Dynamical vertex approximation for the attractive Hubbard model

In this work, we adapt the formalism of the dynamical vertex approximation (D\u393A), a diagrammatic approach including many-body correlations beyond the dynamical mean-field theory, to the case of attractive on-site interactions. We start by exploiting the ladder approximation of the D\u393A scheme, in order to derive the corresponding equations for the nonlocal self-energy and vertex functions of the attractive Hubbard model. Second, we prove the validity of our derivation by showing that the results obtained in the particle-hole symmetric case fully preserve the exact mapping between the attractive and the repulsive models. It will be shown how this property can be related to the structure of the ladders, which makes our derivation applicable for any approximation scheme based on ladder diagrams. Finally, we apply our D\u393A algorithm to the attractive Hubbard model in three dimensions, for different fillings and interaction values. Specifically, we focus on the parameters region in the proximity of the second-order transition to the superconducting and charge-density wave phases, respectively, and calculate (i) their phase-diagrams, (ii) their critical behavior, as well as (iii) the effects of the strong nonlocal correlations on the single-particle properties

Application of a pharmacokinetic/pharmacogenetic approach to assess the nicotine metabolic profile of smokers in the real-life setting

The nicotine metabolite ratio, i.e., the ratio 3-hydroxycotinine/cotinine, is used to assess the nicotine metabolic status and has been proven to predict the response to smoking cessation treatments in randomized clinical trials. In the current study, a pharmacokinetic-pharmacogenetic integrated approach is described, based on the development of a liquid chromatography–tandem mass spectrometry (LC/MS/MS) method for nicotine metabolite ratio assay in plasma and a real-time PCR analysis for fast genotyping of CYP2A6. The pharmacokinetic-pharmacogenetic approach was validated in 66 subjects with different smoking status. The LC/MS/MS assay was rapid and sensitive enough to detect plasma cotinine levels also in second-hand exposed abstainers. In the cohort of patients of the present study the following results were obtained: (i) the frequencies of CYP2A6 genetic variants were comparable with those from clinical trials carried out in Caucasian populations; (ii) all the subjects carrying the CYP2A6 deficient allele also had a slow metabolizer phenotype; (iii) slow metabolizers had mean nicotine metabolite ratio approximately 50% of that of the normal/fast metabolizers; (iv) women had higher nicotine metabolite ratio than men; and (v) salivary nicotine metabolite ratio measures were comparable to plasma levels. Overall, the findings of the current study demonstrate that the simultaneous assessment of nicotine metabolite ratio and CYP2A6 genotype from human blood samples is feasible and accurate and could be used in a smoking cessation program to optimize treatments and identify those smokers who inherit metabolically deficient CYP2A6 alleles

N-Palmitoyl-D-Glucosamine Inhibits TLR-4/NLRP3 and Improves DNBS-Induced Colon Inflammation through a PPAR-α-Dependent Mechanism

Similar to canine inflammatory enteropathy, inflammatory bowel disease (IBD) is a chronic idiopathic condition characterized by remission periods and recurrent flares in which diarrhea, visceral pain, rectal bleeding/bloody stools, and weight loss are the main clinical symptoms. Intestinal barrier function alterations often persist in the remission phase of the disease without ongoing inflammatory processes. However, current therapies include mainly anti-inflammatory compounds that fail to promote functional symptoms-free disease remission, urging new drug discoveries to handle patients during this step of the disease. ALIAmides (ALIA, autacoid local injury antagonism) are bioactive fatty acid amides that recently gained attention because of their involvement in the control of inflammatory response, prompting the use of these molecules as plausible therapeutic strategies in the treatment of several chronic inflammatory conditions. N-palmitoyl-D-glucosamine (PGA), an under-researched ALIAmide, resulted in being safe and effective in preclinical models of inflammation and pain, suggesting its potential engagement in the treatment of IBD. In our study, we demonstrated that micronized PGA significantly and dose-dependently reduces colitis severity, improves intestinal mucosa integrity by increasing the tight junction proteins expression, and downregulates the TLR-4/NLRP3/iNOS pathway via PPAR-α receptors signaling in DNBS-treated mice. The possibility of clinically exploiting micronized PGA as support for the treatment and prevention of inflammation-related changes in IBD patients would represent an innovative, effective, and safe strategy

A palmitoylethanolamide producing lactobacillus paracasei improves clostridium difficile toxin a-induced colitis

Genetically engineered probiotics, able to in situ deliver therapeutically active compounds while restoring gut eubiosis, could represent an attractive therapeutic alternative in Clostridium difficile infection (CDI). Palmitoylethanolamide is an endogenous lipid able to exert immunomodulatory activities and restore epithelial barrier integrity in human models of colitis, by binding the peroxisome proliferator–activated receptor-α (PPARα). The aim of this study was to explore the efficacy of a newly designed PEA-producing probiotic (pNAPE-LP) in a mice model of C. difficile toxin A (TcdA)-induced colitis. The human N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), a key enzyme involved in the synthesis of PEA, was cloned and expressed in a Lactobacillus paracasei that was intragastrically administered to mice 7 days prior the induction of the colitis. Bacteria carrying the empty vector served as negative controls (pLP).In the presence of palmitate, pNAPE-LP was able to significantly increase PEA production by 27,900%, in a time- and concentration-dependent fashion. Mice treated with pNAPE-LP showed a significant improvement of colitis in terms of histological damage score, macrophage count, and myeloperoxidase levels (−53, −82, and −70.4%, respectively). This was paralleled by a significant decrease both in the expression of toll-like receptor-4 (−71%), phospho-p38 mitogen-activated protein kinase (−72%), hypoxia-inducible factor-1-alpha (−53%), p50 (−74%), and p65 (−60%) and in the plasmatic levels of interleukin-6 (−86%), nitric oxide (−59%), and vascular endothelial growth factor (−71%). Finally, tight junction protein expression was significantly improved by pNAPE-LP treatment as witnessed by the rescue of zonula occludens-1 (+304%), Ras homolog family member A-GTP (+649%), and occludin expression (+160%). These protective effects were mediated by the specific release of PEA by the engineered probiotic as they were abolished in PPARα knockout mice and in wild-type mice treated with pLP. Herein, we demonstrated that pNAPE-LP has therapeutic potential in CDI by inhibiting colonic inflammation and restoring tight junction protein expression in mice, paving the way to next generation probiotics as a promising strategy in CDI prevention

High Voltage System for the CMS Electromagnetic Calorimeter

The CMS electromagnetic calorimeter (ECAL) is made of about 75000 lead tungstate crystals. The 61200 crystals of the barrel part are read by avalanche photodiodes (APD) with internal amplification of the signal. Since the gain strongly depends on the bias voltage, the APDs require a very stable power supply system. To preserve the high energy resolution of the calorimeter, a stability of the bias voltage of the order of 10^-4 is required over several months, a typical interval between absolute calibrations of the full read-out chain with physics events. This paper describes the High Voltage power supply system developed for CMS ECAL and its performances as measured in laboratory tests and during test-beam operations of several modules of the calorimeter

Nutraceuticals and Diet Supplements in Crohn's Disease: A General Overview of the Most Promising Approaches in the Clinic

: Crohn's disease (CD) is a chronic inflammatory gastrointestinal disorder requiring lifelong medications. The currently approved drugs for CD are associated with relevant side effects and several studies suggest an increased use of nutraceuticals among CD patients, seeking for what is perceived as a more "natural" approach in controlling this highly morbid condition. Nutraceuticals are foods or foods' components with beneficial health properties that could aid in CD treatment for their anti-inflammatory, analgesic and immunoregulatory activities that come along with safety, high tolerability, easy availability and affordability. Depending on their biological effect, nutraceuticals' support could be employed in different subsets of CD patients, both those with active disease, as adjunctive immunomodulatory therapies, and/or in quiescent disease to provide symptomatic relief in patients with residual functional symptoms. Despite the increasing interest of the general public, both limited research and lack of education from healthcare professionals regarding their real clinical effectiveness account for the increasing number of patients turning to unconventional sources. Professionals should recognize their widespread use and the evidence base for or against their efficacy to properly counsel IBD patients. Overall, nutraceuticals appear to be safe complements to conventional therapies; nonetheless, little quality evidence supports a positive impact on underlying inflammatory activity

Contribution of KRAS mutations and c.2369C > T (p.T790M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA

INTRODUCTION: KRAS oncogene mutations (MUTKRAS) drive resistance to EGFR inhibition by providing alternative signaling as demonstrated in colo-rectal cancer. In non-small cell lung cancer (NSCLC), the efficacy of treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) depends on activating EGFR mutations (MUTEGFR). However, inhibition of EGFR may select resistant cells displaying alternative signaling, i.e., KRAS, or restoration of EGFR activity due to additional MUTEGFR, i.e., the c.2369C > T (p.T790MEGFR). AIM: The aim of this study was to investigate the appearance of MUTKRAS during EGFR-TKI treatment and their contribution to drug resistance. METHODS: This study used cell-free circulating tumor DNA (cftDNA) to evaluate the appearance of codon 12 MUTKRAS and p.T790MEGFR mutations in 33 advanced NSCLC patients progressing after an EGFR-TKI. RESULTS: p.T790MEGFR was detected in 11 (33.3%) patients, MUTKRAS at codon 12 in 3 (9.1%) while both p.T790MEGFR and MUTKRAS codon 12 were found in 13 (39.4%) patients. Six patients (18.2%) were KRAS wild-type (WTKRAS) and negative for p.T790MEGFR. In 8 subjects paired tumor re-biopsy/plasma samples were available; the percent concordance of tissue/plasma was 62.5% for p.T790MEGFR and 37.5% for MUTKRAS. The analysis of time to progression (TTP) and overall survival (OS) in WTKRAS vs. MUTKRAS were not statistically different, even if there was a better survival with WTKRAS vs. MUTKRAS, i.e., TTP 14.4 vs. 11.4 months (p = 0.97) and OS 40.2 vs. 35.0 months (p = 0.56), respectively. CONCLUSIONS: MUTKRAS could be an additional mechanism of escape from EGFR-TKI inhibition and cftDNA is a feasible approach to monitor the molecular development of drug resistance

Multiplicity of periodic solutions for systems of weakly coupled parametrized second order differential equations

We prove a multiplicity result of periodic solutions for a system of second order differential equations having asymmetric nonlinearities. The proof is based on a recent generalization of the Poincar\ue9\u2013Birkhoff fixed point theorem provided by Fonda and Ure\uf1a