Urban Air Mobility Airspace Integration Concepts and Considerations

Urban Air Mobility (UAM) - defined as safe and efficient air traffic operations in a metropolitan area for manned aircraft and unmanned aircraft systems - is being researched and developed by industry, academia, and government. Significant resources have been invested toward cultivating an ecosystem for Urban Air Mobility that includes manufacturers of electric vertical takeoff and landing aircraft, builders of takeoff and landing areas, and researchers of the airspace integration concepts, technologies, and procedures needed to conduct Urban Air Mobility operations safely and efficiently alongside other airspace users. This paper provides high-level descriptions of both emergent and early expanded operational concepts for Urban Air Mobility that NASA is developing. The scope of this work is defined in terms of missions, aircraft, airspace, and hazards. Past and current Urban Air Mobility operations are also reviewed, and the considerations for the data exchange architecture and communication, navigation, and surveillance requirements are also discussed. This paper will serve as a starting point to develop a framework for NASA's Urban Air Mobility airspace integration research and development efforts with partners and stakeholders that could include fast-time simulations, human-in-the-loop (HITL) simulations, and flight demonstrations

Radiative Decay Modes of the D0D^{0} Meson

Using data recorded by the CLEO-II detector at CESR we have searched for four radiative decay modes of the $D^0$ meson: $D^0\to\phi\gamma$, $D^0\to\omega\gamma$, $D^0\to\bar{K}^{*}\gamma$, and $D^0\to\rho^0\gamma$. We obtain 90% CL upper limits on the branching ratios of these modes of $1.9\times 10^{-4}$, $2.4\times 10^{-4}$, $7.6\times 10^{-4}$ and $2.4\times 10^{-4}$ respectively.Comment: 15 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment

During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch-activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus 'poising' function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b expression, these inputs act in a stage-specific manner, providing a multitiered mechanism for developmental gene regulation

Using matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling in order to predict clinical outcomes of patients with heart failure

Background Current risk prediction models in heart failure (HF) including clinical characteristics and biomarkers only have moderate predictive value. The aim of this study was to use matrix assisted laser desorption ionisation mass spectrometry (MALDI-MS) profiling to determine if a combination of peptides identified with MALDI-MS will better predict clinical outcomes of patients with HF. Methods A cohort of 100 patients with HF were recruited in the biomarker discovery phase (50 patients who died or had a HF hospital admission vs. 50 patients who did not have an event). The peptide extraction from plasma samples was performed using reversed phase C18. Then samples were analysed using MALDI-MS. A multiple peptide biomarker model was discovered that was able to predict clinical outcomes for patients with HF. Finally, this model was validated in an independent cohort with 100 patients with HF. Results After normalisation and alignment of all the processed spectra, a total of 11,389 peptides (m/z) were detected using MALDI-MS. A multiple biomarker model was developed from 14 plasma peptides that was able to predict clinical outcomes in HF patients with an area under the receiver operating characteristic curve (AUC) of 1.000 (p = 0.0005). This model was validated in an independent cohort with 100 HF patients that yielded an AUC of 0.817 (p = 0.0005) in the biomarker validation phase. Addition of this model to the BIOSTAT risk prediction model increased the predictive probability for clinical outcomes of HF from an AUC value of 0.643 to an AUC of 0.823 (p = 0.0021). Moreover, using the prediction model of fourteen peptides and the composite model of the multiple biomarker of fourteen peptides with the BIOSTAT risk prediction model achieved a better predictive probability of time-to-event in prediction of clinical events in patients with HF (p = 0.0005). Conclusions The results obtained in this study suggest that a cluster of plasma peptides using MALDI-MS can reliably predict clinical outcomes in HF that may help enable precision medicine in HF

Subtype-specific CpG island shore methylation and mutation patterns in 30 breast cancer cell lines

BACKGROUND: Aberrant epigenetic modifications, including DNA methylation, are key regulators of gene activity in tumorigenesis. Breast cancer is a heterogeneous disease, and large-scale analyses indicate that tumor from normal and benign tissues, as well as molecular subtypes of breast cancer, can be distinguished based on their distinct genomic, transcriptomic, and epigenomic profiles. In this study, we used affinity-based methylation sequencing data in 30 breast cancer cell lines representing functionally distinct cancer subtypes to investigate methylation and mutation patterns at the whole genome level. RESULTS: Our analysis revealed significant differences in CpG island (CpGI) shore methylation and mutation patterns among breast cancer subtypes. In particular, the basal-like B type, a highly aggressive form of the disease, displayed distinct CpGI shore hypomethylation patterns that were significantly associated with downstream gene regulation. We determined that mutation rates at CpG sites were highly correlated with DNA methylation status and observed distinct mutation rates among the breast cancer subtypes. These findings were validated by using targeted bisulfite sequencing of differentially expressed genes (n=85) among the cell lines. CONCLUSIONS: Our results suggest that alterations in DNA methylation play critical roles in gene regulatory process as well as cytosine substitution rates at CpG sites in molecular subtypes of breast cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-016-0356-2) contains supplementary material, which is available to authorized users

Rapid semi-automated quantitative multiplex tandem PCR (MT-PCR) assays for the differential diagnosis of influenza-like illness

<p>Abstract</p> <p>Background</p> <p>Influenza A, including avian influenza, is a major public health threat in developed and developing countries. Rapid and accurate detection is a key component of strategies to contain spread of infection, and the efficient diagnosis of influenza-like-illness is essential to protect health infrastructure in the event of a major influenza outbreak.</p> <p>Methods</p> <p>We developed a multiplexed PCR (MT-PCR) assay for the simultaneous diagnosis of respiratory viruses causing influenza-like illness, including the specific recognition of influenza A haemagglutinin subtypes H1, H3, and H5. We tested several hundred clinical specimens in two diagnostic reference laboratories and compared the results with standard techniques.</p> <p>Results</p> <p>The sensitivity and specificity of these assays was higher than individual assays based on direct antigen detection and standard PCR against a range of control templates and in several hundred clinical specimens. The MT-PCR assays provided differential diagnoses as well as potentially useful quantitation of virus in clinical samples.</p> <p>Conclusions</p> <p>MT-PCR is a potentially powerful tool for the differential diagnosis of influenza-like illness in the clinical diagnostic laboratory.</p

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Asynchronous combinatorial action of four regulatory factors activates Bcl11b for T cell commitment

During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch-activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus 'poising' function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b expression, these inputs act in a stage-specific manner, providing a multitiered mechanism for developmental gene regulation

Dietary iron intake in the first 4 months of infancy and the development of type 1 diabetes: a pilot study

<p>Abstract</p> <p>Aims</p> <p>To investigate the impact of iron intake on the development of type 1 diabetes (T1DM).</p> <p>Methods</p> <p>Case-control study with self-administered questionnaire among families of children with T1DM who were less than 10 years old at the time of the survey and developed diabetes between age 1 and 6 years. Data on the types of infant feeding in the first 4 months of life was collected from parents of children with T1DM (n = 128) and controls (n = 67) <10 years old. Because some cases had sibling controls, we used conditional logistic regression models to analyze the data in two ways. First we performed a case-control analysis of all 128 cases and 67 controls. Next, we performed a case-control analysis restricted to cases (n = 59) that had a sibling without diabetes (n = 59). Total iron intake was modeled as one standard deviation (SD) increase in iron intake. The SD for iron intake was 540 mg in the total sample and 539 mg in the restricted sample as defined above.</p> <p>Results</p> <p>The median (min, max) total iron intake in the first 4 months of life was 1159 (50, 2399) mg in T1DM cases and 466 (50, 1224) mg among controls (<it>P </it>< 0.001). For each one standard deviation increase in iron intake, the odds ratio (95% confidence interval) for type 1 diabetes was 2.01 (1.183, 3.41) among all participants (128 cases and 67 controls) while it was 2.26 (1.27, 4.03) in a restricted sample of T1 D cases with a control sibling (59 cases and 59 controls) in models adjusted for birth weight, age at the time of the survey, and birth order.</p> <p>Conclusion</p> <p>In this pilot study, high iron intake in the first 4 months of infancy is associated with T1DM. Whether iron intake is causal or a marker of another risk factor warrants further investigation.</p

Malarial Hemozoin Activates the NLRP3 Inflammasome through Lyn and Syk Kinases

The intraerythrocytic parasite Plasmodium—the causative agent of malaria—produces an inorganic crystal called hemozoin (Hz) during the heme detoxification process, which is released into the circulation during erythrocyte lysis. Hz is rapidly ingested by phagocytes and induces the production of several pro-inflammatory mediators such as interleukin-1β (IL-1β). However, the mechanism regulating Hz recognition and IL-1β maturation has not been identified. Here, we show that Hz induces IL-1β production. Using knockout mice, we showed that Hz-induced IL-1β and inflammation are dependent on NOD-like receptor containing pyrin domain 3 (NLRP3), ASC and caspase-1, but not NLRC4 (NLR containing CARD domain). Furthermore, the absence of NLRP3 or IL-1β augmented survival to malaria caused by P. chabaudi adami DS. Although much has been discovered regarding the NLRP3 inflammasome induction, the mechanism whereby this intracellular multimolecular complex is activated remains unclear. We further demonstrate, using pharmacological and genetic intervention, that the tyrosine kinases Syk and Lyn play a critical role in activation of this inflammasome. These findings not only identify one way by which the immune system is alerted to malarial infection but also are one of the first to suggest a role for tyrosine kinase signaling pathways in regulation of the NLRP3 inflammasome