Mutation-Simulator: fine-grained simulation of random mutations in any genome.

SUMMARY: Mutation-Simulator allows the introduction of various types of sequence alterations in reference sequences, with reasonable compute-time even for large eukaryotic genomes. Its intuitive system for fine-grained control over mutation rates along the sequence enables the mimicking of natural mutation patterns. Using standard file formats for input and output data, it can easily be integrated into any development and benchmarking workflow for high-throughput sequencing applications. AVAILABILITY AND IMPLEMENTATION: Mutation-Simulator is written in Python 3 and the source code, documentation, help and use cases are available on the Github page at https://github.com/mkpython3/Mutation-Simulator. It is free for use under the GPL 3 license.

Ultracold neutron storage and transport at the PSI UCN source.

Efficient neutron transport is a key ingredient to the performance of ultracold neutron (UCN) sources, important to meeting the challenges placed by high precision fundamental physics experiments. At the Paul Scherrer Institute's UCN source we have been continuously improving our understanding of the UCN source parameters by performing a series of studies to characterize neutron production and moderation, and UCN production, extraction, and transport efficiency to the beamport. The present study on the absolute UCN transport efficiency completes our previous publications. We report on complementary measurements, namely one on the height-dependent UCN density and a second on the transmission of a calibrated quantity of UCN over a ∼ 16  m long UCN guide section connecting one beamport via the source storage vessel to another beamport. These allow us quantifying and optimizing the performance of the guide system based on extensive Monte Carlo simulations.

Data blinding for the nEDM experiment at PSI.

Psychological bias towards, or away from, prior measurements or theory predictions is an intrinsic threat to any data analysis. While various methods can be used to try to avoid such a bias, e.g. actively avoiding looking at the result, only data blinding is a traceable and trustworthy method that can circumvent the bias and convince a public audience that there is not even an accidental psychological bias. Data blinding is nowadays a standard practice in particle physics, but it is particularly difficult for experiments searching for the neutron electric dipole moment (nEDM), as several cross measurements, in particular of the magnetic field, create a self-consistent network into which it is hard to inject a false signal. We present an algorithm that modifies the data without influencing the experiment. Results of an automated analysis of the data are used to change the recorded spin state of a few neutrons within each measurement cycle. The flexible algorithm may be applied twice (or more) to the data, thus providing the option of sequentially applying various blinding offsets for separate analysis steps with independent teams. The subtle manner in which the data are modified allows one subsequently to adjust the algorithm and to produce a re-blinded data set without revealing the initial blinding offset. The method was designed for the 2015/2016 measurement campaign of the nEDM experiment at the Paul Scherrer Institute. However, it can be re-used with minor modification for the follow-up experiment n2EDM, and may be suitable for comparable projects elsewhere.

Highly stable atomic vector magnetometer based on free spin precession.

We present a magnetometer based on optically pumped Cs atoms that measures the magnitude and direction of a 1 µT magnetic field. Multiple circularly polarized laser beams were used to probe the free spin precession of the Cs atoms. The design was optimized for long-time stability and achieves a scalar resolution better than 300 fT for integration times ranging from 80 ms to 1000 s. The best scalar resolution of less than 80 fT was reached with integration times of 1.6 to 6 s. We were able to measure the magnetic field direction with a resolution better than 10 µrad for integration times from 10 s up to 2000 s.

Observation of Gravitationally Induced Vertical Striation of Polarized Ultracold Neutrons by Spin-Echo Spectroscopy.

We describe a spin-echo method for ultracold neutrons (UCNs) confined in a precession chamber and exposed to a |B0|=1 µT magnetic field. We have demonstrated that the analysis of UCN spin-echo resonance signals in combination with knowledge of the ambient magnetic field provides an excellent method by which to reconstruct the energy spectrum of a confined ensemble of neutrons. The method takes advantage of the relative dephasing of spins arising from a gravitationally induced striation of stored UCNs of different energies, and also permits an improved determination of the vertical magnetic-field gradient with an exceptional accuracy of 1.1 pT/cm. This novel combination of a well-known nuclear resonance method and gravitationally induced vertical striation is unique in the realm of nuclear and particle physics and should prove to be invaluable for the assessment of systematic effects in precision experiments such as searches for an electric dipole moment of the neutron or the measurement of the neutron lifetime.

Achieving ultra-low and -uniform residual magnetic fields in a very large magnetically shielded room for fundamental physics experiments.

High-precision searches for an electric dipole moment of the neutron (nEDM) require stable and uniform magnetic field environments. We present the recent achievements of degaussing and equilibrating the magnetically shielded room (MSR) for the n2EDM experiment at the Paul Scherrer Institute. We present the final degaussing configuration that will be used for n2EDM after numerous studies. The optimized procedure results in a residual magnetic field that has been reduced by a factor of two. The ultra-low field is achieved with the full magnetic-field-coil system, and a large vacuum vessel installed, both in the MSR. In the inner volume of ∼1.4m3, the field is now more uniform and below 300 pT. In addition, the procedure is faster and dissipates less heat into the magnetic environment, which in turn, reduces its thermal relaxation time from 12h down to 1.5h.

A large 'Active Magnetic Shield' for a high-precision experiment: nEDM collaboration.

We present a novel Active Magnetic Shield (AMS), designed and implemented for the n2EDM experiment at the Paul Scherrer Institute. The experiment will perform a high-sensitivity search for the electric dipole moment of the neutron. Magnetic-field stability and control is of key importance for n2EDM. A large, cubic, 5 m side length, magnetically shielded room (MSR) provides a passive, quasi-static shielding-factor of about 105 for its inner sensitive volume. The AMS consists of a system of eight complex, feedback-controlled compensation coils constructed on an irregular grid spanned on a volume of less than 1000 m3 around the MSR. The AMS is designed to provide a stable and uniform magnetic-field environment around the MSR, while being reasonably compact. The system can compensate static and variable magnetic fields up to ±50µT (homogeneous components) and ±5µT/m (first-order gradients), suppressing them to a few µT in the sub-Hertz frequency range. The presented design concept and implementation of the AMS fulfills the requirements of the n2EDM experiment and can be useful for other applications, where magnetically silent environments are important and spatial constraints inhibit simpler geometrical solutions.

The very large n2EDM magnetically shielded room with an exceptional performance for fundamental physics measurements.

We present the magnetically shielded room (MSR) for the n2EDM experiment at the Paul Scherrer Institute, which features an interior cubic volume with each side of length 2.92 m, thus providing an accessible space of 25 m3. The MSR has 87 openings of diameter up to 220 mm for operating the experimental apparatus inside and an intermediate space between the layers for housing sensitive signal processing electronics. The characterization measurements show a remanent magnetic field in the central 1 m3 below 100 pT and a field below 600 pT in the entire inner volume, up to 4 cm to the walls. The quasi-static shielding factor at 0.01 Hz measured with a sinusoidal 2 µT peak-to-peak signal is about 100 000 in all three spatial directions and increases rapidly with frequency to reach 108 above 1 Hz.

The design of the n2EDM experiment: nEDM Collaboration.

We present the design of a next-generation experiment, n2EDM, currently under construction at the ultracold neutron source at the Paul Scherrer Institute (PSI) with the aim of carrying out a high-precision search for an electric dipole moment of the neutron. The project builds on experience gained with the previous apparatus operated at PSI until 2017, and is expected to deliver an order of magnitude better sensitivity with provision for further substantial improvements. An overview is of the experimental method and setup is given, the sensitivity requirements for the apparatus are derived, and its technical design is described.

Crop wild relative populations of Beta vulgaris allow direct mapping of agronomically important genes.

Rapid identification of agronomically important genes is of pivotal interest for crop breeding. One source of such genes are crop wild relative (CWR) populations. Here we used a CWR population of <200 wild beets (B. vulgaris ssp. maritima), sampled in their natural habitat, to identify the sugar beet (Beta vulgaris ssp. vulgaris) resistance gene Rz2 with a modified version of mapping-by-sequencing (MBS). For that, we generated a draft genome sequence of the wild beet. Our results show the importance of preserving CWR in situ and demonstrate the great potential of CWR for rapid discovery of causal genes relevant for crop improvement. The candidate gene for Rz2 was identified by MBS and subsequently corroborated via RNA interference (RNAi). Rz2 encodes a CC-NB-LRR protein. Access to the DNA sequence of Rz2 opens the path to improvement of resistance towards rhizomania not only by marker-assisted breeding but also by genome editing.

MHV nucleocapsid synthesis in the presence of cycloheximide and accumulation of negative strand MHV RNA.

We have found that genomic RNA synthesis is inhibited by cycloheximide in cells infected with mouse hepatitis virus, strain A59 (MHV-A59), in agreement with previously published results (Sawicki, S.G. and Sawicki, D.L. (1986) J. Virol, 57, 328-334). In the present study, the fate of the residual genomic RNA synthesized in the presence of cycloheximide was determined. Nearly all of the genomic RNA synthesized in the presence of drug was incorporated into nucleocapsid structures, suggesting that even in the absence of protein synthesis, genomic RNA synthesis and encapsidation are coupled in MHV-infected cells. Sufficient free nucleocapsid N protein was available for this purpose, since the pool of soluble N protein was determined to decay with a half-life of approximately one hour. Negative strand RNA is the template for the synthesis of both genomic and subgenomic positive strand RNA, and would be predicted to accumulate primarily during the early phases of the lytic cycle. In agreement with this prediction, negative strand RNA accumulated during the first 5-6 h of infection, with little additional accumulation occurring over the next 2.5 h. In marked contrast, positive strand RNA increased 5-6-fold over the same 2.5 h period. These results, taken in conjunction with published data, suggest that negative strand RNA is synthesized during the early period of the infectious cycle and is stable in infected cells and also suggest that treatment with cycloheximide at late times does not inhibit positive strand RNA synthesis indirectly by blocking the formation of negative strand templates.

Maternal antibody-modulated MHV-JHM infection in C57BL/6 and BALB/c mice.

1. Maternal antibody protected C57BL/6 and BALB/c suckling mice from the acute, fatal encephalomyelitis caused by MHV-JHM. 2. 40% of the C57BL/6 mice and 25% of the BALB/c mice which were protected by maternal antibody developed neurological disease days to weeks later. Although the clinical syndromes developed by the two different strains were different, in both cases the mice developed a demyelinating encephalomyelitis with fewer inflammatory changes present in the grey matter. 3. Presence or absence of neutralizing antibody in the sera of maternal antibody-protected C57BL/6 mice did not correlate with the development of clinically evident neurological disease. 4. Infectious virus could only be isolated from C57BL/6 mice with neurological disease, although viral antigen could be detected in most mice whether symptomatic or not. 5. This model should be useful for the study of the viral and immune factors important in MHV-induced viral demyelination.

The peaked audiometric configuration in Meniere's disease: disease related?

A retrospective analysis of audiograms was completed for persons from 3 different patient groups. These 3 groups were (1) persons with unilateral Meniere's disease, (2) persons with unilateral acoustic tumor, and (3) persons from the general clinical population of an audiology clinic in a major medical center. As Paparella, McDermott, Luiz, and de Sousa (1982) also report, the most common audiometric configuration in the Meniere's disease group was peaked, a condition in which poorer hearing is reported in the low and high frequencies, and an island of better hearing sensitivity occurs at either 1.0 or 2.0 kHz. Some of the peaked audiograms from persons in our Meniere's disease group could be a result of a low-frequency hearing loss caused by Meniere's disease combined with a high-frequency hearing loss due to aging or other environmental factors. However, 27% (13/48) of the peaked audiograms in ears with Meniere's disease were found in persons with no hearing loss in the high frequencies of their nondiseased ear. Thus, the peaked audiometric configuration is associated with Meniere's disease, as suggested by research results from animals with experimentally induced endolymphatic hydrops. Peaked audiometric configurations were also observed in roughly 9% of the general clinical population and in 12.5% of ears of persons with acoustic tumors. A rule--based on the audiometric configurations that maximized identification of patients with Meniere's disease--using the general clinical population as a control did not fare as well when the tumor group was used as a control. This finding provides further evidence that peaked audiograms, although common to Meniere's disease, are not pathognomonic of this disease. Furthermore, these results indicate that the diagnosis of Meniere's disease from audiometric profiles is risky, at best.

[External humeral fixation in war injuries].

Type III open fractures of the humerus caused by high energy missiles or shrapnel in 26 male soldiers were treated by external fixation. 12 suffered from associated injuries involving the head and chest, 12 had 14 nerve injuries, and 4 required simultaneous repair of the brachial artery. Results in 19 examined after an average of 6.5 years were excellent in 22%, good in 52%, fair in 16%, and poor in 10%. The aim of external fixation is functional limb salvage. We think high-energy gunshot fractures should be classified as III-d because of the severe damage to the soft tissue, which differs from that of low-velocity, gunshot fractures or farm injuries. We conclude that external fixation is the preferred form of primary stabilization of severe open fractures of the humerus. It has reduced the incidence of chronic infection and has improved the prognosis of vascular repairs. The treatment of the soft tissues, skin coverage, and ultimately reconstructive surgery are facilitated. Early limb function allows for a better final result. For delayed union and pin-tract infection a different definitive method, such as internal fixation or a plaster case, is required.

Suffer the little children. Poverty's blight taints new life--and out country's future.

Socioeconomic patterns that compromise the ability of some to obtain adequate housing, education, resources, and healthcare are putting the health of our children, and the future of our nation, at risk. Our children and their health must become a national priority. A look at some major health indicators reveals an alarming picture of children's healthcare in this country. For instance, prenatal care is important to an uncomplicated pregnancy and delivery of a healthy baby. Since the late 1970s, however, no significant reduction has occurred in the percentage of pregnant women receiving only late care or no prenatal care at all. Child abuse is a significant health indicator, since it probably will result in physical disfigurement and disability, not to mention profound psychosocial disturbances. Despite increased recognition and reporting of child abuse, funds and services to treat the victims have not kept pace. Preventable injury in the home and on the road is one health indicator that has improved during the past 10 years, but injuries are still the leading cause of death among children under the age of one, and motor vehicle accidents are still the leading cause of death among children between the ages of 1 and 14. Many low-birthweight infants who once would have died are now surviving, primarily because of modern medical technology, but the cost of their care usually far exceeds the resources of most families.

Episodic crises: does dementia make a difference?

Preventing episodic crises in residents with and without dementia is possible when staff learns how to identify "signaling events": changes in behavior or life status, physiological symptoms, or other complaints.