Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Fragile X mental retardation protein (FMRP), a putative translation suppressor, is absent or significantly ...reduced in FXS. One prevailing hypothesis is that rates of protein synthesis are increased by the absence of this regulatory protein. In accord with this hypothesis, we have previously reported increased rates of cerebral protein synthesis (rCPS) in the Fmr1 knockout mouse model of FXS and others have reported similar effects in hippocampal slices. To address the hypothesis in human subjects, we applied the L1-11Cleucine PET method to measure rCPS in adults with FXS and healthy controls. All subjects were males between the ages of 18 and 24 years and free of psychotropic medication. As most fragile X participants were not able to undergo the PET study awake, we used dexmedetomidine for sedation during the imaging studies. We found no differences between rCPS measured during dexmedetomidine-sedation and the awake state in ten healthy controls. In the comparison of rCPS in dexmedetomidine-sedated fragile X participants (n = 9) and healthy controls (n = 14) we found no statistically significant differences. Our results from in vivo measurements in human brain do not support the hypothesis that rCPS are elevated due to the absence of FMRP. This hypothesis is based on findings in animal models and in vitro measurements in human peripheral cells. The absence of a translation suppressor may produce a more complex response in pathways regulating translation than previously thought. We may need to revise our working hypotheses regarding FXS and our thinking about potential therapeutics.
•Brain protein synthesis rate unaffected under dexmedetomidine sedation in young men.•Brain protein synthesis rates not higher in sedated fragile X men than healthy controls.•Absence of FMRP may have complex effects on protein synthesis.
A typical human being carries billions of silicon‐based field‐effect transistors in his/her pockets. What makes these transistors work is Fermi level control, both by doping and field effect. Organic ...semiconductors are the core of a novel flexible electronics age, but the key effect of doping is still little understood. Here, precise handling is demonstrated for molar doping ratios as low as 10−5 in p‐ and n‐doped organic thin‐films by vacuum co‐sublimation, allowing comprehensive studying of the Fermi level control over the whole electronic gap of an organic semiconductor. In particular, dopant saturation and reserve regimes are observed for the first time in organic semiconductors. These results will allow for completely new design rules of organic transistors with improved long term stability and precise parameter control.
Fermi level control over the whole electronic gap of an organic semiconductor is demonstrated by applying the concept of molecular p‐ and n‐type doping. In particular, the observation of the dopant saturation and reserve regimes is shown for the first time in organic semiconductors, substantiating the cross‐link to classical semiconductor theory. At ultralow concentrations, doping provides filling of trap states.
To examine effects of scan duration on estimates of regional rates of cerebral protein synthesis (rCPS), we reanalyzed data from thirty-nine previously reported L-1-11Cleucine PET studies. Subjects ...consisted of 12 healthy volunteers studied twice, awake and under propofol sedation, and 15 subjects with fragile X syndrome (FXS) studied once under propofol sedation. All scans were acquired on a high resolution scanner. We used a basis function method for voxelwise estimation of parameters of the kinetic model of L-1-11Cleucine and rCPS over the interval beginning at the time of tracer injection and ending 30, 45, 60, 75 or 90 min later. For each study and scan interval, regional estimates in nine regions and whole brain were obtained by averaging voxelwise estimates over all voxels in the region. In all three groups rCPS was only slightly affected by scan interval length and was very stable between 60 and 90 min. Furthermore, statistical comparisons of rCPS between awake and sedated healthy volunteers provided almost identical results when they were based on 60 min scan data as when they were based on data from the full 90 min interval. Statistical comparisons between sedated healthy volunteers and sedated subjects with FXS also yielded almost identical results when based on 60 and 90 min scan intervals. We conclude that, under the conditions of our studies, scan duration can be shortened to 60 min without loss of precision.
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Fragile X mental retardation protein, a putative translation suppressor, is significantly reduced in FXS. The ...prevailing hypothesis is that rates of cerebral protein synthesis (rCPS) are increased by the absence of this regulatory protein. We have previously reported increased rCPS in the Fmr1 knockout mouse model of FXS. To address the hypothesis in human subjects, we measured rCPS in young men with FXS with L-1-11Cleucine PET. In previous studies we had used sedation during imaging, and we did not find increases in rCPS as had been seen in the mouse model. Since mouse measurements were conducted in awake animals, we considered the possibility that sedation may have confounded our results. In the present study we used a modified and validated PET protocol that made it easier for participants with FXS to undergo the study awake. We compared rCPS in 10 fragile X participants and 16 healthy controls all studied while awake. Contrary to the prevailing hypothesis and findings in Fmr1 knockout mice, results indicate that rCPS in awake participants with FXS are decreased in whole brain and most brain regions by 13–21% compared to healthy controls.
We developed and validated a method to estimate input functions for determination of regional rates of cerebral protein synthesis (rCPS) with L-1-11Cleucine PET without arterial sampling. The method ...is based on a population-derived input function (PDIF) approach, with venous samples for calibration. Population input functions were constructed from arterial blood data measured in 25 healthy 18–24-year-old males who underwent L-1-11Cleucine PET scans while awake. To validate the approach, three additional groups of 18–27-year-old males underwent L-1-11Cleucine PET scans with both arterial and venous blood sampling: 13 awake healthy volunteers, 10 sedated healthy volunteers, and 5 sedated subjects with fragile X syndrome. Rate constants of the L-1-11Cleucine kinetic model were estimated voxel-wise with measured arterial input functions and with venous-calibrated PDIFs. Venous plasma leucine measurements were used with venous-calibrated PDIFs for rCPS computation. rCPS determined with PDIFs calibrated with 30–60 min venous samples had small errors (RMSE: 4–9%), and no statistically significant differences were found in any group when compared to rCPS determined with arterial input functions. We conclude that in young adult males, PDIFs calibrated with 30–60 min venous samples can be used in place of arterial input functions for determination of rCPS with L-1-11Cleucine PET.
During sleep, reduced brain energy demands provide an opportunity for biosynthetic processes like protein synthesis. Sleep is required for some forms of memory consolidation which requires de novo ...protein synthesis. We measured regional cerebral protein synthesis rates (rCPS) in human subjects to ascertain how rCPS is affected during sleep. Subjects underwent three consecutive L-1-11Cleucine PET scans with simultaneous polysomnography: 1. rested awake, 2. sleep-deprived awake, 3. sleep. Measured rCPS were similar across the three conditions. Variations in sleep stage times during sleep scans were used to estimate rCPS in sleep stages under the assumption that measured rCPS is the weighted sum of rCPS in each stage, with weights reflecting time and availability of 11Cleucine in that stage. During sleep scans, subjects spent most of the time in N2, N3, and awake and very little time in N1 and REM; rCPS in N1 and REM could not be reliably estimated. When stages N1 and N2 were combined N1,N2, estimates of rCPS were more robust. In selective regions, estimated rCPS were statistically significantly higher (30–39%) in N1,N2 compared with N3; estimated rCPS in N3 were similar to values measured in sleep-deprived awake scans. Results indicate increased rates of protein synthesis linked to N1,N2 sleep.
All previously known localities of Pyrgophorus parvulus (Guilding, 1828) on the Caribbean island of Montserrat were destroyed by volcanic eruptions starting in 1995. Here we document a population in ...a freshwater stream only indirectly affected by that eruption. Specimens collected on Montserrat are morphologically consistent with P. parvulus and 16S DNA sequences indicate genetic consistency.
Functional quantification with PET is generally based on modeling that assumes tissue regions are kinetically homogeneous. Even in regions sufficiently small to approach homogeneity, spillover due to ...resolution limitations of PET scanners may introduce heterogeneous kinetics into measured data. Herein we consider effects of kinetic heterogeneity at the smallest volume accessible, the single image voxel. We used L-1-
Cleucine PET and compared rates of cerebral protein synthesis (rCPS) estimated voxelwise with methods that do (Spectral Analysis Iterative Filter, SAIF) and do not (Basis Function Method, BFM) allow for kinetic heterogeneity. In high resolution PET data with good counting statistics BFM produced estimates of rCPS comparable to SAIF, but at lower computational cost; thus the simpler, less costly method can be applied. With poorer counting statistics (lower injected radiotracer doses), BFM estimates were more biased. In data smoothed to simulate lower resolution PET, BFM produced estimates of rCPS 9-14% higher than SAIF, overestimation consistent with applying a homogeneous tissue model to kinetically heterogeneous data. Hence with lower resolution data it is necessary to account for kinetic heterogeneity in the analysis. Kinetic heterogeneity may impact analyses of other tracers and scanning protocols differently; assessments should be made on a case by case basis.
Voluntary isolation is one of the most effective methods for individuals to help prevent the transmission of diseases such as COVID-19. Understanding why people leave their homes when advised not to ...do so and identifying what contextual factors predict this non-compliant behavior is essential for policymakers and public health officials. To provide insight on these factors, we collected data from 42,169 individuals across 16 countries. Participants responded to items inquiring about their socio-cultural environment, such as the adherence of fellow citizens, as well as their mental states, such as their level of loneliness and boredom. We trained random forest models to predict whether someone had left their home during a one week period during which they were asked to voluntarily isolate themselves. The analyses indicated that overall, an increase in the feeling of being caged leads to an increased probability of leaving home. In addition, an increased feeling of responsibility and an increased fear of getting infected decreased the probability of leaving home. The models predicted compliance behavior with between 54% and 91% accuracy within each country’s sample. In addition, we modeled factors leading to risky behavior in the pandemic context. We observed an increased probability of visiting risky places as both the anticipated number of people and the importance of the activity increased. Conversely, the probability of visiting risky places increased as the perceived putative effectiveness of social distancing decreased. The variance explained in our models predicting risk ranged from < .01 to .54 by country. Together, our findings can inform behavioral interventions to increase adherence to lockdown recommendations in pandemic conditions.
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