Human mutations often cause amino acid changes (variants) that can alter protein function or stability. Some variants fall at protein positions that experimentally exhibit "rheostatic" mutation outcomes (different amino acid substitutions lead to a range of functional outcomes). In ongoing studies of rheostat positions, we encountered the need to aggregate experimental results from multiple variants, to describe the overall roles of individual positions. Here, we present "RheoScale" which generates quantitative scores to discriminate rheostat positions from those with "toggle" (most substitutions abolish function) or "neutral" (most substitutions have wild-type function) outcomes. RheoScale scores facilitate correlations of experimental data (such as binding affinity or stability) with structural and bioinformatic analyses. The RheoScale calculator is encoded into a Microsoft Excel workbook and an R script. Example analyses are shown for three model protein systems, including one assessed via deep mutational scanning. The RheoScale calculator quickly and efficiently provided quantitative descriptions that were in good agreement with prior qualitative observations. As an example application, scores were compared to the example proteins' structures; strong rheostat positions tended to occur in dynamic locations. In the future, RheoScale scores can be easily integrated into computational studies to facilitate improved algorithms for predicting outcomes of human variants.

Recent Fe results have suggested that the estimated distances of supernovae in the last few million years should be reduced from ∼100 to ∼50 pc. Two events or series of events are suggested, one about 2.7 million years to 1.7 million years ago, and another about 6.5-8.7 million years ago. We ask what effects such supernovae are expected to have on the terrestrial atmosphere and biota. Assuming that the Local Bubble was formed before the event being considered, and that the supernova and the Earth were both inside a weak, disordered magnetic field at that time, TeV-PeV cosmic rays (CRs) at Earth will increase by a factor of a few hundred. Tropospheric ionization will increase proportionately, and the overall muon radiation load on terrestrial organisms will increase by a factor of ∼150. All return to pre-burst levels within 10 kyr. In the case of an ordered magnetic field, effects depend strongly on the field orientation. The upper bound in this case is with a largely coherent field aligned along the line of sight to the supernova, in which case, TeV-PeV CR flux increases are ∼10; in the case of a transverse field they are below current levels. We suggest a substantial increase in the extended effects of supernovae on Earth and in the "lethal distance" estimate; though more work is needed. This paper is an explicit follow-up to Thomas et al. We also provide more detail on the computational procedures used in both works.

Recent results have strongly confirmed that multiple supernovae happened at distances of ∼100 pc, consisting of two main events: one at 1.7-3.2 million years ago, and the other at 6.5-8.7 million years ago. These events are said to be responsible for excavating the Local Bubble in the interstellar medium and depositing Fe on Earth and the Moon. Other events are indicated by effects in the local cosmic ray (CR) spectrum. Given this updated and refined picture, we ask whether such supernovae are expected to have had substantial effects on the terrestrial atmosphere and biota. In a first look at the most probable cases, combining photon and CR effects, we find that a supernova at 100 pc can have only a small effect on terrestrial organisms from visible light and that chemical changes such as ozone depletion are weak. However, tropospheric ionization right down to the ground, due to the penetration of ⩾TeV CRs, will increase by nearly an order of magnitude for thousands of years, and irradiation by muons on the ground and in the upper ocean will increase twentyfold, which will approximately triple the overall radiation load on terrestrial organisms. Such irradiation has been linked to possible changes in climate and increased cancer and mutation rates. This may be related to a minor mass extinction around the Pliocene-Pleistocene boundary, and further research on the effects is needed.

Local recurrence represents a significant challenge in the management of patients with glioblastoma multiforme. Salvage treatment options are limited by lack of clinical efficacy. Recent studies have demonstrated a significant response rate and acceptable toxicity with the use of fractionated stereotactic radiosurgery in this patient population. Our primary objective was to determine the efficacy and toxicity of fractionated stereotactic radiosurgery combined with concurrent temozolomide chemotherapy as a salvage treatment for recurrent glioblastoma multiforme. We prospectively collected treatment and outcome data for patients having fractionated stereotactic radiosurgery for locally recurrent glioblastoma multiforme after radical radiotherapy. Eligible patients had a maximum recurrence diameter of 60 mm without causing significant mass effect. The gross tumor volume was defined as the enhancing lesion on an enhanced fine-slice T1 (spin–lattice) magnetic resonance imaging, and a circumferential setup margin of 1 mm was used to define the planning target volume. All patients were treated using robotic radiosurgery with three dose/fractionation schedules ranging from 25 to 35 Gy in five fractions, depending on the maximum tumor diameter. Concurrent temozolomide 75 mg/m2 was prescribed to all patients. Tumor response was judged using the Macdonald criteria, and toxicity was assessed using the CTCAE (Common Terminology Criteria for Adverse Events). A total of 31 patients were enrolled in this study. The median overall survival was 9 months, and progression-free survival was 7 months. The 6-month progression-free survival was 60% with a 95% confidence interval of 43%–77%. The a priori stratification factor of small tumor diameter was shown to predict overall survival, while time to recurrence was not predictive of progression-free or overall survival. Three patients experienced grade 3 acute toxicity that responded to increased steroid dosing. One patient experienced a grade 4 acute toxicity that did not respond to increased steroids but did respond to anti-angiogenic therapy. Fractionated stereotactic radiosurgery with concurrent temozolomide has shown good short-term clinical and radiologic control with manageable acute toxicity. This regimen appears to provide superior efficacy to either temozolomide or fractionated radiosurgery alone. The results of this study support the continued evaluation of this regimen.

Recent 60 Fe results have suggested that the estimated distances of supernovae in the last few million years should be reduced from ~100 pc to ~50 pc. Two events or series of events are suggested, one about 2.7 million years to 1.7 million years ago, and another may at 6.5 to 8.7 million years ago. We ask what effects such supernovae are expected to have on the terrestrial atmosphere and biota. Assuming that the Local Bubble was formed before the event being considered, and that the supernova and the Earth were both inside a weak, disordered magnetic field at that time, TeV-PeV cosmic rays at Earth will increase by a factor of a few hundred. Tropospheric ionization will increase proportionately, and the overall muon radiation load on terrestrial organisms will increase by a factor of ~150. All return to pre-burst levels within 10kyr. In the case of an ordered magnetic field, effects depend strongly on the field orientation. The upper . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx

We re-examine past suggestions of a close link between terrestrial climate change and the Sun's transit of spiral arms in its path through the Milky Way galaxy. These links produced concrete fits, deriving the unknown spiral pattern speed from terrestrial climate correlations. We test these fits against new data on spiral structure based on CO data that does not make simplifying assumptions about symmetry and circular rotation. If we compare the times of these transits to changes in the climate of Earth, not only do the claimed correlations disappear, but also we find that they cannot be resurrected for any reasonable pattern speed.

[1] Neutrons contribute a significant radiation dose at commercial passenger airplane altitudes. With cosmic ray energies > 1 GeV, these effects could, in principle, be propagated to ground level. Under current conditions, the cosmic ray spectrum incident on the Earth is dominated by particles with energies < 1 GeV. Astrophysical shocks from events such as supernovae accelerate high-energy cosmic rays (HECRs) well above this range. The Earth is likely episodically exposed to a greatly increased HECR flux from such events. Solar events of smaller energies are much more common and short lived but still remain a topic of interest due to the ground level enhancements they produce. The air showers produced by cosmic rays (CRs) ionize the atmosphere and produce harmful secondary particles such as muons and neutrons. Although the secondary spectra from current day terrestrial cosmic ray flux are well known, this is not true for spectra produced by many astrophysical events. This work shows the results of Monte Carlo simulations quantifying the neutron flux due to CRs at various primary energies and altitudes. We provide here look-up tables that can be used to determine neutron fluxes from proton primaries with kinetic energies of 1 MeV-1 PeV. By convolution, one can compute the neutron flux for any arbitrary CR spectrum. This contrasts with all other similar works, which are spectrum dependent. Our results demonstrate the difficulty in deducing the nature of primaries from the spectrum of ground level neutron enhancements.

We explore the idea that detectable excursions in 26 Al may arise from direct deposition by any bolide, and excursions in 14 C and 10 Be abundances in the atmosphere may result from long-period comet impacts. This is very different from the usual processes of production by cosmic rays within Earth's atmosphere. Long-period comets experience greatly increased cosmic ray flux beyond the protection of the sun's magnetic field. We report the computed amount of 14 C, 10 Be, and 26 Al present on long-period comets as a function of comet mass. We find that the amount of nuclide mass on large long-period comets entering the Earth's atmosphere may be sufficient for creating anomalies in the records of 14 C and 10 Be from past impacts. In particular, the estimated mass of the proposed Younger Dryas comet is consistent with its having deposited sufficient isotopes to account for recorded 14 C and 10