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Cost-effective yet safe creation of high-permeability reservoirs within deep bedrock is the primary challenge for the viability of enhanced geothermal systems (EGS) and unconventional oil/gas recovery. Although fracturing fluids are commonly used for oil/gas, standard fracturing methods are not developed or proven for EGS temperatures and pressures. Furthermore, the environmental impacts of currently used fracturing methods are only recently being determined. Widespread concerns about the environmental contamination have resulted in a number of regulations for fracturing fluids advocating for greener fracturing processes. To enable EGS feasibility and lessen environmental impact of reservoir stimulation, an environmentally benign, CO2-activated, rheoreversible fracturing fluid that enhances permeability through fracturing due to in situ volume expansion and gel formation is investigated herein. The chemical mechanism, stability, phase-change behavior, and rheology for a novel polyallylamine (PAA)-CO2 fracturing fluid was characterized at EGS temperatures and pressures. Hydrogel is formed upon reaction with CO2, and this process is reversible (via CO2 depressurization or solubilizing with a diluted acid) allowing potential removal from the formation and recycling, decreasing environmental impact. Rock obtained from the Coso geothermal field was fractured in laboratory-scale experiments under various EGS temperatures and pressures at significantly (at least an order of magnitude) lower effective stress than standard fracturing fluids, and the fractures were characterized with imaging, permeability measurement, and flow modeling. Although additional work is required to further understand the fluid properties, potential and limitations, this novel fracturing fluid and process represent a potential alternative to conventional fracturing fluids to vastly reduce water usage and the environmental impact of fracturing practices and effectively make EGS production and unconventional oil/gas exploitation cost-effective and cleaner. [ABSTRACT FROM AUTHOR]

This study examines factors that contribute to depressive symptoms and to co-occurring depression, substance abuse, and conduct problems among 602 runaway and homeless adolescents. The respondents were interviewed in shelters, drop-in centers, and directly on the streets in four Midwestern states (Missouri, Iowa, Nebraska, and Kansas). Results indicate that although family-of-origin factors contribute to depressive symptoms and comorbidity among runaway and homeless adolescents, experiences and behaviors when the adolescents are on their own also have powerful effects. The authors discuss the findings from a life-course perspective focusing on mechanisms through which street experiences accentuate or amplify already high levels of psychological distress and behavioral problems among this population of young people. [ABSTRACT FROM AUTHOR]

During the last few decades the study of racial differences in occupational and economic attainment has progressed rapidly, both in terms of theory and research. The ecological study of the racial and ethnic organization of local labor markets has not. The use of odds ratios and occupation-specific categories may provide a fruitful avenue for future research in the study of inequality across space and time. [ABSTRACT FROM AUTHOR]

Full development of the frontal sinus is not achieved until approximately 19 years of age. An evaluation of frontal sinus injuries isolated to the subset of patients less than 20 years old has yet to be reported. In order to determine whether age was a factor in the clinical course of patients with frontal sinus fractures, 209 patients who sustained frontal sinus fractures from January 1985 to April 1990 were identified using the trauma registry from all six major trauma centers, one of which is a pediatric trauma center, in a county of 2.5 million people. Forty patients (19%) were between the ages of 6 and 19 years at the time of their injury. Computed tomography imaging of these pediatric patients identified associated head and neck fractures in 37 (93%) as well as significant central nervous system injury in 22 (55%). Seventeen pediatric patients were treated nonoperatively and 1 died prior to the planned surgery. A detailed analysis of extent of injury and treatment together with a comparison of the 169 adult and the 40 pediatric patients is presented. [ABSTRACT FROM AUTHOR]

While zinc oxide (ZnO) has potential for optoelectronic applications, the lack of reliable p-type doping remains a major challenge. We provide evidence that ZnO nanocrystals contain uncompensated acceptors. IR absorption peaks at liquid-helium temperatures suggest a hydrogenic acceptor with a hole binding energy of 0.4-0.5 eV. Electron paramagnetic resonance (EPR) measurements in the dark showed a resonance at g=2.003, characteristic of acceptors that involve a zinc vacancy. An EPR resonance due to vacancy hydrogen complexes was observed after exposure to light. Given the lack of alternatives, vacancy complexes may provide a feasible route toward p-type conductivity. [ABSTRACT FROM AUTHOR]

Abstract Background Targeting Signal Transducer and Activator of Transcription 3 (STAT3) signaling is an attractive therapeutic approach for most types of human cancers with constitutively activated STAT3. A novel small molecular STAT3 inhibitor, FLLL32 was specifically designed from dietary agent, curcumin to inhibit constitutive STAT3 signaling in multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells. Results FLLL32 was found to be a potent inhibitor of STAT3 phosphorylation, STAT3 DNA binding activity, and the expression of STAT3 downstream target genes in vitro, leading to the inhibition of cell proliferation as well as the induction of Caspase-3 and PARP cleavages in human multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cell lines. However, FLLL32 exhibited little inhibition on some tyrosine kinases containing SH2 or both SH2 and SH3 domains, and other protein and lipid kinases using a kinase profile assay. FLLL32 was also more potent than four previously reported JAK2 and STAT3 inhibitors as well as curcumin to inhibit cell viability in these cancer cells. Furthermore, FLLL32 selectively inhibited the induction of STAT3 phosphorylation by Interleukin-6 but not STAT1 phosphorylation by IFN-γ. Conclusion Our findings indicate that FLLL32 exhibits potent inhibitory activity to STAT3 and has potential for targeting multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells expressing constitutive STAT3 signaling.

Abstract Background We characterized the biologic effects of a novel small molecule STAT3 pathway inhibitor that is derived from the natural product curcumin. We hypothesized this lead compound would specifically inhibit the STAT3 signaling pathway to induce apoptosis in melanoma cells. Results FLLL32 specifically reduced STAT3 phosphorylation at Tyr705 (pSTAT3) and induced apoptosis at micromolar amounts in human melanoma cell lines and primary melanoma cultures as determined by annexin V/propidium iodide staining and immunoblot analysis. FLLL32 treatment reduced expression of STAT3-target genes, induced caspase-dependent apoptosis, and reduced mitochondrial membrane potential. FLLL32 displayed specificity for STAT3 over other homologous STAT proteins. In contrast to other STAT3 pathway inhibitors (WP1066, JSI-124, Stattic), FLLL32 did not abrogate IFN-γ-induced pSTAT1 or downstream STAT1-mediated gene expression as determined by Real Time PCR. In addition, FLLL32 did not adversely affect the function or viability of immune cells from normal donors. In peripheral blood mononuclear cells (PBMCs), FLLL32 inhibited IL-6-induced pSTAT3 but did not reduce signaling in response to immunostimulatory cytokines (IFN-γ, IL 2). Treatment of PBMCs or natural killer (NK) cells with FLLL32 also did not decrease viability or granzyme b and IFN-γ production when cultured with K562 targets as compared to vehicle (DMSO). Conclusions These data suggest that FLLL32 represents a lead compound that could serve as a platform for further optimization to develop improved STAT3 specific inhibitors for melanoma therapy.

Abstract Background The peptidyl-proline isomerase, Protein Never in Mitosis Gene A Interacting-1 (PIN1), regulates turnover of inducible nitric oxide synthase (iNOS) in murine aortic endothelial cells (MAEC) stimulated with E. coli endotoxin (LPS) and interferon-γ (IFN). Degradation of iNOS was reduced by a calpain inhibitor, suggesting that PIN1 may affect induction of other calpain-sensitive inflammatory proteins, such as cyclooxygenase (COX)-2, in MAEC. Methods MAEC, transduced with lentivirus encoding an inactive control short hairpin (sh) RNA or one targeting PIN1 that reduced PIN1 by 85%, were used. Cells were treated with LPS/IFN, calpain inhibitors (carbobenzoxy-valinyl-phenylalaninal (zVF), PD150606), cycloheximide and COX inhibitors to determine the effect of PIN1 depletion on COX-2 and calpain. Results LPS or IFN alone did not induce COX-2. However, treatment with 10 μg LPS plus 20 ng IFN per ml induced COX-2 protein 10-fold in Control shRNA MAEC. Induction was significantly greater (47-fold) in PIN1 shRNA cells. COX-2-dependent prostaglandin E2 production increased 3-fold in KD MAEC, but did not increase in Control cells. The additional increase in COX-2 protein due to PIN1 depletion was post-transcriptional, as induction of COX-2 mRNA by LPS/IFN was the same in cells containing or lacking PIN1. Instead, the loss of COX-2 protein, after treatment with cycloheximide to block protein synthesis, was reduced in cells lacking PIN1 in comparison with Control cells, indicating that degradation of the enzyme was reduced. zVF and PD150606 each enhanced the induction of COX-2 by LPS/IFN. zVF also slowed the loss of COX-2 after treatment with cycloheximide, and COX-2 was degraded by exogenous μ-calpain in vitro. In contrast to iNOS, physical interaction between COX-2 and PIN1 was not detected, suggesting that effects of PIN1 on calpain, rather than COX-2 itself, affect COX-2 degradation. While cathepsin activity was unaltered, depletion of PIN1 reduced calpain activity by 55% in comparison with Control shRNA cells. Conclusion PIN1 reduced calpain activity and slowed the degradation of COX-2 in MAEC, an effect recapitulated by an inhibitor of calpain. Given the sensitivity of COX-2 and iNOS to calpain, PIN1 may normally limit induction of these and other calpain substrates by maintaining calpain activity in endothelial cells.

Abstract Background It was hypothesized that a pro-atherogenic, high saturated fat and cholesterol diet (HCD) would increase the inflammatory response to E. coli endotoxin (LPS) and increase its concentration in plasma after administration to mice. Methods C57Bl/6 mice were fed a HCD or a control diet (CD) for 4 weeks, and then treated with saline, 0.5, 1 or 2 mg LPS/kg, ip. Liver injury (alanine:2-oxoglutarate aminotransferase and aspartate aminotransferase, collagen staining), circulating cytokines (tumor necrosis factor-α, interleukin-6 and interferon-γ), factors that can bind LPS (serum amyloid A, apolipoprotein A1, LPS binding protein, and CD14), and plasma levels of LPS were measured. The hepatic response was assessed by measuring vascular cell adhesion molecule (VCAM)-1, inducible nitric oxide synthase (iNOS) and signal transducer and activator of transcription-1 proteins, and VCAM-1 and iNOS mRNAs. Hepatic mRNA encoding the LPS receptor, Toll like receptor 4, was also determined. Results Two mg LPS/kg killed 100% of mice fed HCD within 5 d, while no mice fed CD died. All mice treated with 0 to 1 mg LPS/kg survived 24 h. HCD increased plasma alanine:2-oxoglutarate aminotransferase and aspartate aminotransferase, and the enzymes were increased more by LPS in HCD than CD mice. Induction of plasma tumor necrosis factor-α, interleukin-6, and interferon-γ by LPS was greater with HCD than CD. Hepatic VCAM-1 and iNOS protein and mRNA were induced by LPS more in mice fed HCD than CD. Tyrosine phosphorylation of signal transducer and activator of transcription-1 caused by LPS was prolonged in HCD compared with CD mice. Despite the hepatic effects of HCD, diet had no effect on the LPS plasma concentration-time profile. HCD alone did not affect circulating levels of plasma apolipoprotein A1 or LPS binding protein. However, plasma concentrations of serum amyloid A and CD14, and hepatic toll-like receptor-4 mRNA were increased in mice fed HCD. Conclusion HCD increased the sensitivity of mice to LPS without affecting its plasma level. Although increased serum amyloid A and CD14 in the circulation may inhibit LPS actions, their overexpression, along with hepatic toll-like receptor-4 or other factors, may contribute to the heightened sensitivity to LPS.