Nanopore‐Based, Rapid Characterization of Individual Amyloid Particles in Solution: Concepts, Challenges, and Prospects

Aggregates of misfolded proteins are associated with several devastating neurodegenerative diseases. These so‐called amyloids are therefore explored as biomarkers for the diagnosis of dementia and other disorders, as well as for monitoring disease progression and assessment of the efficacy of therapeutic interventions. Quantification and characterization of amyloids as biomarkers is particularly demanding because the same amyloid‐forming protein can exist in different states of assembly, ranging from nanometer‐sized monomers to micrometer‐long fibrils that interchange dynamically both in vivo and in samples from body fluids ex vivo. Soluble oligomeric amyloid aggregates, in particular, are associated with neurotoxic effects, and their molecular organization, size, and shape appear to determine their toxicity. This concept article proposes that the emerging field of nanopore‐based analytics on a single molecule and single aggregate level holds the potential to account for the heterogeneity of amyloid samples and to characterize these particles—rapidly, label‐free, and in aqueous solution—with regard to their size, shape, and abundance. The article describes the concept of nanopore‐based resistive pulse sensing, reviews previous work in amyloid analysis, and discusses limitations and challenges that will need to be overcome to realize the full potential of amyloid characterization on a single‐particle level.Information about amyloid aggregation states is critical to understanding the pathological progression of many neurodegenerative diseases. Resistive pulse‐based nanopore sensing is a unique single‐molecule approach to studying these aggregation states because it can determine information about individual amyloids, oligomeric species, or fibrils in an aqueous solution without fluorescent labels or chemical modifications.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146577/1/smll201802412_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146577/2/smll201802412.pd

The origin of pine pollen grains captured from air at Calypsobyen, Svalbard

Spitsbergen is the largest island in the Svalbard Archipelago (Norway) that has been permanently populated. The harsh Arctic climate prevents development of large vascular plants such as trees. A two-year aerobiological survey was conducted within the framework of two consecutive polar expeditions (2014 and 2015) in Spitsbergen (Calypsobyen, Bellsund). The air quality was measured continuously from June/July to August using a 7-day volumetric air sampler, Tauber trap and moss specimens. Collected air samples and gravimetric pollen deposits were processed following transfer to sterile laboratory conditions and analyzed with the aid of light microscopy. Days when pine pollen grains were detected in the air were selected for further analysis. Clusters of back-trajectories, computed using the Hybrid Single Particle Lagrangian Integrated Trajectory model in combination with ArcGIS software as well as the Flextra trajectory model, showed the movement of air masses to the sampling location at Hornsund, and thus indicated the likely origin of pollen grains. The GlobCover 2009 and CORINE Land Cover 2012 datasets were employed to establish the distribution of coniferous forests in the areas of interest. Conclusions were drawn based on the analyses of the circulation of air masses, using visualization of global weather conditions forecast to supercomputers. For the first time, we have demonstrated that pine pollen grains occurring in pine-free Spitsbergen, could originate from numerous locations, including Scandinavia, Iceland, Siberia and northern Canada. Pollen grains were transported via air masses for distances exceeding ~2000 km. Both air samples and gravimetric pollen deposits revealed the same pattern of Pinus pollen distributio

Radiolytic effects of plutonium.

Plutonium isotopes, most of them a-emitters, cause radiolytic changes in the matrix, in whic h they are embedded. The internal irradiation of Pu metal or its alloys results in physical changes, largel y as a result of the formation of helium bubbles, well-known to material scientists and weapons specialists . In all other media where plutonium occurs, usually as Pu'+ in an ionic form, the results of irradiation ar e chemical in nature. Homogenous media containing Pu, are often aqueous or non-aqueous solutions o f plutonium compounds, mostly originating during processing of spent nuclear fuel or from Pu processing . Heterogenous matrices containing plutonium are more complex from the point of view of radiolysis; they usually contain a variety of combinations of common materials contaminated with radionuclides . This class of radioactive materials represents a challenge for the management of plutonium waste . One has to consider a range of time scales for radiolytic effects (and consequently a several orders o f magnitude range of the cumulative dose) beginning with waste generation, through packaging, transportation, to the period of final storage . Final storage could be for thousands of years in deep geologic repositories . At every ' stage of that time scale, radiolysis proceeds continuously an d cumulative effects c an complicate operating procedures and final disposition . The results presented here have been obtained from experiments that have irradiated of model materials, which are typically the objects of contamination with plutonium . They were irradiated with linearly accelerated electrons up to very high dose rates, adjusted to simulate any contamination at any point on the time scale

Built environment change and change in BMI and waist circumference: Multi‐ethnic S tudy of A therosclerosis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109571/1/oby20873.pd

Inhaled nitric oxide to control platelet hyper-reactivity in patients with acute submassive pulmonary embolism

Background: We test if inhaled nitric oxide (NO) attenuates platelet functional and metabolic hyper-reactivity in subjects with submassive pulmonary embolism (PE). Methods: Participants with PE were randomized to either 50 ppm NO + O2 or O2 only for 24 h with blood sampling at enrollment and after treatment; results were compared with healthy controls. Platelet metabolic activity was assessed by oxygen consumption (basal and uncoupled) and reactivity was assessed with agonist-stimulated thromboelastography (TEG) and fluorometric measurement of agonist-stimulated cytosolic [Ca++] without and with pharmacological soluble guanylate (sGC) modulation. Results: Participants (N = 38 per group) were well-matched at enrollment for PE severity, comorbidities as well as TEG parameters and platelet O2 consumption. NO treatment doubled the mean plasma [NO3-] (P < 0.001) indicating successful delivery, but placebo treatment produced no change. After 24 h, neither TEG nor O2 consumption parameters differed significantly between treatment groups. Platelet cytosolic [Ca++] was elevated with PE versus controls, and was decreased by treatment with cinaciguat (an sGC activator), but not riociguat (an sGC stimulator). Stimulated platelet lysate sGC activity was increased with PE compared with controls. Conclusions: In patients with acute submassive PE, despite evidence of adequate drug delivery, inhaled NO had no major effect on platelet O2 consumption or agonist-stimulated parameters on TEG. Pharmacological activation, but not stimulation, of sGC effectively decreased platelet cytosolic [Ca++], and platelet sGC activity was increased with PE, confirming the viability of sGC as a therapeutic target

Angiotensin II Induces Neutrophil Accumulation In Vivo Through Generation and Release of CXC Chemokines

Background— Angiotensin II (Ang II) is implicated in the development of cardiac ischemic disorders in which prominent neutrophil accumulation occurs. Ang II can be generated intravascularly by the renin-angiotensin system or extravascularly by mast cell chymase. In this study, we characterized the ability of Ang II to induce neutrophil accumulation. Methods and Results— Intraperitoneal administration of Ang II (1 nmol/L) induced significant neutrophil recruitment within 4 hours (13.3±2.3x106 neutrophils per rat versus 0.7±0.5x106 in control animals), which disappeared by 24 hours. Maximal levels of CXC chemokines were detected 1 hour after Ang II injection (577±224 pmol/L cytokine-inducible neutrophil chemoattractant [CINC]/keratinocyte-derived chemokine [KC] versus 5±3, and 281±120 pmol/L macrophage inflammatory protein [MIP-2] versus 14±6). Intravital microscopy within the rat mesenteric microcirculation showed that the short-term (30 to 60 minutes) leukocyte–endothelial cell interactions induced by Ang II were attenuated by an anti-rat CINC/KC antibody and nearly abolished by the CXCR2 antagonist SB-517785-M. In human umbilical vein endothelial cells (HUVECs) or human pulmonary artery media in culture, Ang II induced interleukin (IL)-8 mRNA expression at 1, 4, and 24 hours and the release of IL-8 at 4 hours through interaction with Ang II type 1 receptors. When HUVECs were pretreated with IL-1 for 24 hours to promote IL-8 storage in Weibel-Palade bodies, the Ang II–induced IL-8 release was more rapid and of greater magnitude. Conclusions— Ang II provokes rapid neutrophil recruitment, mediated through the release of CXC chemokines such as CINC/KC and MIP-2 in rats and IL-8 in humans, and may contribute to the infiltration of neutrophils observed in acute myocardial infarction.Mata Roig, Manuel, [email protected] ; Cortijo Gimeno, Julio, [email protected] ; Morcillo Sanchez, Esteban Jesus, [email protected] ; Jose, Peter J., [email protected] ; Sanz Ferrando, Maria Jesus, [email protected]

Panspermia, Past and Present: Astrophysical and Biophysical Conditions for the Dissemination of Life in Space

Astronomically, there are viable mechanisms for distributing organic material throughout the Milky Way. Biologically, the destructive effects of ultraviolet light and cosmic rays means that the majority of organisms arrive broken and dead on a new world. The likelihood of conventional forms of panspermia must therefore be considered low. However, the information content of dam-aged biological molecules might serve to seed new life (necropanspermia).Comment: Accepted for publication in Space Science Review