Vortex-carrying matter waves, such as chiral electron beams, are of significant interest in both applied and fundamental science. Continuous-wave electron vortex beams are commonly prepared via ...passive phase masks imprinting a transverse phase modulation on the electron's wavefunction. Here, we show that femtosecond chiral plasmonic near fields enable the generation and dynamic control on the ultrafast timescale of an electron vortex beam. The vortex structure of the resulting electron wavepacket is probed in both real and reciprocal space using ultrafast transmission electron microscopy. This method offers a high degree of scalability to small length scales and a highly efficient manipulation of the electron vorticity with attosecond precision. Besides the direct implications in the investigation of nanoscale ultrafast processes in which chirality plays a major role, we further discuss the perspectives of using this technique to shape the wavefunction of charged composite particles, such as protons, and how it can be used to probe their internal structure.
The in vivo imaging probe 11C-PIB (Pittsburgh Compound B, N-methyl11C2-(4′-methylaminophenyl-6-hydroxybenzathiazole) is under evaluation as a key imaging tool in Alzheimer's disease (AD) and to date ...has been assumed to bind with high affinity and specificity to the amyloid structures associated with classical plaques (CPs), one of the pathological hallmarks of the disease. However, no studies have systematically investigated PIB binding to human neuropathological brain specimens at the tracer concentrations achieved during in vivo imaging scans. Using a combination of autoradiography and histochemical techniques, we demonstrate that PIB, in addition to binding CPs clearly delineates diffuse plaques and cerebrovascular amyloid angiopathy (CAA). The interaction of PIB with CAA was not fully displaceable and this may be linked to the apolipoprotein E-ε4 allele. PIB was also found to label neurofibrillary tangles, although the overall intensity of this binding was markedly lower than that associated with the amyloid-beta (Aβ) pathology. The data provide a molecular explanation for PIB's limited specificity in diagnosing and monitoring disease progression in AD and instead indicate that the ligand is primarily a non-specific marker of Aβ-peptide related cerebral amyloidosis.
Abstract
Background
Sedentary behaviour (SB) has been identified as an important mortality risk factor. Health organizations have recognised SB as a public health challenge with major health, social, ...and economic consequences. Researchers have alerted the need to develop specific strategies, to monitor, prevent, and reduce SB. However, there is no systematic analysis of the SB changes in European Union adults. We aimed to examine SB changes between 2002 and 2017 in the European Union (EU) adult population.
Methods
SB prevalence (>4h30mins of sitting time/day) of 96,004 adults as a whole sample and country-by-country was analysed in 2002, 2005, 2013, and 2017 of the Sport and Physical Activity EU Special Eurobarometers’ data. The SB question of a modified version of the International Physical Activity Questionnaire was considered. SB prevalence between countries and within years was analysed with a χ2 test, and SB between genders was analysed with the Z-Score test for two population proportions.
Results
An association between the SB prevalence and the years was found (
p
< 0.001), with increases for the whole sample (2002: 49.3%, 48.5–50.0 95% confidence interval (CI); 2017: 54.5%, 53.9–55.0 95% CI) and men (2002: 51.2%, 50.0–52.4 95% CI; 2017: 55.8%, 55.0–56.7 95% CI) and women (2002: 47.6%, 46.6–48.7 95% CI; 2017: 53.4%, 52.6–54.1 95% CI) separately. The adjusted standardised residuals showed an increase in the observed prevalence versus the expected during 2013 and 2017 for the whole sample and women and during 2017 for men. For all years, differences were observed in the SB prevalence between countries for the whole sample, and men and women separately (
p
< 0.001). Besides, the SB prevalence was always higher in men versus women in the overall EU sample (
p
< 0.001).
Conclusions
SB prevalence increased between 2002 and 2017 for the EU as a whole and for both sexes separately. Additionally, differences in SB prevalence were observed for all years between EU countries in the whole sample and both sexes separately. Lastly, SB was consistently higher in men than women. These findings reveal a limited impact of current policies and interventions to tackle SB at the EU population level.
Light-electron interaction is the seminal ingredient in free-electron lasers and dynamical investigation of matter. Pushing the coherent control of electrons by light to the attosecond timescale and ...below would enable unprecedented applications in quantum circuits and exploration of electronic motions and nuclear phenomena. Here we demonstrate attosecond coherent manipulation of a free-electron wave function, and show that it can be pushed down to the zeptosecond regime. We make a relativistic single-electron wavepacket interact in free-space with a semi-infinite light field generated by two light pulses reflected from a mirror and delayed by fractions of the optical cycle. The amplitude and phase of the resulting electron-state coherent oscillations are mapped in energy-momentum space via momentum-resolved ultrafast electron spectroscopy. The experimental results are in full agreement with our analytical theory, which predicts access to the zeptosecond timescale by adopting semi-infinite X-ray pulses.
Key points
If skeletal muscle fibres are subjected to excessive activation, or stretched whilst contracting, they subsequently display long‐term reductions in their force response, apparently due in ...part to structural or molecular changes at the triad junction, where excitation of the surface membrane triggers Ca2+ release from the internal Ca2+ store.
The changes appear to be due to excessive or prolonged increases in intracellular Ca2+ levels, which activate Ca2+‐dependent proteases known as calpains, but their target proteins are currently unknown.
This study shows that excessive muscle stimulation, or directly raising intracellular Ca2+ levels, causes calpain activation in tandem with proteolysis of junctophilin, a key protein thought to hold the triad junction together.
Proteolysis of junctophilin is also seen in muscle of mice with muscular dystrophy and in cardiac muscle following ischaemic damage.
Proteolysis of junctophilin may be a major factor causing muscle weakness and cardiac dysfunction in a range of circumstances.
Excessive increases in intracellular Ca2+ in skeletal muscle fibres cause failure of excitation–contraction coupling by disrupting communication between the dihydropyridine receptors in the transverse tubular system and the Ca2+ release channels (RyRs) in the sarcoplasmic reticulum (SR), but the exact mechanism is unknown. Previous work suggested a possible role of Ca2+‐dependent proteolysis in this uncoupling process but found no proteolysis of the dihydropyridine receptors, RyRs or triadin. Junctophilin‐1 (JP1; ∼90 kDa) stabilizes close apposition of the transverse tubular system and SR membranes in adult skeletal muscle; its C‐terminal end is embedded in the SR and its N‐terminal associates with the transverse tubular system membrane. Exposure of skeletal muscle homogenates to precisely set Ca2+ revealed that JP1 undergoes Ca2+‐dependent proteolysis over the physiological Ca2+ range in tandem with autolytic activation of endogenous μ‐calpain. Cleavage of JP1 occurs close to the C‐terminal, yielding a ∼75 kDa diffusible fragment and a fixed ∼15 kDa fragment. Depolarization‐induced force responses in rat skinned fibres were abolished following 1 min exposure to 40 μm Ca2+, with accompanying loss of full‐length JP1. Supraphysiological stimulation of rat skeletal muscle in vitro by repeated tetanic stimulation in 30 mm caffeine also produced marked proteolysis of JP1 (and not RyR1). In dystrophic mdx mice, JP1 proteolysis is seen in limb muscles at 4 and not at 10 weeks of age. Junctophilin‐2 in cardiac and skeletal muscle also undergoes Ca2+‐dependent proteolysis, and junctophilin‐2 levels are reduced following cardiac ischaemia–reperfusion. Junctophilin proteolysis may contribute to skeletal muscle weakness and cardiac dysfunction in a range of circumstances.
Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease ...treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine.
Antibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared with a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin α4β7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3-10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/mL), and antibody responses following past infection or a second dose of the BNT162b2 vaccine.
Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL (5.9) vs 28.8 U/mL (5.4) p<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL (4.9)) vs 13.8 U/mL (5.9) p<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change (FC) 0.29 (95% CI 0.21 to 0.40), p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 (95% CI 0.30 to 0.51), p<0.0001) vaccines. In both models, age ≥60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine.
Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab.
ISRCTN45176516.
We report the most precise observations to date concerning the spin structure of magnetic skyrmions in a nanowedge specimen of cubic B20 structured FeGe. Enabled by our development of advanced ...differential phase contrast (DPC) imaging (in a scanning transmission electron microscope (STEM)) we have obtained high spatial resolution quantitative measurements of skyrmion internal spin profile. For hexagonal skyrmion lattice cells, stabilised by an out-plane applied magnetic field, mapping of the in-plane component of magnetic induction has revealed precise spin profiles and that the internal structure possesses intrinsic six-fold symmetry. With increasing field strength, the diameter of skyrmion cores was measured to decrease and accompanied by a nonlinear variation of the lattice periodicity. Variations in structure for individual skyrmions across an area of the lattice were also studied utilising a new increased sensitivity DPC detection scheme and a variety of symmetry lowering distortions were observed. To provide insight into fundamental energetics we have constructed a phenomenological model, with which our experimental observations of spin profiles and field induced core diameter variation are in good agreement with predicted structure in the middle of the nanowedge crystal. In the vicinity of the crystal surfaces, our model predicts the existence of in-plane twisting distortions which our current experimental observations were not sensitive to. As an alternative to the requirement for as yet unidentified sources of magnetic anisotropy, we demonstrate that surface states could provide the energetic stabilisation needed for predomination over the conical magnetic phase.
Addiction is continued drug use despite its harm. As one always has alternatives, addiction can be construed as a decision to allocate behavior to drug use. While decision making is commonly ...discussed and studied as if it resulted from deliberative, evaluative processes, such processes are actually only rarely involved in behavior allocation. These deliberative processes are too slow, effortful and inefficient to guide behavior other than when necessary. Rather, most actions are guided by faster, more automatic processes, often labeled habits. Habits are mostly adaptive, and result from repeated reinforcement leading to over-learned behavior. Habitual behavior occurs rapidly in response to particular contexts, and the behavior occurring first is that which occurs, i.e., the behavior that is decided upon. Thus, as drug use becomes habitual, drug use is likely to be chosen over other available activities in that particular context. However, while drug use becoming habitual is necessary for addiction to develop, it is not sufficient. Typically, constraints limit even habitual drug use to safer levels. These constraints might include limiting occasions for use; and, almost always, constraints on amount consumed. However, in a minority of individuals, drug use is not sufficiently constrained and addiction develops. This review discusses the nature of these constraints, and how they might fail. These failures do not result from abnormal learning processes, but rather unfortunate interactions between a person and their environment over time. These accumulate in the maladaptive allocation of behavior to drug use. This Behavior Allocation Disorder (BAD) can be reversed; occasionally easily when the environment significantly changes, but more often by the arduous application of deliberative processes generally absent from decision making. These deliberative processes must continue until new more adaptive habits become the most probable behavior in the contexts encountered. As alternatives to drug use become the most probable behavior, relapse risk diminishes.
•Addiction is a Behavioral Allocation Disorder, a BAD.•BADs result from learning, the cumulative experiences of a person with an environment.•Of the behaviors that could occur, the most probable, the fastest one occurs.•Habitual behavior is rapid; thus as drug use becomes habitual, it becomes more likely.•Habits are naturally constrained, when habits escape constraints a BAD may occur.
Periods of engaging in an alternative behavior diminishes behavioral control by stimuli occasioning alcohol use. This increase in relapse resistance with increasing recovery suggests that changing ...stimulus control over substance use may be a mechanism responsible for decreased relapse rates with longer recovery. However, the generality of this phenomenon to other drugs of abuse, including opioid self-administration, remains unclear. This study tests the generality of these findings with etonitazene to determine whether the shift in attention represents a behavioral process that generalizes from conditions we previously reported.
Five adult male Lewis rats were trained to respond on levers under two stimulus conditions; high-cost food (food FR150 and etonitazene FR5) and low-cost food (both food and etonitazene FR 5). Next, only the high-cost food stimulus (occasioning etonitazene responding) was presented for 20 sessions (Use Phase) followed by 9 sessions in which only the low-cost food stimulus (occasioning food responding) was presented (Recovery Phase). During the Recovery Phase, testing occurred during the first component of sessions 0, 1, 2, 4, and 8 when rats were re-exposed to the high-cost food stimulus. The number of food responses prior to completing the etonitazene response requirement during this stimulus exposure was the primary measure.
Food responses during stimulus re-exposure increased significantly as a function of recovery sessions completed with a slope 95 % CI of 2.49 responses/recovery session 0.16, 4.81. The average number of etonitazene deliveries per use session was 32 ± 6.6 or an average daily dose of 48.8 ± 10.1 μg/kg. During Recovery Phase, etonitazene deliveries decreased to 2.4 ± 1 or 3.6 ± 1.5 μg/kg.
The decrease in stimulus control observed for ethanol self-administration appears to generalize to opioid self-administration, indicating this change in stimulus control may play a general role in recovery.
•Providing concurrently available alternative reinforcement decreases opioid use.•Unexpected loss of the alternative can be considered as frustration stress.•Unsignaled extinction of the alternative ...returned opioid use to prior levels.•Frustration stress might reflect loss of the alternative that constrains drug use.
Engaging in alternative activities in the context where opioid use had occurred can constrain opioid use and helps to maintain recovery. However, “frustration stress” that occurs when contingencies on these alternative activities unexpectedly change (e.g., job loss or divorce) is thought to threaten recovery by prompting a return to drug use. Yet it remains unclear whether frustration stress can result in a return to drug use, and if so, whether it returns to prior levels or to even greater levels.
We examine the impact of unsignaled extinction of alternative reinforcement on opioid use. Rats were trained to respond for an etonitazene solution (5μg/ml, p.o.), then for food in alternating daily sessions. Subsequently, food and etonitazene were made concurrently available. Under concurrent availability conditions, rats were exposed to 1, 2, or 4 sessions of unsignaled food extinction, and effects on responding for etonitazene and food measured.
When etonitazene was the only reinforcer available, rats earned 58.3±20.3μg/kg/session (mean±S.E.M.). When food was available in alternating sessions, etonitazene earned was unchanged (65.3±19.2μg/kg/session). Concurrent food availability decreased etonitazene earned (13.5±4.5μg/kg/session). Unsignaled food extinction returned etonitazene earnedto levels similar to (60.5±18.4μg/kg/session), but not greater than, those observed previously when etonitazene alone was available.
Unsignaled extinction of alternative behavior controlling opioid use can result in increased opioid use, but this use does not rise beyond previous levels observed when opioid use is unconstrained by alternative reinforced behavior.
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