Anterior basolateral amygdala neurons comprise a remote fear memory engram

IntroductionThreatening environmental cues often generate enduring fear memories, but how these are formed and stored remains actively investigated. Recall of a recent fear memory is thought to reflect reactivation of neurons, in multiple brain regions, activated during memory formation, indicating that anatomically distributed and interconnected neuronal ensembles comprise fear memory engrams. The extent to which anatomically specific activation-reactivation engrams persist during long-term fear memory recall, however, remains largely unexplored. We hypothesized that principal neurons in the anterior basolateral amygdala (aBLA), which encode negative valence, acutely reactivate during remote fear memory recall to drive fear behavior.MethodsUsing adult offspring of TRAP2 and Ai14 mice, persistent tdTomato expression was used to “TRAP” aBLA neurons that underwent Fos-activation during contextual fear conditioning (electric shocks) or context only conditioning (no shocks) (n = 5/group). Three weeks later, mice were re-exposed to the same context cues for remote memory recall, then sacrificed for Fos immunohistochemistry.ResultsTRAPed (tdTomato +), Fos +, and reactivated (double-labeled) neuronal ensembles were larger in fear- than context-conditioned mice, with the middle sub-region and middle/caudal dorsomedial quadrants of aBLA displaying the greatest densities of all three ensemble populations. Whereas tdTomato + ensembles were dominantly glutamatergic in context and fear groups, freezing behavior during remote memory recall was not correlated with ensemble sizes in either group.DiscussionWe conclude that although an aBLA-inclusive fear memory engram forms and persists at a remote time point, plasticity impacting electrophysiological responses of engram neurons, not their population size, encodes fear memory and drives behavioral manifestations of long-term fear memory recall

What’s in a Name? Use of Brand versus Generic Drug Names in United States Outpatient Practice

BACKGROUND: The use of brand rather than generic names for medications can increase health care costs. However, little is known at a national level about how often physicians refer to drugs using their brand or generic names. OBJECTIVE: To evaluate how often physicians refer to drugs using brand or generic terminology. DESIGN AND PARTICIPANTS: We used data from the 2003 National Ambulatory Medical Care Survey (NAMCS), a nationally representative survey of 25,288 community-based outpatient visits in the United States. After each visit, patient medications were recorded on a survey encounter form by the treating physician or transcribed from office notes. MEASUREMENTS: Our main outcome measure was the frequency with which medications were recorded on the encounter form using their brand or generic names. RESULTS: For 20 commonly used drugs, the median frequency of brand name use was 98% (interquartile range, 81–100%). Among 12 medications with no generic competition at the time of the survey, the median frequency of brand name use was 100% (range 92–100%). Among 8 medications with generic competition at the time of the survey (“multisource” drugs), the median frequency of brand name use was 79% (range 0–98%; P < .001 for difference between drugs with and without generic competition). CONCLUSIONS: Physicians refer to most medications by their brand names, including drugs with generic formulations. This may lead to higher health care costs by promoting the use of brand-name products when generic alternatives are available

Does Seed Sanitization Affect the Plant Rhizosphere Microbiome and Its Ability to Compete with the Human Associated Pathogen, E. coli on Salad Crops?

Cultivation of crops in controlled environmental agricultural systems may limit microbial colonization and reduce diversity of the microbial communities. Practices like seed and growth medium sanitization may further impact microbial communities in the mature plant and the plants capacity to limit the growth of pathogens through competition. As humans expand their travels to space, understanding plant growth, health, and development in closed environments will be critical to the success of producing a safe, supplemental food source for astronauts. To determine the persistence of a potential human pathogen in plant growth and development, sanitized and unsanitized seeds from, mizuna (Brassica rapa var japonica) and red romaine lettuce (Lactuca sativa cultivar Outredgeous), were inoculated with Escherichia coli, ATCC 21445, germinated under simulated International Space Station (ISS) environmental conditions and harvested every 7 days until maturity. The persistence of E. coli in the rhizosphere was determined by plating on selective media, real time PCR (Polymerase Chain Reaction) and community sequencing of the rhizosphere communities. E. coli was detected in the crops roots and leaves for several weeks post germination. At day 28, plants from sanitized seeds had significantly higher counts of E. coli on the roots than those from unsanitized seeds. E. coli was also detected on a few uninoculated plants indicating airborne cross contamination among plants in the same growth chamber and suggesting an influence of the natural microbiome on human pathogen survival and persistence in leafy greens. Sequencing analysis revealed variations in composition and diversity between the communities. Understanding the microbial community of the rhizospheric microbiome is only the first step in determining the relationships between plants. Additional studies to include genotypic and phenotypic variations in the plants should be considered to determine if the natural microbes in the rhizosphere may contribute to the health and therefore, safety of the edible plants

In Vivo Response to Methotrexate Forecasts Outcome of Acute Lymphoblastic Leukemia and Has a Distinct Gene Expression Profile

William Evans and colleagues investigate the genomic determinants of methotrexate resistance and interpatient differences in methotrexate response in patients newly diagnosed with childhood acute lymphoblastic leukemia

Priming Immunization with DNA Augments Immunogenicity of Recombinant Adenoviral Vectors for Both HIV-1 Specific Antibody and T-Cell Responses

Induction of HIV-1-specific T-cell responses relevant to diverse subtypes is a major goal of HIV vaccine development. Prime-boost regimens using heterologous gene-based vaccine vectors have induced potent, polyfunctional T cell responses in preclinical studies.The first opportunity to evaluate the immunogenicity of DNA priming followed by recombinant adenovirus serotype 5 (rAd5) boosting was as open-label rollover trials in subjects who had been enrolled in prior studies of HIV-1 specific DNA vaccines. All subjects underwent apheresis before and after rAd5 boosting to characterize in depth the T cell and antibody response induced by the heterologous DNA/rAd5 prime-boost combination.rAd5 boosting was well-tolerated with no serious adverse events. Compared to DNA or rAd5 vaccine alone, sequential DNA/rAd5 administration induced 7-fold higher magnitude Env-biased HIV-1-specific CD8(+) T-cell responses and 100-fold greater antibody titers measured by ELISA. There was no significant neutralizing antibody activity against primary isolates. Vaccine-elicited CD4(+) and CD8(+) T-cells expressed multiple functions and were predominantly long-term (CD127(+)) central or effector memory T cells and that persisted in blood for >6 months. Epitopes mapped in Gag and Env demonstrated partial cross-clade recognition.Heterologous prime-boost using vector-based gene delivery of vaccine antigens is a potent immunization strategy for inducing both antibody and T-cell responses.ClinicalTrials.gov NCT00102089, NCT00108654

Targeted expression of the arsenate reductase HAC1 identifies cell type specificity of arsenic metabolism and transport in plant roots

High Arsenic Concentration 1 (HAC1), an Arabidopsis thaliana arsenate reductase, plays a key role in arsenate [As(V)] tolerance. Through conversion of As(V) to arsenite [As(III)], HAC1 enables As(III) export from roots, and restricts translocation of As(V) to shoots. To probe the ability of different root tissues to detoxify As(III) produced by HAC1, we generated A. thaliana lines expressing HAC1 in different cell types. We investigated the As(V) tolerance phenotypes: root growth, As(III) efflux, As translocation, and As chemical speciation. We showed that HAC1 can function in the outer tissues of the root (epidermis, cortex, and endodermis) to confer As(V) tolerance, As(III) efflux, and limit As accumulation in shoots. HAC1 is less effective in the stele at conferring As(V) tolerance phenotypes. The exception is HAC1 activity in the protoxylem, which we found to be sufficient to restrict As translocation, but not to confer As(V) tolerance. In conclusion, we describe cell type-specific functions of HAC1 that spatially separate the control of As(V) tolerance and As translocation. Further, we identify a key function of protoxylem cells in As(V) translocation, consistent with the model where endodermal passage cells, above protoxylem pericycle cells, form a 'funnel' loading nutrients and potentially toxic elements into the vasculature

Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk

Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, resequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ2 = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ2 = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π = 0.0072, Tajima's D= 3.31, 14 SNPs) and the Japanese (π = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer. © 2008 Ding et al