Amyloid Beta-Related Alterations to Glutamate Signaling Dynamics During Alzheimer\u27s Disease Progression.

Alzheimer’s disease (AD) ranks sixth on the Centers for Disease Control and Prevention Top 10 Leading Causes of Death list for 2016, and the Alzheimer’s Association attributes 60% to 80% of dementia cases as AD related. AD pathology hallmarks include accumulation of senile plaques and neurofibrillary tangles; however, evidence supports that soluble amyloid beta (Aβ), rather than insoluble plaques, may instigate synaptic failure. Soluble Aβ accumulation results in depression of long-term potentiation leading to cognitive deficits commonly characterized in AD. The mechanisms through which Aβ incites cognitive decline have been extensively explored, with a growing body of evidence pointing to modulation of the glutamatergic system. The period of glutamatergic hypoactivation observed alongside long-term potentiation depression and cognitive deficits in later disease stages may be the consequence of a preceding period of increased glutamatergic activity. This review will explore the Aβ-related changes to the tripartite glutamate synapse resulting in altered cell signaling throughout disease progression, ultimately culminating in oxidative stress, synaptic dysfunction, and neuronal loss

Formation of Centauro and Strangelets in Nucleus-Nucleus Collisions at the LHC and their Identification by the ALICE Experiment

We present a phenomenological model which describes the formation of a Centauro fireball in nucleus-nucleus interactions in the upper atmosphere and at the LHC, and its decay to non-strange baryons and Strangelets. We describe the CASTOR detector for the ALICE experiment at the LHC. CASTOR will probe, in an event-by-event mode, the very forward, baryon-rich phase space 5.6 < \eta < 7.2 in 5.5 A TeV central Pb + Pb collisions. We present results of simulations for the response of the CASTOR calorimeter, and in particular to the traversal of Strangelets.Comment: 4 pages, 4 figures, to appear in the proceedings of the 26th ICR

CASTOR: Centauro and Strange Object Research in nucleus-nucleus collisions at LHC

We describe the CASTOR detector designed to probe the very forward, baryon-rich rapidity region in nucleus-nucleus collisions at the LHC. We present a phenomenological model describing the formation of a QGP fireball in a high baryochemical potential environment, and its subsequent decay into baryons and strangelets. The model explains Centauros and the long-penetrating component and makes predictions for the LHC. Simulations of Centauro-type events were done. To study the response of the apparatus to new effects different exotic species (DCC, Centauros, strangelets etc.) were passed through the deep calorimeter. The energy deposition pattern in the calorimeter appears to be a new clear signature of the QGP.Comment: Talk given by E. Gladysz-Dziadus for the CASTOR group, Intern. Workshop on Nuclear Theory, 10-15 June, 2002, Bulgaria, Rila Mountains, 15 pages, 14 figure

Comment on ``Strangeness enhancement in p+Ap+A and S+A+A interactions at energies near 200 AA GeV"

We argue that the recent analysis of strangeness production in nuclear collisions at 200 $A$ GeV/$c$ performed by Topor Pop {\it et al.} \cite{To:95} is flawed. The conclusions are based on an erroneous interpretation of the data and the numerical model results. The term ``strangeness enhancement" is used in a misleading way.Comment: 4 pages REVTEX 3.0, no figures; Comment submitted to Physical Review

Transient early food restriction leads to hypothalamic changes in the long‐lived crowded litter female mice

Transient nutrient restriction in the 3 weeks between birth and weaning (producing “crowded litter” or CL mice) leads to a significant increase in lifespan and is associated with permanent changes in energy homeostasis, leptin, and insulin sensitivity. Here, we show this brief period of early food restriction leads to permanent modulation of the arcuate nucleus of the hypothalamus (ARH), markedly increasing formation of both orexigenic agouti‐related peptide (AgRP) and anorexigenic proopiomelanocortin (POMC) projections to the paraventricular nucleus of the hypothalamus (PVH). An additional 4 weeks of caloric restriction, after weaning, does not further intensify the formation of AgRP and POMC projections. Acute leptin stimulation of 12‐month‐old mice leads to a stronger increase in the levels of hypothalamic pStat3 and cFos activity in CL mice than in controls, suggesting that preweaning food restriction leads to long‐lasting enhancement of leptin signaling. In contrast, FoxO1 nuclear exclusion in response to insulin is equivalent in young adult CL and control mice, suggesting that hypothalamic insulin signaling is not modulated by the crowded litter intervention. Markers of hypothalamic reactive gliosis associated with aging, such as Iba1‐positive microglia and GFAP‐positive astrocytes, are significantly reduced in CL mice as compared to controls at 12 and 22 months of age. Lastly, age‐associated overproduction of TNF‐α in microglial cells is reduced in CL mice than in age‐matched controls. Together, these results suggest that transient early life nutrient deprivation leads to long‐term hypothalamic changes which may contribute to the longevity of CL mice.e12379Transient nutrient restriction in the 3 weeks between birth and weaning (producing “crowded litter” or CL mice) leads to long‐term hypothalamic changes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111266/1/phy212379.pd

Association of Bcl-2 with misfolded prion protein is linked to the toxic potential of cytosolic PrP

Protein misfolding is linked to different neurodegenerative disorders like Alzheimer’s disease, polyglutamine, and prion diseases. We investigated the cytotoxic effects of aberrant conformers of the prion protein (PrP) and show that toxicity is specifically linked to misfolding of PrP in the cytosolic compartment and involves binding of PrP to the anti-apoptotic protein Bcl-2. PrP targeted to different cellular compartments, including the cytosol, nucleus, and mitochondria, adopted a misfolded and partially proteinase K–resistant conformation. However, only in the cytosol did the accumulation of misfolded PrP induce apoptosis. Apoptotic cell death was also induced by two pathogenic mutants of PrP, which are partially localized in the cytosol. A mechanistic analysis revealed that the toxic potential is linked to an internal domain of PrP (amino acids 115–156) and involves coaggregation of cytosolic PrP with Bcl-2. Increased expression of the chaperones Hsp70 and Hsp40 prevented the formation of PrP/Bcl-2 coaggregates and interfered with PrP-induced apoptosis. Our study reveals a compartment-specific toxicity of PrP misfolding that involves coaggregation of Bcl-2 and indicates a protective role of molecular chaperones

Local orientational order in the Stockmayer liquid

Phase behaviour of the Stockmayer fluid is studied with a method similar to the Monte-Carlo annealing scheme. We introduce a novel order parameter which is sensitive to the local co-orientation of the dipoles of particles in the fluid. We exhibit a phase diagram based on the behaviour of the order parameter in the density region 0.1 \leq {\rho}\ast \leq 0.32. Specifically, we observe and analyse a second order locally disordered fluid \rightarrow locally oriented fluid phase transition.Comment: 13 pages, 7 figure

Anti-aging interventions affect lifespan variability in sex, strain, diet and drug dependent fashion

Decreased forkhead box O1 (FoxO1) activity induces hyperlipidemia and increased PPARγ, leading to hyperlipidemia in association with endoplasmic reticulum (ER) stress. In the liver, aging and comorbidities such as hyperlipidemia and diabetes significantly influence a wide variety of steatosis, but the underlying mechanisms are complex and remain elusive.To establish the modulatory role of FoxO1 and the functional consequences of its altered interaction with PPARγ in the present study, we utilized a cell culture system, aged rats and diabetic db/db mice.We found that, under ER stress, FoxO1 induces PPARγ-mediated lipid accumulation in aged rat livers. Our data showed that the FoxO1-induced hepatic lipid accumulation was negatively regulated by Akt signaling. PPARγ, a key lipogenesis transcription factor, was increased in aged liver, resulting in lipid accumulation via hepatic ER stress under hyperglycemic conditions. We further demonstrated that loss of FoxO1 causes a decline in PPARγ expression and reduces lipid accumulation. In addition, the interaction between FoxO1 and PPARγ was shown to induce hepatic steatosis in aging and db/db mice.We provide evidence that, in aged rats, FoxO1 interaction with PPARγ promotes hepatic steatosis, due to hyperglycemia-induced ER stress, which causes an impairment in Akt signaling, such in aging-related diabetes.Environmental Biolog

Particle abundances and spectra in the hydrodynamical description of relativistic nuclear collisions with light projectiles

We show that a hydrodynamical model with continuous particle emission instead of sudden freeze out may explain both the observed strange particle and pion abundances and transverse mass spectra for light projectile at SPS energy. We found that the observed enhancement of pion production corresponds, within the context of continuous emission, to the maximal entropy production.Comment: 11 pages, 2 figure