutant exposures were analyzed both as quintiles and continuous variables, adjusting for matching variables and potential confounders.
RESULTS: We observed no statistically significant overall association between PM or NO2 exposures and PD risk. However, in pre-planned subgroup analyses, a higher risk of PD was associated with higher exposure to PM10 (ORQ5vs.Q1=1.65; 95% CI: 1.11, 2.45; p-trend=0.02) among women, and to PM2.5 (ORQ5vs.Q1=1.29; 95% CI: 0.94, 1.76; p-trend=0.04) among never smokers. In post-hoc analyses among female never smokers, both PM2.5 (OR for Q5vs.Q1=1.79; 95% CI: 1.01, 3.17; p-trend=0.05) and PM10 (OR for Q5vs.Q1=2.34; 95% CI: 1.29, 4.26; p-trend=0.01) showed positive associations with PD risk. Analyses based on continuous exposure variables generally showed similar but non-significant associations.
CONCLUSIONS: Overall we found limited evidence for an association between exposures to ambient PM10, PM2.5, or NO2 and PD risk. The suggestive evidence that exposures to PM2.5 and PM10 may increase PD risk among female never smokers warrants further investigations.