The 3D OrbiSIMS—label-free metabolic imaging with subcellular lateral resolution and high mass-resolving power

We report the development of a 3D OrbiSIMS instrument for label-free biomedical imaging. It combines the high spatial resolution of secondary ion mass spectrometry (SIMS; under 200 nm for inorganic species and under 2 μm for biomolecules) with the high mass-resolving power of an Orbitrap (>240,000 at m/z 200). This allows exogenous and endogenous metabolites to be visualized in 3D with subcellular resolution. We imaged the distribution of neurotransmitters—gamma-aminobutyric acid, dopamine and serotonin—with high spectroscopic confidence in the mouse hippocampus. We also putatively annotated and mapped the subcellular localization of 29 sulfoglycosphingolipids and 45 glycerophospholipids, and we confirmed lipid identities with tandem mass spectrometry. We demonstrated single-cell metabolomic profiling using rat alveolar macrophage cells incubated with different concentrations of the drug amiodarone, and we observed that the upregulation of phospholipid species and cholesterol is correlated with the accumulation of amiodarone

Transcriptional analysis of abdominal fat in chickens divergently selected on bodyweight at two ages reveals novel mechanisms controlling adiposity: validating visceral adipose tissue as a dynamic endocrine and metabolic organ

Decades of intensive genetic selection in the domestic chicken (Gallus gallus domesticus) have enabled the remarkable rapid growth of today’s broiler (meat-type) chickens. However, this enhanced growth rate was accompanied by several unfavorable traits (i.e., increased visceral fatness, leg weakness, and disorders of metabolism and reproduction). The present descriptive analysis of the abdominal fat transcriptome aimed to identify functional genes and biological pathways that likely contribute to an extreme difference in visceral fatness of divergently selected broiler chickens. We used the Del-Mar 14 K Chicken Integrated Systems microarray to take time-course snapshots of global gene transcription in abdominal fat of juvenile [1-11 weeks of age (wk)] chickens divergently selected on bodyweight at two ages (8 and 36 wk). Further, a RNA sequencing analysis was completed on the same abdominal fat samples taken from high-growth (HG) and low-growth (LG) cockerels at 7 wk, the age with the greatest divergence in body weight (3.2-fold) and visceral fatness (19.6-fold). Time-course microarray analysis revealed 312 differentially expressed genes (FDR ≤ 0.05) as the main effect of genotype (HG versus LG), 718 genes in the interaction of age and genotype, and 2918 genes as the main effect of age. The RNA sequencing analysis identified 2410 differentially expressed genes in abdominal fat of HG versus LG chickens at 7 wk. The HG chickens are fatter and over-express numerous genes that support higher rates of visceral adipogenesis and lipogenesis. In abdominal fat of LG chickens, we found higher expression of many genes involved in hemostasis, energy catabolism and endocrine signaling, which likely contribute to their leaner phenotype and slower growth. Many transcription factors and their direct target genes identified in HG and LG chickens could be involved in their divergence in adiposity and growth rate. The present analyses of the visceral fat transcriptome in chickens divergently selected for a large difference in growth rate and abdominal fatness clearly demonstrate that abdominal fat is a very dynamic metabolic and endocrine organ in the chicken. The HG chickens overexpress many transcription factors and their direct target genes, which should enhance in situ lipogenesis and ultimately adiposity. Our observation of enhanced expression of hemostasis and endocrine-signaling genes in diminished abdominal fat of LG cockerels provides insight into genetic mechanisms involved in divergence of abdominal fatness and somatic growth in avian and perhaps mammalian species, including humans.https://doi.org/10.1186/s12864-017-4035-

TOF-SIMS depth profiling of multilayer amino-acid films using large Argon cluster Arn

The performance of Cs+, C60 + and Ar n + (with n ≈ 1700) sputtering ions have been compared for depth profiling multilayer films made from three evaporated phenylalanine layers sandwiched between four thicker evaporated tyrosine layers. Using Cs +, the ion signals and depth resolution degrade with depth and were significantly affected beyond a 200-nm depth. The depth profiling quality was more successful using C60 +. However, in this case, the depth resolution and the layer width values still degrade with the sputtered depth and are particularly poor after reaching a depth of about 400 nm. When Ar1700 + clusters were used, a depth resolution as low as 6 nm was obtained, and this value never exceeds 9 nm. Moreover, the experimental layer width is found to be of the same order of magnitude as the real value. Copyright © 2012 John Wiley & Sons, Ltd. Copyright © 2012 John Wiley & Sons, Ltd

Alzheimer's disease medication and outcomes of hospitalisation among patients with dementia

Aims. The use of Alzheimer disease medication for the treatment of dementia symptoms has shown significant benefits with regards to functional and cognitive outcomes as well as nursing home placement (NHP) and mortality. Hospitalisations in these patient groups are characterised by extended length of stays (LOS), frequent readmissions, frequent NHP and high-mortality rates. The impact of Alzheimer disease medication on the aforementioned outcomes remains still unknown. This study assessed the association of Alzheimer disease medication with outcomes of hospitalisation among patients with Alzheimer disease and other forms of dementia. Methods. A dynamic retrospective cohort study from 2004 to 2015 was conducted which claims data from a German health insurance company. People with dementia (PWD) were identified using ICD-10 codes and diagnostic measures. The main predictor of interest was the use of Alzheimer disease medication. Hospitalisation outcomes included LOS, readmissions, NHP and mortality during and after hospitalisation across four hospitalisations. Confounding was addressed using a propensity score throughout all analyses. Results. A total of 1380 users of Alzheimer disease medication and 6730 non-users were identified. The use of Alzheimer disease medication was associated with significantly shorter LOS during the first hospitalisations with estimates for the second, third and fourth showed a tendency towards shorter hospital stays. In addition, current users of Alzheimer disease medication had a lower risk of hospital readmission after the first two hospitalisations. These associations were not significant for the third and fourth hospitalisations. Post-hospitalisation NHP and mortality rates also tended to be lower among current users than among non-users but differences did not reach statistical significance. Conclusions. Our results indicate that Alzheimer disease medication might contribute to a reduction of the LOS and the number of readmissions in PWD

Self-Healing Vesicles Deposit Lipid-Coated Janus Particles into Nanoscopic Trenches

Using dissipative particle dynamics (DPD) simulations, we model the interaction between nanoscopic lipid vesicles and Janus nanoparticles localized on an adhesive substrate in the presence of an imposed flow. The system is immersed in a hydrophilic solution, and the hydrophilic substrate contains nanoscopic trenches, which are either step- or wedge-shaped. The fluid-driven vesicle successfully picks up Janus particles on the substrate, transports these particles as cargo along the surface, and then drops off the particles into the trenches. For Janus particles with a relatively large hydrophobic region, lipids from the bilayer membrane become detached from the vesicle and bound to the hydrophobic domain of the deposited particle. While the detachment of these lipids rips the vesicle, it provides a coating that effectively shields the hydrophobic portion of the nanoparticle from the outer solution. After the particle has been dropped off, the torn vesicle undergoes structural rearrangement, reforming into a closed structure that resembles its original shape. In effect, the vesicle displays pronounced adaptive behavior, shedding lipids to form a protective coating around the particle and undergoing a self-healing process after the particle has been deposited. This responsive, adaptive behavior is observed in cases involving both the step- and wedge-shaped trenches, but the step trench is more effective at inducing particle drop off. The results reveal that the introduction of grooves or trenches into a hydrophilic surface can facilitate the targeted delivery of amphiphilic particles by self-healing vesicles, which could be used for successive delivery events

Entwicklung einer gepulsten sub-#mu#m-Fluessigmetallionenquelle und Integration in ein abbildendes Flugzeit-Sekundaerionen-Massenspektrometer (TOF-SIMS) Schlussbericht

Available from TIB Hannover: F94B0405+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman

Genetic predisposition, A beta misfolding in blood plasma, and Alzheimer's disease

Alzheimer's disease is highly heritable and characterized by amyloid plaques and tau tangles in the brain. The aim of this study was to investigate the association between genetic predisposition, A beta misfolding in blood plasma, a unique marker of Alzheimer associated neuropathological changes, and Alzheimer's disease occurrence within 14 years. Within a German community-based cohort, two polygenic risk scores (clinical Alzheimer's disease and A beta (42) based) were calculated, APOE genotype was determined, and A beta misfolding in blood plasma was measured by immuno-infrared sensor in 59 participants diagnosed with Alzheimer's disease during 14 years of follow-up and 581 participants without dementia diagnosis. Associations between each genetic marker and A beta misfolding were assessed through logistic regression and the ability of each genetic marker and A beta misfolding to predict Alzheimer's disease was determined. The Alzheimer's disease polygenic risk score and APOE epsilon 4 presence were associated to A beta misfolding (odds ratio, 95% confidence interval: per standard deviation increase of score: 1.25, 1.03-1.51; APOE epsilon 4 presence: 1.61, 1.04-2.49). No association was evident for the A beta polygenic risk score. All genetic markers were predictive of Alzheimer's disease diagnosis albeit much less so than A beta misfolding (areas under the curve: A beta polygenic risk score: 0.55; AD polygenic risk score: 0.59; APOE epsilon 4: 0.63; A beta misfolding: 0.84). Clinical Alzheimer's genetic risk was associated to early pathological changes (A beta misfolding) measured in blood, however, predicted Alzheimer's disease less accurately than A beta misfolding itself. Genetic predisposition may provide information regarding disease initiation, while A beta misfolding could be important in clinical risk prediction