A precision measurement of the nitrogen flux with rigidity (momentum per unit charge) from 2.2 GV to 3.3 TV based on 2.2×10^{6} events is presented. The detailed rigidity dependence of the nitrogen ...flux spectral index is presented for the first time. The spectral index rapidly hardens at high rigidities and becomes identical to the spectral indices of primary He, C, and O cosmic rays above ∼700 GV. We observed that the nitrogen flux Φ_{N} can be presented as the sum of its primary component Φ_{N}^{P} and secondary component Φ_{N}^{S}, Φ_{N}=Φ_{N}^{P}+Φ_{N}^{S}, and we found Φ_{N} is well described by the weighted sum of the oxygen flux Φ_{O} (primary cosmic rays) and the boron flux Φ_{B} (secondary cosmic rays), with Φ_{N}^{P}=(0.090±0.002)×Φ_{O} and Φ_{N}^{S}=(0.62±0.02)×Φ_{B} over the entire rigidity range. This corresponds to a change of the contribution of the secondary cosmic ray component in the nitrogen flux from 70% at a few GV to <30% above 1 TV.
Defining the microanatomic differences between the human brain and that of other mammals is key to understanding its unique computational power. Although much effort has been devoted to comparative ...studies of neurons, astrocytes have received far less attention. We report here that protoplasmic astrocytes in human neocortex are 2.6-fold larger in diameter and extend 10-fold more GFAP (glial fibrillary acidic protein)-positive primary processes than their rodent counterparts. In cortical slices prepared from acutely resected surgical tissue, protoplasmic astrocytes propagate Ca(2+) waves with a speed of 36 microm/s, approximately fourfold faster than rodent. Human astrocytes also transiently increase cystosolic Ca(2+) in response to glutamatergic and purinergic receptor agonists. The human neocortex also harbors several anatomically defined subclasses of astrocytes not represented in rodents. These include a population of astrocytes that reside in layers 5-6 and extend long fibers characterized by regularly spaced varicosities. Another specialized type of astrocyte, the interlaminar astrocyte, abundantly populates the superficial cortical layers and extends long processes without varicosities to cortical layers 3 and 4. Human fibrous astrocytes resemble their rodent counterpart but are larger in diameter. Thus, human cortical astrocytes are both larger, and structurally both more complex and more diverse, than those of rodents. On this basis, we posit that this astrocytic complexity has permitted the increased functional competence of the adult human brain.
Meta-analysis is essential to combine the results of genome-wide association studies (GWASs). Recent large-scale meta-analyses have combined studies of different ethnicities, environments and even ...studies of different related phenotypes. These differences between studies can manifest as effect size heterogeneity. We previously developed a modified random effects model (RE2) that can achieve higher power to detect heterogeneous effects than the commonly used fixed effects model (FE). However, RE2 cannot perform meta-analysis of correlated statistics, which are found in recent research designs, and the identified variants often overlap with those found by FE.
Here, we propose RE2C, which increases the power of RE2 in two ways. First, we generalized the likelihood model to account for correlations of statistics to achieve optimal power, using an optimization technique based on spectral decomposition for efficient parameter estimation. Second, we designed a novel statistic to focus on the heterogeneous effects that FE cannot detect, thereby, increasing the power to identify new associations. We developed an efficient and accurate p -value approximation procedure using analytical decomposition of the statistic. In simulations, RE2C achieved a dramatic increase in power compared with the decoupling approach (71% vs. 21%) when the statistics were correlated. Even when the statistics are uncorrelated, RE2C achieves a modest increase in power. Applications to real genetic data supported the utility of RE2C. RE2C is highly efficient and can meta-analyze one hundred GWASs in one day.
The software is freely available at http://software.buhmhan.com/RE2C .
buhm.han@amc.seoul.kr.
Supplementary data are available at Bioinformatics online.
We report that the spin current generated by the spin Seebeck effect (SSE) in yttrium iron garnet (YIG) can be detected by a ferromagnetic metal (NiFe). By using the ferromagnetic/antiferromagnetic ...(FM/AFM) exchange bias structure (NiFe/IrMn), the inverse spin Hall effect (ISHE) and planar Nernst effect (PNE) of NiFe can be unambiguously separated, allowing us to observe a pure ISHE signal. After eliminating the in-plane temperature gradient in NiFe, we can even observe a pure ISHE signal without PNE from NiFe itself. It is worth noting that a large spin Hall angle (0.098) of NiFe is obtained, which is comparable with Pt. This work provides a kind of FM/AFM exchange bias structure to detect the spin current by charge signals, and highlights that ISHE in ferromagnetic metals can be used in spintronic research and applications.
Protoplasmic astrocytes are critically important to energy metabolism in the CNS. Our current understanding of the metabolic interactions between neurons and glia is based on studies using cultured ...cells, from which mainly inferential conclusions have been drawn as to the relative roles of neurons and glia in brain metabolism. In this study, we used functional genomics to establish the relative compartmentalization of neuronal and astrocytic metabolic pathways in the adult brain. To this end, fluorescence-activated cell sorting was used to directly isolate neurons and protoplasmic astrocytes from the cortex of adult mice. Microarray analysis showed that astrocytes and neurons each express transcripts predicting individual self-sufficiency in both glycolysis and oxidative metabolism. Surprisingly, most enzymes in the tricarboxylic acid (TCA) cycle were expressed at higher relative levels in astrocytes than in neurons. Mass spectrometric analysis of the TCA cycle intermediates confirmed that freshly isolated adult astrocytes maintained an active TCA cycle, whereas immuno-electron microscopy revealed that fine astrocytic processes encompassing synapses contained a higher density of mitochondria than surrounding cells. These observations indicate that astrocytes exhibit robust oxidative metabolism in the intact adult brain and suggest a prominent contribution of astrocytic metabolism to functional brain imaging, including BOLD (blood-oxygen level-dependent) functional magnetic resonance imaging signals.
To investigate the dynamic stereochemical inversion behavior of pillar5arenes (P5s) in more detail, we synthesized a series of novel rim-differentiated P5s with various substituents and examined ...their rapid rotations by variable-temperature NMR (203–298 K). These studies revealed for the first time the barrier of “methyl-through-the-annulus” rotation (ΔG ‡ = 47.4 kJ·mol–1 in acetone) and indicated that for rim-differentiated P5s with two types of alkyl substituents, the smaller rim typically determines the rate of rotation. However, substituents with terminal CC or CC bonds give rise to lower inversion barriers, presumably as a result of attractive π–π interactions in the transition state. Finally, data on a rim-differentiated penta-methyl-penta-propargyl P5 exhibited the complexity of the overall inversion dynamics.
No randomized controlled trials have evaluated the comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia.
A prospective observational ...cohort study including all S. aureus bacteraemia was conducted at 10 hospitals. Patients (≥15 years) with MSSA bacteraemia who received cefazolin or nafcillin as definitive antibiotics were included. The rates of treatment failure (premature discontinuation of antibiotics because of adverse effects, switching of antibiotics because of clinical failure, all-cause mortality within 1 month, or recurrence) were compared between the cefazolin and nafcillin groups. Propensity score matching analyses were performed to balance the factors influencing the selection of antibiotics.
Among the 242 included cases, the bones and joints (36.8%) were the most common sites of infection and 60.7% of the patients had sepsis. The overall treatment failure rate was 43.8% (106/242). All-cause mortality within 1 month was 6.2% (15/242). After propensity score matching, the treatment failure rate of cefazolin was lower than that of nafcillin (30.4% (24/79) vs. 49.4% (39/79), p 0.015) because of a higher rate of discontinuation caused by adverse events. When the data were limited to patients with sepsis, the treatment failure rates of both groups were not significantly different. Approximately 22% (24/110) of MSSA isolates exhibited a cefazolin-inoculum effect (CIE) that had significant impact on the failure rate and mortality of the cefazolin group.
Cefazolin might be recommended as an adequate and better-tolerated treatment for MSSA bacteraemia in the absence of CIE.
Ultrasound-driven microbubbles can trigger reversible membrane perforation (sonoporation), open interendothelial junctions and stimulate endocytosis, thereby providing a temporary and reversible ...time-window for the delivery of macromolecules across biological membranes and endothelial barriers. This time-window is related not only to cavitation events, but also to biological regulatory mechanisms. Mechanistic understanding of the interaction between cavitation events and cells and tissues, as well as the subsequent cellular and molecular responses will lead to new design strategies with improved efficacy and minimized side effects. Recent important progress on the spatiotemporal characteristics of sonoporation, cavitation-induced interendothelial gap and endocytosis, and the spatiotemporal bioeffects and the preliminary biological mechanisms in cavitation-enhanced permeability, has been made. On the basis of the summary of this research progress, this Review outlines the underlying bioeffects and the related biological regulatory mechanisms involved in cavitation-enhanced permeability; provides a critical commentary on the future tasks and directions in this field, including developing a standardized methodology to reveal mechanism-based bioeffects in depth, and designing biology-based treatment strategies to improve efficacy and safety. Such mechanistic understanding the bioeffects that contribute to cavitation-enhanced delivery will accelerate the translation of this approach to the clinic.
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In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor–naive advanced ALK-positive NSCLC, brigatinib exhibited ...superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results.
Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy.
A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio HR = 0.48, 95% confidence interval CI: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed.
In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study.
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