We present a practical guide for the implementation of recently revised National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). ...Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.
Palmitic acid esters of hydroxy stearic acids (PAHSAs) are bioactive lipids with antiinflammatory and antidiabetic effects. PAHSAs reduce ambient glycemia and improve glucose tolerance and insulin ...sensitivity in insulin-resistant aged chow- and high-fat diet-fed (HFD-fed) mice. Here, we aimed to determine the mechanisms by which PAHSAs improve insulin sensitivity. Both acute and chronic PAHSA treatment enhanced the action of insulin to suppress endogenous glucose production (EGP) in chow- and HFD-fed mice. Moreover, chronic PAHSA treatment augmented insulin-stimulated glucose uptake in glycolytic muscle and heart in HFD-fed mice. The mechanisms by which PAHSAs enhanced hepatic insulin sensitivity included direct and indirect actions involving intertissue communication between adipose tissue and liver. PAHSAs inhibited lipolysis directly in WAT explants and enhanced the action of insulin to suppress lipolysis during the clamp in vivo. Preventing the reduction of free fatty acids during the clamp with Intralipid infusion reduced PAHSAs' effects on EGP in HFD-fed mice but not in chow-fed mice. Direct hepatic actions of PAHSAs may also be important, as PAHSAs inhibited basal and glucagon-stimulated EGP directly in isolated hepatocytes through a cAMP-dependent pathway involving Gαi protein-coupled receptors. Thus, this study advances our understanding of PAHSA biology and the physiologic mechanisms by which PAHSAs exert beneficial metabolic effects.
Multiferroics, where (anti-) ferromagnetic, ferroelectric and ferroelastic order parameters coexist, enable manipulation of magnetic ordering by an electric field through switching of the electric ...polarization. It has been shown that realization of magnetoelectric coupling in a single-phase multiferroic such as BiFeO3 requires ferroelastic (71 , 109 ) rather than ferroelectric (180 ) domain switching. However, the control of such ferroelastic switching in a single-phase system has been a significant challenge as elastic interactions tend to destabilize small switched volumes, resulting in subsequent ferroelastic back-switching at zero electric field, and thus the disappearance of non-volatile information storage. Guided by our phase-field simulations, here we report an approach to stabilize ferroelastic switching by eliminating the stress-induced instability responsible for back-switching using isolated monodomain BiFeO3 islands. This work demonstrates a critical step to control and use non-volatile magnetoelectric coupling at the nanoscale. Beyond magnetoelectric coupling, it provides a framework for exploring a route to control multiple order parameters coupled to ferroelastic order in other low-symmetry materials.
Flexoelectricity refers to electric polarization generated by heterogeneous mechanical strains, namely strain gradients, in materials of arbitrary crystal symmetries. Despite more than 50 years of ...work on this effect, an accurate identification of its coupling strength remains an experimental challenge for most materials, which impedes its wide recognition. Here, we show the presence of flexoelectricity in the recently discovered polar vortices in PbTiO3/SrTiO3 superlattices based on a combination of machine-learning analysis of the atomic-scale electron microscopy imaging data and phenomenological phase-field modeling. By scrutinizing the influence of flexocoupling on the global vortex structure, we match theory and experiment using computer vision methodologies to determine the flexoelectric coefficients for PbTiO3 and SrTiO3. Our findings highlight the inherent, nontrivial role of flexoelectricity in the generation of emergent complex polarization morphologies and demonstrate a viable approach to delineating this effect, conducive to the deeper exploration of both topics.
Cognitively intact elderly research volunteers at the University of Kentucky have been recruited, followed longitudinally, and autopsied with extensive neuropathological evaluations since 1989. To ...date, the cohort has recruited 1,030 individuals with 552 participants being actively followed, 363 deceased, and 273 autopsied. An extensive database has been constructed with continuous updates that include textured clinical, neuropsychological, neuroimaging, and pathological information. The history, demographics, clinical observations, and pathological features of this research cohort are described. We also explain some of the evolving methodologies and the academic contributions that have been made due to this motivated group of older Kentuckians.
Polarization switching in ferroelectric thin films occurs via nucleation and growth of 180° domains through a highly inhomogeneous process in which the kinetics are largely controlled by defects, ...interfaces and pre-existing domain walls. Here we present the first real-time, atomic-scale observations and phase-field simulations of domain switching dominated by pre-existing, but immobile, ferroelastic domains in Pb(Zr0.2 Ti0.8 )O3 thin films. Our observations reveal a novel hindering effect, which occurs via the formation of a transient layer with a thickness of several unit cells at an otherwise charged interface between a ferroelastic domain and a switched domain. This transient layer possesses a low-magnitude polarization, with a dipole glass structure, resembling the dead layer. The present study provides an atomic level explanation of the hindering of ferroelectric domain motion by ferroelastic domains. Hindering can be overcome either by applying a higher bias or by removing the as-grown ferroelastic domains in fabricated nanostructures.
Background: Next generation sequencing is transforming our understanding of transcriptomes. It can determine the expression level of transcripts with a dynamic range of over six orders of magnitude ...from multiple tissues, developmental stages or conditions. Patterns of gene expression provide insight into functions of genes with unknown annotation. Results: The RNA Seq-Atlas presented here provides a record of high-resolution gene expression in a set of fourteen diverse tissues. Hierarchical clustering of transcriptional profiles for these tissues suggests three clades with similar profiles: aerial, underground and seed tissues. We also investigate the relationship between gene structure and gene expression and find a correlation between gene length and expression. Additionally, we find dramatic tissue-specific gene expression of both the most highly-expressed genes and the genes specific to legumes in seed development and nodule tissues. Analysis of the gene expression profiles of over 2,000 genes with preferential gene expression in seed suggests there are more than 177 genes with functional roles that are involved in the economically important seed filling process. Finally, the Seq-atlas also provides a means of evaluating existing gene model annotations for the Glycine max genome. Conclusions: This RNA-Seq atlas extends the analyses of previous gene expression atlases performed using Affymetrix GeneChip technology and provides an example of new methods to accommodate the increase in transcriptome data obtained from next generation sequencing. Data contained within this RNA-Seq atlas of Glycine max can be explored at http://www.soybase.org/soyseq.
The miR-15/107 group of microRNA (miRNA) gene is increasingly appreciated to serve key functions in humans. These miRNAs regulate gene expression involved in cell division, metabolism, stress ...response, and angiogenesis in vertebrate species. The miR-15/107 group has also been implicated in human cancers, cardiovascular disease and neurodegenerative disease, including Alzheimer's disease. Here we provide an overview of the following: (1) the evolution of miR-15/107 group member genes; (2) the expression levels of miRNAs in mammalian tissues; (3) evidence for overlapping gene-regulatory functions by different miRNAs; (4) the normal biochemical pathways regulated by miR-15/107 group miRNAs; and (5) the roles played by these miRNAs in human diseases. Membership in this group is defined based on sequence similarity near the mature miRNAs' 5′ end: all include the sequence AGCAGC. Phylogeny of this group of miRNAs is incomplete; thus, a definitive taxonomic classification (e.g., designation as a “superfamily”) is currently not possible. While all vertebrates studied to date express miR-15a, miR-15b, miR-16, miR-103, and miR-107, mammals alone are known to express miR-195, miR-424, miR-497, miR-503, and miR-646. Multiple different miRNAs in the miR-15/107 group are expressed at moderate to high levels in human tissues. We present data on the expression of all known miR-15/107 group members in human cerebral cortical gray matter and white matter using new miRNA profiling microarrays. There is extensive overlap in the mRNAs targeted by miR-15/107 group members. We show new data from cultured H4 cancer cells that demonstrate similarities in mRNAs targeted by miR-16 and miR-103 and also support the importance of the mature miRNAs' 5′ seed region in mRNA target recognition. In conclusion, the miR-15/107 group of miRNA genes is a fascinating topic of study for evolutionary biologists, miRNA biochemists, and clinically oriented translational researchers alike.
The increasing air temperatures central to climate change predictions have the potential to alter forest ecosystem function and structure by exceeding temperatures optimal for carbon gain. Such ...changes are projected to threaten survival of sensitive species, leading to local extinctions, range migrations, and altered forest composition. This study investigated photosynthetic sensitivity to temperature and the potential for acclimation in relation to the climatic provenance of five species of deciduous trees, Liquidambar styraciflua, Quercus rubra, Quercus falcata, Betula alleghaniensis, and Populus grandidentata. Open-top chambers supplied three levels of warming (+0, +2, and +4 °C above ambient) over 3 years, tracking natural temperature variability. Optimal temperature for CO₂ assimilation was strongly correlated with daytime temperature in all treatments, but assimilation rates at those optima were comparable. Adjustment of thermal optima was confirmed in all species, whether temperatures varied with season or treatment, and regardless of climate in the species' range or provenance of the plant material. Temperature optima from 17° to 34° were observed. Across species, acclimation potentials varied from 0.55 °C to 1.07 °C per degree change in daytime temperature. Responses to the temperature manipulation were not different from the seasonal acclimation observed in mature indigenous trees, suggesting that photosynthetic responses should not be modeled using static temperature functions, but should incorporate an adjustment to account for acclimation. The high degree of homeostasis observed indicates that direct impacts of climatic warming on forest productivity, species survival, and range limits may be less than predicted by existing models.
PDF
