Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein

The oncogenic MUC1-C subunit is aberrantly overexpressed in most human breast cancers by mechanisms that are not well understood. The present studies demonstrate that stimulation of non- malignant MCF-10A cells with epidermal growth factor (EGF) or heregulin (HRG) results in marked upregulation of MUC1-C translation. Growth factor-induced MUC1-C translation was found to be mediated by PI3K->AKT, and not MEK->ERK1/2, signaling. We also show that activation of the mTORC1->S6K1 pathway decreases PDCD4, an inhibitor of the eIF4A RNA helicase, and contributes to the induction of MUC1-C translation. In concert with these results, treatment of growth factor-stimulated MCF-10A cells with the eIF4A RNA helicase inhibitors, silvestrol and CR-1-31-B, blocked increases in MUC1-C abundance. The functional significance of the increase in MUC1-C translation is supported by the demonstration that MUC1-C, in turn, forms complexes with EGFR and promotes EGFR-mediated activation of the PI3K->AKT pathway and the induction of growth. Compared to MCF-10A cells, constitutive overexpression of MUC1-C in breast cancer cells was unaffected by EGF stimulation, but was blocked by inhibiting PI3K->AKT signaling. The overexpression of MUC1-C in breast cancer cells was also inhibited by blocking eIF4A RNA helicase activity with silvestrol and CR-1-31-B. These findings indicate that EGF-induced MUC1-C expression is mediated by the PI3K->AKT pathway and the eIF4A RNA helicase, and that this response promotes EGFR signaling in an autoinductive loop. The findings also indicate that targeting the eIF4A RNA helicase is a novel approach for blocking MUC1-C overexpression in breast cancer cells.P50 CA100707 - NCI NIH HHS; R01 CA042802 - NCI NIH HHS; R01 CA097098 - NCI NIH HHS; R01 GM073855 - NIGMS NIH HH

ANALISIS BELANJA PEMERINTAH TERHADAP PENINGKATAN SUB-SEKTOR TRANSPORTASI (STUDI KASUS KOTA MANADO 2007-2013)

ABSTRAK Sektor tranportasi merupakan salah satu komponen utama dalam peningkatan arus perekonomian, baik untuk memaksimalkan potensi daerah yang selama ini dimiliki namun juga untuk membuka sektor-sektor ekonomi baru yang berujung pada  peningkatan perekonomian sebuah daerah. Guna memanfaatkan potensi-potensi yang dimiliki maupun membuka potensi-potensi perekonomian yang baru maka peran serta pemerintah dalam mengatur alokasi belanjanya perlu untuk lebih dimaksimalkan. Untuk melihat seberapa besar pengaruh belanja pemerintah dalam bentuk belanja langsung dan belanja tidak langsung mempengaruhi peningkatan sub-sektor transportasi. Penelitian ini menggunakan Ordinary least square dengan  metode regresi berganda, dari hasil penelitian didapatkan hasil r square sebesar 96,7. Dengan hasil ini maka dapat terlihat pengaruh belanja pemerintah terhadap peningkatan sub-sektor transportasi hampir mencapai angka 97 persen, yang artinya hanya tersisa 3 persen tingkat pengaruh variabel lain.   Kata kunci : Belanja Langsung (BL), Belanja Tidak Langsung (BTL), Otonomi, Transportasi   ABSTRACT Transport sector is one of the main components to increase the flow of the economy, to maximize the potential of the area that had been held, but also to open up new economic sectors which resulted in an increase in the economy of a region. In order to utilize the potential that may or unlock the potential of the new economy, the role of government in regulating the allocation of spending needs to be maximized. To see how much influence government spending in the form of direct expenditure and indirect expenditure affect the improvement of the transport sub-sector. This study using the Ordinary least squares multiple regression method, the result showed the the r-square of 96.7. With that, it can be seen the effect of government spending to increase transport sub-sector almost reached 97 percent, which means that only the remaining 3 percent the level of influence of other variables.   Keywords: Direct Expenditure, Indirect Expenditure, Autonomy, Transportation Â

Simulations of snow distribution and hydrology in a mountain basin

We applied a version of the Regional Hydro‐Ecologic Simulation System (RHESSys) that implements snow redistribution, elevation partitioning, and wind‐driven sublimation to Loch Vale Watershed (LVWS), an alpine‐subalpine Rocky Mountain catchment where snow accumulation and ablation dominate the hydrologic cycle. We compared simulated discharge to measured discharge and the simulated snow distribution to photogrammetrically rectified aerial (remotely sensed) images. Snow redistribution was governed by a topographic similarity index. We subdivided each hillslope into elevation bands that had homogeneous climate extrapolated from observed climate. We created a distributed wind speed field that was used in conjunction with daily measured wind speeds to estimate sublimation. Modeling snow redistribution was critical to estimating the timing and magnitude of discharge. Incorporating elevation partitioning improved estimated timing of discharge but did not improve patterns of snow cover since wind was the dominant controller of areal snow patterns. Simulating wind‐driven sublimation was necessary to predict moisture losses

Balancing Uncertainty and Complexity to Incorporate Fire Spread in an Eco-Hydrological Model

Wildfire affects the ecosystem services of watersheds, and climate change will modify fire regimes and watershed dynamics. In many eco-hydrological simulations, fire is included as an exogenous force. Rarely are the bidirectional feedbacks between watersheds and fire regimes integrated in a simulation system because the eco-hydrological model predicts variables that are incompatible with the requirements of fire models. WMFire is a fire-spread model of intermediate complexity designed to be integrated with the Regional Hydro-ecological Simulation System (RHESSys). Spread in WMFire is based on four variables that (i) represent known influences on fire spread: litter load, relative moisture deficit, wind direction and topographic slope, and (ii) are derived directly from RHESSys outputs. The probability that a fire spreads from pixel to pixel depends on these variables as predicted by RHESSys. We tested a partial integration between WMFire and RHESSys on the Santa Fe (New Mexico) and the HJ Andrews (Oregon State) watersheds. Model assessment showed correspondence between expected spatial patterns of spread and seasonality in both watersheds. These results demonstrate the efficacy of an approach to link eco-hydrologic model outputs with a fire spread model. Future work will develop a fire effects module in RHESSys for a fully coupled, bidirectional model

Linked CSF reduction of phosphorylated tau and IL-8 in HIV associated neurocognitive disorder.

HIV-associated neurocognitive disorder (HAND) is a common condition in both developed and developing nations, but its cause is largely unknown. Previous research has inconsistently linked Alzheimer's disease (AD), viral burden, and inflammation to the onset of HAND in HIV-infected individuals. Here we simultaneously measured cerebrospinal fluid (CSF) levels of established amyloid and tau biomarkers for AD, viral copy numbers, and six key cytokines in 41 HIV-infected individuals off combination anti-retroviral therapy (14 with HAND) who underwent detailed clinical and neuropsychological characterization, and compared their CSF patterns with those from young healthy subjects, older healthy subjects with normal cognition, and older people with AD. HAND was associated with the lowest CSF levels of phosphorylated tau (p-Tau181) after accounting for age and race. We also found very high CSF levels of the pro-inflammatory interferon gamma-induced protein 10 (IP-10/CXCL10) in HIV regardless of cognition, but elevated CSF interleukin 8 (IL-8/CXCL8) only in HIV-NC but not HAND. Eleven HIV-infected subjects underwent repeat CSF collection six months later and showed strongly correlated longitudinal changes in p-Tau181 and IL-8 levels (R = 0.841). These data suggest reduced IL-8 relative to IP-10 and reduced p-Tau181 to characterize HAND

Evaluation of eastern gamagrass as dual-purpose complementary bioenergy and forage feedstock to switchgrass

Switchgrass (SG) is considered a model bioenergy crop and a warm-season perennial grass (WSPG) that traditionally served as forage feedstock in the United States. To avoid the sole dependence on SG for bioenergy production, evaluation of other crops to diversify the pool of feedstock is needed. We conducted a 3-year field experiment evaluating eastern gamagrass (GG), another WSPG, as complementary feedstock to SG in one- and two-cut systems, with or without intercropping with crimson clover or hairy vetch, and under different nitrogen (N) application rates. Our results showed that GG generally produced lower biomass (by 29.5%), theoretical ethanol potential (TEP, by 2.8%), and theoretical ethanol yield (TEY, by 32.9%) than corresponding SG under the same conditions. However, forage quality measures, namely acid detergent fiber (ADF), crude protein (CP), and elements P, K, Ca, and Mg were significantly higher in GG than those in SG. Nitrogen fertilizer significantly enhanced biomass (by 1.54 Mg ha−1), lignin content (by 2.10 g kg−1), and TEY (787.12 L ha−1) in the WSPGs compared to unfertilized treatments. Intercropping with crimson clover or hairy vetch did not significantly increase biomass of the WSPGs, or TEP and TEY in unfertilized plots. This study demonstrated that GG can serve as a complementary crop to SG and could be used as a dual-purpose crop for bioenergy and forage feedstock in farmers\u27 rotations

Assessment of Pharmacist Attitudes Regarding Introductory Pharmacy Practice Experience Hours

Introductory pharmacy practice experience (IPPE) hours are a means of integrating experiential education as a key role early on in pharmacy education. The Accreditation Council for Pharmacy Education (ACPE) has offered little guidance on mandatory and specific objectives to accomplish during IPPE hours, thus it is possible that preceptors do not feel adequately prepared, nor do they have a full understanding of what is required of them when they agree to precept an IPPE student. Given the lack of previous research conducted, the objective of this study was to obtain an understanding of the general attitude that preceptors have toward IPPE hours. A self-administered Internet-based questionnaire was completed by 100 respondents. The survey included multiple choice, Likert-type scale (1 =strongly disagree to 7 =strongly agree), sliding scale, and open-ended questions assessing preceptor\u27s knowledge of academic IPPE hour requirements, college of pharmacy expectations, time commitment and work site issues, expectations of the student, formality of IPPE hours, personal experience as a preceptor, an open-ended response and demographic information. Upon analyzing the data, researchers found that respondents presented with a generally positive attitude regarding IPPE hours (5.79 ± 1.03). Respondents expressed a desire to receive a zero to two hour online preceptor training (5.17 ± 1.25). In general, pharmacists indicated sufficient staffing to accommodate IPPE students (3.92 ± 1.38) and were undecided regarding monetary reimbursement (4.39 ± 1.53). Survey participants preferred receiving a guided checklist of activities for completion (S.45 ± 1.27), student resume (5.19 ± 1.30) and previous didactic course work (S.33 ± 1.41); however, survey participants expressed a desire for flexibility in determining the specifics of the experience (5.41 ± 1.11) while having students complete hours in a more concentrated time frame (5.19 ± 1.44). This exploratory research project was conducted to serve as baseline data to stimulate further investigation regarding IPPE hours

Interleukin-1 signaling in the basolateral amygdala is necessary for heroin-conditioned immunosuppression

Heroin administration suppresses the production of inducible nitric oxide (NO), as indicated by changes in splenic inducible nitric oxide synthase (iNOS) and plasma nitrate/nitrite. Since NO is a measure of host defense against infection and disease, this provides evidence that heroin can increase susceptibility to pathogens by directly interacting with the immune system. Previous research in our laboratory has demonstrated that these immunosuppressive effects of heroin can also be conditioned to environmental stimuli by repeatedly pairing heroin administration with a unique environmental context. Re-exposure to a previously drug-paired context elicits immunosuppressive effects similar to heroin administration alone. In addition, our laboratory has reported that the basolateral amygdala (BLA) and medial nucleus accumbens shell (mNAcS) are critical neural substrates that mediate this conditioned effect. However, our understanding of the contributing mechanisms within these brain regions is limited. It is known that the cytokine interleukin-1 (IL-1) plays an important role in learning and memory. In fact, our laboratory has demonstrated that inhibition of IL-1β expression in the dorsal hippocampus (DH) prior to reexposure to a heroin-paired context prevents the suppression of measures of NO production. Therefore, the present studies sought to further investigate the role of IL-1 in heroin-conditioned immunosuppression. Blockade of IL-1 signaling in the BLA, but not in the caudate putamen or mNAcS, using IL-1 receptor antagonist (IL-1Ra) attenuated heroin-conditioned immunosuppression of NO production as measured by plasma nitrate/nitrite and iNOS mRNA expression in spleen tissue. Taken together, these findings suggest that IL-1 signaling in the BLA is necessary for the expression of heroin-conditioned immunosuppression of NO production and may be a target for interventions that normalize immune function in heroin users and patient populations exposed to opiate regimens