Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5′-untranslated region: Implications in Alzheimer’s disease

In addition to the devastating symptoms of dementia, Alzheimer’s disease (AD) is characterized by accumulation of the processing products of the amyloid-β (Aβ) peptide precursor protein (APP). APP’s non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3′-untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5′-UTR to upregulate APP translation and Aβ production. This upregulation is reduced but not eliminated by knockdown of argonaute 2. The target site for miR-346 overlaps with active sites for an iron-responsive element (IRE) and an interleukin-1 (IL-1) acute box element. IREs interact with iron response protein1 (IRP1), an iron-dependent translational repressor. In primary human brain cultures, miR-346 activity required chelation of Fe. In addition, miR-346 levels are altered in late-Braak stage AD. Thus, miR-346 plays a role in upregulation of APP in the CNS and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. Further work will be necessary to integrate other metals, and IL-1 into the Fe-miR-346 activity network. We, thus, propose a “FeAR” (Fe, APP, RNA) nexus in the APP 5′-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a “healthy FeAR” exists, activities of miR-346 and IRP/Fe interact to maintain APP homeostasis. Disruption of an element that targets the FeAR nexus would lead to pathogenic disruption of APP translation and protein production

Effects of Oxygen Partial Pressure on the Surface Tension of Liquid Nickel

The NASA Marshall Space Flight Center's electrostatic levitation (ESL) laboratory has been recently upgraded with an oxygen partial pressure controller. This system allows the oxygen partial pressure within the vacuum chamber to be measured and controlled, theoretically in the range from 1036 to 100 bar. The oxygen control system installed in the ESL laboratory's main chamber consists of an oxygen sensor, oxygen pump, and a control unit. The sensor is a potentiometric device that determines the difference in oxygen activity in two gas compartments (inside the chamber and the air outside of the chamber) separated by an electrolyte, which is yttriastabilized zirconia. The pump utilizes coulometric titration to either add or remove oxygen. The system is controlled by a desktop control unit, which can also be accessed via a computer. The controller performs temperature control for the sensor and pump, PID-based current loop, and a control algorithm. Oxygen partial pressure has been shown to play a significant role in the surface tension of liquid metals. Oxide films or dissolved oxygen may lead to significant changes in surface tension. The effects of oxygen partial pressure on the surface tension of undercooled liquid nickel will be analyzed, and the results will be presented. The surface tension will be measured at several different oxygen partial pressures while the sample is undercooled. Surface tension will be measured using the oscillating drop method. While undercooled, each sample will be oscillated several times consecutively to investigate how the surface tension behaves with time while at a particular oxygen partial pressure

Fate of internal waves on a shallow shelf

Author Posting. © American Geophysical Union, 2020. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Oceans 125(5), (2020): e2019JC015377, doi:10.1029/2019JC015377.Internal waves strongly influence the physical and chemical environment of coastal ecosystems worldwide. We report novel observations from a distributed temperature sensing (DTS) system that tracked the transformation of internal waves from the shelf break to the surf zone over a narrow shelf slope region in the South China Sea. The spatially continuous view of temperature fields provides a perspective of physical processes commonly available only in laboratory settings or numerical models, including internal wave reflection off a natural slope, shoreward transport of dense fluid within trapped cores, and observations of internal rundown (near‐bed, offshore‐directed jets of water preceding a breaking internal wave). Analysis shows that the fate of internal waves on this shelf—whether transmitted into shallow waters or reflected back offshore—is mediated by local water column density structure and background currents set by the previous shoaling internal waves, highlighting the importance of wave‐wave interactions in nearshore internal wave dynamics.We are grateful for the support of the Dongsha Atoll Research Station (DARS) and the Dongsha Atoll Marine National Park, whose efforts made this research possible. The authors would also like to thank A. Hall, S. Tyler, and J. Selker from the Center for Transformative Environmental Monitoring Programs (CTEMPs) funded by the National Science Foundation (EAR awards 1440596 and 1440506), G. Lohmann from WHOI, A. Safaie from UC Irvine, G. Wong, L. Hou, F. Shiah, and K. Lee from Academia Sinica for providing logistical and field support, as well as E. Pawlak, S. Lentz, B. Sanders, and S. Grant for equipment, and B. Raubenheimer, S. Elgar, R. Walter and D. Lucas for informative discussions that improved this work. We acknowledge the US Army Research Laboratory DoD Supercomputing Resource Center for computer time on Excalibur, which was used for the numerical simulations in this work. Funding for this work supported by Academia Sinica and for K.D. and E.R. from NSF‐OCE 1753317 and for O.F., J.R., and R.A. from ONR Grant 1182789‐1‐TDZZM. A portion of this work (R.A.) was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE‐AC52‐07NA27344.2020-10-2

Multidimensional en-face OCT imaging of the retina.

Fast T-scanning (transverse scanning, en-face) was used to build B-scan or C-scan optical coherence tomography (OCT) images of the retina. Several unique signature patterns of en-face (coronal) are reviewed in conjunction with associated confocal images of the fundus and B-scan OCT images. Benefits in combining T-scan OCT with confocal imaging to generate pairs of OCT and confocal images similar to those generated by scanning laser ophthalmoscopy (SLO) are discussed in comparison with the spectral OCT systems. The multichannel potential of the OCT/SLO system is demonstrated with the addition of a third hardware channel which acquires and generates indocyanine green (ICG) fluorescence images. The OCT, confocal SLO and ICG fluorescence images are simultaneously presented in a two or a three screen format. A fourth channel which displays a live mix of frames of the ICG sequence superimposed on the corresponding coronal OCT slices for immediate multidimensional comparison, is also included. OSA ISP software is employed to illustrate the synergy between the simultaneously provided perspectives. This synergy promotes interpretation of information by enhancing diagnostic comparisons and facilitates internal correction of movement artifacts within C-scan and B-scan OCT images using information provided by the SLO channel

Adeno-Associated Virus-Mediated Rescue of the Cognitive Defects in a Mouse Model for Angelman Syndrome

Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, an ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. However, we have determined that abnormal calcium/calmodulin-dependent protein kinase II (CaMKII) regulation is seen in the maternal UBE3A deletion AS mouse model and is responsible for the major phenotypes. Specifically, there is an increased αCaMKII phosphorylation at the autophosphorylation sites Thr286 and Thr305/306, resulting in an overall decrease in CaMKII activity. CaMKII is not produced until after birth, indicating that the deficits associated with AS are not the result of developmental abnormalities. The present studies are focused on exploring the potential to rescue the learning and memory deficits in the adult AS mouse model through the use of an adeno-associated virus (AAV) vector to increase neuronal UBE3A expression. These studies show that increasing the levels of E6-AP in the brain using an exogenous vector can improve the cognitive deficits associated with AS. Specifically, the associative learning deficit was ameliorated in the treated AS mice compared to the control AS mice, indicating that therapeutic intervention may be possible in older AS patients

Unsupervised discovery and comparison of structural families across multiple samples in untargeted metabolomics

In untargeted metabolomics approaches, the inability to structurally annotate relevant features and map them to biochemical pathways is hampering the full exploitation of many metabolomics experiments. Furthermore, variable metabolic content across samples result in sparse feature matrices that are statistically hard to handle. Here, we introduce MS2LDA+ that tackles both above-mentioned problems. Previously, we presented MS2LDA, which extracts biochemically relevant molecular substructures (“Mass2Motifs”) from a collection of fragmentation spectra as sets of co-occurring molecular fragments and neutral losses, thereby recognizing building blocks of metabolomics. Here, we extend MS2LDA to handle multiple metabolomics experiments in one analysis, resulting in MS2LDA+. By linking Mass2Motifs across samples, we expose the variability in prevalence of structurally related metabolite families. We validate the differential prevalence of substructures between two distinct samples groups and apply it to fecal samples. Subsequently, within one sample group of urines, we rank the Mass2Motifs based on their variance to assess whether xenobiotic-derived substructures are among the most-variant Mass2Motifs. Indeed, we could ascribe 22 out of the 30 most-variant Mass2Motifs to xenobiotic-derived substructures including paracetamol/acetaminophen mercapturate and dimethylpyrogallol. In total, we structurally characterized 101 Mass2Motifs with biochemically or chemically relevant substructures. Finally, we combined the discovered metabolite families with full scan feature intensity information to obtain insight into core metabolites present in most samples and rare metabolites present in small subsets now linked through their common substructures. We conclude that by biochemical grouping of metabolites across samples MS2LDA+ aids in structural annotation of metabolites and guides prioritization of analysis by using Mass2Motif prevalence

Detection of intrinsic source structure at ~3 Schwarzschild radii with Millimeter-VLBI observations of SAGITTARIUS A*

We report results from very long baseline interferometric (VLBI) observations of the supermassive black hole in the Galactic center, Sgr A*, at 1.3 mm (230 GHz). The observations were performed in 2013 March using six VLBI stations in Hawaii, California, Arizona, and Chile. Compared to earlier observations, the addition of the APEX telescope in Chile almost doubles the longest baseline length in the array, provides additional {\it uv} coverage in the N-S direction, and leads to a spatial resolution of $\sim$30 $\mu$as ($\sim$3 Schwarzschild radii) for Sgr A*. The source is detected even at the longest baselines with visibility amplitudes of $\sim$4-13% of the total flux density. We argue that such flux densities cannot result from interstellar refractive scattering alone, but indicate the presence of compact intrinsic source structure on scales of $\sim$3 Schwarzschild radii. The measured nonzero closure phases rule out point-symmetric emission. We discuss our results in the context of simple geometric models that capture the basic characteristics and brightness distributions of disk- and jet-dominated models and show that both can reproduce the observed data. Common to these models are the brightness asymmetry, the orientation, and characteristic sizes, which are comparable to the expected size of the black hole shadow. Future 1.3 mm VLBI observations with an expanded array and better sensitivity will allow a more detailed imaging of the horizon-scale structure and bear the potential for a deep insight into the physical processes at the black hole boundary.Comment: 11 pages, 5 figures, accepted to Ap