3,747 research outputs found
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Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer's disease.
Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), increasing risk and decreasing age of disease onset. Many studies have demonstrated the detrimental effects of apoE4 in varying cellular contexts. However, the underlying mechanisms explaining how apoE4 leads to cognitive decline are not fully understood. Recently, the combination of human induced pluripotent stem cell (hiPSC) modeling of neurological diseases in vitro and electrophysiological studies in vivo have begun to unravel the intersection between apoE4, neuronal subtype dysfunction or loss, subsequent network deficits, and eventual cognitive decline. In this review, we provide an overview of the literature describing apoE4's detrimental effects in the central nervous system (CNS), specifically focusing on its contribution to neuronal subtype dysfunction or loss. We focus on γ-aminobutyric acid (GABA)-expressing interneurons in the hippocampus, which are selectively vulnerable to apoE4-mediated neurotoxicity. Additionally, we discuss the importance of the GABAergic inhibitory network to proper cognitive function and how dysfunction of this network manifests in AD. Finally, we examine how apoE4-mediated GABAergic interneuron loss can lead to inhibitory network deficits and how this deficit results in cognitive decline. We propose the following working model: Aging and/or stress induces neuronal expression of apoE. GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death. In turn, GABAergic interneuron loss causes hyperexcitability and dysregulation of neural networks in the hippocampus and cortex. This dysfunction results in learning, memory, and other cognitive deficits that are the central features of AD
COMPUTATIONAL MODEL OF ALENDRONATE EFFECTS ON CANINE RIB REMODELING AND MICRODAMAGE
Bisphosphonates are a class of drugs used to prevent and treat bone diseases by inhibiting the resorption of bone by osteoclasts and suppressing bone remodeling. Osteoporosis is a bone disease that develops when bone resorption exceeds bone formation which results in an increase in bone porosity and fracture risk. The risk for fractures can be reduced by increasing bone mass. Alendronate is type of bisphosphonate that is approved by the Food and Drug Administration (FDA) to treat postmenopausal osteoporosis by suppressing basic multicellular unit (BMU) remodeling and increasing bone mass. The long term effects of bisphosphonates are still unclear due to the difficulty in obtaining long term data; therefore, developing a mathematical model based on data and relationships from short term studies can be a useful method in predicting the effects of the drug.
The purpose of this study was to develop a computer model that could simulate the long term effects of alendronate treatment on canine rib remodeling, bone volume, and microdamage by matching 1 and 3 year experimental data results. The experimental effects of alendronate (ALN) were studied at the Indiana University School of Medicine. In two separate experiments, skeletally mature female beagles were subjected to 1 and 3 year treatments of saline vehicle (CON), or one of two doses of ALN (ALN0.2 or ALN1.0 mg/kg/day). The lower dose (ALN0.2) corresponds to the clinical dosage used to treat postmenopausal osteoporosis and the higher dose (ALN1.0) is the dose used to treat Paget’s disease. Bone volume fraction (BV/TV), damage, and remodeling activation frequency (Ac.f) of the rib were quantified using standard histomorphometric techniques.
The mathematical model was developed by modifying a previous mathematical algorithm for trabecular bone remodeling, to create an equilibrium for cortical bone remodeling that matched the experimental control data from 1 year studies. Using the equilibrium conditions as a baseline model, ALN was modeled by suppressing activation frequency and reducing the resorption area. The changes in BV/TV, damage accumulation, and Ac.f were followed for 3 years and compared to the experimental results. The results for BV/TV, Ac.f, and damage for the 1 year model and the results for BV/TV and damage for the 3 year model were consistent with experimental studies. BV/TV results for both doses showed increases from 1 to 3 years with alendronate treatment. Ac.f results for both treatment doses at 1 year and ALN1.0 at 3 years were also within range of the experimental data; however, ALN0.2 for 3 years was not consistent with the experimental results. While the predicted Ac.f for ALN0.2 does show an initial decrease, it is not nearly as extreme as the results from the experimental data and the data remains fairly constant between 1 and 3 years, which is in contrast to the experimental results. The model also predicts damage accumulation is greatest early during bisphosphonate treatment, due to the initial suppression of bone resorption. This increase in microdamage accumulation was previously thought to impair the mechanical properties of bone; however, recent experimental studies show that while the initial increase in microdamage may contribute to alterations in bone properties at 1 year of treatment, other factors appear to contribute to their reduction long term. The simulation results are consistent with the experimental data, which suggest that damage increases for up to 1 year of treatment and then levels off thereafter. The results of the simulation suggest that since bisphosphonates do not cause further increases in microdamage accumulation after 1 year of treatment, ALN may not lead to increased bone fragility associated with microdamage long term and rather, may decrease fracture risk
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Anaerobic 4-hydroxyproline utilization: Discovery of a new glycyl radical enzyme in the human gut microbiome uncovers a widespread microbial metabolic activity.
The discovery of enzymes responsible for previously unappreciated microbial metabolic pathways furthers our understanding of host-microbe and microbe-microbe interactions. We recently identified and characterized a new gut microbial glycyl radical enzyme (GRE) responsible for anaerobic metabolism of trans-4-hydroxy-l-proline (Hyp). Hyp dehydratase (HypD) catalyzes the removal of water from Hyp to generate Δ1-pyrroline-5-carboxylate (P5C). This enzyme is encoded in the genomes of a diverse set of gut anaerobes and is prevalent and abundant in healthy human stool metagenomes. Here, we discuss the roles HypD may play in different microbial metabolic pathways as well as the potential implications of this activity for colonization resistance and pathogenesis within the human gut. Finally, we present evidence of anaerobic Hyp metabolism in sediments through enrichment culturing of Hyp-degrading bacteria, highlighting the wide distribution of this pathway in anoxic environments beyond the human gut
Synaptic plasticity: Going through phases with LTP
AbstractEarly and late expressing components of synaptic plasticity may underlie the temporal phases of behavioral memory. New studies argue that a balance between kinase and phosphatase activity regulates the transition between different phases of synaptic plasticity and memory
Live-Learn Cal Poly: A New-Urbanist Vision for a More Livable and Sustainable Campus
Universities across the nation have begun a mixed-use initiative in an effort to densify campuses and diversify retail and housing choices to increase student residency on campus. The movement to model the built environment after traditional mixed-use urbanism has been shown to improve capital flow within the local submarket on campus, foster flexible learning environments to support student success, and reduce automobile dependency. In order to reflect Cal Poly’s Master Plan moving forward, this report intends to follow the guiding principles outlined in the Master Plan while proposing sustainable and efficient land use designs to accommodate future growth at Cal Poly
Synaptic plasticity: Regulated translation in dendrites
AbstractSynaptic activity can induce neurons to synthesize proteins important for cognition and brain development. Recent results suggest this activity-induced protein synthesis is partially mediated by regulated translation within neuronal dendrites
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Draft Genome Sequence of Bacillus velezensis CE2, Which Genetically Encodes a Novel Multicomponent Lantibiotic.
Bacillus velezensis CE2 produces potent antimicrobial compound(s). The draft genome sequence of the strain reported here is 4.1 Mb with a G+C content of 46.1%. Whole-genome sequencing revealed that the strain genetically encodes a novel multicomponent lantibiotic, velezensicidin
Three-dimensional fluorescent microscopy via simultaneous illumination and detection at multiple planes.
The conventional optical microscope is an inherently two-dimensional (2D) imaging tool. The objective lens, eyepiece and image sensor are all designed to capture light emitted from a 2D 'object plane'. Existing technologies, such as confocal or light sheet fluorescence microscopy have to utilize mechanical scanning, a time-multiplexing process, to capture a 3D image. In this paper, we present a 3D optical microscopy method based upon simultaneously illuminating and detecting multiple focal planes. This is implemented by adding two diffractive optical elements to modify the illumination and detection optics. We demonstrate that the image quality of this technique is comparable to conventional light sheet fluorescent microscopy with the advantage of the simultaneous imaging of multiple axial planes and reduced number of scans required to image the whole sample volume
A 'one-size-fits-most' walking recognition method for smartphones, smartwatches, and wearable accelerometers
The ubiquity of personal digital devices offers unprecedented opportunities
to study human behavior. Current state-of-the-art methods quantify physical
activity using 'activity counts,' a measure which overlooks specific types of
physical activities. We proposed a walking recognition method for sub-second
tri-axial accelerometer data, in which activity classification is based on the
inherent features of walking: intensity, periodicity, and duration. We
validated our method against 20 publicly available, annotated datasets on
walking activity data collected at various body locations (thigh, waist, chest,
arm, wrist). We demonstrated that our method can estimate walking periods with
high sensitivity and specificity: average sensitivity ranged between 0.92 and
0.97 across various body locations, and average specificity for common daily
activities was typically above 0.95. We also assessed the method's algorithmic
fairness to demographic and anthropometric variables and measurement contexts
(body location, environment). Finally, we have released our method as
open-source software in MATLAB and Python.Comment: 39 pages, 4 figures (incl. 1 supplementary), and 5 tables (incl. 2
supplementary
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