Modular multilevel TMS device with wide output range and ultrabrief pulse capability for sound reduction

ObjectiveThis article presents a novel transcranial magnetic stimulation (TMS) pulse generator with a wide range of pulse shape, amplitude, and width.ApproachBased on a modular multilevel TMS (MM-TMS) topology we had proposed previously, we realized the first such device operating at full TMS energy levels. It consists of ten cascaded H-bridge modules, each implemented with insulated-gate bipolar transistors, enabling both novel high-amplitude ultrabrief pulses as well as pulses with conventional amplitude and duration. The MM-TMS device can output pulses including up to 21 voltage levels with a step size of up to 1100 V, allowing relatively flexible generation of various pulse waveforms and sequences. The circuit further allows charging the energy storage capacitor on each of the ten cascaded modules with a conventional TMS power supply.Main resultsThe MM-TMS device can output peak coil voltages and currents of 11 kV and 10 kA, respectively, enabling suprathreshold ultrabrief pulses (> 8.25 μs active electric field phase). Further, the MM-TMS device can generate a wide range of near-rectangular monophasic and biphasic pulses, as well as more complex staircase-approximated sinusoidal, polyphasic, and amplitude-modulated pulses. At matched estimated stimulation strength, briefer pulses emit less sound, which could enable quieter TMS. Finally, the MM-TMS device can instantaneously increase or decrease the amplitude from one pulse to the next in discrete steps by adding or removing modules in series, which enables rapid pulse sequences and paired-pulse protocols with variable pulse shapes and amplitudes.SignificanceThe MM-TMS device allows unprecedented control of the pulse characteristics which could enable novel protocols and quieter pulses.

Holocene thinning and grounding-line retreat of Darwin and Hatherton Glaciers, Antarctica

We present exposure ages of glacial deposits at three locations alongside Darwin Glacier and its tributary Hatherton Glacier that record several hundred meters of late Pleistocene to early Holocene thickening relative to present. As the grounding-line of the Ross Sea Ice Sheet retreated rapidly southward, Hatherton Glacier thinned steadily from about 9 kyr BP until about 3 kyr BP. Our data are equivocal about the maximum thickness and mid-to-early Holocene history at the mouth of Darwin Glacier, allowing for two possible deglaciation scenarios: (1) ~500 m of steady thinning from 9 kyr BP to 3 kyr BP, similar to Hatherton Glacier, or (2) ~950 m of thinning, with a rapid pulse of ~600 m thinning at around 5 kyr BP. We test these two scenarios using a 1.5-dimensional flowband model of Darwin and Hatherton Glaciers, forced by ice-thickness changes at the mouth of Darwin Glacier and evaluated by fit to the chronology of deposits at Hatherton Glacier. Our modeling shows that the constraints from Hatherton Glacier are consistent with the interpretation that the mouth of Darwin Glacier thinned steadily by ~500 m from 9 kyr BP to 3 kyr BP; rapid pulses of thinning at the mouth of Darwin Glacier are ruled out by the data at Hatherton Glacier. This contrasts with some of the available records from the mouths of other outlet glaciers in the Transantarctic Mountains, many of which thinned by hundreds of meters over roughly a one-thousand-year period in the early Holocene. The deglaciation histories of Darwin and Hatherton Glaciers are best matched by a steady decrease in catchment area through the Holocene, suggesting that Byrd and/or Mulock glaciers may have captured roughly half of the catchment area of Darwin and Hatherton Glaciers during the last deglaciation. An ensemble of three-dimensional ice-sheet model simulations suggest that Darwin and Hatherton Glaciers are strongly buttressed by convergent flow with ice from neighboring Byrd and Mulock glaciers, and by lateral drag past Minna Bluff, which could have led to a pattern of retreat distinct from other glaciers throughout the Transantarctic Mountains.

The effectiveness of inhaled Cannabis flower for the treatment of agitation/irritability, anxiety, and common stress

Background An observational research design was used to evaluate which types of commonly labeled Cannabis flower product characteristics are associated with changes in momentary feelings of distress-related symptoms. Methods We used data from 2306 patient-directed cannabis administration sessions among 670 people who used the real-time Cannabis effects recording software, Releaf App, between June 6, 2016, and February 23, 2019, for tracking the effects of Cannabis flower consumption. Fixed effects multivariable panel regression techniques were used to establish overall relief by symptom type and to determine which labeled product characteristics (e.g., subspecies/subtype, inhalation method, and major cannabinoid contents) showed the strongest correlation with changes in momentary feelings of agitation/irritability, anxiety, and stress, along with experienced side effects. Results In total, a decrease in symptom intensity levels was reported in 95.51% of Cannabis usage sessions, an increase in 2.32% of sessions, and no change in 2.16% of sessions. Fixed effects models showed, on average, respondents recorded a maximum symptom intensity reduction of 4.33 points for agitation/irritability (SE = 0.20, p < 0.01), 3.47 points for anxiety (SE = 0.13, p < 0.01), and 3.98 for stress (SE = 0.12, p < 0.01) on an 11-point visual analog scale. Fixed effects regressions showed that, controlling for time-invariant user characteristics, mid and high tetrahydrocannabinol (THC) levels were the primary independent predictor of increased symptom relief, and that when broken out by symptom type, this effect was only statistically significant for our largest sample of users, those reporting anxiety rather than agitation/irritability or stress. Cannabidiol (CBD) levels were generally not associated with changes in symptom intensity levels. In a minority of cannabis use sessions (< 13%), cannabis users reported anxiogenic-related negative side effects (e.g., feeling anxious, irritable, paranoid, rapid pulse, or restless), whereas in a majority of sessions (about 66%), users reported positive anxiolytic side effects (e.g., feeling chill, comfy, happy, optimistic, peaceful, or relaxed). Conclusions The findings suggest the majority of patients in our sample experienced relief from distress-related symptoms following consumption of Cannabis flower, and that among product characteristics, higher THC levels were the strongest predictors of relief.

Fructosyl transfer from sucrose and oligosaccharides during fructan synthesis in excised leaves of Lolium temulentum L.

Fructan biosynthesis begins with the transfer of a fructosyl moiety from one sucrose molecule to another to yield a trisaccharide. Trisaccharides may also arise by the reversible transfer of a fructosyl moiety from higher oligomers to sucrose but in this case there is no net fructan synthesis. Short‐term and long‐term exposure of detached illuminated leaf blades of Lolium temulentum (L.I to 14CO2 was used to examine the mechanism of transfer of fructosyl residues to sucrose. Two trisaccharides, 1‐kestose and neokestose, were found to be radioactive when leaves excised and illuminated for 15 h ‐were exposed to NCO2 for 30 min. The label increased in neokestose during the chase period, while that in 1‐kestose increased for the first 2 h of the chase period then declined for the remaining 4h. With a longer exposure to 14CO2 during the first 6 h of the induction period, three trisaccharides, neokestose, 1‐kestose and 6‐kestose were radiolabelled. The label turned over in neokestose and 1‐kestose, but continued to accumulate in 6‐kestose during a subsequent 18 h chase period. The specific activities of glucose and fructose of the sucrosyl portion and the terminal fructosyl moiety of the various trisaccharides were compared. In the rapid pulse‐chase experiment the specific activity of the1 terminal fructosyl moiety was consistently less than that of the sucrosyl moiety. During the chase period, the specific activity of the terminal and internal fructose moieties became similar. These results indicate that in addition to trisaccharide formed by transfer of fructosyl units from sucrose, substantial amounts of both neokestose and 1‐kestose are made by transfer of fructosyl units from higher oligomers onto sucrose in reactions probably localized in the vacuole. Copyright © 1991, Wiley Blackwell. All rights reserved

Fructosyl transfer from sucrose and oligosaccharides during fructan synthesis in excised leaves of Lolium temulentum L.

Fructan biosynthesis begins with the transfer of a fructosyl moiety from one sucrose molecule to another to yield a trisaccharide. Trisaccharides may also arise by the reversible transfer of a fructosyl moiety from higher oligomers to sucrose but in this case there is no net fructan synthesis. Short‐term and long‐term exposure of detached illuminated leaf blades of Lolium temulentum (L.I to 14CO2 was used to examine the mechanism of transfer of fructosyl residues to sucrose. Two trisaccharides, 1‐kestose and neokestose, were found to be radioactive when leaves excised and illuminated for 15 h ‐were exposed to NCO2 for 30 min. The label increased in neokestose during the chase period, while that in 1‐kestose increased for the first 2 h of the chase period then declined for the remaining 4h. With a longer exposure to 14CO2 during the first 6 h of the induction period, three trisaccharides, neokestose, 1‐kestose and 6‐kestose were radiolabelled. The label turned over in neokestose and 1‐kestose, but continued to accumulate in 6‐kestose during a subsequent 18 h chase period. The specific activities of glucose and fructose of the sucrosyl portion and the terminal fructosyl moiety of the various trisaccharides were compared. In the rapid pulse‐chase experiment the specific activity of the1 terminal fructosyl moiety was consistently less than that of the sucrosyl moiety. During the chase period, the specific activity of the terminal and internal fructose moieties became similar. These results indicate that in addition to trisaccharide formed by transfer of fructosyl units from sucrose, substantial amounts of both neokestose and 1‐kestose are made by transfer of fructosyl units from higher oligomers onto sucrose in reactions probably localized in the vacuole. Copyright © 1991, Wiley Blackwell. All rights reserved

First Experiments in Structural Biology at the European X-ray Free-Electron Laser

Ultrabright pulses produced in X-ray free-electron lasers (XFELs) offer new possibilities for industry and research, particularly for biochemistry and pharmaceuticals. The unprecedented brilliance of these next-generation sources enables structure determination from sub-micron crystals as well as radiation-sensitive proteins. The European X-Ray Free-Electron Laser (EuXFEL), with its first light in 2017, ushered in a new era for ultrabright X-ray sources by providing an unparalleled megahertz-pulse repetition rate, with orders of magnitude more pulses per second than previous XFEL sources. This rapid pulse frequency has significant implications for structure determination; not only will data collection be faster (resulting in more structures per unit time), but experiments requiring large quantities of data, such as time-resolved structures, become feasible in a reasonable amount of experimental time. Early experiments at the SPB/SFX instrument of the EuXFEL demonstrate how such closely-spaced pulses can be successfully implemented in otherwise challenging experiments, such as time-resolved studies.

Membrane protein megahertz crystallography at the European XFEL

The world’s first superconducting megahertz repetition rate hard X-ray free-electron laser (XFEL), the European XFEL, began operation in 2017, featuring a unique pulse train structure with 886 ns between pulses. With its rapid pulse rate, the European XFEL may alleviate some of the increasing demand for XFEL beamtime, particularly for membrane protein serial femtosecond crystallography (SFX), leveraging orders-of-magnitude faster data collection. Here, we report the first membrane protein megahertz SFX experiment, where we determined a 2.9 Å-resolution SFX structure of the large membrane protein complex, Photosystem I, a > 1 MDa complex containing 36 protein subunits and 381 cofactors. We address challenges to megahertz SFX for membrane protein complexes, including growth of large quantities of crystals and the large molecular and unit cell size that influence data collection and analysis. The results imply that megahertz crystallography could have an important impact on structure determination of large protein complexes with XFELs.