Ground-state configuration space heterogeneity of random finite-connectivity spin glasses and random constraint satisfaction problems

We demonstrate through two case studies, one on the p-spin interaction model and the other on the random K-satisfiability problem, that a heterogeneity transition occurs to the ground-state configuration space of a random finite-connectivity spin glass system at certain critical value of the constraint density. At the transition point, exponentially many configuration communities emerge from the ground-state configuration space, making the entropy density s(q) of configuration-pairs a non-concave function of configuration-pair overlap q. Each configuration community is a collection of relatively similar configurations and it forms a stable thermodynamic phase in the presence of a suitable external field. We calculate s(q) by the replica-symmetric and the first-step replica-symmetry-broken cavity methods, and show by simulations that the configuration space heterogeneity leads to dynamical heterogeneity of particle diffusion processes because of the entropic trapping effect of configuration communities. This work clarifies the fine structure of the ground-state configuration space of random spin glass models, it also sheds light on the glassy behavior of hard-sphere colloidal systems at relatively high particle volume fraction.Comment: 26 pages, 9 figures, submitted to Journal of Statistical Mechanic

1-Butanol dehydration and oxidation over vanadium phosphate catalysts

The transformation of 1-butanol into either butenes or maleic anhydride was carried out both with and without oxygen, using V/P/O catalysts. With vanadyl pyrophosphate prepared by coprecipitation, at temperature lower than 240 ◦C and without oxygen, selectivity to butenes was higher than 90%, but a slow deactivation took place. At temperature higher than 300 ◦C and in the presence of air, maleic and phthalic anhydrides were the prevailing products, with selectivity of 60% and 14%, respectively. Catalytic performance was affected by crystallinity and acidity. αI-VOPO4 showed a poor performance in the absence of air, with a quick deactivation due to coke accumulation; but it displayed an excellent selectivity to butenes (close to 98%) at temperatures lower than 320 ◦C in the presence of air, with stable performance. At temperature higher than 360 ◦C, α I-VOPO4 was reduced to vanadyl pyrophosphate and catalyzed the direct oxidation of 1-butanol into maleic anhydride, but with 35% selectivit

Synaptic Therapy in Alzheimer’s Disease: A CREB-centric Approach

Therapeutic attempts to cure Alzheimer’s disease (AD) have failed, and new strategies are desperately needed. Motivated by this reality, many laboratories (including our own) have focused on synaptic dysfunction in AD because synaptic changes are highly correlated with the severity of clinical dementia. In particular, memory formation is accompanied by altered synaptic strength, and this phenomenon (and its dysfunction in AD) has been a recent focus for many laboratories. The molecule cyclic adenosine monophosphate response element-binding protein (CREB) is at a central converging point of pathways and mechanisms activated during the processes of synaptic strengthening and memory formation, as CREB phosphorylation leads to transcription of memory-associated genes. Disruption of these mechanisms in AD results in a reduction of CREB activation with accompanying memory impairment. Thus, it is likely that strategies aimed at these mechanisms will lead to future therapies for AD. In this review, we will summarize literature that investigates 5 possible therapeutic pathways for rescuing synaptic dysfunction in AD: 4 enzymatic pathways that lead to CREB phosphorylation (the cyclic adenosine monophosphate cascade, the serine/threonine kinases extracellular regulated kinases 1 and 2, the nitric oxide cascade, and the calpains), as well as histone acetyltransferases and histone deacetylases (2 enzymes that regulate the histone acetylation necessary for gene transcription)

Exact relations between damage spreading and thermodynamic functions for the N-color Ashkin-Teller model

Exact results are derived relating quantities computable by the so-called damage spreading method and thermodynamic functions for the N-color Ashkin-Teller model. The results are valid for any ergodic dynamics. Since we restrict our analysis to the ferromagnetic case the results are also valid for any translational invariant lattice. The derived relations should be used in order to determine numerically the N-color Ashkin-Teller critical exponents with better accuracy and less computational efforts than standard Monte Carlo simulations.Comment: 6 pages, to be published in JSTAT (Journal of Statistical Mechanics: Theory and Experiment). The results of a computer simulation were included for N=3 as an example on how to use the analytical relations derived in the paper as a guide to obtain the critical temperature and critical exponent

Fluoxetine and vortioxetine reverse depressive-like phenotype and memory deficits induced by Aβ1-42 oligomers in mice: A key role of transforming growth factor-β1

Depression is a risk factor for the development of Alzheimer's disease (AD), and the presence of depressive symptoms significantly increases the conversion of mild cognitive impairment (MCI) into AD. A long-term treatment with antidepressants reduces the risk to develop AD, and different second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are currently being studied for their neuroprotective properties in AD. In the present work, the SSRI fluoxetine and the new multimodal antidepressant vortioxetine were tested for their ability to prevent memory deficits and depressive-like phenotype induced by intracerebroventricular injection of amyloid-beta (1-42) (A beta(1-42)) oligomers in 2-month-old C57BL/6 mice. Starting from 7 days before A beta injection, fluoxetine (10 mg/kg) and vortioxetine (5 and 10 mg/kg) were intraperitoneally injected daily for 24 days. Chronic treatment with fluoxetine and vortioxetine (both at the dose of 10 mg/kg) was able to rescue the loss of memory assessed 14 days after A beta injection by the passive avoidance task and the object recognition test. Both antidepressants reversed the increase in immobility time detected 19 days after A beta injection by forced swim test. Vortioxetine exerted significant antidepressant effects also at the dose of 5 mg/kg. A significant deficit of transforming growth factor-beta 1 (TGF-beta 1), paralleling memory deficits and depressive-like phenotype, was found in the hippocampus of A beta -injected mice in combination with a significant reduction of the synaptic proteins synaptophysin and PSD-95. Fluoxetine and vortioxetine completely rescued hippocampal TGF-beta 1 levels in A beta -injected mice as well as synaptophysin and PSD-95 levels. This is the first evidence that a chronic treatment with fluoxetine or vortioxetine can prevent both cognitive deficits and depressive-like phenotype in a non-transgenic animal model of AD with a key contribution of TGF-beta 1

Genetic deletion of α7 nicotinic acetylcholine receptors induces an age-dependent Alzheimer's disease-like pathology

none8siThe accumulation of amyloid-beta peptide (Aβ) and the failure of cholinergic transmission are key players in Alzheimer's disease (AD). However, in the healthy brain, Aβ contributes to synaptic plasticity and memory acting through α7 subtype nicotinic acetylcholine receptors (α7nAChRs). Here, we hypothesized that the α7nAChR deletion blocks Aβ physiological function and promotes a compensatory increase in Aβ levels that, in turn, triggers an AD-like pathology. To validate this hypothesis, we studied the age-dependent phenotype of α7 knock out mice. We found that α7nAChR deletion caused an impairment of hippocampal synaptic plasticity and memory at 12 months of age, paralleled by an increase of Amyloid Precursor Protein expression and Aβ levels. This was accompanied by other classical AD features such as a hyperphosphorylation of tau at residues Ser 199, Ser 396, Thr 205, a decrease of GSK-3β at Ser 9, the presence of paired helical filaments and neurofibrillary tangles, neuronal loss and an increase of GFAP-positive astrocytes. Our findings suggest that α7nAChR malfunction might precede Aβ and tau pathology, offering a different perspective to interpret the failure of anti-Aβ therapies against AD and to find novel therapeutical approaches aimed at restoring α7nAChRs-mediated Aβ function at the synapse.openTropea M.R.; Li Puma D.D.; Melone M.; Gulisano W.; Arancio O.; Grassi C.; Conti F.; Puzzo D.Tropea, M. R.; Li Puma, D. D.; Melone, M.; Gulisano, W.; Arancio, O.; Grassi, C.; Conti, F.; Puzzo, D

Dopaminergic-GABAergic interplay and alcohol binge drinking

© 2019 Elsevier Ltd The dopamine D 3 receptor (D 3 R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D 3 R increases GABA A α6 subunit in the ventral striatum. Here we tested the hypothesis that D 3 R-dependent changes in GABA A α6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D 3 R knockout (D 3 R −/− ) mice and wild type littermates (D 3 R +/+ ). Ro 15-4513, a high affinity α6-GABA A ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in D 3 R +/+ , whereas it was robust in D 3 R −/− ; other relevant GABA A subunits were not changed. In situ hybridization and qPCR confirmed α6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D 3 R +/+ , but increased it in D 3 R −/− ; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABA A antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D 3 R −/− compared to D 3 R +/+ ; Ro 15-4513 reduced the peak amplitude in the NAc of D 3 R −/− , but not in D 3 R +/+ . We conclude that D 3 R-dependent enhanced expression of α6 GABA A subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc

Histopathologic and mr imaging appearance of spontaneous and radiation-induced necrosis in uveal melanomas: Initial results

Necrosis in uveal melanomas can be spontaneous or induced by radiotherapy. The purpose of our study was to compare the histopathologic and MRI findings of radiation-induced necrosis of a group of proton beam-irradiated uveal melanomas with those of spontaneous necrosis of a control group of patients undergoing primary enucleation. 11 uveal melanomas who had undergone proton beam radiotherapy, MRI and secondary enucleation, and a control group of 15 untreated uveal melanomas who had undergone MRI and primary enucleation were retrospectively identi-fied. Within the irradiated and nonirradiated group, 7 and 6 eyes with histological evidence of necrosis respectively, were furtherly selected for the final analysis; the appearance of necrosis was assessed at histopathologic examination and MRI. Irradiated melanomas showed a higher degree of necrosis as compared with nonirradiated tumors. Irradiated and nonirradiated lesions differed based on the appearance and distribution of necrosis. Irradiated tumors showed large necrotic foci, sharply demarcated from the viable neoplastic tissue; nonirradiated tumors demonstrated small, distinct foci of necrosis. Radiation-induced necrosis, more pigmented than surrounding viable tumor, displayed high signal intensity on T1-weighted and low signal intensity on T2-weighted images. The hemorrhagic/coagulative necrosis, more prevalent in nonirradiated tumors (4 out of 6 vs. 1 out of 7 cases), appeared hyperintense on T2-weighted and hypointense on T1-weighted images. Our study boosts the capability to recognize radiation-induced alterations in uveal melanomas at MRI and may improve the accuracy of radiologists in the evaluation of follow-up MR examination after radiotherapy

LTP and memory impairment caused by extracellular A\u3b2 and Tau oligomers is APP-dependent

The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oA\u3b2) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oA\u3b2 and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oA\u3b2, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oA\u3b2 and oTau requires expression of APP. Finally, the toxic effect of both extracellular oA\u3b2 and oTau on memory and LTP is dependent upon APP since APP-KO mice were resistant to oA\u3b2- and oTau-induced defects in spatial/associative memory and LTP. Thus, APP might serve as a common therapeutic target against Alzheimer's Disease (AD) and a host of other neurodegenerative diseases characterized by abnormal levels of A\u3b2 and/or Tau