The Hippocampal Neuroproteome with Aging and Cognitive Decline: Past Progress and Future Directions

Although steady progress on understanding brain aging has been made over recent decades through standard anatomical, immunohistochemical, and biochemical techniques, the biological basis of non-neurodegenerative cognitive decline with aging remains to be determined. This is due in part to technical limitations of traditional approaches, in which only a small fraction of neurobiologically relevant proteins, mRNAs or metabolites can be assessed at a time. With the development and refinement of proteomic technologies that enable simultaneous quantitative assessment of hundreds to thousands of proteins, neuroproteomic studies of brain aging and cognitive decline are becoming more widespread. This review focuses on the contributions of neuroproteomic investigations to advances in our understanding of age-related deficits of hippocampus-dependent spatial learning and memory. Accumulating neuroproteomic data demonstrate that hippocampal aging involves common themes of dysregulated metabolism, increased oxidative stress, altered protein processing, and decreased synaptic function. Additionally, growing evidence suggests that cognitive decline does not represent a “more aged” phenotype, but rather is associated with specific neuroproteomic changes that occur in addition to age-related alterations. Understanding if and how age-related changes in the hippocampal neuroproteome contribute to cognitive decline and elucidating the pathways and processes that lead to cognitive decline are critical objectives that remain to be achieved. Progress in the field and challenges that remain to be addressed with regard to animal models, behavioral testing, and proteomic reporting are also discussed

Composite repetition-aware data structures

In highly repetitive strings, like collections of genomes from the same species, distinct measures of repetition all grow sublinearly in the length of the text, and indexes targeted to such strings typically depend only on one of these measures. We describe two data structures whose size depends on multiple measures of repetition at once, and that provide competitive tradeoffs between the time for counting and reporting all the exact occurrences of a pattern, and the space taken by the structure. The key component of our constructions is the run-length encoded BWT (RLBWT), which takes space proportional to the number of BWT runs: rather than augmenting RLBWT with suffix array samples, we combine it with data structures from LZ77 indexes, which take space proportional to the number of LZ77 factors, and with the compact directed acyclic word graph (CDAWG), which takes space proportional to the number of extensions of maximal repeats. The combination of CDAWG and RLBWT enables also a new representation of the suffix tree, whose size depends again on the number of extensions of maximal repeats, and that is powerful enough to support matching statistics and constant-space traversal.Comment: (the name of the third co-author was inadvertently omitted from previous version

Fluctuations of water near extended hydrophobic and hydrophilic surfaces

We use molecular dynamics simulations of the SPC-E model of liquid water to derive probability distributions for water density fluctuations in probe volumes of different shapes and sizes, both in the bulk as well as near hydrophobic and hydrophilic surfaces. To obtain our results, we introduce a biased sampling of coarse-grained densities, which in turn biases the actual solvent density. The technique is easily combined with molecular dynamics integration algorithms. Our principal result is that the probability for density fluctuations of water near a hydrophobic surface, with or without surface-water attractions, is akin to density fluctuations at the water-vapor interface. Specifically, the probability of density depletion near the surface is significantly larger than that in bulk. In contrast, we find that the statistics of water density fluctuations near a model hydrophilic surface are similar to that in the bulk

Rapid generation of chromosome-specific alphoid DNA probes using the polymerase chain reaction

Non-isotopic in situ hybridization of chromosome-specific alphoid DNA probes has become a potent tool in the study of numerical aberrations of specific human chromosomes at all stages of the cell cycle. In this paper, we describe approaches for the rapid generation of such probes using the polymerase chain reaction (PCR), and demonstrate their chromosome specificity by fluorescence in situ hybridization to normal human metaphase spreads and interphase nuclei. Oligonucleotide primers for conserved regions of the alpha satellite monomer were used to generate chromosome-specific DNA probes from somatic hybrid cells containing various human chromosomes, and from DNA libraries from sorted human chromosomes. Oligonucleotide primers for chromosome-specific regions of the alpha satellite monomer were used to generate specific DNA probes for the pericentromeric heterochromatin of human chromosomes 1, 6, 7, 17 and X directly from human genomic DNA

Effect of Field-Line Curvature on the Ionospheric Accessibility of Relativistic Electron Beam Experiments

Magnetosphere-ionosphere coupling is a particularly important process that regulates and controls magnetospheric dynamics such as storms and substorms. However, in order to understand magnetosphere-ionosphere coupling it is necessary to understand how regions of the magnetosphere are connected to the ionosphere. It has been proposed that this connection may be established by firing electron beams from satellites that can reach an ionospheric footpoint creating detectable emissions. This type of experiment would greatly aid in identifying the relationship between convection processes in the magnetotail and the ionosphere and how the plasma sheet current layer evolves during the growth phase preceding substorms. For practical purposes, the use of relativistic electron beams with kinetic energy on the order of 1 MeV would be ideal for detectability. However, Porazik et al. (2014) has shown that, for relativistic particles, higher order terms of the magnetic moment are necessary for consideration of the ionospheric accessibility of the beams. These higher order terms are related to gradients and curvature in the magnetic field and are typically unimportant unless the beam is injected along the magnetic field direction, such that the zero order magnetic moment is small. In this article, we address two important consequences related to these higher order terms. First, we investigate the consequences for satellites positioned in regions subject to magnetotail stretching and demonstrate systematically how curvature affects accessibility. We find that curvature can reduce accessibility for beams injected from the current sheet, but can increase accessibility for beams injected just above the current sheet. Second, we investigate how detectability of ionospheric precipitation of variable energy field-aligned electron beams could be used as a constraint on field-line curvature, which would be valuable for field-line reconstruction and/or stability analysis

Method for Approximating Field-Line Curves Using Ionospheric Observations of Energy-Variable Electron Beams Launched From Satellites

Using electron beam accelerators attached to satellites in Earth orbit, it may be possible to measure arc length and curvature of field-lines in the inner magnetosphere if the accelerator is designed with the capability to vary the beam energy. In combination with additional information, these measurements would be very useful in modeling the magnetic field of the inner magnetosphere. For this purpose, a three step data assimilation modeling approach is discussed. The first step in the procedure would be to use prior information to obtain an initial forecast of the inner magnetosphere. Then, a family of curves would be defined that satisfies the observed geometric attributes measured by the experiments, and the prior forecast would then be used to optimize the curve with respect to the allowed degrees of freedom. Finally, this approximation of the field-line would be used to improve the initial forecast of the inner magnetosphere, resulting in a description of the system that is optimally consistent with both the prior information and the measured curvature and arc length. This article details the method by which a family of possible approximations of the field-line may be defined via a numerical procedure, which is central to the three step approach. This method serves effectively as a pre-conditioner for parameter estimation problems using field-line curvature and arc length measurements in combination with other measurements

Explanation of the Gibbs paradox within the framework of quantum thermodynamics

The issue of the Gibbs paradox is that when considering mixing of two gases within classical thermodynamics, the entropy of mixing appears to be a discontinuous function of the difference between the gases: it is finite for whatever small difference, but vanishes for identical gases. The resolution offered in the literature, with help of quantum mixing entropy, was later shown to be unsatisfactory precisely where it sought to resolve the paradox. Macroscopic thermodynamics, classical or quantum, is unsuitable for explaining the paradox, since it does not deal explicitly with the difference between the gases. The proper approach employs quantum thermodynamics, which deals with finite quantum systems coupled to a large bath and a macroscopic work source. Within quantum thermodynamics, entropy generally looses its dominant place and the target of the paradox is naturally shifted to the decrease of the maximally available work before and after mixing (mixing ergotropy). In contrast to entropy this is an unambiguous quantity. For almost identical gases the mixing ergotropy continuously goes to zero, thus resolving the paradox. In this approach the concept of ``difference between the gases'' gets a clear operational meaning related to the possibilities of controlling the involved quantum states. Difficulties which prevent resolutions of the paradox in its entropic formulation do not arise here. The mixing ergotropy has several counter-intuitive features. It can increase when less precise operations are allowed. In the quantum situation (in contrast to the classical one) the mixing ergotropy can also increase when decreasing the degree of mixing between the gases, or when decreasing their distinguishability. These points go against a direct association of physical irreversibility with lack of information.Comment: Published version. New title. 17 pages Revte

Correction accuracy and collateral laxity in open versus closed wedge high tibial osteotomy. A one-year randomised controlled study

In a randomised clinical trial in 50 patients with symptomatic osteoarthritis of the medial compartment of the knee, the clinical results of high tibial osteotomy (HTO) according to the open wedge osteotomy (OWO) and closed wedge osteotomy (CWO) were compared. In both groups locked plate fixation was used. Clinical and radiological assessments were performed preoperatively and after one year. Postoperative hip-knee-ankle (HKA) correction angles were monitored on standing leg X-rays. The effect of HTO on collateral laxity of the knee was measured with a specially designed varus-valgus device. The WOMAC osteoarthritis index, the modified knee society score (KS) and visual analogue scales (VAS) were used to assess symptoms of osteoarthritis, function, pain and patient satisfaction. At one-year follow-up we found accurate corrections in both groups and the planned correction angles were achieved. No loss of correction was observed. Furthermore, the medial collateral laxity and the patellar height significantly decreased after OWO. Significant improvements of WOMAC and KS scores were found in both groups. All patients had significantly less pain and were very satisfied with the results. Surgery time was significantly longer in the CWO group, and complications were more frequent in this group. Both techniques led to good and comparable clinical results. The choice of whether to perform an open or a closed wedge osteotomy may be based on preoperative patellar height or concomitant collateral laxity