Opinions of 4-H Club Members, Adult Leaders, Parents, and Extension Agents Concerning the Benefits of Competitive Activities in Five Northwest Arkansas Counties

Agricultural Educatio

Housing and Business Investment in Nebraska\u27s Non-metropolitan Communities and Declining Urban Neighborhoods

This study focuses on one subject area of the Urban Affairs Committee\u27s charge: housing and business investment in Nebraska\u27s declining urban neighborhoods and non-metropolitan communities. From its beginning the study has had two primary objectives: First, to ascertain the demand for housing and business investment funds in the declining urban neighborhoods of Nebraska\u27s two major metropolitan cities, Omaha and Lincoln, and in the State\u27s non-metropolitan communities; and the perceptions of homeowners, renters, landlords and businessmen in these communities and neighborhoods regarding the availability to them of such funds. Second, to identify factors which discourage or hamper housing and business investment in the declining urban neighborhoods of Omaha and Lincoln and in the State\u27s non-metropolitan communities, and to recommend legislation and other measures to eliminate such factors and to provide incentives for increased investment in these neighborhoods and communities

RNA-Seq of Huntington's disease patient myeloid cells reveals innate transcriptional dysregulation associated with proinflammatory pathway activation

Innate immune activation beyond the central nervous system is emerging as a vital component of the pathogenesis of neurodegeneration. Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The systemic innate immune system is thought to act as a modifier of disease progression; however, the molecular mechanisms remain only partially understood. Here we use RNA-sequencing to perform whole transcriptome analysis of primary monocytes from thirty manifest HD patients and thirty-three control subjects, cultured with and without a proinflammatory stimulus. In contrast with previous studies that have required stimulation to elicit phenotypic abnormalities, we demonstrate significant transcriptional differences in HD monocytes in their basal, unstimulated state. This includes previously undetected increased resting expression of genes encoding numerous proinflammatory cytokines, such as IL6. Further pathway analysis revealed widespread resting enrichment of proinflammatory functional gene sets, while upstream regulator analysis coupled with Western blotting suggests that abnormal basal activation of the NFOEB pathway plays a key role in mediating these transcriptional changes. That HD myeloid cells have a proinflammatory phenotype in the absence of stimulation is consistent with a priming effect of mutant huntingtin, whereby basal dysfunction leads to an exaggerated inflammatory response once a stimulus is encountered. These data advance our understanding of mutant huntingtin pathogenesis, establish resting myeloid cells as a key source of HD immune dysfunction, and further demonstrate the importance of systemic immunity in the potential treatment of HD and the wider study of neurodegeneration

Complete Clinical Remission of Stage IV Triple-Negative Breast Cancer Lung Metastasis Administering Low-Dose Immune Checkpoint Blockade in Combination With Hyperthermia and Interleukin-2

The prognosis of triple-negative breast cancer with metastases after chemotherapy remains dismal. We report the case of a 50-year-old female with first disease recurrence at the axillary lymph node and, later on, bilateral pulmonary metastases with severe shortness of breath. The patient received low-dose immune checkpoint blockade (concurrent nivolumab and ipilimumab) weekly over 3 weeks with regional hyperthermia 3 times a week, followed by systemic fever-range hyperthermia induced by interleukin-2 for 5 days. She went into complete remission of her pulmonary metastases with transient WHO I-II diarrhea and skin rash. The patient remained alive for 27 months after the start of treatment, with recurrence of metastases as a sternal mass, and up to 3 cm pleural metastases. This exceptional response should instigate further research efforts with this protocol, which consists only of approved drugs and treatments

Annual Report 2010 - Operation and Utilisation of the High Flux Reactor

The High Flux Reactor (HFR) at Petten is managed by the Institute for Energy (IE) of the EC - DG JRC and operated by NRG who are also licence holder and responsible for commercial activities. The HFR operates at 45 MW and is of the tank-in-pool type, light water cooled and moderated. It is one of the most powerful multi-purpose materials testing reactors in the world and one of the world leaders in target irradiation for the production of medical radioisotopes.JRC.F.4-Nuclear Reactor Integrity Assessment and Knowledge Managemen

A genomic and evolutionary approach reveals non-genetic drug resistance in malaria

Background: Drug resistance remains a major public health challenge for malaria treatment and eradication. Individual loci associated with drug resistance to many antimalarials have been identified, but their epistasis with other resistance mechanisms has not yet been elucidated. Results: We previously described two mutations in the cytoplasmic prolyl-tRNA synthetase (cPRS) gene that confer resistance to halofuginone. We describe here the evolutionary trajectory of halofuginone resistance of two independent drug resistance selections in Plasmodium falciparum. Using this novel methodology, we discover an unexpected non-genetic drug resistance mechanism that P. falciparum utilizes before genetic modification of the cPRS. P. falciparum first upregulates its proline amino acid homeostasis in response to halofuginone pressure. We show that this non-genetic adaptation to halofuginone is not likely mediated by differential RNA expression and precedes mutation or amplification of the cPRS gene. By tracking the evolution of the two drug resistance selections with whole genome sequencing, we further demonstrate that the cPRS locus accounts for the majority of genetic adaptation to halofuginone in P. falciparum. We further validate that copy-number variations at the cPRS locus also contribute to halofuginone resistance. Conclusions: We provide a three-step model for multi-locus evolution of halofuginone drug resistance in P. falciparum. Informed by genomic approaches, our results provide the first comprehensive view of the evolutionary trajectory malaria parasites take to achieve drug resistance. Our understanding of the multiple genetic and non-genetic mechanisms of drug resistance informs how we will design and pair future anti-malarials for clinical use. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0511-2) contains supplementary material, which is available to authorized users

Olfactory working memory: exploring the differences in n-back memory for high and low verbalisable odorants

We describe four experiments each examining n-back performance for high and low verbalisable odorants. Participants were presented with a sequence of odorants and were required to state if the current odorant was the same or different to the odorant presented two items earlier. Experiment 1 reported superior performance for high, relative to low, verbalisable odorants and was evident despite above chance memory performance for the low verbalisable odorants. Experiment 2 showed that such superiority persisted with a concurrent articulation condition, suggesting that the memory benefit was not a consequence of verbal recording and rehearsal. Experiment 3 employed metacognitive judgments and showed that correct 2-back responses for high verbalisable odorants received more recollection responses compared to low verbalisable odorants. Experiment 4 compared n-back performance across different stimulus types and showed that, for high verbalisable odorants, performance correlated with both letters and abstract shapes, but such correlations were absent for low verbalisable odorants. Taken together, these findings show differences in n-back performance between high and low verbalisable odorants, and show that high verbalisable odorants exhibit performance similarities with both verbal and visual stimuli. We further argue that n-back performance for low verbalisable odorants operates differently to that of high verbalisable odorants

Defective monocyte enzymatic function and an inhibitory immune phenotype in HIV-exposed uninfected African infants in the era of antiretroviral therapy

BACKGROUND: HIV-Exposed Uninfected (HEU) infants are a rapidly expanding population in sub-Saharan Africa, highly susceptible to encapsulated bacterial disease in the first year of life. The mechanism of this increased risk is still poorly understood. We investigated if HIV-exposure dysregulates HEU immunity, vaccine-antibody production and human herpes virus (HHV) amplify this effect. METHODS: 34 HIV-infected and 44 HIV-uninfected pregnant women were recruited into the birth cohort, followed up to 6 weeks of age; and 43 HIV-infected and 61 HIV-uninfected mother-infant pairs into a longitudinal infant cohort, at either: 5-7 to 14-15; or 14-15 to 18-23 weeks of age. We compared monocyte function, innate and adaptive immune cell phenotype, and vaccine-induced antibody responses between HEU and HU infants. RESULTS: We demonstrate altered monocyte phagosomal function and B cell subset homeostasis, and lower vaccine-induced anti-Haemophilus influenzae type b (Hib) and anti-Tetanus Toxoid (TT) IgG titers in HEU compared to HU infants. HHV infection was similar between HEU and HU infants. CONCLUSION: In the era of antiretroviral therapy (ART)-mediated viral suppression, HIV-exposure may dysregulate monocyte and B cell function, during the vulnerable period of immune maturation. This may contribute to the high rates of invasive bacterial disease and pneumonia in HEU infants

Ex vivo 18F-fluoride uptake and hydroxyapatite deposition in human coronary atherosclerosis

Early microcalcification is a feature of coronary plaques with an increased propensity to rupture and to cause acute coronary syndromes. In this ex vivo imaging study of coronary artery specimens, the non-invasive imaging radiotracer, 18F-fluoride, was highly selective for hydroxyapatite deposition in atherosclerotic coronary plaque. Specifically, coronary 18F-fluoride uptake had a high signal to noise ratio compared with surrounding myocardium that makes it feasible to identify coronary mineralisation activity. Areas of 18F-fluoride uptake are associated with osteopontin, an inflammation-associated glycophosphoprotein that mediates tissue mineralisation, and Runt-related transcription factor 2, a nuclear protein involved in osteoblastic differentiation. These results suggest that 18F-fluoride is a non-invasive imaging biomarker of active coronary atherosclerotic mineralisation