Aims
CLARITY is a novel technique which enables three‐dimensional visualization of immunostained tissue for the study of circuitry and spatial interactions between cells and molecules in the brain. ...In this study, we aimed to compare methodological differences in the application of CLARITY between rodent and large human post mortem brain samples. In addition, we aimed to investigate if this technique could be used to visualize Lewy pathology in a post mortem Parkinson's brain.
Methods
Rodent and human brain samples were clarified and immunostained using the passive version of the CLARITY technique. Samples were then immersed in different refractive index matching media before mounting and visualizing under a confocal microscope.
Results
We found that tissue clearing speed using passive CLARITY differs according to species (human vs. rodents), brain region and degree of fixation (fresh vs. formalin‐fixed tissues). Furthermore, there were advantages to using specific refractive index matching media. We have applied this technique and have successfully visualized Lewy body inclusions in three dimensions within the nucleus basalis of Meynert, and the spatial relationship between monoaminergic fibres and Lewy pathologies among nigrostriatal fibres in the midbrain without the need for physical serial sectioning of brain tissue.
Conclusions
The effective use of CLARITY on large samples of human tissue opens up many potential avenues for detailed pathological and morphological studies.
By refining the method for CLARITY studies in human brain tissue the authors pave the way for advancing the contribution of three‐dimensional microscopic analysis in the investigation of neurological disorders.
Brown carbon aerosol consists of light‐absorbing organic particulate matter with wavelength‐dependent absorption. Aerosol optical extinction, absorption, size distributions, and chemical composition ...were measured in rural Alabama during summer 2013. The field site was well located to examine sources of brown carbon aerosol, with influence by high biogenic organic aerosol concentrations, pollution from two nearby cities, and biomass burning aerosol. We report the optical closure between measured dry aerosol extinction at 365 nm and calculated extinction from composition and size distribution, showing agreement within experiment uncertainties. We find that aerosol optical extinction is dominated by scattering, with single‐scattering albedo values of 0.94 ± 0.02. Black carbon aerosol accounts for 91 ± 9% of the total carbonaceous aerosol absorption at 365 nm, while organic aerosol accounts for 9 ± 9%. The majority of brown carbon aerosol mass is associated with biomass burning, with smaller contributions from biogenically derived secondary organic aerosol.
Key Points
Aerosol optical extinction in the southeastern U.S. is dominated by scattering
Black carbon is a more significant absorber than organic carbon at 365 nm
Biomass burning makes the largest contribution to organic aerosol absorption
Transversus abdominis plane (TAP) block is an alternative to spinal morphine for analgesia after Caesarean section but there are few data on its comparative efficacy. We compared the analgesic ...efficacy of the TAP block with and without spinal morphine after Caesarean section in a prospective, randomized, double-blinded placebo-controlled trial.
Eighty patients were randomized to one of four groups to receive (in addition to spinal anaesthesia) either spinal morphine 100 µg (SM) or saline (SS) and a postoperative bilateral TAP block with either bupivacaine (TLA) 2 mg kg−1 or saline (TS).
Pain on movement and early morphine consumption were lowest in groups receiving spinal morphine and was not improved by TAP block. The rank order of median pain scores on movement at 6 h was: SMTLA (20 mm)<SMTS (27.5 mm)<SSTS (51.5 mm)<SSTLA (52.0 mm) (P<0.05, highest vs lowest). The rank order of median morphine consumption at 6 h was: SMTS (4.0 mg)<SMTLA (5.0 mg)<SSTLA (8.0 mg)<SSTS (12.0 mg) and at 24 h was: SMTLA (5.0 mg)<SMTS (6.0 mg)<SSTS (9.5 mg)<SSTLA (15.0 mg) (P<0.05, highest vs lowest). Sedation scores and patient satisfaction did not differ between groups. Anti-emetic use and pruritus were highest in the SMTLA group.
Spinal morphine—but not TAP block—improved analgesia after Caesarean section. The addition of TAP block with bupivacaine 2 mg kg−1 to spinal morphine did not further improve analgesia.
To use structural equation modelling (SEM) to determine (1) the direct and indirect associations of strength of paretic lower limb muscles with the level of community integration, and (2) the direct ...association of walking endurance and balance performance with the level of community integration in community-dwelling stroke survivors.
In this cross-sectional study of 105 stroke survivors, the Subjective Index of Physical and Social Outcome (SIPSO) was used to measure the level of community integration. Lower-limb strength measures included isometric paretic ankle strength and isokinetic paretic knee peak torque. The Berg Balance Scale (BBS) and the 6-minute walk test (6MWT) were used to evaluate balance performance and walking endurance, respectively.
SEM revealed that the distance walked on the 6MWT had the strongest direct association with the SIPSO score (β = 0.41, p <0.001). An increase of one standard deviation in the 6MWT distance resulted in an increase of 0.41 standard deviations in the SIPSO score. Moreover, dorsiflexion strength (β = 0.18, p = 0.044) and the BBS score (β = 0.21, p = 0.021) had direct associations with the SIPSO score.
The results of the proposed model suggest that rehabilitation training of community-dwelling stroke survivors could focus on walking endurance, balance performance and dorsiflexor muscle strengthening if the aim is to augment the level of community integration.
Effective targeted therapy for non-small-cell lung cancer (NSCLC) patients with human epidermal growth factor receptor 2 (HER2) mutations remains an unmet need. This study investigated the antitumor ...effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib.
Using patient-derived organoids and xenografts established from an HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the antitumor activity of pyrotinib. Preliminary safety and efficacy of pyrotinib in 15 HER2-mutant NSCLC patients in a phase II clinical trial are also presented.
Pyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P = 0.0038). In the PDX model, pyrotinib showed a superior antitumor effect than afatinib (P = 0.0471) and T-DM1 (P = 0.0138). Mice treated with pyrotinib displayed significant tumor burden reduction (mean tumor volume, −52.2%). In contrast, afatinib (25.4%) and T-DM1 (10.9%) showed no obvious reduction. Moreover, pyrotinib showed a robust ability to inhibit pHER2, pERK and pAkt. In the phase II cohort of 15 patients with HER2-mutant NSCLC, pyrotinib 400 mg resulted in a objective response rate of 53.3% and a median progression-free survival of 6.4 months.
Pyrotinib showed activity against NSCLC with HER2 exon 20 mutations in both patient-derived organoids and a PDX model. In the clinical trial, pyrotinib showed promising efficacy.
NCT02535507.
The transformation of organic amendments (OA) in soil is in large part performed by soil microbial communities. These processes are strongly affected by the carbon composition of the OAs. We examined ...microbial community responses to three types of OA: green waste, composted green waste and pyrolysed green waste added to two contrasting agricultural soils. We investigated the relationship between the soil carbon composition (as determined by 13C-solid state NMR), microbial community composition (as determined by phospholipid fatty acid analysis) and microbial activity (as determined by soil enzyme assays). We found that alkyl-C, O-aryl-C, aryl-C and carbonyl-C were able to explain most of the variations (≥50%) in soil microbial community composition and activity. Aryl-C content (reflecting relatively stable carbon forms) strongly influenced microbial composition, while carbonyl-C content (reflecting relatively labile carbon forms) strongly influenced the microbial activity. Our results confirm that there is a tight relationship between carbon composition and soil microbial community composition and function. Results are discussed in the context of examining the relationship between carbon forms, microbial community composition and activity following the addition of different OAs to the soil.
•Composting and pyrolysis alters carbon forms and stabilises green waste.•Soil C forms explain 57% and 46% variations in microbial composition and activity.•Aryl-C content (∼stable C forms) strongly influenced microbial composition.•Carbonyl-C content (∼labile C forms) strongly influenced microbial activity.•Knowledge of soil C composition improves prediction of organic amendment turnover.
Background Traumatic events are common globally; however, comprehensive population-based cross-national data on the epidemiology of posttraumatic stress disorder (PTSD), the paradigmatic ...trauma-related mental disorder, are lacking. Methods Data were analyzed from 26 population surveys in the World Health Organization World Mental Health Surveys. A total of 71 083 respondents ages 18+ participated. The Composite International Diagnostic Interview assessed exposure to traumatic events as well as 30-day, 12-month, and lifetime PTSD. Respondents were also assessed for treatment in the 12 months preceding the survey. Age of onset distributions were examined by country income level. Associations of PTSD were examined with country income, world region, and respondent demographics. Results The cross-national lifetime prevalence of PTSD was 3.9% in the total sample and 5.6% among the trauma exposed. Half of respondents with PTSD reported persistent symptoms. Treatment seeking in high-income countries (53.5%) was roughly double that in low-lower middle income (22.8%) and upper-middle income (28.7%) countries. Social disadvantage, including younger age, female sex, being unmarried, being less educated, having lower household income, and being unemployed, was associated with increased risk of lifetime PTSD among the trauma exposed. Conclusions PTSD is prevalent cross-nationally, with half of all global cases being persistent. Only half of those with severe PTSD report receiving any treatment and only a minority receive specialty mental health care. Striking disparities in PTSD treatment exist by country income level. Increasing access to effective treatment, especially in low- and middle-income countries, remains critical for reducing the population burden of PTSD.
Aims/hypothesis
Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the ...aim of identifying novel variants for type 2 diabetes in Asians.
Methods
We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.
Results
We identified
CDKN2A/B
and four novel type 2 diabetes association signals with
p
< 1 × 10
−5
from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (
p
meta
= 2.6 × 10
−8
; OR 95% CI 1.18 1.11, 1.25). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (
p
meta
= 2.3 × 10
−10
) and a population of European descent (
p
= 8.6 × 10
−3
). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.
Conclusions/interpretation
Our study identifies rs10229583 near
PAX4
as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.
We report on four radio-detected cosmic-ray (CR) or CR-like events observed with the Antarctic Impulsive Transient Antenna (ANITA), a NASA-sponsored long-duration balloon payload. Two of the four ...were previously identified as stratospheric CR air showers during the ANITA-I flight. A third stratospheric CR was detected during the ANITA-II flight. Here, we report on characteristics of these three unusual CR events, which develop nearly horizontally, 20-30 km above the surface of Earth. In addition, we report on a fourth steeply upward-pointing ANITA-I CR-like radio event which has characteristics consistent with a primary that emerged from the surface of the ice. This suggests a possible τ-lepton decay as the origin of this event, but such an interpretation would require significant suppression of the standard model τ-neutrino cross section.
Controlling vibrations in solids is crucial to tailor their elastic properties and interaction with light. Thermal vibrations represent a source of noise and dephasing for many physical processes at ...the quantum level. One strategy to avoid these vibrations is to structure a solid such that it possesses a phononic stop band, that is, a frequency range over which there are no available elastic waves. Here we demonstrate the complete absence of thermal vibrations in a nanostructured silicon membrane at room temperature over a broad spectral window, with a 5.3-GHz-wide bandgap centred at 8.4 GHz. By constructing a line-defect waveguide, we directly measure gigahertz guided modes without any external excitation using Brillouin light scattering spectroscopy. Our experimental results show that the shamrock crystal geometry can be used as an efficient platform for phonon manipulation with possible applications in optomechanics and signal processing transduction.Nanopatterned materials provide control over mechanical vibrations. This allows for the complete damping of vibrations over more than 5 GHz and for the propagation of hypersonic guided modes at room temperature.
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