Phosphorylation of the actin binding protein Drebrin at S647 and is regulated by neuronal activity and PTEN

Defects in actin dynamics affect activity-dependent modulation of synaptic transmission and neuronal plasticity, and can cause cognitive impairment. A salient candidate actin-binding protein linking synaptic dysfunction to cognitive deficits is Drebrin (DBN). However, the specific mode of how DBN is regulated at the central synapse is largely unknown. In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN. Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus - serine 647. PTEN and pS647-DBN segregate into distinct and complimentary compartments in neurons, supporting the idea that PTEN negatively regulates DBN phosphorylation at this site. We further demonstrate that neuronal activity increases phosphorylation of DBN at S647 in hippocampal neurons in vitro and in ex vivo hippocampus slices exhibiting seizure activity, potentially by inducing rapid dissociation of the PTEN:DBN complex. Our results identify a novel mechanism by which PTEN is required to maintain DBN phosphorylation at dynamic range and signifies an unusual regulation of an actin-binding protein linked to cognitive decline and degenerative conditions at the CNS synapse

The mitochondrial calcium uniporter is crucial for the generation of fast cortical network rhythms

The role of the mitochondrial calcium uniporter (MCU) gene (Mcu) in cellular energy homeostasis and generation of electrical brain rhythms is widely unknown. We investigated this issue in mice and rats using Mcu-knockout and -knockdown strategies in vivo and in situ and determined the effects of these genetic manipulations on hippocampal gamma oscillations (30–70 Hz) and sharp wave-ripples. These physiological network states require precise neurotransmission between pyramidal cells and inhibitory interneurons, support spike-timing and synaptic plasticity and are associated with perception, attention and memory. Absence of the MCU resulted in (i) gamma oscillations with decreased power (by >40%) and lower synchrony, including less precise neural action potential generation (‘spiking'), (ii) sharp waves with decreased incidence (by about 22%) and decreased fast ripple frequency (by about 3%) and (iii) lack of activity-dependent pyruvate dehydrogenase dephosphorylation. However, compensatory adaptation in gene expression related to mitochondrial function and glucose metabolism was not detected. These data suggest that the neuronal MCU is crucial for the generation of network rhythms, most likely by influences on oxidative phosphorylation and perhaps by controlling cytoplasmic Ca(2+) homeostasis. This work contributes to an increased understanding of mitochondrial Ca(2+) uptake in cortical information processing underlying cognition and behaviour

Separation in Biorefineries by Liquid Phase Adsorption: Itaconic Acid as Case Study

In biorefinery processes often the downstream processing is the technological bottleneck for an overall high efficiency. On the basis of recent developments, the selective liquid phase adsorption applying highly hydrophobic porous materials opened up new opportunities for process development. In this contribution, the efficiency of selective liquid phase adsorption is demonstrated for the separation and purification of itaconic acid from aqueous solutions for the first time. A wide range of different adsorbents was screened, revealing the surface polarity as well as textural properties as critical parameters for their performance. Adsorption from mixed solutions of itaconic acid and glucose exhibited extraordinary high selectivities for adsorbents with highly hydrophobic surfaces, especially certain activated carbons and hyper-cross-linked polymers. Evaluation of the pH dependence showed that the respective molecular species of itaconic acid/itaconate has a major impact on the adsorption performance. Additionally, experiments on a continuously operated fixed-bed adsorber were carried out, and the desorption behavior was evaluated. Overall, the technical feasibility of the selective adsorptive removal of itaconic acid from aqueous solutions with hydrophobic adsorbents is demonstrated as a model system for an alternative technology to conventional separation strategies in biorefinery concepts

GRB 221009A, The BOAT

GRB 221009A has been referred to as the Brightest Of All Time (the BOAT). We investigate the veracity of this statement by comparing it with a half century of prompt gamma-ray burst observations. This burst is the brightest ever detected by the measures of peak flux and fluence. Unexpectedly, GRB 221009A has the highest isotropic-equivalent total energy ever identified, while the peak luminosity is at the $\sim99$th percentile of the known distribution. We explore how such a burst can be powered and discuss potential implications for ultra-long and high-redshift gamma-ray bursts. By geometric extrapolation of the total fluence and peak flux distributions GRB 221009A appears to be a once in 10,000 year event. Thus, while it almost certainly not the BOAT over all of cosmic history, it may be the brightest gamma-ray burst since human civilization began.Comment: Resubmitted to ApJ

Age, gender, and bone lamellae elastic moduli

To enhance preventative and therapeutic strategies for metabolic bone diseases and bone fragility disorders, we began to explore the physical properties of bone tissue at the cellular level. Proximal femurs were harvested from 27 cadavera (16 male and 11 female) for in vitro measurement of the mechanical properties. We measured the variations in lamellar-level elastic modulus and hardness in human bone as a function of age and gender to identify microstructural properties responsible for age and gender-related reductions in the mechanical integrity. The lateral femoral necks were examined, and age, gender, height, body mass, and body mass index were not found to correlate with lamellar-level elastic modulus or hardness. This result was consistent for osteonal, interstitial, and trabecular tissue. These data suggest that increased bone mass maintenance, known to occur in heavier individuals, is not accompanied by increases in the lamellar-level elastic modulus or hardness. The independence of elastic modulus and hardness from age and gender suggests that age and gender-related decreases in mechanical integrity do not involve alterations in elastic modulus or hard ness of the extracellular matrix. Lamellar-level ultimate, fatigue, and fracture toughness properties should also be investigated. Other factors, such as tissue mass and organization, may also contribute to age and gender-related decreases in the mechanical integrity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34918/1/1100180315_ftp.pd

Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy

Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta