Combining array tomography with electron tomography provides insights into leakiness of the blood-brain barrier in mouse cortex.

Like other volume electron microscopy approaches, automated tape-collecting ultramicrotomy (ATUM) enables imaging of serial sections deposited on thick plastic tapes by scanning electron microscopy (SEM). ATUM is unique in enabling hierarchical imaging and thus efficient screening for target structures, as needed for correlative light and electron microscopy. However, SEM of sections on tape can only access the section surface, thereby limiting the axial resolution to the typical size of cellular vesicles with an order of magnitude lower than the acquired xy resolution.

Metabolomic profiling of upper GI malignancies in blood and tissue: a systematic review and meta-analysis.

Objective: To conduct a systematic review and meta-analysis of case-control and cohort human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on esophageal cancer (EC), cancer of the gastroesophageal junction (GEJ), and gastric cancer (GC) in blood and tissue.

Background: Upper gastrointestinal cancers (UGC), predominantly EC, GEJ, and GC, are malignant tumour types with high morbidity and mortality rates. Numerous studies have focused on metabolomic profiling of UGC in recent years.

To see or not to see: In vivo nanocarrier detection methods in the brain and their challenges.

Nanoparticles have a great potential to significantly improve the delivery of therapeutics to the brain and may also be equipped with properties to investigate brain function. The brain, being a highly complex organ shielded by selective barriers, requires its own specialized detection system. However, a significant hurdle to achieve these goals is still the identification of individual nanoparticles within the brain with sufficient cellular, subcellular, and temporal resolution.

Safety and Suitability of Infant Formula Manufactured from Extensively Hydrolyzed Whey Protein Compared to Intact Protein: A Combined Analysis of Two Randomized Controlled Studies.

Our aim was to assess the nutritional safety and suitability of an infant formula manufactured from extensively hydrolyzed protein in comparison to infant formula manufactured from intact protein (both with low and standard protein content). We performed a combined analysis of raw data from two randomized infant feeding studies. An analysis of covariance (ANCOVA) model was used to determine the non-inferiority of daily weight gain (primary outcome; margin -3 g/day), with the intervention group as a fixed factor and geographic region, sex, and baseline weight as covariates (main model).

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel).

Automated sample preparation with 6-Aminoquinolyl-N-hydroxysuccinimidyl carbamate and iodoacetamide derivatization reagents for enantioselective liquid chromatography tandem mass spectrometry amino acid analysis.

Enantioselective amino acid analysis is gaining increasing importance in pharmaceutical, biomedical and food sciences. While there are many methods available for enantiomer separation of amino acids, the simultaneous analysis of all chiral proteinogenic amino acids by a single method with one column and a single condition is still challenging. Herein, we report an enantioselective high-performance liquid chromatography-tandem mass spectrometry (LC-MS) assay using Chiralpak QN-AX as chiral column.

Comprehensive reversed-phase×chiral two-dimensional liquid chromatography coupled to quadrupole-time-of-flight tandem mass spectrometry with post-first dimension flow splitting for untargeted enantioselective amino acid analysis.

This work describes a comprehensive achiral × chiral two-dimensional liquid chromatography separation for enantioselective amino acid analysis coupled to electrospray ionization-tandem mass spectrometry detection using data-independent acquisition. Flow splitting after the first and second dimension separation was utilized for volumetric flow reduction and for enabling a multi-detector approach (with ultraviolet, fluorescence, charged aerosol, and MS detection), respectively. Derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate provided a chromophore, a fluorophore, and an efficient mass tag for efficient ionization in positive electrospray ionization-mass spectrometry.

Asymmetric Transfer Hydrogenation as a Key Step in the Synthesis of the Phosphonic Acid Analogs of Aminocarboxylic Acids.

α-Aminophosphonic acids have a remarkably broad bioactivity spectrum. They can function as highly efficient transition state mimics for a variety of hydrolytic and angiotensin-converting enzymes, which makes them interesting target structures for synthetic chemists. In particular, the phosphonic acid analogs to α-aminocarboxylic acids (P AAs) are potent enzyme inhibitors, but many of them are only available by chiral or enzymatic resolution; sometimes only one enantiomer is accessible, and several have never been prepared in enantiopure form at all.

DNA methylation as a potential mediator of the association between indoor air pollution and neurodevelopmental delay in a South African birth cohort.

Background: Exposure to indoor air pollution during pregnancy has been linked to neurodevelopmental delay in toddlers. Epigenetic modification, particularly DNA methylation (DNAm), may explain this link. In this study, we employed three high-dimensional mediation analysis methods (HIMA, DACT, and gHMA) followed by causal mediation analysis to identify differentially methylated CpG sites and genes that mediate the association between indoor air pollution and neurodevelopmental delay.

Comprehensive Online Reversed-Phase × Chiral Two-Dimensional Liquid Chromatography-Mass Spectrometry with Data-Independent Sequential Window Acquisition of All Theoretical Fragment-Ion Spectra-Acquisition for Untargeted Enantioselective Amino Acid Analysis.

This work presents an advanced analytical platform for untargeted enantioselective amino acid analysis (eAAA) by comprehensive achiral × chiral 2D-LC hyphenated to ESI-QTOF-MS/MS utilizing data-independent SWATH (sequential window acquisition of all theoretical fragment-ion spectra) technology. The methodology involves -terminal pre-column derivatization with 6-aminoquinolyl--hydroxysuccinimidyl carbamate (AQC; AccQ) as retention, selectivity, and MS tag, supporting retention and UV detection in RPLC (D), chiral recognition, and thus enantioselectivity by the core-shell tandem column composed of a quinine carbamate weak anion exchanger (QN-AX) and a zwitterionic chiral ion-exchanger (ZWIX(+)) (D) as well as the ionization efficiency during positive electrospray ionization due to a high proton affinity of the AQC label. Furthermore, the urea-type MS tag gives rise to the generation of AQC-tag characteristic signature fragments in MS.

DNA methylation as a potential mediator of the association between prenatal tobacco and alcohol exposure and child neurodevelopment in a South African birth cohort.

Prenatal tobacco exposure (PTE) and prenatal alcohol exposure (PAE) have been associated with an increased risk of delayed neurodevelopment in children as well as differential newborn DNA methylation (DNAm). However, the biological mechanisms connecting PTE and PAE, DNAm, and neurodevelopment are largely unknown. Here we aim to determine whether differential DNAm mediates the association between PTE and PAE and neurodevelopment at 6 (N = 112) and 24 months (N = 184) in children from the South African Drakenstein Child Health Study.

DNA methylation and aeroallergen sensitization: The chicken or the egg?

Background: DNA methylation (DNAm) is considered a plausible pathway through which genetic and environmental factors may influence the development of allergies. However, causality has yet to be determined as it is unknown whether DNAm is rather a cause or consequence of allergic sensitization. Here, we investigated the direction of the observed associations between well-known environmental and genetic determinants of allergy, DNAm, and aeroallergen sensitization using a combination of high-dimensional and causal mediation analyses.

Allergic disease trajectories up to adolescence: Characteristics, early-life, and genetic determinants.

Background: Allergic diseases often develop jointly during early childhood but differ in timing of onset, remission, and progression. Their disease course over time is often difficult to predict and determinants are not well understood.

Objectives: We aimed to identify trajectories of allergic diseases up to adolescence and to investigate their association with early-life and genetic determinants and clinical characteristics.

A genome-wide association study of total child psychiatric problems scores.

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium.

Airway inflammation in adolescents and elderly women: Chronic air pollution exposure and polygenic susceptibility.

Background And Aim: The fractional exhaled nitric oxide (FeNO) concentration in the exhaled breath is a biomarker for eosinophilic airway inflammation. We explored the interplay between chronic air pollution exposure and polygenic susceptibility to airway inflammation at different critical age stages.

Methods: Adolescents (15 yr) enrolled in the GINIplus/LISA birth cohorts (n = 2434) and 220 elderly women (75 yr on average) enrolled in the SALIA cohort with FeNO measurements available were investigated.

Methylation risk scores for childhood aeroallergen sensitization: Results from the LISA birth cohort.

Background: Epigenomic (e.g., DNA methylation [DNAm]) changes have been hypothesized as intermediate step linking environmental exposures with allergic disease.

Size-Selective Transfer of Lipid Nanoparticle-Based Drug Carriers Across the Blood Brain Barrier Via Vascular Occlusions Following Traumatic Brain Injury.

The current lack of understanding about how nanocarriers cross the blood-brain barrier (BBB) in the healthy and injured brain is hindering the clinical translation of nanoscale brain-targeted drug-delivery systems. Here, the bio-distribution of lipid nano-emulsion droplets (LNDs) of two sizes (30 and 80 nm) in the mouse brain after traumatic brain injury (TBI) is investigated. The highly fluorescent LNDs are prepared by loading them with octadecyl rhodamine B and a bulky hydrophobic counter-ion, tetraphenylborate.

Machine learning based analysis of stroke lesions on mouse tissue sections.

An unbiased, automated and reliable method for analysis of brain lesions in tissue after ischemic stroke is missing. Manual infarct volumetry or by threshold-based semi-automated approaches is laborious, and biased to human error or biased by many false -positive and -negative data, respectively. Thereby, we developed a novel machine learning, atlas-based method for fully automated stroke analysis in mouse brain slices stained with 2% Triphenyltetrazolium-chloride (2% TTC), named "StrokeAnalyst", which runs on a user-friendly graphical interface.

Perfusion pressure determines vascular integrity and histomorphological quality following perfusion fixation of the brain.

Introduction: Histology on fixed brain tissue is a key technique to investigate the pathophysiology of neurological disorders. Best results are obtained by perfusion fixation, however, multiple protocols are available and so far the optimal perfusion pressure (PP) for the preservation of brain tissue while also maintaining vascular integrity is not defined. Therefore, the aim of our study was to investigate the effect of different PPs on the cerebral vasculature and to define the PP optimal for the preservation of both vascular integrity and tissue fixation.

Adhesion of Leukocytes to Cerebral Venules Precedes Neuronal Cell Death and Is Sufficient to Trigger Tissue Damage After Cerebral Ischemia.

Background: Leukocytes contribute to tissue damage after cerebral ischemia; however, the mechanisms underlying this process are still unclear. This study investigates the temporal and spatial relationship between vascular leukocyte recruitment and tissue damage and aims to uncover which step of the leukocyte recruitment cascade is involved in ischemic brain injury.

Methods: Male wild-type, ICAM-1-deficient, anti-CD18 antibody treated, or selectin-deficient [fucusyltransferase (FucT IV/VII)] mice were subjected to 60 min of middle cerebral artery occlusion (MCAo).

A Primeval Mechanism of Tolerance to Desiccation Based on Glycolic Acid Saves Neurons in Mammals from Ischemia by Reducing Intracellular Calcium-Mediated Excitotoxicity.

Stroke is the second leading cause of death and disability worldwide. Current treatments, such as pharmacological thrombolysis or mechanical thrombectomy, reopen occluded arteries but do not protect against ischemia-induced damage that occurs before reperfusion or neuronal damage induced by ischemia/reperfusion. It has been shown that disrupting the conversion of glyoxal to glycolic acid (GA) results in a decreased tolerance to anhydrobiosis in Caenorhabditis elegans dauer larva and that GA itself can rescue this phenotype.