Comparisons of global topographic/isostatic models to the Earth's observed gravity field

The Earth's gravitational potential, as described by a spherical harmonic expansion to degree 180, was compared to the potential implied by the topography and its isostatic compensation using five different hypothesis. Initially, series expressions for the Airy/Heiskanen topographic isostatic model were developed to the third order in terms of (h/R), where h is equivalent rock topography and R is a mean Earth radius. Using actual topographic developments for the Earth, it was found that the second and third terms of the expansion contributed 30 and 3 percents, of the first of the expansion. With these new equations it is possible to compute depths (D) of compensation, by degree, using 3 different criteria. The results show that the average depth implied by criterion I is 60 km while it is about 33 km for criteria 2 and 3 with smaller compensation depths at the higher degrees. Another model examined was related to the Vening-Meinesz regional hypothesis implemented in the spectral domain. Finally, oceanic and continental response functions were derived for the global data sets and comparisons made to locally determined values

A highly conserved circular RNA is required to keep neural cells in a progenitor state in the mammalian brain

circSLC45A4 is the main RNA splice isoform produced from its genetic locus and one of the highest expressed circRNAs in the developing human frontal cortex. Knockdown of this highly conserved circRNA in a human neuroblastoma cell line is sufficient to induce spontaneous neuronal differentiation, measurable by increased expression of neuronal marker genes. Depletion of circSlc45a4 in the developing mouse cortex causes a significant reduction of the basal progenitor pool and increases the expression of neurogenic regulators. Furthermore, knockdown of circSlc45a4a induces a significant depletion of cells in the cortical plate. In addition, deconvolution of the bulk RNA-seq data with the help of single-cell RNA-seq data validates the depletion of basal progenitors and reveals an increase in Cajal-Retzius cells. In summary, we present a detailed study of a highly conserved circular RNA that is necessary to maintain the pool of neural progenitors in vitro and in vivo

A proteomics analysis of 5xFAD mouse brain regions reveals the lysosome-associated protein Arl8b as a candidate biomarker for Alzheimer’s disease

BACKGROUND: Alzheimer's disease (AD) is characterized by the intra- and extracellular accumulation of amyloid-ß (Aß) peptides. How Aß aggregates perturb the proteome in brains of patients and AD transgenic mouse models, remains largely unclear. State-of-the-art mass spectrometry (MS) methods can comprehensively detect proteomic alterations, providing relevant insights unobtainable with transcriptomics investigations. Analyses of the relationship between progressive Aß aggregation and protein abundance changes in brains of 5xFAD transgenic mice have not been reported previously. METHODS: We quantified progressive Aß aggregation in hippocampus and cortex of 5xFAD mice and controls with immunohistochemistry and membrane filter assays. Protein changes in different mouse tissues were analyzed by MS-based proteomics using label-free quantification; resulting MS data were processed using an established pipeline. Results were contrasted with existing proteomic data sets from postmortem AD patient brains. Finally, abundance changes in the candidate marker Arl8b were validated in cerebrospinal fluid (CSF) from AD patients and controls using ELISAs. RESULTS: Experiments revealed faster accumulation of Aß42 peptides in hippocampus than in cortex of 5xFAD mice, with more protein abundance changes in hippocampus, indicating that Aß42 aggregate deposition is associated with brain region-specific proteome perturbations. Generating time-resolved data sets, we defined Aß aggregate-correlated and anticorrelated proteome changes, a fraction of which was conserved in postmortem AD patient brain tissue, suggesting that proteome changes in 5xFAD mice mimic disease-relevant changes in human AD. We detected a positive correlation between Aß42 aggregate deposition in the hippocampus of 5xFAD mice and the abundance of the lysosome-associated small GTPase Arl8b, which accumulated together with axonal lysosomal membranes in close proximity of extracellular Aß plaques in 5xFAD brains. Abnormal aggregation of Arl8b was observed in human AD brain tissue. Arl8b protein levels were significantly increased in CSF of AD patients. CONCLUSIONS: We report a comprehensive biochemical and proteomic investigation of hippocampal and cortical brain tissue derived from 5xFAD transgenic mice, providing a valuable resource to the neuroscientific community. We identified Arl8b, with significant abundance changes in 5xFAD and AD patient brains. Arl8b might enable the measurement of progressive lysosome accumulation in AD patients and have clinical utility as a candidate biomarker

Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN

Circular RNAs (circRNAs) are a regulatory RNA class. While cancer-driving functions have been identified for single circRNAs, how they modulate gene expression in cancer is not well understood. We investigate circRNA expression in the pediatric malignancy, neuroblastoma, through deep whole-transcriptome sequencing in 104 primary neuroblastomas covering all risk groups. We demonstrate that MYCN amplification, which defines a subset of high-risk cases, causes globally suppressed circRNA biogenesis directly dependent on the DHX9 RNA helicase. We detect similar mechanisms in shaping circRNA expression in the pediatric cancer medulloblastoma implying a general MYCN effect. Comparisons to other cancers identify 25 circRNAs that are specifically upregulated in neuroblastoma, including circARID1A. Transcribed from the ARID1A tumor suppressor gene, circARID1A promotes cell growth and survival, mediated by direct interaction with the KHSRP RNA-binding protein. Our study highlights the importance of MYCN regulating circRNAs in cancer and identifies molecular mechanisms, which explain their contribution to neuroblastoma pathogenesis

Gait analysis with wearables predicts conversion to Parkinson disease

Objective Quantification of gait with wearable technology is promising; recent cross-sectional studies showed that gait characteristics are potential prodromal markers for Parkinson disease (PD). The aim of this longitudinal prospective observational study was to establish gait impairments and trajectories in the prodromal phase of PD, identifying which gait characteristics are potentially early diagnostic markers of PD. Methods The 696 healthy controls (mean age = 63 ± 7 years) recruited in the Tubingen Evaluation of Risk Factors for Early Detection of Neurodegeneration study were included. Assessments were performed longitudinally 4 times at 2-year intervals, and people who converted to PD were identified. Participants were asked to walk at different speeds under single and dual tasking, with a wearable device placed on the lower back; 14 validated clinically relevant gait characteristics were quantified. Cox regression was used to examine whether gait at first visit could predict time to PD conversion after controlling for age and sex. Random effects linear mixed models (RELMs) were used to establish longitudinal trajectories of gait and model the latency between impaired gait and PD diagnosis. Results Sixteen participants were diagnosed with PD on average 4.5 years after first visit (converters; PDC). Higher step time variability and asymmetry of all gait characteristics were associated with a shorter time to PD diagnosis. RELMs indicated that gait (lower pace) deviates from that of non-PDC approximately 4 years prior to diagnosis. Interpretation Together with other prodromal markers, quantitative gait characteristics can play an important role in identifying prodromal PD and progression within this phase. ANN NEUROL 2019;86:357–36

Instrumented gait analysis identifies potential predictors for Parkinson’s disease converters [abstract]

Objective: This longitudinal prospective observational study investigated if gait can predict Parkinson’s disease (PD) conversion from a cohort of community-dwelling older adults. Background: PD is a progressive disorder including a prodromal period when definitive motor/non-motor symptoms to permit a diagnosis have not yet appeared. Quantification of gait with wearable technology (WT) may serve as an accurate tool to identify surrogate markers of incipient disease manifestation. Recently arm swing and selective gait characteristics measured with WT have been shown to be potential prodromal markers for people at risk for PD [1]; however these data were obtained from a cross-sectional assessment; the potential of gait to predict PD conversion has not been investigated yet in a longitudinal cohort. Methods: 16 participants (69±5 years (yrs)) who were diagnosed with PD on average 4.5 yrs after baseline assessment (converters (PDC)) and 48 age-matched old healthy adults (HA) recruited in the TREND study were included. Assessments were performed longitudinally 4 times at 2-year intervals. Participants were asked to walk at their preferred speed, performing 2 straight-line trials over 20m with a WT device placed on the lower back; 14 validated clinically relevant gait characteristics were quantified [2]. ANCOVA was used to examine gait between-group differences; the value of baseline gait in predicting PDC was explored using AUC and stepwise, forward, logistic regression analyses. Random effects linear mixed-models (RELM) were used to predict latency gait deterioration and diagnosis of PD. Results: PDC walked with significantly lower pace, higher variability and asymmetry than HA (p≤0.027). Pace, variability and asymmetry characteristics were able to significantly predict PDC (AUC≥0.695). Step time variability was the best predictor for the stepwise, forward, logistic regression (sensitivity 25%, specificity 98%, accuracy of 80%). RELMs indicate gait impairment (step velocity and step length) is evident 4-6 yrs prior to diagnosis. Conclusions: Our preliminary results suggest that pace, variability and asymmetry of gait represent sensitive predictors of prodromal PD and that gait impairment starts 4-5 years prior to diagnosis. Therefore, gait assessment may play an important role in concert with other biomarkers to identify people at high risk of PD and aid early diagnosis

Struktureller Ultraschall des medialen Temporallappens bei Alzheimer-Demenz

Abstract Purpose One of the anatomical hallmarks of Alzheimer’s disease (AD) is the atrophy of the medial temporal lobe (MTL), yet cost-effective and broadly available methodological alternatives to the current imaging tools for screening of this brain area are not currently available. Materials and Methods Using structural transcranial ultrasound (TCS), we attempted to visualize and measure the MTL, and compared the results of 32 AD patients and 84 healthy controls (HC). The MTL and the surrounding space were defined in the coronal plane on TCS. A ratio of the height of the MTL/height of the choroidal fissure (M/F) was calculated in order to obtain a regional proportion. Results An insufficient temporal bone window was identified in 22 % of the AD patients and 12 % of the HCs. The results showed that the ratio of M/F was significantly smaller in the AD group on both sides (p = 0.004 right, p = 0.007 left side). Furthermore, the M/F ratio made it possible to discriminate AD patients from HCs with a sensitivity of 83 % (right)/73 % (left) and a specificity of 76 % (right)/72 % (left) which is basically comparable to results published for magnetic resonance imaging. The measurements showed substantial intra/interrater reliability (ICC:0.79/0.69). Conclusion These results suggest that utilization of structural TCS may possibly constitute a cheap and easy-to-use supplement to other techniques for the diagnosis of AD. It may be especially useful as a screening tool in the large population of individuals with cognitive decline. Further studies are needed to validate this novel method.</jats:p