Among topological solitons, magnetic skyrmions are two-dimensional particle-like objects with a continuous winding of the magnetization, and magnetic Hopfions are three-dimensional objects that can ...be formed from a closed loop of twisted skyrmion strings. Theoretical models suggest that magnetic Hopfions can be stabilized in frustrated or chiral magnetic systems, and target skymions can be transformed into Hopfions by adapting their perpendicular magnetic anisotropy, but their experimental verification has been elusive so far. Here, we present an experimental study of magnetic Hopfions that are created in Ir/Co/Pt multilayers shaped into nanoscale disks, known to host target skyrmions. To characterize three-dimensional spin textures that distinguish Hopfions from target skyrmions magnetic images are recorded with surface-sensitive X-ray photoemission electron microscopy and bulk-sensitive soft X-ray transmission microscopy using element-specific X-ray magnetic circular dichroism effects as magnetic contrast. These results could stimulate further investigations of Hopfions and their potential application in three-dimensional spintronics devices.
It is now recognized that extensive maturational changes take place in the human brain during adolescence, and that the trajectories of these changes are best studied longitudinally. We report the ...first longitudinal study of the adolescent decline in non-rapid eye movement (NREM) delta (1-4 Hz) and theta (4-8 Hz) EEG. Delta and theta are the homeostatic frequencies of human sleep. We recorded sleep EEG in 9- and 12-year-old cohorts twice yearly over a 5-year period. Delta power density (PD) was unchanged between age 9 and 11 years and then fell precipitously, decreasing by 66% between age 11 and 16.5 years (P < .000001). The decline in theta PD began significantly earlier than that in delta PD and also was very steep (by 60%) between age 11 and 16.5 years (P < .000001). These data suggest that age 11-16.5 years is a critically important maturational period for the brain processes that underlie homeostatic NREM EEG, a finding not suggested in previous cross-sectional data. We hypothesize that these EEG changes reflect synaptic pruning. Comparing our data with published longitudinal declines in MRI-estimated cortical thickness suggests the theta age curve parallels the earlier maturational thinning in 3-layer cortex, whereas the delta curve tracks the later changes in 5-layer cortex. This comparison also reveals that adolescent declines in NREM delta and theta are substantially larger than decreases in cortical thickness (>60% vs. <20%). The magnitude, interindividual difference, and tight link to age of these EEG changes indicate that they provide excellent noninvasive tools for investigating neurobehavioral correlates of adolescent brain maturation.
Delta (1–4
Hz) EEG power in non-rapid eye movement (NREM) sleep declines massively during adolescence. This observation stimulated the hypothesis that during adolescence the human brain undergoes an ...extensive reorganization driven by synaptic elimination. The parallel declines in synaptic density, delta wave amplitude and cortical metabolic rate during adolescence further support this model. These late brain changes probably represent the final ontogenetic manifestation of nature’s strategy for constructing nervous systems: an initial overproduction of neural elements followed by elimination. Errors in adolescent brain reorganization may cause mental illness; this could explain the typical age of onset of schizophrenia. Longitudinal studies of sleep EEG are enhancing our knowledge of adolescent brain maturation. Our longitudinal study of sleep EEG changes in adolescence showed that delta power, which may reflect frontal cortex maturation, begins its decline between ages 11 and 12
years and falls by 65% by age 17
years. In contrast, NREM theta power begins its decline much earlier. Delta and theta EEG frequencies are important to sleep theory because they behave homeostatically. Surprisingly, these brain changes are unrelated to pubertal maturation but are strongly linked to age. In addition to these (and other) maturational EEG changes, sleep schedules in adolescence change in response to a complex interaction of circadian, social and other influences. Our data demonstrate that the daytime sleepiness that emerges in adolescence is related to the decline in NREM delta as well as to altered sleep schedules. These longitudinal sleep data provide guideposts for studying cognitive and behavioral correlates of adolescent brain reorganization.
Increasing evidence indicates that tumor–stromal cell interactions have a crucial role in tumor initiation and progression. These interactions modify cellular compartments, leading to the ...co-evolution of tumor cells and their microenvironment. Although the importance of microenvironmental alterations in tumor development is recognized, the molecular mechanisms underlying these changes are only now beginning to be understood. Epigenetic and gene expression changes have consistently been reported in cancer-associated stromal cells and the influence of the host genotype on tumorigenesis is also well documented. However, the presence of clonally selected somatic genetic alterations within the tumor microenvironment has been controversial. A thorough understanding of the co-evolution of these two cellular compartments will require carefully executed molecular studies combined with mathematical modeling.
To further evaluate adolescent brain maturation by determining the longitudinal trajectories of nonrapid eye movement (NREM) sigma (11-15 Hz) power across childhood-adolescence.
The maturational ...trend for sigma (11-15 Hz) power was evaluated in an accelerated longitudinal study of three overlapping age cohorts (n = 92) covering ages 6 to 18 y. Semiannually, sleep electroencephalography (EEG) was recorded from participants sleeping at home in their normal sleep environment while keeping their current school night schedules.
Sigma frequencies became faster with age. The frequency of the 11-15 Hz spectral peak increased linearly. Sigma frequency power (SFP) declined with age, but its trajectory was complex (cubic). Power in a group of low sigma subfrequencies declined with age. Power in a group of high sigma frequencies increased with age. Power in subfrequencies within 11-15 Hz also showed different trends across the night, with lower frequencies increasing across NREM periods and higher frequencies decreasing across NREM periods. The upper and lower boundaries for the sigma frequencies that changed across NREMPs shifted upward with age.
We hypothesize that these maturational brain changes result from synaptic elimination which decreases sleep depth and streamlines circuits. SFP displays a maturational trajectory different from both delta and theta power. Theories on the function of sigma must be reconciled with its maturational trajectory. These findings further demonstrate the value of sleep EEG for studying noninvasively the complex developmental brain changes of adolescence.
New longitudinal sleep data spanning ages 6-10 yr are presented and combined with previous data to analyze maturational trajectories of delta and theta EEG across ages 6-18 yr in non-rapid eye ...movement (NREM) and rapid eye movement (REM) sleep. NREM delta power (DP) increased from age 6 to age 8 yr and then declined. Its highest rate of decline occurred between ages 12 and 16.5 yr. We attribute the delta EEG trajectories to changes in synaptic density. Whatever their neuronal underpinnings, these age curves can guide research into the molecular-genetic mechanisms that underlie adolescent brain development. The DP trajectories in NREM and REM sleep differed strikingly. DP in REM did not initially increase but declined steadily from age 6 to age 16 yr. We hypothesize that the DP decline in REM reflects maturation of the same brain arousal systems that eliminate delta waves in waking EEG. Whereas the DP age curves differed in NREM and REM sleep, theta age curves were similar in both, roughly paralleling the age trajectory of REM DP. The different maturational curves for NREM delta and theta indicate that they serve different brain functions despite having similar within-sleep dynamics and responses to sleep loss. Period-amplitude analysis of NREM and REM delta waveforms revealed that the age trends in DP were driven more by changes in wave amplitude rather than incidence. These data further document the powerful and complex link between sleep and brain maturation. Understanding this relationship would shed light on both brain development and the function of sleep.
In light of the increasing adoption of targeted resequencing (TR) as a cost-effective strategy to identify disease-causing variants, a robust method for copy number variation (CNV) analysis is needed ...to maximize the value of this promising technology.
We present a method for CNV detection for TR data, including whole-exome capture data. Our method calls copy number gains and losses for each target region based on normalized depth of coverage. Our key strategies include the use of base-level log-ratios to remove GC-content bias, correction for an imbalanced library size effect on log-ratios, and the estimation of log-ratio variations via binning and interpolation. Our methods are made available via CONTRA (COpy Number Targeted Resequencing Analysis), a software package that takes standard alignment formats (BAM/SAM) and outputs in variant call format (VCF4.0), for easy integration with other next-generation sequencing analysis packages. We assessed our methods using samples from seven different target enrichment assays, and evaluated our results using simulated data and real germline data with known CNV genotypes.
The steep adolescent decline in the slow wave (delta, 1–4 Hz) electroencephalogram (EEG) of nonrapid eye movement (NREM) sleep is a dramatic maturational change in brain electrophysiology thought to ...be driven by cortical synaptic pruning. A perennial question is whether this change in brain electrophysiology is related to sexual maturation. Applying Gompertz growth models to longitudinal data spanning ages 9–18 y, we found that the timing of the delta decline was significantly (P < 0.0001) linked to timing of pubertal maturation. This timing relation remained significant when sex differences in the timing of the delta decline were statistically controlled. Sex differences and the relation to the timing of puberty jointly explained 67% of the between-subject variance in the timing of the delta decline. These data provide a demonstration of a temporal relation between puberty and an electrophysiological marker of adolescent brain development. They can guide research into whether the neuroendocrine events of puberty are mechanistically linked to cortical maturation or whether, instead, the two maturational processes are parallel but independent programs of human ontogenesis.
Lysosomes are essential organelles that function to degrade and recycle unwanted, damaged and toxic biological components. Lysosomes also act as signalling platforms in activating the ...nutrient‐sensing kinase mTOR. mTOR regulates cellular growth, but it also helps to maintain lysosome identity by initiating lysosomal tubulation through a process termed autophagosome‐lysosome reformation (ALR). Here we identify a lysosomal pool of phosphatidylinositol 3‐phosphate that, when depleted by specific inhibition of the class III phosphoinositide 3‐kinase VPS34, results in prolonged lysosomal tubulation. This tubulation requires mTOR activity, and we identified two direct mTOR phosphorylation sites on UVRAG (S550 and S571) that activate VPS34. Loss of these phosphorylation sites reduced VPS34 lipid kinase activity and resulted in an increase in number and length of lysosomal tubules. In cells in which phosphorylation at these UVRAG sites is disrupted, the result of impaired lysosomal tubulation alongside ALR activation is massive cell death. Our data imply that ALR is critical for cell survival under nutrient stress and that VPS34 is an essential regulatory element in this process.
Synopsis
During starvation, VPS34 activity at the lysosomes controls autophagosome‐lysosome reformation and cell viability, illustrating a novel role for this autophagy‐initiating lipid kinase at late stages of autophagy.
A small pool of phosphatidylinositol 3‐phosphate is present on lysosomes.
Pharmacological inhibition of VPS34 with low doses of VPS34‐IN1 results in increased autolysosomal tubulation.
mTOR directly phosphorylates UVRAG at serine 550 and serine 571 to activate VPS34.
Loss of mTOR phosphorylation sites on UVRAG leads to increased lysosomal tubulation and cell death upon prolonged starvation.
During starvation, VPS34 activity at the lysosomes controls autophagosome‐lysosome reformation and cell viability, illustrating a novel role for this autophagy‐initiating lipid kinase at late stages of autophagy.
IN MEMORIAM - Irwin Feinberg, MD Campbell, Ian G.; Rosenlicht, Nicholas; March, Jonathan D.
Neuropsychopharmacology (New York, N.Y.),
12/2022, Letnik:
47, Številka:
13
Journal Article
PDF
