Low noise buffer amplifiers and buffered phase comparators for precise time and frequency measurement and distribution

Extremely low noise, high performance, wideband buffer amplifiers and buffered phase comparators were developed. These buffer amplifiers are designed to distribute reference frequencies from 30 KHz to 45 MHz from a hydrogen maser without degrading the hydrogen maser's performance. The buffered phase comparators are designed to intercompare the phase of state of the art hydrogen masers without adding any significant measurement system noise. These devices have a 27 femtosecond phase stability floor and are stable to better than one picosecond for long periods of time. Their temperature coefficient is less than one picosecond per degree C, and they have shown virtually no voltage coefficients

A systematic review of moral reasons on orphan drug reimbursement

The number of market approvals of orphan medicinal products (OMPs) has been increasing steadily in the last 3 decades. While OMPs can offer a unique chance for patients suffering from rare diseases, they are usually very expensive. The growing number of approved OMPs increases their budget impact despite their low prevalence, making it pressing to find solutions to ethical challenges on how to fairly allocate scarce healthcare resources under this context. One potential solution could be to grant OMPs special status when considering them for reimbursement, meaning that they are subject to different, and less stringent criteria than other drugs. This study aims to provide a systematic analysis of moral reasons for and against such a special status for the reimbursement of OMPs in publicly funded healthcare systems from a multidisciplinary perspective.; With a systematic review of reasons, we identified 39 reasons represented in 243 articles (scientific and grey literature) for and against special status for the reimbursement of OMPs, then categorized them into nine topics. Taking a multidisciplinary perspective, we found that most articles came from health policy (n = 103) and health economics (n = 49). More articles took the position for a special status of OMPs (n = 97) than those against it (n = 31) and there was a larger number of reasons identified in favour (29 reasons) than against (10 reasons) this special status.; Results suggest that OMP reimbursement issues should be assessed and analysed from a multidisciplinary perspective. Despite the higher occurrence of reasons and articles in favour of a special status, there is no clear-cut solution for this ethical challenge. The binary perspective of whether or not OMPs should be granted special status oversimplifies the issue: both OMPs and rare diseases are too heterogeneous in their characteristics for such a binary perspective. Thus, the scientific debate should focus less on the question of disease prevalence but rather on how the important variability of different OMPs concerning e.g. target population, cost-effectiveness, level of evidence or mechanism of action could be meaningfully addressed and implemented in Health Technology Assessments

Sensitivity of age of air trends to the derivation method for non-linear increasing inert SF6

Mean age of air (AoA) is a diagnostic of transport along the stratospheric Brewer–Dobson circulation. While models consistently show negative trends, long-term time series (1975–2016) of AoA derived from observations show non-significant positive trends in mean AoA in the Northern Hemisphere. This discrepancy between observed and modelled mean AoA trends is still not resolved. There are uncertainties and assumptions required when deriving AoA from trace gas observations. At the same time, AoA from climate models is subject to uncertainties, too. In this paper, we focus on the uncertainties due to the parameter selection in the method that is used to derive mean AoA from SF$_{6}$ measurements in Engel et al. (2009, 2017). To correct for the non-linear increase in SF$_{6}$ concentrations, a quadratic fit to the time series at the reference location, i.e. the tropical surface, is used. For this derivation, the width of the AoA distribution (age spectrum) has to be assumed. In addition, to choose the number of years the quadratic fit is performed for, the fraction of the age spectrum to be considered has to be assumed. Even though the uncertainty range due to all different aspects has already been taken into account for the total errors in the AoA values, the systematic influence of the parameter selection on AoA trends is described for the first time in the present study. For this, we use the EMAC (ECHAM MESSy Atmospheric Chemistry) climate model as a test bed, where AoA derived from a linear tracer is available as a reference and modelled age spectra exist to diagnose the actual spatial age spectra widths. The comparison of mean AoA from the linear tracer with mean AoA from a SF$_{6}$ tracer shows systematic deviations specifically in the trends due to the selection of the parameters. However, for an appropriate parameter selection, good agreement for both mean AoA and its trend can be found, with deviations of about 1 % in mean AoA and 12 % in AoA trend. In addition, a method to derive mean AoA is evaluated that applies a convolution to the reference time series. The resulting mean AoA and its trend only depend on an assumption about the ratio of moments. Also in that case, it is found that the larger the ratio of moments, the more the AoA trend gravitates towards the negative. The linear tracer and SF$_{6}$ AoA are found to agree within 0.3 % in the mean and 6 % in the trend. The different methods and parameter selections were then applied to the balloon-borne SF$_{6}$ and CO$_{2}$ observations. We found the same systematic changes in mean AoA trend dependent on the specific selection. When applying a parameter choice that is suggested by the model results, the AoA trend is reduced from 0.15 to 0.07 years per decade. It illustrates that correctly constraining those parameters is crucial for correct mean AoA and trend estimates and still remains a challenge in the real atmosphere

Increased bacterial growth efficiency with environmental variability: results from DOC degradation by bacteria in pure culture experiments.

This paper assesses how considering variation in DOC availability and cell maintenance in bacterial models affects Bacterial Growth Efficiency (BGE) estimations. For this purpose, we conducted two biodegradation experiments simultaneously. In experiment one, a given amount of substrate was added to the culture at the start of the experiment whilst in experiment two, the same amount of substrate was added, but using periodic pulses over the time course of the experiment. Three bacterial models, with different levels of complexity, (the Monod, Marr-Pirt and the dynamic energy budget – DEB – models), were used and calibrated using the above experiments. BGE has been estimated using the experimental values obtained from discrete samples and from model generated data. Cell maintenance was derived experimentally, from respiration rate measurements. The results showed that the Monod model did not reproduce the experimental data accurately, whereas the Marr-Pirt and DEB models demonstrated a good level of reproducibility, probably because cell maintenance was built into their formula. Whatever estimation method was used, the BGE value was always higher in experiment two (the periodically pulsed substrate) as compared to the initially one-pulsed-substrate experiment. Moreover, BGE values estimated without considering cell maintenance (Monod model and empirical formula) were always smaller than BGE values obtained from models taking cell maintenance into account. Since BGE is commonly estimated using constant experimental systems and ignore maintenance, we conclude that these typical methods underestimate BGE values. On a larger scale, and for biogeochemical cycles, this would lead to the conclusion that, for a given DOC supply rate and a given DOC consumption rate, these BGE estimation methods overestimate the role of bacterioplankton as CO<sub>2</sub> producers

Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation : a tale of the unexpected

ObjectiveTo assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state.MethodsWe studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals.ResultsThe index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.ConclusionWe report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms

Science fiction and human enhancement: radical life-extension in the movie ‘In Time’ (2011)

The ethics of human enhancement has been a hotly debated topic in the last 15 years. In this debate, some advocate examining science fiction stories to elucidate the ethical issues regarding the current phenomenon of human enhancement. Stories from science fiction seem well suited to analyze biomedical advances, providing some possible case studies. Of particular interest is the work of screenwriter Andrew Niccol (Gattaca, S1m0ne, In Time, and Good Kill), which often focuses on ethical questions raised by the use of new technologies. Examining the movie In Time (2011), the aim of this paper is to show how science fiction can contribute to the ethical debate of human enhancement. In Time provides an interesting case study to explore what could be some of the consequences of radical life-extension technologies. In this paper, we will show how arguments regarding radical life-extension portrayed in this particular movie differ from what is found in the scientific literature. We will see how In Time gives flesh to arguments defending or rejecting radical life-extension. It articulates feelings of unease, alienation and boredom associated with this possibility. Finally, this article will conclude that science fiction movies in general, and In Time in particular, are a valuable resource for a broad and comprehensive debate about our coming future

Size-resolved aerosol emission factors and new particle formation/growth activity occurring in Mexico City during the MILAGRO 2006 Campaign

Measurements of the aerosol size distribution from 11 nm to 2.5 microns were made in Mexico City in March 2006, during the MILAGRO (Megacity Initiative: Local and Global Research Observations) field campaign. Observations at the urban supersite, referred to as T0, could often be characterized by morning conditions with high particle mass concentrations, low mixing heights, and highly correlated particle number and CO<sub>2</sub> concentrations, indicative that particle number is controlled by primary emissions. Average size-resolved and total number- and volume-based emission factors for combustion sources impacting T0 have been determined using a comparison of peak sizes in particle number and CO<sub>2</sub> concentration. Peaks are determined by subtracting the measured concentration from a calculated baseline concentration time series. The number emission and volume emission factors for particles from 11 nm to 494 nm are 1.56 × 10<sup>15</sup> particles, and 9.48 × 10<sup>11</sup> cubic microns per kg of carbon, respectively. The uncertainty of the number emission factor is approximately plus or minus 50 %. The mode of the number emission factor was between 25 and 32 nm, while the mode of the volume factor was between 0.25 and 0.32 microns. These emission factors are reported as log normal model parameters and are compared with multiple emission factors from the literature. In Mexico City in the afternoon, the CO<sub>2</sub> concentration drops during ventilation of the polluted layer, and the coupling between CO<sub>2</sub> and particle number breaks down, especially during new particle formation events when particle number is no longer controlled by primary emissions. Using measurements of particle number and CO<sub>2</sub> taken aboard the NASA DC-8, the determined primary emission factor was applied to the Mexico City Metropolitan Area (MCMA) plume to quantify the degree of secondary particle formation in the plume; the primary emission factor accounts for less than 50 % of the total particle number and the surplus particle count is not correlated with photochemical age. Primary particle volume and number in the size range 0.1–2 μm are similarly too low to explain the observed volume distribution. Contrary to the case for number, the apparent secondary volume increases with photochemical age. The size distribution of the apparent increase, with a mode at ~250 nm, is reported

The Dictyostelium genome encodes numerous RasGEFs with multiple biological roles

BACKGROUND: Dictyostelium discoideum is a eukaryote with a simple lifestyle and a relatively small genome whose sequence has been fully determined. It is widely used for studies on cell signaling, movement and multicellular development. Ras guanine-nucleotide exchange factors (RasGEFs) are the proteins that activate Ras and thus lie near the top of many signaling pathways. They are particularly important for signaling in development and chemotaxis in many organisms, including Dictyostelium. RESULTS: We have searched the genome for sequences encoding RasGEFs. Despite its relative simplicity, we find that the Dictyostelium genome encodes at least 25 RasGEFs, with a few other genes encoding only parts of the RasGEF consensus domains. All appear to be expressed at some point in development. The 25 genes include a wide variety of domain structures, most of which have not been seen in other organisms. The LisH domain, which is associated with microtubule binding, is seen particularly frequently; other domains that confer interactions with the cytoskeleton are also common. Disruption of a sample of the novel genes reveals that many have clear phenotypes, including altered morphology and defects in chemotaxis, slug phototaxis and thermotaxis. CONCLUSION: These results suggest that the unexpectedly large number of RasGEF genes reflects an evolutionary expansion of the range of Ras signaling rather than functional redundancy or the presence of multiple pseudogenes

Tube Models for Rubber-Elastic Systems

In the first part of the paper we show that the constraining potentials introduced to mimic entanglement effects in Edwards' tube model and Flory's constrained junction model are diagonal in the generalized Rouse modes of the corresponding phantom network. As a consequence, both models can formally be solved exactly for arbitrary connectivity using the recently introduced constrained mode model. In the second part, we solve a double tube model for the confinement of long paths in polymer networks which is partially due to crosslinking and partially due to entanglements. Our model describes a non-trivial crossover between the Warner-Edwards and the Heinrich-Straube tube models. We present results for the macroscopic elastic properties as well as for the microscopic deformations including structure factors.Comment: 15 pages, 8 figures, Macromolecules in pres

A reassessment of the discrepancies in the annual variation of δD-H₂O in the tropical lower stratosphere between the MIPAS and ACE-FTS satellite data sets

The annual variation of δD in the tropical lower stratosphere is a critical indicator for the relative importance of different processes contributing to the transport of water vapour through the cold tropical tropopause region into the stratosphere. Distinct observational discrepancies of the δD annual variation were visible in the works of Steinwagner et al. (2010) and Randel et al. (2012). Steinwagner et al. (2010) analysed MIPAS (Michelson Interferometer for Passive Atmospheric Sounding) observations retrieved with the IMK/IAA (Institut für Meteorologie und Klimaforschung in Karlsruhe, Germany, in collaboration with the Instituto de Astrofísica de Andalucía in Granada, Spain) processor, while Randel et al. (2012) focused on ACE-FTS (Atmospheric Chemistry Experiment Fourier Transform Spectrometer) observations. Here we reassess the discrepancies based on newer MIPAS (IMK/IAA) and ACE-FTS data sets, also showing for completeness results from SMR (Sub-Millimetre Radiometer) observations and a ECHAM/MESSy (European Centre for Medium-Range Weather Forecasts Hamburg and Modular Earth Submodel System) Atmospheric Chemistry (EMAC) simulation (Eichinger et al., 2015b). Similar to the old analyses, the MIPAS data set yields a pronounced annual variation (maximum about 75 ‰), while that derived from the ACE-FTS data set is rather weak (maximum about 25 ‰). While all data sets exhibit the phase progression typical for the tape recorder, the annual maximum in the ACE-FTS data set precedes that in the MIPAS data set by 2 to 3 months. We critically consider several possible reasons for the observed discrepancies, focusing primarily on the MIPAS data set. We show that the δD annual variation in the MIPAS data up to an altitude of 40 hPa is substantially impacted by a “start altitude effect”, i.e. dependency between the lowermost altitude where MIPAS retrievals are possible and retrieved data at higher altitudes. In itself this effect does not explain the differences with the ACE-FTS data. In addition, there is a mismatch in the vertical resolution of the MIPAS HDO and H2O data (being consistently better for HDO), which actually results in an artificial tape-recorder-like signal in δD. Considering these MIPAS characteristics largely removes any discrepancies between the MIPAS and ACE-FTS data sets and shows that the MIPAS data are consistent with a δD tape recorder signal with an amplitude of about 25 ‰ in the lowermost stratosphere