Search

Barrier dysfunction of airway epithelium contributes to the development of allergies, airway hyper-responsiveness and immunological respiratory diseases. Short-chain fatty acids (SCFA) enhance and restore the barrier function of the intestinal epithelium. This study investigated whether acetate, propionate and butyrate enhance the integrity of bronchial epithelial cells. Differentiating human bronchial epithelial cells (16HBE) grown on transwells were exposed to butyrate, propionate and acetate while trans-epithelial electrical resistance was monitored over time. Restorative effects of SCFA were investigated by subsequent incubation of cells with IL-4, IL-13 or house dust mite extract and SCFA. SCFA effects on IL-4-induced cytokine production and the expression of zonula occludens-1 (ZO-1) and Mitogen-activated protein kinases (MAPK) signalling pathways were investigated by ELISA and Western blot assays. Propionate and butyrate enhanced the barrier function of differentiating 16HBE cells and induced complete recovery of the barrier function after exposure to the above-mentioned stimuli. Butyrate decreased IL-4-induced IL-6 production. IL-4 decreased ZO-1 protein expression and induced phosphorylation of extracellular signal-regulated protein kinases 1/2 (ERK1/2) and c-Jun N-terminal kinases (JNK) in 16HBE cells, both of which could be restored by SCFA. SCFA showed prophylactic and restorative effects on airway epithelial barrier function, which might be induced by increased ZO-1 expression.

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.Good-bad binary classifications fail to describe reactive astrocytes in CNS disorders. Here, 81 researchers reach consensus on widespread misconceptions and provide definitions and recommendations for future research on reactive astrocytes.

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.Good-bad binary classifications fail to describe reactive astrocytes in CNS disorders. Here, 81 researchers reach consensus on widespread misconceptions and provide definitions and recommendations for future research on reactive astrocytes.

Background: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. Methods: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. Results: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10−6) associated with exacerbations despite LABA use. Conclusion: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day between those from Slovenia Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day in those starting anti-IgE (Slovenia Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m-2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day-1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day-1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

In this thesis we explore the problem of inference for Bayesian model averaging. Many popular topics in Bayesian analysis, such as Bayesian nonparametrics, can be cast as model averaging problems. Model averaging problems offer unique difficulties for inference, as the parameter space is not fixed, and may be infinite. As such, there is little existing work on general purpose MCMC algorithms in this area. We introduce a new MCMC sampler, which we call Retrospective Jump sampling, that is suitable for general purpose model averaging. In the development of Retrospective Jump, some practical issues arise in the need for a MCMC sampler for finite dimensions that is suitable for multimodal target densities; we introduce Refractive Sampling as a sampler suitable in this regard. Finally, we evaluate Retrospective Jump on several model averaging and Bayesian nonparametric problems, and develop a novel latent feature model with hierarchical column structure which uses Retrospective Jump for inference.

In this thesis we explore the problem of inference for Bayesian model averaging. Many popular topics in Bayesian analysis, such as Bayesian nonparametrics, can be cast as model averaging problems. Model averaging problems offer unique difficulties for inference, as the parameter space is not fixed, and may be infinite. As such, there is little existing work on general purpose MCMC algorithms in this area. We introduce a new MCMC sampler, which we call Retrospective Jump sampling, that is suitable for general purpose model averaging. In the development of Retrospective Jump, some practical issues arise in the need for a MCMC sampler for finite dimensions that is suitable for multimodal target densities; we introduce Refractive Sampling as a sampler suitable in this regard. Finally, we evaluate Retrospective Jump on several model averaging and Bayesian nonparametric problems, and develop a novel latent feature model with hierarchical column structure which uses Retrospective Jump for inference.

People of the Central Plains tradition (A.D. 900 to 1450) practiced a lifestyle of diversified subsistence while occupying isolated to small clusters of earth lodges, or earthen dwellings. The Albert Bell site, in Sheridan County, Kansas, in 1990, was the location for the excavation of an earth lodge dating from this time. The objective of this study was to explore the site for the presence of another earth lodge or artifacts by utilizing geophysical methods and providing the data to archaeologists before excavation began for the 2002 field season. The geophysical methods used in this study included magnetometry and electrical resistivity. Magnetometer data revealed one magnetic anomaly in the northeast comer of the site at a location that was excavated in 1990. The anomaly may be a tool or iron bearing marker left behind. Distinct areas of high and low resistivity values appeared in the electrical resistivity survey. The areas of high resistivity are found in the lower elevations of the ridges side slopes, a location that least likely held an earth lodge. High and low resistivity anomalies indicate alluvial sands underlying a clay loam. All suspected anomalies and the area surrounding them were groundtruthed by excavating test pits and acquiring soil core samples. The results of the geophysical survey produced no indication that another earth lodge, or fire pits were located at the Albert Bell site. However, geophysical data in similar applications have been successful. Data collected in this study did provide a good representation of the subsurface at the site. The techniques used in this survey can be considered for future studies.

People of the Central Plains tradition (A.D. 900 to 1450) practiced a lifestyle of diversified subsistence while occupying isolated to small clusters of earth lodges, or earthen dwellings. The Albert Bell site, in Sheridan County, Kansas, in 1990, was the location for the excavation of an earth lodge dating from this time. The objective of this study was to explore the site for the presence of another earth lodge or artifacts by utilizing geophysical methods and providing the data to archaeologists before excavation began for the 2002 field season. The geophysical methods used in this study included magnetometry and electrical resistivity. Magnetometer data revealed one magnetic anomaly in the northeast comer of the site at a location that was excavated in 1990. The anomaly may be a tool or iron bearing marker left behind. Distinct areas of high and low resistivity values appeared in the electrical resistivity survey. The areas of high resistivity are found in the lower elevations of the ridges side slopes, a location that least likely held an earth lodge. High and low resistivity anomalies indicate alluvial sands underlying a clay loam. All suspected anomalies and the area surrounding them were groundtruthed by excavating test pits and acquiring soil core samples. The results of the geophysical survey produced no indication that another earth lodge, or fire pits were located at the Albert Bell site. However, geophysical data in similar applications have been successful. Data collected in this study did provide a good representation of the subsurface at the site. The techniques used in this survey can be considered for future studies.

People of the Central Plains tradition (A.D. 900 to 1450) practiced a lifestyle of diversified subsistence while occupying isolated to small clusters of earth lodges, or earthen dwellings. The Albert Bell site, in Sheridan County, Kansas, in 1990, was the location for the excavation of an earth lodge dating from this time. The objective of this study was to explore the site for the presence of another earth lodge or artifacts by utilizing geophysical methods and providing the data to archaeologists before excavation began for the 2002 field season. The geophysical methods used in this study included magnetometry and electrical resistivity. Magnetometer data revealed one magnetic anomaly in the northeast comer of the site at a location that was excavated in 1990. The anomaly may be a tool or iron bearing marker left behind. Distinct areas of high and low resistivity values appeared in the electrical resistivity survey. The areas of high resistivity are found in the lower elevations of the ridges side slopes, a location that least likely held an earth lodge. High and low resistivity anomalies indicate alluvial sands underlying a clay loam. All suspected anomalies and the area surrounding them were groundtruthed by excavating test pits and acquiring soil core samples. The results of the geophysical survey produced no indication that another earth lodge, or fire pits were located at the Albert Bell site. However, geophysical data in similar applications have been successful. Data collected in this study did provide a good representation of the subsurface at the site. The techniques used in this survey can be considered for future studies.

People of the Central Plains tradition (A.D. 900 to 1450) practiced a lifestyle of diversified subsistence while occupying isolated to small clusters of earth lodges, or earthen dwellings. The Albert Bell site, in Sheridan County, Kansas, in 1990, was the location for the excavation of an earth lodge dating from this time. The objective of this study was to explore the site for the presence of another earth lodge or artifacts by utilizing geophysical methods and providing the data to archaeologists before excavation began for the 2002 field season. The geophysical methods used in this study included magnetometry and electrical resistivity. Magnetometer data revealed one magnetic anomaly in the northeast comer of the site at a location that was excavated in 1990. The anomaly may be a tool or iron bearing marker left behind. Distinct areas of high and low resistivity values appeared in the electrical resistivity survey. The areas of high resistivity are found in the lower elevations of the ridges side slopes, a location that least likely held an earth lodge. High and low resistivity anomalies indicate alluvial sands underlying a clay loam. All suspected anomalies and the area surrounding them were groundtruthed by excavating test pits and acquiring soil core samples. The results of the geophysical survey produced no indication that another earth lodge, or fire pits were located at the Albert Bell site. However, geophysical data in similar applications have been successful. Data collected in this study did provide a good representation of the subsurface at the site. The techniques used in this survey can be considered for future studies.

People of the Central Plains tradition (A.D. 900 to 1450) practiced a lifestyle of diversified subsistence while occupying isolated to small clusters of earth lodges, or earthen dwellings. The Albert Bell site, in Sheridan County, Kansas, in 1990, was the location for the excavation of an earth lodge dating from this time. The objective of this study was to explore the site for the presence of another earth lodge or artifacts by utilizing geophysical methods and providing the data to archaeologists before excavation began for the 2002 field season. The geophysical methods used in this study included magnetometry and electrical resistivity. Magnetometer data revealed one magnetic anomaly in the northeast comer of the site at a location that was excavated in 1990. The anomaly may be a tool or iron bearing marker left behind. Distinct areas of high and low resistivity values appeared in the electrical resistivity survey. The areas of high resistivity are found in the lower elevations of the ridges side slopes, a location that least likely held an earth lodge. High and low resistivity anomalies indicate alluvial sands underlying a clay loam. All suspected anomalies and the area surrounding them were groundtruthed by excavating test pits and acquiring soil core samples. The results of the geophysical survey produced no indication that another earth lodge, or fire pits were located at the Albert Bell site. However, geophysical data in similar applications have been successful. Data collected in this study did provide a good representation of the subsurface at the site. The techniques used in this survey can be considered for future studies.

People of the Central Plains tradition (A.D. 900 to 1450) practiced a lifestyle of diversified subsistence while occupying isolated to small clusters of earth lodges, or earthen dwellings. The Albert Bell site, in Sheridan County, Kansas, in 1990, was the location for the excavation of an earth lodge dating from this time. The objective of this study was to explore the site for the presence of another earth lodge or artifacts by utilizing geophysical methods and providing the data to archaeologists before excavation began for the 2002 field season. The geophysical methods used in this study included magnetometry and electrical resistivity. Magnetometer data revealed one magnetic anomaly in the northeast comer of the site at a location that was excavated in 1990. The anomaly may be a tool or iron bearing marker left behind. Distinct areas of high and low resistivity values appeared in the electrical resistivity survey. The areas of high resistivity are found in the lower elevations of the ridges side slopes, a location that least likely held an earth lodge. High and low resistivity anomalies indicate alluvial sands underlying a clay loam. All suspected anomalies and the area surrounding them were groundtruthed by excavating test pits and acquiring soil core samples. The results of the geophysical survey produced no indication that another earth lodge, or fire pits were located at the Albert Bell site. However, geophysical data in similar applications have been successful. Data collected in this study did provide a good representation of the subsurface at the site. The techniques used in this survey can be considered for future studies.

People of the Central Plains tradition (A.D. 900 to 1450) practiced a lifestyle of diversified subsistence while occupying isolated to small clusters of earth lodges, or earthen dwellings. The Albert Bell site, in Sheridan County, Kansas, in 1990, was the location for the excavation of an earth lodge dating from this time. The objective of this study was to explore the site for the presence of another earth lodge or artifacts by utilizing geophysical methods and providing the data to archaeologists before excavation began for the 2002 field season. The geophysical methods used in this study included magnetometry and electrical resistivity. Magnetometer data revealed one magnetic anomaly in the northeast comer of the site at a location that was excavated in 1990. The anomaly may be a tool or iron bearing marker left behind. Distinct areas of high and low resistivity values appeared in the electrical resistivity survey. The areas of high resistivity are found in the lower elevations of the ridges side slopes, a location that least likely held an earth lodge. High and low resistivity anomalies indicate alluvial sands underlying a clay loam. All suspected anomalies and the area surrounding them were groundtruthed by excavating test pits and acquiring soil core samples. The results of the geophysical survey produced no indication that another earth lodge, or fire pits were located at the Albert Bell site. However, geophysical data in similar applications have been successful. Data collected in this study did provide a good representation of the subsurface at the site. The techniques used in this survey can be considered for future studies.

People of the Central Plains tradition (A.D. 900 to 1450) practiced a lifestyle of diversified subsistence while occupying isolated to small clusters of earth lodges, or earthen dwellings. The Albert Bell site, in Sheridan County, Kansas, in 1990, was the location for the excavation of an earth lodge dating from this time. The objective of this study was to explore the site for the presence of another earth lodge or artifacts by utilizing geophysical methods and providing the data to archaeologists before excavation began for the 2002 field season. The geophysical methods used in this study included magnetometry and electrical resistivity. Magnetometer data revealed one magnetic anomaly in the northeast comer of the site at a location that was excavated in 1990. The anomaly may be a tool or iron bearing marker left behind. Distinct areas of high and low resistivity values appeared in the electrical resistivity survey. The areas of high resistivity are found in the lower elevations of the ridges side slopes, a location that least likely held an earth lodge. High and low resistivity anomalies indicate alluvial sands underlying a clay loam. All suspected anomalies and the area surrounding them were groundtruthed by excavating test pits and acquiring soil core samples. The results of the geophysical survey produced no indication that another earth lodge, or fire pits were located at the Albert Bell site. However, geophysical data in similar applications have been successful. Data collected in this study did provide a good representation of the subsurface at the site. The techniques used in this survey can be considered for future studies.

People of the Central Plains tradition (A.D. 900 to 1450) practiced a lifestyle of diversified subsistence while occupying isolated to small clusters of earth lodges, or earthen dwellings. The Albert Bell site, in Sheridan County, Kansas, in 1990, was the location for the excavation of an earth lodge dating from this time. The objective of this study was to explore the site for the presence of another earth lodge or artifacts by utilizing geophysical methods and providing the data to archaeologists before excavation began for the 2002 field season. The geophysical methods used in this study included magnetometry and electrical resistivity. Magnetometer data revealed one magnetic anomaly in the northeast comer of the site at a location that was excavated in 1990. The anomaly may be a tool or iron bearing marker left behind. Distinct areas of high and low resistivity values appeared in the electrical resistivity survey. The areas of high resistivity are found in the lower elevations of the ridges side slopes, a location that least likely held an earth lodge. High and low resistivity anomalies indicate alluvial sands underlying a clay loam. All suspected anomalies and the area surrounding them were groundtruthed by excavating test pits and acquiring soil core samples. The results of the geophysical survey produced no indication that another earth lodge, or fire pits were located at the Albert Bell site. However, geophysical data in similar applications have been successful. Data collected in this study did provide a good representation of the subsurface at the site. The techniques used in this survey can be considered for future studies.

People of the Central Plains tradition (A.D. 900 to 1450) practiced a lifestyle of diversified subsistence while occupying isolated to small clusters of earth lodges, or earthen dwellings. The Albert Bell site, in Sheridan County, Kansas, in 1990, was the location for the excavation of an earth lodge dating from this time. The objective of this study was to explore the site for the presence of another earth lodge or artifacts by utilizing geophysical methods and providing the data to archaeologists before excavation began for the 2002 field season. The geophysical methods used in this study included magnetometry and electrical resistivity. Magnetometer data revealed one magnetic anomaly in the northeast comer of the site at a location that was excavated in 1990. The anomaly may be a tool or iron bearing marker left behind. Distinct areas of high and low resistivity values appeared in the electrical resistivity survey. The areas of high resistivity are found in the lower elevations of the ridges side slopes, a location that least likely held an earth lodge. High and low resistivity anomalies indicate alluvial sands underlying a clay loam. All suspected anomalies and the area surrounding them were groundtruthed by excavating test pits and acquiring soil core samples. The results of the geophysical survey produced no indication that another earth lodge, or fire pits were located at the Albert Bell site. However, geophysical data in similar applications have been successful. Data collected in this study did provide a good representation of the subsurface at the site. The techniques used in this survey can be considered for future studies.

Despite common characterizations of modern wind energy technology as mature, there remains a persistent disconnect between the vast global wind energy resource—which is 20 times greater than total global power consumption—and the limited penetration of existing wind energy technologies as a means for electricity generation worldwide. We describe an approach to wind energy harvesting that has the potential to resolve this disconnect by geographically distributing wind power generators in a manner that more closely mirrors the physical resource itself. To this end, technology development is focused on large arrays of small wind turbines that can harvest wind energy at low altitudes by using new concepts of biology-inspired engineering. This approach dramatically extends the reach of wind energy, as smaller wind turbines can be installed in many places that larger systems cannot, especially in built environments. Moreover, they have lower visual, acoustic, and radar signatures, and they may pose significantly less risk to birds and bats. These features can be leveraged to attain cultural acceptance and rapid adoption of this new technology, thereby enabling significantly faster achievement of state and national renewable energy targets than with existing technology alone. Favorable economics stem from an orders-of-magnitude reduction in the number of components in a new generation of simple, mass-manufacturable (even 3D-printable), vertical-axis wind turbines. However, this vision can only be achieved by overcoming significant scientific challenges that have limited progress over the past three decades. The following essay summarizes our approach as well as the opportunities and challenges associated with it, with the aim of motivating a concerted effort in basic and applied research in this area.

16q24 is frequently deleted in multiple tumors including cancers of nasopharynx, esophagus, breast, prostate and liver. By array comparative genomic hybridization (aCGH), we refined a 16q24 hemizygous deletion in nasopharyngeal carcinoma (NPC) cell lines. Semi-quantitative RT-PCR analysis revealed interferon regulatory factor 8 (IRF8) as the only downregulated gene within this deletion. IRF8 belongs to a family of interferon (IFN) regulatory factors that modulate various important physiologic processes including host defense, cell growth and differentiation and immune regulation. In contrast to the broad expression of IRF8 in normal adult and fetal tissues, transcriptional silencing and promoter methylation of IRF8 were frequently detected in multiple carcinoma (except for hepatocellular) cell lines (100\% in NPC, 88\% in esophageal and 18-78\% in other carcinoma cell lines) and in a large collection of primary carcinomas (78\% in NPC, 36-71\% in other carcinomas). Methylation of the IRF8 promoter led to the disruption of its response to IFN-gamma stimulation. Pharmacological and genetic demethylation could restore IRF8 expression, indicating a direct epigenetic mechanism. Ectopic expression of IRF8 in tumor cells lacking its expression strongly inhibited their clonogenicity, confirming its tumor suppressor function. Thus, IRF8 was identified as a functional tumor suppressor, which is frequently silenced by epigenetic mechanism in multiple carcinomas.

16q24 is frequently deleted in multiple tumors including cancers of nasopharynx, esophagus, breast, prostate and liver. By array comparative genomic hybridization (aCGH), we refined a 16q24 hemizygous deletion in nasopharyngeal carcinoma (NPC) cell lines. Semi-quantitative RT-PCR analysis revealed interferon regulatory factor 8 (IRF8) as the only downregulated gene within this deletion. IRF8 belongs to a family of interferon (IFN) regulatory factors that modulate various important physiologic processes including host defense, cell growth and differentiation and immune regulation. In contrast to the broad expression of IRF8 in normal adult and fetal tissues, transcriptional silencing and promoter methylation of IRF8 were frequently detected in multiple carcinoma (except for hepatocellular) cell lines (100\% in NPC, 88\% in esophageal and 18-78\% in other carcinoma cell lines) and in a large collection of primary carcinomas (78\% in NPC, 36-71\% in other carcinomas). Methylation of the IRF8 promoter led to the disruption of its response to IFN-gamma stimulation. Pharmacological and genetic demethylation could restore IRF8 expression, indicating a direct epigenetic mechanism. Ectopic expression of IRF8 in tumor cells lacking its expression strongly inhibited their clonogenicity, confirming its tumor suppressor function. Thus, IRF8 was identified as a functional tumor suppressor, which is frequently silenced by epigenetic mechanism in multiple carcinomas.

16q24 is frequently deleted in multiple tumors including cancers of nasopharynx, esophagus, breast, prostate and liver. By array comparative genomic hybridization (aCGH), we refined a 16q24 hemizygous deletion in nasopharyngeal carcinoma (NPC) cell lines. Semi-quantitative RT-PCR analysis revealed interferon regulatory factor 8 (IRF8) as the only downregulated gene within this deletion. IRF8 belongs to a family of interferon (IFN) regulatory factors that modulate various important physiologic processes including host defense, cell growth and differentiation and immune regulation. In contrast to the broad expression of IRF8 in normal adult and fetal tissues, transcriptional silencing and promoter methylation of IRF8 were frequently detected in multiple carcinoma (except for hepatocellular) cell lines (100\% in NPC, 88\% in esophageal and 18-78\% in other carcinoma cell lines) and in a large collection of primary carcinomas (78\% in NPC, 36-71\% in other carcinomas). Methylation of the IRF8 promoter led to the disruption of its response to IFN-gamma stimulation. Pharmacological and genetic demethylation could restore IRF8 expression, indicating a direct epigenetic mechanism. Ectopic expression of IRF8 in tumor cells lacking its expression strongly inhibited their clonogenicity, confirming its tumor suppressor function. Thus, IRF8 was identified as a functional tumor suppressor, which is frequently silenced by epigenetic mechanism in multiple carcinomas.

This specification establishes the design of Function PRE14, Generate Request Processor Driver, one of the major functions of the Configuration Item Precompiler to be built and formally accepted by the ICAM Program Office. This CI constitutes one of the subsystems of the Common Data Model Processor (CDMP). The purpose of this Computer Program Configuration Item (CPCI) is to generate a main program for each Request Processor needed to handle all of the NDML requests found in a user's logical unit of work grouping of user software modules. The following function will be performed by this CPCI: (1) Sort the table listing all generated Request Processors on database identifier; and (2) For each database, generate a COBOL, FORTRAN, or C Request Processor driver module: (a) Use a macro to generate the Identification, Environment and Data Divisions of the program. (b) Use a macro to generate the case test and the call syntax in the Procedure Division of the program. (c) Use a macro for the error handling and termination of the program., See also Volume 5, Part 26, AD-A250 463.

This specification establishes the design of Function PRE7, Change NDML to DML, one of the major functions of the Configuration Item Precompiler to be built and formally accepted by the ICAM Program Office. The purpose of this Computer Program Configuration Item (CPCI) is to translate an internal schema access path to generic CODASYL DML. The function that will be performed by this CPCI is to transform access path specifications into generic CODASYL access and data manipulation codes., See also Volume 5, Part 19, ADA250457.

This specification establishes the design of Function PRE9.3, Generate CODASYL Request Processor, one of the major functions of the Configuration Item (CI) Precompiler to be built and formally accepted by the ICAM Program Office. This CI constitutes one of the subsystems of the Common Data Model Processor (CDMP)., See also Volume 5, Part 22, ADA250459.

This specification establishes the design of Function PRE9.1, Request Processor Generator Support Routines, one of the major functions of the Configuration Item (CI) Precompiler to be built and formally accepted by the ICAM Program Office. This CI constitutes one of the subsystems of the Common Data Model Processor (CDMP)., See also Volume 5, Part 25, AD-A250 462.

This specification establishes the design of Function PRE9.2, Generate ORACLE Request Processor, one of the major functions of the Configuration Item (CI) Precompiler to be built and formally accepted by the ICAM Program office. This CI constitutes one of the subsystems of the Common Data Model Processor (CDMP). The purpose of this Computer Program Configuration Item (CPCI) is to generate a COBOL, c, or FORTRAN program that will satisfy a retrieval or update NDML or SQL subtransaction against an ORACLE database., See also Volume 5, Part 20, ADA250458.

This specification establishes the design of Function PRE3, Parse NDML, one of the major functions of the Configuration Item Precompiler to be built and formally accepted by the ICAM Program Office. This CPCI constitutes one of the subsystems of the Common Data Model Processor (CDMP). This function parses the NDML or SQL statements into tokenized form. Legal syntax is checked and syntax error messages issued., See also Volume 5, Part 14, ADA250454.

This specification establishes the design of Function Pre11, Build Source Code, one of the major functions of the Configurations Item Precompiler to be built and formally accepted by the ICAM Program Office. This CI constitutes one of the subsystems of the Common Data Model Processor (CDMP). The purpose of this Computer Program Configuration Item (CPCI) is to combine previously constructed parcels into a modified application process capable of servicing NDML or SQL requests. The following functions will be preformed by this CPCI based on the source language of the applications: (1) Write contents of parcel 2 onto the first parcel; (2) Write contents of parcel 3 onto the first parcel; (3) Write contents of parcel 4 onto the first parcel; and (4) Delete parcels 1, 2 and 3., See also Volume 5, Part 24, ADA250461.

This specification establishes the design of function PRE5, decompose CS NDML, one of the major functions of the configuration item precompiler to be built and formally accepted by the ICAM program office. This CI constitutes one of the subsystems of the common data model processor (CDMP). The purpose of this computer program configuration item (CPCI) is to break down a CS NDML transaction, or request, into its various CS NDML subtransactions. The following functions will be performed by this CPCI: (1) Map all CS attribute use classes, entity classes and relation classes; (2) Identify all unions, intra database joins, inter database joins and unions and not in set operators; (3) Reformat the original request into single database subtransactions; and (4) Control further code generation of request processors., See also Volume 5, Part 17, ADA250456.

This specification establishes the design of Function PRE4, Transform ES/CS, one of the major functions of the Configuration Item Precompiler to be built and formally accepted by the ICAM program Office. This CI constitutes one of the subsystems of the Common Data Model Processor (CDMP). The purpose of this Computer Program Configuration Item (CPCI) is to convert an NDML or SQL request, expressed in an external schema, and to terminate one or more NDML or SQL requests expressed in conceptual schema terms. The following functions will be performed by this CPCI: (1) Translate each user view into the corresponding entity classes and each data item into the corresponding attribute use class; (2) Identify the relational join operations needed to construct each user view table; and (3) Identify the integrity tests that will be employed with each NDML or SQL update request., See also Volume 5, Part 15, ADA250455.

This specification establishes the design of Function PRE10, Build Calls Messages into the Users AP, one of the major functions of the Configuration Item Precompiler to be built and formally accepted by the ICAM program Office. This CI constitutes one of the subsystems of the Common Data Model Processor (CDMP). The purpose of this Computer Program Configuration Item (CPCI) is to generate into the User Application process code to assemble tables and parameters needed by both the Distributed Request Supervisor and conceptual to external transformer to satisfy an NDML request. The following functions will be performed by the CPCI: (1) Generate working storage for external schema variables to hold the ES results in the user specified structure or variable, and temporary conceptual schema variables necessary for the transformation; (2) Generate working storage variables to hold the precompile tables namely the Join Query Graph, Attribute Pair List, results table and conceptual schema Action List to satisfy the NDML request; (3) Generate Working Storage and Procedure Division statements for domain and assertion checks; and (4) Generate Procedure Division statements to call the DRS, return with the results and call the conceptual to external transformer and move the ES results into the user variables or structure., See also Volume 5, Part 23, ADA250460.

This specification establishes the design of a number of software modules necessary for the precompiler that were not addressed in any of the NDML Precompiler Development Specification. They can be referred to as PRE0, NDML control Modules, to be built and formally accepted by the ICAM Program Office. This CI constitutes one of the subsystems of the Common Data Model Processor (CDMP)., See also Volume 5, Part 12, ADA250452.

This specification establishes the design of Function PRE2, Parse Procedure Division, one of the major functions of the configuration Item Precompiler to be built and formally accepted by the ICAM Program office. This CI constitutes one of the subsystems of the Common Data Model Processor (CDMP). The purpose of this Computer Program Configuration Item (CPCI) is to identify all Neutral Data Manipulation Language (NDML or SQL) commands contained within the Application Program and for each command, insure all other Precompiler activities are performed., See also Volume 5, Part 13, ADA250453.

This document establishes the design of Function PRE8, Transform CS/ES, one of the major functions of the Configuration item Precompiler to be built and formally accepted by the ICAM program office.

This specification establishes the design of the 'Aggregator Functions' one of the major functions of the Configuration Item 'Common Data Model Processor (CDMP)' to be built and formally accepted by the ICAM Program Office. This CI constitutes one of the subsystems of the Common Data Model Processor (CDM). The purpose of this Computer Program Configuration Item (CPCI) is to aggregate the query output files and produce the result file of the aggregation., See also Volume 5, Part 30, AD-A250 464.

This document establishes the design of Function PRE1, Parcel Application Program , one of the major functions of the Configuration Item Precompiler to be built and formally accepted by the ICAM program office., See also Volume 5, Part 12, AD-A250 452.

This document establishes the design of Function PRE6, "Select IS Access Path" one of the major functions of the Configuration Item "Precompiler" to be built and formally accepted by the ICAM program office., See also Volume 5, Part 17, AD-A250 456.

This document establishes the design of the File Utilities Function, one of the major functions of the Configuration Item Precompiler to be built and formally accepted by the ICAM program office., See also Volume 5, Part 32, AD-A250 466.

This document establishes the design of Function PRE9.4, "Generate TOTAL Request Processor" one of the major functions of the Configuration Item (CI) Precompiler to be built and formally accepted by the ICAM program office., See also Volume 5, Part 22, AD-A250 459.