Miracle-dz/UniFAR-FTUs huggingface dataset:
Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies

Purpose: Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term “rebound immune suppression,” limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy. Experimental Design: We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial. Results: In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8+ T-cell–dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects. Conclusions: These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328–40. ©2016 AACR.
Overexpression of protein kinase C delta represses expression of proliferin in NIH3T3 cells that regulates cell proliferation.

Protein kinase C (PKC) delta is known to inhibit proliferation of many cell types. In this study we found that overexpression of PKCdelta reduced proliferation of NIH3T3 cells. To identify specific genes regulated by PKCdelta in regulation of cell proliferation, we used differential display-polymerase chain reaction in PKCdelta-overexpressing NIH3T3 cells and found that the expression of proliferin, a secreted protein known to stimulate cell proliferation, was significantly repressed. Transient transfection study indicated that the repression of proliferin expression was inversely proportional to the expression levels of PKCdelta. Addition of an anti-proliferin antibody to culture medium to neutralize the secreted proliferin decreased cell proliferation in a dose-dependent manner. Our results, therefore, suggest that overexpression of PKCdelta induces transcriptional repression of proliferin, thereby resulting in inhibition of cell proliferation.
Vitamin D Regulation of OX40 Ligand in Immune Responses to Aspergillus fumigatus

ABSTRACT OX40 ligand (OX40L) is a costimulatory molecule involved in Th2 allergic responses. It has been shown that vitamin D deficiency is associated with increased OX40L expression in peripheral CD11c+ cells and controls Th2 responses to Aspergillus fumigatus in vitro in cystic fibrosis (CF) patients with allergic bronchopulmonary aspergillosis (ABPA). To investigate if vitamin D deficiency regulated OX40L and Th2 responses in vivo, we examined the effect of nutritional vitamin D deficiency on costimulatory molecules in CD11c+ cells and A. fumigatus-induced Th2 responses. Vitamin D-deficient mice showed increased expression of OX40L on lung CD11c+ cells, and OX40L was critical for enhanced Th2 responses to A. fumigatus in vivo. In in vitro assays, vitamin D treatment led to vitamin D receptor (VDR) binding in the promoter region of OX40L and significantly decreased the promoter activity of the OX40L promoter. In addition, vitamin D altered NF-κB p50 binding in the OX40L promoter that may be responsible for repression of OX40L expression. These data show that vitamin D can act directly on OX40L, which impacts Th2 responses and supports the therapeutic use of vitamin D in diseases regulated by OX40L.
The Association Between Depression and Leptin Is Mediated by Adiposity

Objective Animal models suggest that impaired leptin production, or leptin resistance despite increased leptin levels, may contribute to depression. The link between leptin and depression could be mediated by obesity, which is more common in depression and increases leptin production. Methods We administered the Beck Depression Inventory–II (BDI-II) to 537 participants (mean [standard deviation (SD)] age = 51 [9] years; female, 61%) enrolled in the Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) study. Leptin levels were examined as continuous log-transformed values. Results Participants with moderate to severe depression had higher levels of leptin (median [interquartile range] 37.7 [17.6–64.9] ng/mL) than those with mild depression (22.9 [7.0–57.9] ng/mL) or minimal to no depression (19.8 ng/mL [7.8–39.1], p = .003). Participants with moderate to severe depression had higher body mass index (BMI) than those with mild or minimal depression (mean [SD] = 33 [8] versus 31 [9] versus 29 [7] kg/m2, p = .001). After multivariate adjustment for age, sex, race, smoking status, hypertension, diabetes, blood pressure, lipids, and C-reactive protein, the BDI-II score remained a significant predictor of leptin levels (&bgr; = 0.093, p = .01). Further adjustment for BMI eliminated the association between the BDI-II score and leptin (&bgr; = 0.03, p = .3). Adjusting for waist circumference in place of BMI revealed similar findings. Conclusions The association between depression and leptin seems to be mediated by increased adiposity in depressed individuals. Abbreviations BDI-II = Beck Depression Inventory–II BMI = body mass index HDL-C = high-density lipoprotein cholesterol
Identifying and understanding entrepreneurial decision-making logics in entrepreneurship education

It is unclear how nascent entrepreneurs make decisions during the venture creation process. The purpose of this paper is to investigate decision-making logics and their transformation over time among student entrepreneurs who aim to create new business ventures in the higher education setting. ,The study employs the mixed methods approach through the use of survey and observation data. The longitudinal survey data comprise three surveys collected via an internet-aided tool. The constructs of causation and effectuation are measured using previously tested scales (Chandler et al., 2011). Non-participant observation data were collected during the course, focussing on the venture creation processes of four different start-ups, and were analysed thematically. ,The findings show three transformation patterns – doubts in how to proceed, unwillingness to proceed, and unsatisfactory team dynamics – that led individuals towards a coping decision-making logic in which no causation or effectuation is emphasised. The findings illustrate that, despite this stage of decision-making logic, the learning process continues: Even if no new business venture is launched, entrepreneurship education can still generate learning outcomes that improve students’ understanding of entrepreneurship as well as understanding of themselves as entrepreneurs. ,This study brings the theories of causation and effectuation into the teaching of entrepreneurship. Of particular value to scholars is the fact that the study generates new understanding of the decision-making logics during new venture creation. Accordingly, this study sheds new light on the transformation and complementarity of the decision-making logic of an individual as new ventures emerge in an educational context reflecting the real-life start-up context.
Enhanced suppressor of cytokine signaling 3 in arthritic cartilage dysregulates human chondrocyte function.

OBJECTIVE To determine the expression of suppressor of cytokine signaling 3 (SOCS-3) in human articular chondrocytes and its functional consequences. METHODS Chondrocytes were isolated from the cartilage of patients with osteoarthritis (OA), patients with rheumatoid arthritis (RA), and trauma patients and from the healthy cartilage of patients with a femoral neck fracture. The human chondrocyte cell line G6 and primary bovine chondrocytes were used in validation experiments. SOCS-3 messenger RNA (mRNA) expression was measured by quantitative polymerase chain reaction, and SOCS-3 protein levels were determined by Western blotting and immunohistochemical analysis. To ascertain the role of SOCS-3 in the chondrocyte response to interleukin-1β (IL-1β) or lipopolysaccharide (LPS), the expression of SOCS3 was either reduced by small interfering RNA or enhanced by viral transduction. RESULTS The expression of SOCS-3 mRNA (but not that of SOCS-1 mRNA) was significantly enhanced in chondrocytes obtained from OA cartilage (mean ± SD ΔC(t) 3.4 ± 1.0) and RA cartilage (ΔC(t) 3.4 ± 1.4) compared with cartilage obtained from patients with femoral neck fracture (ΔC(t) 5.3 ± 1.2). The expression of SOCS3 correlated significantly with that of other genes known to be expressed in arthritic chondrocytes, such as MMP13 (r = 0.743), ADAMTS4 (r = 0.779), and ADAMTS5 (r = 0.647), and an inverse relationship was observed with COL2A1 (r = -0.561). Up-regulation of SOCS-3 by IL-1 in G6 chondrocytes and its spontaneous expression in OA chondrocytes were reduced by mithramycin, a specific inhibitor of transcription factor Sp-1. Overexpression of SOCS-3 in bovine chondrocytes reduced IL-1- and LPS-induced nitric oxide production and insulin-like growth factor 1-induced proteoglycan synthesis. Interestingly, a similar impairment of function was observed in OA chondrocytes, which was partially restored by SOCS-3 gene knockdown. CONCLUSION This study demonstrated that both SOCS-3 mRNA and SOCS-3 protein are expressed in human arthritic chondrocytes and affect cellular responses involved in cartilage pathology.
HYBRID FUZZY NEURAL NETWORK TO PREDICT PRICE DIRECTION IN THE GERMAN DAX-30 INDEX

Intraday trading rules require accurate information about the future short term market evolution. For that reason, next-day market trend prediction has attracted the attention of both academics and practitioners. This interest has increased in recent years, as different methodologies have been applied to this end. Usually, machine learning techniques are used such as artificial neural networks, support vector machines and decision trees. The input variables of most of the studies are traditional technical indicators which are used by professional traders to implement investment strategies. We analyse if these indicators have predictive power on the German DAX-30 stock index by applying a hybrid fuzzy neural network to predict the one-day ahead direction of index. We implement different models depending on whether all the indicators and oscillators are used as inputs, or if a linear combination of them obtained through a factor analysis is used instead. In order to guarantee for the robustness of the results, we train and apply the HyFIS models on randomly selected subsamples 10,000 times. The results show that the reduction of the dimension through the factorial analysis generates more profitable and less risky strategies.
Undecidability of static analysis

Static analysis of programs is indispensable to any software tool, environment, or system that requires compile-time information about the semantics of programs. With the emergence of languages like C and LISP, static analysis of programs with dynamic storage and recursive data structures has become a field of active research. Such analysis is difficult, and the static-analysis community has recognized the need for simplifying assumptions and approximate solutions. However, even under the common simplifying assumptions, such analyses are harder than previously recognized. Two fundamental static-analysis problems are may alias and must alias. The former is not recursive (is undecidable), and the latter is not recursively enumerable (is uncomputable), even when all paths are executable in the program being analyzed for languages with if statements, loops, dynamic storage, and recursive data structures.
Kidney and Pancreas Transplantation in the United States, 1998–2007: Access for Patients with Diabetes and End‐Stage Renal Disease

Although the number of candidates on the kidney transplant waiting list at year‐end rose from 40 825 to 76 070 (86%) between 1998 and 2007, recent growth principally reflects increases in the number of patients in inactive status. The number of active patients increased by ‘only’ 4510 between 2002 and 2007, from 44 263 to 48 773. There were 6037 living donor and 10 082 deceased donor kidney transplants in 2007. Patient and allograft survival was best for recipients of living donor kidneys, least for expanded criteria donor (ECD) deceased donor kidneys, and intermediate for non‐ECD deceased donor kidneys. The total number of pancreas transplants peaked at 1484 in 2004 and has since declined to 1331. Among pancreas recipients, those with simultaneous pancreas‐kidney (SPK) transplants experienced the best pancreas graft survival rates: 86% at 1 year and 53% at 10 years. Between 1998 and 2006, among diabetic patients with end‐stage renal disease (ESRD) who were under the age of 50 years, 23% of all and 62% of those waitlisted received a kidney‐alone or SPK transplant. In contrast, 6% of diabetic patients aged 50–75 years with ESRD were transplanted, representing 46% of those waitlisted from this cohort. Access to kidney‐alone or SPK transplantation varies widely by state.
Multi-beam leaky wave pillbox antenna for millimetre-wave applications

This work proposes a novel multi-beam leaky-wave pillbox antenna. The antenna system is based on three main parts: feeding part, quasi-optical system and radiating part. The radiating and input parts are placed in two different double grounded substrates connected by a quasi-optical system. Each part of the antenna structure can be optimized independently, thus facilitating and speeding up the complete antenna design. The quasi-optical system is made by a pin-made integrated parabola and several coupling slots, and is used to shape and focus the energy coming from the input part to the radiating part. The latter consists of a printed lealy-wave antenna: an array of slots etched on the uppermost metal layer. Seven pinmade integrated horns are placed in the focal plane of the integrated parabola to radiate seven beams in the far field. The proposed antenna is suitable for low-cost printed circuit board fabrication process and its low profile, compactness and efficiency make it a very promising solution for applications in the millimetre-wave range.
Contribution of SAR11 Bacteria to Dissolved Dimethylsulfoniopropionate and Amino Acid Uptake in the North Atlantic Ocean

ABSTRACT SAR11 bacteria are abundant in marine environments, often accounting for 35% of total prokaryotes in the surface ocean, but little is known about their involvement in marine biogeochemical cycles. Previous studies reported that SAR11 bacteria are very small and potentially have few ribosomes, indicating that SAR11 bacteria could have low metabolic activities and could play a smaller role in the flux of dissolved organic matter than suggested by their abundance. To determine the ecological activity of SAR11 bacteria, we used a combination of microautoradiography and fluorescence in situ hybridization (Micro-FISH) to measure assimilation of 3H-amino acids and [35S]dimethylsulfoniopropionate (DMSP) by SAR11 bacteria in the coastal North Atlantic Ocean and the Sargasso Sea. We found that SAR11 bacteria were often abundant in surface waters, accounting for 25% of all prokaryotes on average. SAR11 bacteria were typically as large as, if not larger than, other prokaryotes. Additionally, more than half of SAR11 bacteria assimilated dissolved amino acids and DMSP, whereas about 40% of other prokaryotes assimilated these compounds. Due to their high abundance and activity, SAR11 bacteria were responsible for about 50% of amino acid assimilation and 30% of DMSP assimilation in surface waters. The contribution of SAR11 bacteria to amino acid assimilation was greater than would be expected based on their overall abundance, implying that SAR11 bacteria outcompete other prokaryotes for these labile compounds. These data suggest that SAR11 bacteria are highly active and play a significant role in C, N, and S cycling in the ocean.
Market Volatility, Liquidity Shocks, and Stock Returns: Worldwide Evidence

We examine the interaction between market volatility, liquidity shocks, and stock returns in 41 countries over the period 1990–2015. We find liquidity is an important channel through which market volatility affects stock returns in international markets and we show this is distinct from the direct volatility–return relation. The influence of the liquidity channel on the link between market volatility and returns is stronger in markets exhibiting higher levels of market volatility and lower trading volume. It is also stronger in countries with better governance, no short-selling constraints, and more high-frequency trading and during crisis periods.
The Impact of Race/Ethnicity on Mother-to-Child HIV Transmission in the United States in Pediatric AIDS Clinical Trials Group Protocol 316

Summary: The present analysis was designed to determine whether race/ethnicity was independently associated with mother-to-child HIV-1 transmission risk in subjects enrolled in a trial of 2-dose intra-partum nevirapine in combination with standard antiretroviral therapy and to determine what factors, including race/ethnicity, predicted maternal viral suppression at the time of delivery. Women enrolled in Pediatric AIDS Clinical Trials Group (PACTG) 316 from sites in the United States and Puerto Rico were included. Distribution of selected maternal disease and treatment characteristics was assessed by race/ethnicity category. Logistic regression models were fit to evaluate possible association of factors with HIV transmission and with viral load at delivery. Variables associated with the outcome at P < 0.05 level were retained in the final models. Of 1052 women randomized at PACTG sites, 891 were included in the present analysis: 572 (64%) were black; 206 (23%) were Hispanic; and 113 (13%) were white. All women who had infected infants were black or Hispanic (11/572 and 3/206, respectively), whereas none of the women identified as white had an infected infant (0/113). This difference was not statistically significant (P = 0.54). White women had higher entry CD4 cell counts and lower HIV-1 RNA at delivery than women of other races/ethnicities. Black and Hispanic women were more likely than white women to start therapy during their current pregnancy but did not initiate prenatal care later. In bivariate models that included antiretroviral type and variables that had values of P ≤ 0.25 in univariate analysis, time of antiretroviral initiation, time of prenatal care initiation, and race/ethnicity each retained significance in predicting viral suppression at delivery. Race/ethnicity remained predictive of viral suppression at delivery in a multivariate model incorporating all of these variables (P = 0.01). Higher HIV-1 RNA and lower CD4 cell counts in women identified as black or Hispanic have significant implications for the health of these women and their newborns. Race/ethnicity is significant in predicting viral suppression at the time of delivery.
The Effects of Media Slant on Firm Behavior

The media can impose reputational costs on firms because of its important role as an information intermediary and its ability to negatively slant coverage. We exploit a quasi-natural experiment that holds constant the information event across firms, but varies the availability of a major news outlet in local markets. We find that firms subject to the threat of slanted coverage suppress the release of negative information before the event and release it subsequently. Our results are consistent with theory on the active role firms can play in managing their reputational capital through anticipatory actions to avoid negative media coverage.
Evaluation of Silage Corn Yield Gap: An Approach for Sustainable Production in the Semi-Arid Region of USA

Water and nitrogen (N) play an important role in closing the yield gap of crops by reducing associated stresses and yield variability. Field research data coupled to the CSM-CERES-Maize model of Decision Support System Agrotechnology Transfer were used to advance our understanding of the effect of water and N on silage corn growth and yield. The objectives of the study were to determine: (i) the best combination of irrigation water and N for optimum biomass yield, and (ii) the yield gap of silage corn grown at different locations in Wyoming, USA. Field experiments were conducted under sub-surface drip irrigation using a randomized complete block design in a split-plot arrangement with four replications. The main plot was irrigation and consisted of 100% crop evapotranspiration (100ETc), 80% (80ETc), and 60% (60ETc), and the sub-plot was N rates, including 0, 90, 180, 270, and 360 kg N ha−1 as urea-ammonium-nitrate. The simulated results indicated full irrigation and at least 150 kg N ha−1 as the best combination for silage corn production in Wyoming. Our observed and simulated results show the potential to increase the biomass and reduce the yield gap of silage corn in the region if irrigation water and N are properly managed.
Scattering from dust in molecular clouds: Constraining the dust grain size distribution through near-infrared cloudshine and infrared coreshine

Context. The largest grains (0.5-1 micron) in the interstellar size distribution are efficient in scattering near- and mid-infrared radiation. These wavelengths are therefore particularly well suited to probe the still uncertain high-end of the size distribution. Aims. We investigate the change in appearance of a typical low-mass molecular core from the Ks (2.2 micron) band to the Spitzer IRAC 3.6 and 8 micron bands, and compare with model calculations, which include variations of the grain size distribution. Methods. We combine Spitzer IRAC and ground-based near-infrared observations to characterize the scattered light observed at the near- and mid-infrared wavelengths from the core L260. Using a spherical symmetric model core, we perform radiative transfer calculations to study the impact of various dust size distributions on the intensity profiles across the core. Results. The observed scattered light patterns in the Ks and 3.6 micron bands are found to be similar. By comparison with radiative transfer models the two profiles place constraints on the relative abundance of small and large (more than 0.25 micron) dust grains. The scattered light profiles are found to be inconsistent with an interstellar silicate grain distribution extending only to 0.25 micron and large grains are needed to reach the observed fluxes and the flux ratios. The shape of the Ks band surface brightness profile limits the largest grains to 1-1.5 micron. Conclusions. In addition to observing coreshine in the Spitzer IRAC channels, the combination with ground-based near-infrared observations are suited to constrain the properties of large grains in cores.