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Fuchs E
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Mentoring the Next Generation: Elaine Fuchs

CELL STEM CELL 2018 NOV 1; 23(5):642-643
Mentor-mentee relationships are essential for professional development, but developing these interpersonal skills is not often highlighted as a priority in scientific endeavors. In a yearlong series, Cell Stem Cell interviews prominent scientists who have prioritized mentorship over the years. Here, we chat with Dr. Elaine Fuchs about her views.
Linton SS, Abraham T, Liao J, Clawson GA, Butler PJ, Fox T, Kester M, Matters GL
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Tumor-promoting effects of pancreatic cancer cell exosomes on THP-1-derived macrophages

PLOS ONE 2018 NOV 1; 13(11):? Article e0206759
Pancreatic ductal adenocarcinoma (PDAC) tumor growth is enhanced by tumor-associated macrophages (TAMs), yet the mechanisms by which tumor cells and TAMs communicate are not fully understood. Here we show that exosomes secreted by PDAC cell lines differed in their surface proteins, lipid composition, and efficiency of fusing with THP-1-derived macrophages in vitro. Exosomes from AsPC-1, an ascites-derived human PDAC cell line, were enriched in ICAM-1, which mediated their docking to macrophages through interactions with surface-exposed CD11c on macrophages. AsPC-1 exosomes also contained much higher levels of arachidonic acid (AA), and they fused at a higher rate with THP-1-derived macrophages than did exosomes from other PDAC cell lines or from an immortalized normal pancreatic ductal epithelial cell line (HPDE) H6c7. Phospholipase A(2) enzymatic cleavage of arachidonic acid from AsPC-1 exosomes reduced fusion efficiency. PGE(2) secretion was elevated in macrophages treated with AsPC-1 exosomes but not in macrophages treated with exosomes from other cell lines, suggesting a functional role for the AsPC-1 exosome-delivered arachidonic acid in macrophages. Non-polarized (M0) macrophages treated with AsPC-1 exosomes had increased levels of surface markers indicative of polarization to an immunosuppressive M2-like phenotype (CD14(hi) CD163(hi) CD206(hi)). Furthermore, macrophages treated with AsPC-1 exosomes had significantly increased secretion of pro-tumoral, bioactive molecules including VEGF, MCP-1, IL-6, IL-1 beta, MMP-9, and TNF alpha. Together, these results demonstrate that compared to exosomes from other primary tumor-derived PDAC cell lines, AsPC-1 exosomes alter THP-1-derived macrophage phenotype and function. AsPC-1 exosomes mediate communication between tumor cells and TAMs that contributes to tumor progression.
Patel NP, Vukmanovic-Stejic M, Suarez-Farinas M, Chambers ES, Sandhu D, Fuentes-Duculan J, Mabbott NA, Rustin MHA, Krueger J, Akbar AN
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Impact of Zostavax Vaccination on T-Cell Accumulation and Cutaneous Gene Expression in the Skin of Older Humans After Varicella Zoster Virus Antigen-Specific Challenge

Background. The live attenuated vaccine Zostavax was developed to prevent varicella zoster virus (VZV) reactivation that causes herpes zoster (shingles) in older humans. However, the impact of vaccination on the cutaneous response to VZV is not known. Methods. We investigated the response to intradermal VZV antigen challenge before and after Zostavax vaccination in participants >70 years of age by immunohistological and transcriptomic analyses of skin biopsy specimens collected from the challenge site. Results. Vaccination increased the proportion of VZV-specific CD4(+) T cells in the blood and promoted the accumulation of both CD4(+) and CD8(+) T cells in the skin after VZV antigen challenge. However, Zostavax did not alter the proportion of resident memory T cells (CD4(+) and CD8(+)) or CD4(+) Foxp3(+) regulatory T cells in unchallenged skin. After vaccination, there was increased cutaneous T-cell proliferation at the challenge site and also increased recruitment of T cells from the blood, as indicated by an elevated T-cell migratory gene signature. CD8(+) T-cell-associated functional genes were also highly induced in the skin after vaccination. Conclusion. Zostavax vaccination does not alter the abundance of cutaneous resident memory T cells but instead increases the recruitment of VZV-specific T cells from the blood and enhances T-cell activation, particularly cells of the CD8(+) subset, in the skin after VZV antigen challenge.
McKenzie SK, Kronauer DJC
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The genomic architecture and molecular evolution of ant odorant receptors

GENOME RESEARCH 2018 NOV; 28(11):1757-1765
The massive expansions of odorant receptor (OR) genes in ant genomes are notable examples of rapid genome evolution and adaptive gene duplication. However, the molecular mechanisms leading to gene family expansion remain poorly understood, partly because available ant genomes are fragmentary. Here, we present a highly contiguous, chromosome-level assembly of the clonal raider ant genome, revealing the largest known OR repertoire in an insect. While most ant ORs originate via local tandem duplication, we also observe several cases of dispersed duplication followed by tandem duplication in the most rapidly evolving OR clades. We found that areas of unusually high transposable element density (TE islands) were depauperate in ORs in the clonal raider ant, and found no evidence for retrotransposition of ORs. However, OR loci were enriched for transposons relative to the genome as a whole, potentially facilitating tandem duplication by unequal crossing over. We also found that ant OR genes are highly AT-rich compared to other genes. In contrast, in flies, OR genes are dispersed and largely isolated within the genome, and we find that fly ORs are not AT-rich. The genomic architecture and composition of ant ORs thus show convergence with the unrelated vertebrate ORs rather than the related fly ORs. This might be related to the greater gene numbers and/or potential similarities in gene regulation between ants and vertebrates as compared to flies.
Furey CG, Zeng X, Dong WL, Jin SC, Choi J, Timberlake AT, Dunbar AM, Allocco AA, Guenel M, Lifton RP, Kahle KT
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Human Genetics and Molecular Mechanisms of Congenital Hydrocephalus

WORLD NEUROSURGERY 2018 NOV; 119(?):441-443
Lu JH, Tang LC, Xu YQ, Ge KK, Huang JJ, Gu MG, Zhong J, Huang QS
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Mir-1287 suppresses the proliferation, invasion, and migration in hepatocellular carcinoma by targeting PIK3R3

Mature microRNAs (miRNAs) are a class of small noncoding RNA molecules involved in regulation of post-translational gene expression. Although aberrant levels of miRNAs have been found in various tumor tissues, their importance in tumor development and the molecular basis of their regulatory role remain unclear. Our bioinformatic analysis on The Cancer Genome Atlas database and microarray-based comparison of miRNA in different cell lines revealed that the level of mir-1287 is suppressed in hepatocellular carcinoma (HCC) cells. When upregulated, mir-1287 can reduce the tumorigenesis phenotypes of HCC cells in several in vitro models. We further found that mir-1287 directly targets messenger RNA encoding PIK3R3, which is a tumor-promoting factor acting in several pathways linked to tumorigenesis. Our study suggests that aberrant suppression of mir-1287 is potentially responsible for the development of HCC, and miRNA-based strategies may be developed for efficient detection and treatment of HCC.
Rodrigues S, Conceicao T, Silva IS, de Lencastre H, Aires-de-Sousa M
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Frequent MRSA nasal colonization among hospitalized children and their parents in Angola and Sao Tome and Principe

Background: The prevalence of nosocomial meticillin-resistant Staphylococcus aureus (MRSA) was previously estimated as 23% in a paediatric hospital in Luanda, Angola and 18% in a general hospital in Sao Tome and Principe. Aim: To evaluate the prevalence of S. aureus/MRSA colonization among hospitalized children and their parents at two hospitals in Angola and Sao Tome and Principe. Methods: In 2017, 127 hospitalized children and 129 of their parents had nasal swabs for S. aureus/MRSA carriage in the two countries. The isolates were tested for the presence of the mecA and Panton-Valentine leukocidin (PVL) genes, and characterized by pulsed-field gel electrophoresis (PFGE), spa typing, multi-locus sequence typing and SCCmec typing. Findings: Twenty of 127 children (15.7%) and 13 of 129 parents (10.1%) were MRSA nasal carriers. Three lineages comprised 88% of the MRSA isolates: (i) PFGE A-ST5-SCCmec IVa (N=15; 45%), associated with spa type t105, recovered in Angola alone; (ii) PFGE N-ST8-IV/ V (N=7; 21%), associated with spa types t008/t121, recovered in Sao Tome and Principe alone; and (iii) PFGE B-ST88-IVa (N=7; 21%), associated with spa types t325/t786, present in both countries. Fifteen child/guardian pairs were colonized with identical MRSA (N=8) or meticillin-susceptible S. aureus (N=7) strains. PVL was detected in 25% of isolates, including two MRSA (ST30-V and ST8-IVa). Conclusion: Hospitalized children and their parents are important reservoirs of MRSA. Infection control measures should focus on parents in order to minimize the spread of MRSA to the community. (C) 2018 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Alvarez J, Del Rio M, Mayorga T, Dominguez S, Flores-Montoya MG, Sobin C
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A Comparison of Child Blood Lead Levels in Urban and Rural Children Ages 5-12 Years Living in the Border Region of El Paso, Texas

Lead exposure is an unresolved pediatric health risk and disproportionately affects children in lower-income neighborhoods. Residences with children younger than age 5 years are the focus of mitigation policies; however, studies have shown that older children between the ages of 5 and 12 years also are at risk of central nervous system effects. Whether historically contaminated neighborhoods present ongoing risk to older children also is of concern. This study compared the blood lead levels (BLLs) of older children from an historically contaminated urban neighborhood to those of demographically matched children from a nearby rural locale and predicted significantly higher BLLs in the urban children. The study included 222 children aged 5-12 years, 111 from the urban neighborhood and 111 from local rural townships, matched for age, sex, race/ethnicity, and family income. Blood lead, cadmium, and mercury were measured using inductively coupled plasma mass spectrometry. General linear models tested whether geographic location (urban vs. rural) predicted child heavy metal levels, controlling for sex and age. Only location predicted only child BLL (R-2=0.36); children living in the urban setting had significantly higher BLLs as compared with matched rural township children (F=125, df(220,2), p<0.001). Neighborhoods with a history of lead contamination can present current risk of lead exposure for older children between the ages of 5 and 12 years, as well as for infants and toddlers. More studies are needed to better characterize the risk of lead exposure to older children, particularly in lower-income neighborhoods with a history of lead contamination.
Galea S, Vaughan RD
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Multilevel Thinking and Life Course Perspectives Inform Public Health Practice: A Public Health of Consequence, November 2018

Milham MP, Ai L, Koo B, Xu T, Amiez C, Balezeau F, Baxter MG, Blezer ELA, Brochier T, Chen AH, Croxson PL, Damatac CG, Dehaene S, Everling S, Fair DA, Fleysher L, Freiwald W, Froudist-Walsh S, Griffiths TD, Guedj C, Hadj-Bouziane F, Ben Hamed S, Harel N, Hiba B, Jarraya B, Jung B, Kastner S, Klink PC, Kwok SC, Laland KN, Leopold DA, Lindenfors P, Mars RB, Menon RS, Messinger A, Meunier M, Mok K, Morrison JH, Nacef J, Nagy J, Rios MO, Petkov CI, Pinsk M, Poirier C, Procyk E, Rajimehr R, Reader SM, Roelfsema PR, Rudko DA, Rushworth MFS, Russ BE, Sallet J, Schmid MC, Schwiedrzik CM, Seidlitz J, Sein J, Shmuel A, Sullivan EL, Ungerleider L, Thiele A, Todorov OS, Tsao D, Wang Z, Wilson CRE, Yacoub E, Ye FQ, Zarco W, Zhou YD, Margulies DS, Schroeder CE
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An Open Resource for Non-human Primate Imaging

NEURON 2018 OCT 10; 100(1):61-74.e2
Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience. Unfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMatE Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design, and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 25 independent data collections aggregated across 22 sites (total = 217 non-human primates). We also outline the unique pitfalls and challenges that should be considered in the analysis of non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.