Studies involving Monte Carlo simulations are common in both diagnostic and therapy medical physics research, as well as other fields of basic and applied science. As with all experimental studies, ...the conditions and parameters used for Monte Carlo simulations impact their scope, validity, limitations, and generalizability. Unfortunately, many published peer‐reviewed articles involving Monte Carlo simulations do not provide the level of detail needed for the reader to be able to properly assess the quality of the simulations. The American Association of Physicists in Medicine Task Group #268 developed guidelines to improve reporting of Monte Carlo studies in medical physics research. By following these guidelines, manuscripts submitted for peer‐review will include a level of relevant detail that will increase the transparency, the ability to reproduce results, and the overall scientific value of these studies. The guidelines include a checklist of the items that should be included in the Methods, Results, and Discussion sections of manuscripts submitted for peer‐review. These guidelines do not attempt to replace the journal reviewer, but rather to be a tool during the writing and review process. Given the varied nature of Monte Carlo studies, it is up to the authors and the reviewers to use this checklist appropriately, being conscious of how the different items apply to each particular scenario. It is envisioned that this list will be useful both for authors and for reviewers, to help ensure the adequate description of Monte Carlo studies in the medical physics literature.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Global Synthetic Aperture Radar (SAR) measurements made over the past decades provide insights into the lateral extent of magmatic domains, and capture volcanic process on scales useful for volcano ...monitoring. Satellite-based SAR imagery has great potential for monitoring topographic change, the distribution of eruptive products and surface displacements (InSAR) at subaerial volcanoes. However, there are challenges in applying it routinely, as would be required for the reliable operational assessment of hazard. The deformation detectable depends upon satellite repeat time and swath widths, relative to the spatial and temporal scales of volcanological processes. We describe the characteristics of InSAR-measured volcano deformation over the past two decades, highlighting both the technique’s capabilities and its limitations as a monitoring tool. To achieve this, we draw on two global datasets of volcano deformation: the Smithsonian Institution Volcanoes of the World database and the Centre for the Observation and Modelling of Earthquakes, Volcanoes and Tectonics volcano deformation catalogue, as well as compiling some measurement characteristics and interpretations from the primary literature.
We find that a higher proportion of InSAR observations capture non-eruptive and non-magmatic processes than those from ground-based instrument networks, and that both transient (< month) and long-duration (> 5 years) deformation episodes are under-represented. However, satellite radar is already used to assess the development of extended periods of unrest and long-lasting eruptions, and improved spatial resolution and coverage have resulted in the detection of previously unrecognised deformation at both ends of the spatial scale (~ 10 to > 1000 km
2
). ‘Baseline’ records of past InSAR measurements, including ‘null’ results, are fundamental for any future interpretation of interferograms in terms of hazard‚ both by providing information about past deformation at an individual volcano, and for assessing the characteristics of deformation that are likely to be detectable (and undetectable) using InSAR.
More than half of all InSAR deformation signals attributed to magmatic processes have sources in the shallow crust (< 5 km depth). While the depth distribution of InSAR-derived deformation sources is affected by measurement limitations, their lateral distribution provides information about the extent of active magmatic domains. Deformation is common (24% of all potentially magmatic events) at loci ≥5 km away from the nearest active volcanic vent. This demonstrates that laterally extensive active magmatic domains are not exceptional, but can comprise the shallowest part of trans-crustal magmatic systems in a range of volcanic settings.
The conformational ensembles of G protein-coupled receptors (GPCRs) include inactive and active states. Spectroscopy techniques, including NMR, show that agonists, antagonists and other ligands shift ...the ensemble toward specific states depending on the pharmacological efficacy of the ligand. How receptors recognize ligands and the kinetic mechanism underlying this population shift is poorly understood. Here, we investigate the kinetic mechanism of neurotensin recognition by neurotensin receptor 1 (NTS
) using
F-NMR, hydrogen-deuterium exchange mass spectrometry and stopped-flow fluorescence spectroscopy. Our results indicate slow-exchanging conformational heterogeneity on the extracellular surface of ligand-bound NTS
. Numerical analysis of the kinetic data of neurotensin binding to NTS
shows that ligand recognition follows an induced-fit mechanism, in which conformational changes occur after neurotensin binding. This approach is applicable to other GPCRs to provide insight into the kinetic regulation of ligand recognition by GPCRs.
Topiramate (TPM), a broad-spectrum antiepileptic drug, has been associated with neuropsychological impairment in patients with epilepsy and in healthy volunteers.
To establish whether TPM-induced ...neuropsychological impairment emerges in a dose-dependent fashion and whether early cognitive response (6-week) predicts later performance (24-week).
Computerized neuropsychological assessment was performed on 188 cognitively normal adults who completed a double-blind, placebo-controlled, parallel-group, 24-week, dose-ranging study which was designed primarily to assess TPM effects on weight. Target doses were 64, 96, 192, or 384 mg per day. The Computerized Neuropsychological Test Battery was administered at baseline and 6, 12, and 24 weeks. Individual cognitive change was established using reliable change index (RCI) analysis.
Neuropsychological effects emerged in a dose-dependent fashion in group analyses (p < 0.0001). RCI analyses showed a dose-related effect that emerged only at the higher dosing, with 12% (64 mg), 8% (96 mg), 15% (192 mg), and 35% (384 mg) of subjects demonstrating neuropsychological decline relative to 5% declining in the placebo group. Neuropsychological change assessed at 6 weeks significantly predicted individual RCI outcome at 24 weeks.
Neuropsychological impairment associated with TPM emerges in a dose-dependent fashion. Subjects more likely to demonstrate cognitive impairment after 24 weeks of treatment can be identified early on during treatment (i.e., within 6 weeks). RCI analysis provides a valuable approach to quantify individual neuropsychological risk.
INTRODUCTIONTraining with low-carbohydrate (CHO) availability enhances markers of aerobic adaptation and has become popular to periodize throughout an endurance-training program. However, ...exercise-induced amino acid oxidation is increased with low muscle glycogen, which may limit substrate availability for postexercise protein synthesis. We aimed to determine the impact of training with low-CHO availability on estimates of dietary protein requirements.
METHODSEight endurance-trained males (27 ± 4 yr, 75 ± 10 kg, 67 ± 10 mL·kg body mass·min) completed two trials matched for energy and macronutrient composition but with differing CHO periodization. In the low-CHO availability trial (LOW), participants consumed 7.8 g CHO·kg before evening high-intensity interval training (10 × 5 min at 10-km race pace, 1 min rest) and subsequently withheld CHO postexercise (0.2 g·kg). In the high-CHO availability trial (HIGH), participants consumed 3 g CHO·kg during the day before high-intensity interval training, and consumed 5 g CHO·kg that evening to promote muscle glycogen resynthesis. A 10-km run (~80% HRmax) was performed the following morning, fasted (LOW) or 1 h after consuming 1.2 g CHO·kg (HIGH). Whole-body phenylalanine flux and oxidation were determined over 8 h of recovery via oral Cphenylalanine ingestion, according to standard indicator amino acid oxidation methodology, while consuming sufficient energy, 7.8 g CHO·kg·d, and suboptimal protein (0.93 g·kg·d).
RESULTSFat oxidation (indirect calorimetry) during the 10-km run was higher in LOW compared with HIGH (0.99 ± 0.35 g·min vs 0.60 ± 0.26 g·min, P < 0.05). phenylalanine flux during recovery was not different between trials (P > 0.05) whereas phenylalanine oxidation (reciprocal of protein synthesis) was higher in LOW compared with HIGH (8.8 ± 2.7 μmol·kg·h vs 7.9 ± 2.4 μmol·kg·h, P < 0.05), suggesting a greater amino acid requirement to support rates of whole-body protein synthesis.
CONCLUSIONSOur findings suggest that performing endurance exercise with low-CHO availability increases protein requirements of endurance athletes.
No study has concurrently measured changes in free-living whole body protein metabolism and exercise performance during recovery from an acute bout of resistance exercise. We aimed to determine if ...whey protein ingestion enhances whole body net protein balance and recovery of exercise performance during overnight (10 h) and 24 h recovery after whole body resistance exercise in trained men. In a double-blind crossover design, 12 trained men (76 ± 8 kg, 24 ± 4 years old, 14% ± 5% body fat; means ± standard deviation (SD)) performed resistance exercise in the evening prior to consuming either 25 g of whey protein (PRO; MuscleTech 100% Whey) or an energy-matched placebo (CHO) immediately post-exercise (0 h), and again the following morning (~10 h of recovery). A third randomized trial, completed by the same participants, involving no exercise and no supplement served as a rested control trial (Rest). Participants ingested
Nglycine to determine whole body protein kinetics and net protein balance over 10 and 24 h of recovery. Performance was assessed pre-exercise and at 0, 10, and 24 h of recovery using a battery of tests. Net protein balance tended to improve in PRO (
= 0.064; effect size (ES) = 0.61, PRO vs. CHO) during overnight recovery. Over 24 h, net balance was enhanced in PRO (
= 0.036) but not in CHO (
= 0.84; ES = 0.69, PRO vs. CHO), which was mediated primarily by a reduction in protein breakdown (PRO < CHO;
< 0.01. Exercise decreased repetitions to failure (REP), maximal strength (MVC), peak and mean power, and countermovement jump performance (CMJ) at 0 h (all
< 0.05 vs. Pre). At 10 h, there were small-to-moderate effects for enhanced recovery of the MVC (ES = 0.56), mean power (ES = 0.49), and CMJ variables (ES: 0.27-0.49) in PRO. At 24 h, protein supplementation improved MVC (ES = 0.76), REP (ES = 0.44), and peak power (ES = 0.55). In conclusion, whey protein supplementation enhances whole body anabolism, and may improve acute recovery of exercise performance after a strenuous bout of resistance exercise.
Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking ...nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite
, namely tyrosine RS (
YRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.
ABSTRACT
Dietary protein supports the remodeling and recovery of lean tissue with consensus recommendations (1.2–2.0 g·kg
−1
·d
−1
), indicating that higher protein intakes are needed in trained ...athletes. Currently, protein intake recommendations are primarily based on research on males and typically confined to laboratory settings.
Purpose
This study aimed to determine the daily protein requirements of female and male endurance athletes in a home-based setting using noninvasive stable isotope methodology (i.e., indicator amino acid oxidation).
Methods
Eight males (30 ± 3 yr; 78.6 ± 10.5 kg; 75.6 ± 7.5 mL·kg
FFM
−1
·min
−1
; mean ± SD) and seven females (30 ± 4 yr; 57.7 ± 5.0 kg; 77.5 ± 7.1 mL·kg
FFM
−1
·min
−1
) during the midluteal phase were studied. After 2 d of controlled diet (1.4 g
protein
·kg
−1
·d
−1
) and training (10 and 5 km run·d
−1
, respectively), participants completed a 20-km run before an at-home indicator amino acid oxidation trial testing a suboptimal, a moderate, and an excess (i.e., 0.2, 1.2, and 2.0 g·kg
−1
·d
−1
, respectively) protein intake. Protein was consumed as a crystalline amino acid mixture containing 1-
13
Cphenylalanine to examine whole-body phenylalanine flux and phenylalanine oxidation (PheOx; the reciprocal of whole-body protein synthesis) through breath and urine sample collection. A modified biphasic linear regression determined the breakpoint in PheOx for each participant to generate an estimated average intake that would maximize whole-body protein synthesis for each sex.
Results
PheOx was different (
P
< 0.01) between all protein intakes with no effect of sex (
P
= 0.63). Using a modified three-point curve resulted in a breakpoint that was not different (
P
= 0.94) between males and females (1.60 and 1.61 g·kg
−1
·d
−1
, respectively). The recommended intake (i.e., upper 95% confidence interval) was estimated to be 1.81 and 1.89 g·kg
−1
·d
−1
for males and females, respectively.
Conclusions
Our findings indicate that endurance athletes consuming a daily protein intake toward the upper end of current consensus recommendations (~1.85 g·kg
−1
·d
−1
) will maximize whole-body protein synthesis during postexercise recovery regardless of sex.
Dietary protein supports resistance exercise–induced anabolism primarily via the stimulation of protein synthesis rates. The indicator amino acid oxidation (IAAO) technique provides a noninvasive ...estimate of the protein intake that maximizes whole-body protein synthesis rates and net protein balance.
We utilized IAAO to determine the maximal anabolic response to postexercise protein ingestion in resistance-trained men.
Seven resistance-trained men (mean ± SD age 24 ± 3 y; weight 80 ± 9 kg; 11 ± 5% body fat; habitual protein intake 2.3 ± 0.6 g·kg-1·d-1) performed a bout of whole-body resistance exercise prior to ingesting hourly mixed meals, which provided a variable amount of protein (0.20–3.00 g·kg-1·d-1) as crystalline amino acids modeled after egg protein. Steady-state protein kinetics were modeled with oral L-1-13C-phenylalanine. Breath and urine samples were taken at isotopic steady state to determine phenylalanine flux (PheRa), phenylalanine excretion (F13CO2; reciprocal of protein synthesis), and net balance (protein synthesis – PheRa). Total amino acid oxidation was estimated from the ratio of urinary urea and creatinine.
Mixed model biphasic linear regression revealed a plateau in F13CO2(mean: 2.00; 95% CI: 1.62, 2.38 g protein·kg-1·d-1) (r2 = 0.64; P < 0.01) and in net balance (mean: 2.01; 95% CI: 1.44, 2.57 g protein·kg-1·d-1) (r2 = 0.63; P < 0.01). Ratios of urinary urea and creatinine concentrations increased linearly (r = 0.84; P < 0.01) across the range of protein intakes.
A breakpoint protein intake of ~2.0 g·kg-1·d-1, which maximized whole-body anabolism in resistance-trained men after exercise, is greater than previous IAAO-derived estimates for nonexercising men and is at the upper range of current general protein recommendations for athletes. The capacity to enhance whole-body net balance may be greater than previously suggested to maximize muscle protein synthesis in resistance-trained athletes accustomed to a high habitual protein intake. This trial was registered at clinicaltrials.gov as NCT03696264.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mutations in copper/zinc superoxide dismutase 1 (SOD1), primary causes of human amyotrophic lateral sclerosis (ALS), provoke motor neuron death through an unidentified toxic property. The known ...neurofilament-dependent slowing of axonal transport, combined with the prominent misaccumulation of neurofilaments in ALS, suggests that an important aspect of toxicity may arise from damage to transport. Here we verify this hypothesis for two SOD1 mutations linked to familial ALS. Reduced transport of selective cargoes of slow transport, especially tubulin, arises months before neurodegeneration. For one mutant, this represents the earliest detectable abnormality. Thus, damage to the cargoes or machinery of slow transport is an early feature of toxicity mediated by mutant SOD1.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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