Delay-constrained shortest paths: approximation algorithms and second-order cone models

Routing real-time traffic with maximum packet delay in contemporary telecommunication networks requires not only choosing a path, but also reserving transmission capacity along its arcs, as the delay is a nonlinear function of both components. The problem is known to be solvable in polynomial time under quite restrictive assumptions, i.e., Equal Rate Allocations (all arcs are reserved the same capacity) and identical reservation costs, whereas the general problem is NP-hard. We first extend the approaches to the ERA version to a pseudo-polynomial Dynamic Programming one for integer arc costs, and a FPTAS for the case of general arc costs. We then show that the general problem can be formulated as a mixed-integer Second-Order Cone (SOCP) program, and therefore solved with off-the-shelf technology. We compare two formulations: one based on standard big-M constraints, and one where Perspective Reformulation techniques are used to tighten the continuous relaxation. Extensive computational experiments on both real-world networks and randomly-generated realistic ones show that the ERA approach is fast and provides an effective heuristic for the general problem whenever it manages to find a solution at all, but it fails for a significant fraction of the instances that the SOCP models can solve. We therefore propose a three-pronged approach that combines the fast running time of the ERA algorithm and the effectiveness of the SOCP models, and show that it is capable of solving realistic-sized instances with high accuracy at different levels of network load in a time compatible with real-time usage in an operating environment

Medication overuse headache, addiction and personality pathology: a controlled study by SWAP-200

Background: Medication Overuse Headache (MOH) is a type of chronic headache, whose mechanisms are still unknown. Some empirical investigations examining the addiction-like behaviors and processes, as well as personality characteristics underlying MOH development, reached contrasting findings. This study aimed at detecting personality and its disorders (PDs) in MOH patients, with a specific attention to the features of addiction. Methods: Eighty-eight MOH patients have been compared with two clinical populations including 99 patients with Substance Use Disorder (SUD) and 91 with PDs using the Shedler-Westen Assessment Procedure-200 (SWAP-200). MANCOVAs were performed to evaluate personality differences among MOH, SUD and PD groups, controlling for age and gender. Results: MOH patients showed lower traits of the SWAP-200’s clusters A and B disorders than SUD and PD patients, whom presented more severe levels of personality impairment. No differences in the SWAP-200’s cluster C have been found, indicating common personality features in these populations. At levels of specific PDs, MOH patients presented higher obsessive and dysphoric traits, as well as better overall psychological functioning than SUD and PD patients. Conclusions: The study supported the presence of a specific pattern of personality in MOH patients including obsessive (perfectionist) and dysphoric characteristics, as well as good enough psychological resources. No similarities with drug addicted and personality-disordered patients were found. Practitioners’ careful understanding of the personality of MOH patients may be useful to provide more effective treatment strategies and patient-tailored intervention programs

A dose-ranging study in older adults to compare the safety and immunogenicity profiles of MF59®-adjuvanted and non-adjuvanted seasonal influenza vaccines following intradermal and intramuscular administration

Strategies to optimize responses to seasonal influenza vaccination in older adults include the use of adjuvants, higher antigen doses, and intradermal delivery. In this study adults aged >= 65 years (n = 450) received a single dose of 1 of 2 non-adjuvanted trivalent influenza vaccine (TIV) formulations administered intradermally (ID), both containing 6 mu g of A/H1N1 and B, differing in A/H3N2 content (6 mu g or 12 mu g), or a single dose of 1 of 8 TIV formulations administered intramuscularly (IM) all containing 15 mu g of A/H1N1 and B, differing in A/H3N2 hemagglutinin (HA) content (15 mu g or 30 mu g) and/or in MF59 (R) adjuvant content (0%, 25%, 50%, or 100% of the standard dose). This paper focuses on the comparisons of low-dose non-adjuvanted ID, full-dose non-adjuvanted IM and full-dose MF59-adjuvanted IM formulations (n = 270). At day 22 post-vaccination, at least one European licensure immunogenicity criterion was met by all groups against all 3 strains; however, all three criteria were met against all 3 vaccine strains by the low-dose non-adjuvanted ID and the full-dose MF59-adjuvanted IM groups only. The full-dose MF59-adjuvanted IM group elicited significantly higher immune response vs. the low-dose non-adjuvanted ID formulations for most comparisons. The full-dose MF59 adjuvanted IM groups were associated with increased pain at the site of injection (P < 0.01) compared to the ID groups, and the low-dose non-adjuvanted ID groups were associated with increased erythema, induration, and swelling at the injection site (P < 0.0001) and unsolicited AEs compared with the IM groups. There were no differences between IM and ID groups in the frequencies of subjects experiencing solicited systemic reactions. Overall, while MF59 adjuvantation increased pain at the site of injection, and intradermal delivery increased unsolicited adverse events, erythema, induration, and swelling at the injection site, both strategies of vaccination strongly enhanced the immunogenicity of seasonal influenza vaccine in older adults compared with conventional non-adjuvanted intramuscular delivery

A recombination-based method to characterize human BRCA1 missense variants

Purpose. Many missense variants in BRCA1 are of unclear clinical significance. Functional and genetic approaches have been proposed for elucidating the clinical significance of such variants. The purpose of the present study was to evaluate BRCA1 missense variants for their effect on both Homologous Recombination (HR) and Non Homologous End Joining (NHEJ). Methods. HR frequency evaluation: HeLaG1 cells, containing a stably integrated plasmid that allows to measure HR events by gene conversion events were transfected with the pcDNA3&#946; expression vector containing the BRCA1-wild type (BRCA1-WT) or the BRCA1-Unclassified Variants (BRCA1-UCVs). The NHEJ was measured by a random plasmid integration assay. Results. This assays suggested a BRCA1 involvement mainly in the NHEJ. As a matter of fact, the Y179C and the A1789T variant altered significantly the NHEJ activity as compared to the wild type, suggesting that they may be related to BRCA1 associated pathogenicity by affecting this function. The variants N550H and I1766S, and the mutation M1775R did not alter the NHEJ frequency. Conclusions. These data, beside proposing a method for the study of BRCA1 variants effect on HR and NHEJ, highlighted the need for a range of functional assays to be performed in order to identify variants with altered function

Expression of bovine cytosolic 5’-nucleotidase (cN-II) in yeast: nucleotide pools disturbance and its consequences on growth and homologous recombination

Cytosolic 5′-nucleotidase II is a widespread IMP hydrolyzing enzyme, essential for cell vitality, whose role in nucleotide metabolism and cell function is still to be exactly determined. Cytosolic 5′-nucleotidase overexpression and silencing have both been demonstrated to be toxic for mammalian cultured cells. In order to ascertain the effect of enzyme expression on a well-known eukaryote simple model, we expressed cytosolic 5′-nucleotidase II in Saccharomyces cerevisiae, which normally hydrolyzes IMP through the action of a nucleotidase with distinct functional and structural features. Heterologous expression was successful. The yeast cells harbouring cytosolic 5′-nucleotidase II displayed a shorter duplication time and a significant modification of purine and pyrimidine derivatives concentration as compared with the control strain. Furthermore the capacity of homologous recombination in the presence of mutagenic compounds of yeast expressing cytosolic 5′-nucleotidase II was markedly impaired

Cytosolic 5'-Nucleotidase II Interacts with the Leucin Rich Repeat of NLR Family Member Ipaf

IMP/GMP preferring cytosolic 5'-nucleotidase II (cN-II) is a bifunctional enzyme whose activities and expression play crucial roles in nucleotide pool maintenance, nucleotide-dependent pathways and programmed cell death. Alignment of primary amino acid sequences of cN-II from human and other organisms show a strong conservation throughout the entire vertebrata taxon suggesting a fundamental role in eukaryotic cells. With the aim to investigate the potential role of this homology in protein-protein interactions, a two hybrid system screening of cN-II interactors was performed in S. cerevisiae. Among the X positive hits, the Leucin Rich Repeat (LRR) domain of Ipaf was found to interact with cN-II. Recombinant Ipaf isoform B (lacking the Nucleotide Binding Domain) was used in an in vitro affinity chromatography assay confirming the interaction obtained in the screening. Moreover, co-immunoprecipitation with proteins from wild type Human Embryonic Kidney 293 T cells demonstrated that endogenous cN-II co-immunoprecipitated both with wild type Ipaf and its LRR domain after transfection with corresponding expression vectors, but not with Ipaf lacking the LRR domain. These results suggest that the interaction takes place through the LRR domain of Ipaf. In addition, a proximity ligation assay was performed in A549 lung carcinoma cells and in MDA-MB-231 breast cancer cells and showed a positive cytosolic signal, confirming that this interaction occurs in human cells. This is the first report of a protein-protein interaction involving cN-II, suggesting either novel functions or an additional level of regulation of this complex enzym

Proposal of a Full Digital Workflow for a Bite Fork to Assess Mandibular Advancement during Drug-Induced Sleep Endoscopy (DISE) for Obstructive Sleep Apnea

Abstract: (1) Background. Drug-induced sleep endoscopy (DISE) is currently regarded as the gold standard diagnostic procedure to assess the site(s) of upper airway collapse in subjects affected by Obstructive Sleep Apnea Syndrome (OSAS). During DISE, a jaw thrust maneuver is performed to advance the mandible and to predict the effectiveness of outcomes of treatment with mandibular advancement devices (MADs). However, the maneuver is not predictable and could be influenced by specific patients’ anatomical/functional conditions. The aim of this work is to propose a full-digital workflow for customizing an individual mandibular advancement fork, usable by otorhinolaryn gologists during DISE. (2) Materials. Two patients with a diagnosis of mild-to-moderate OSAS (AHI ≥ 5 to ≤30/h of sleep) underwent orthodontic examination to verify the usability of the MAD. Intra-oral scans and registration were performed, including bite registration with 65% of mandibular advancement. The latter measurement was used as a reference to design a 3D-printed fork for DISE, as well as for the future MAD. Both patients underwent DISE in the operating room in the presence of an anesthesiologist, otolaryngologist, orthodontic specialist and neurophysiopathology technician. (3) Results. In the intraoperative polysomnography recording, during sleep, the pres ence of obstructive apnea was confirmed based on respiratory parameters (PNG1, PNG2, PNG3) with associated desaturation and increased muscle activities on PNG4 (mylohyoid muscle), EMG1 (right masseter muscle) and EMG2 (left masseter muscle). With the advancement fork in place, the immediate improvement effect on all respiratory parameters with normal saturation values and the complete suppression of masseter muscles were observed. Accordingly, both patients were considered potential good-responders to the MAD treatment. (4) Conclusions. The preliminary data shown are encouraging and would suggest that the fork represents a stable reference for the otorhinolaryngologist to evaluate the airway patency within the physiological range of movement. The efficiency of the work-flow from data registration to the DISE procedure and laboratory process represent two significant advantages that justify the integration of a digital system in the management of patients affected by OSA

Characterisation of gene expression profiles of yeast cells expressing BRCA1 missense variants

Germline mutations in breast cancer susceptibility gene 1 (BRCA1) confer high risk of developing breast and ovarian cancers. Even though most BRCA1 cancer-predisposing mutations produce a non-functional truncated protein, 5-10% of them cause single amino acid substitutions. This second type of mutations represents a useful tool for examining BRCA1 molecular functions. Human BRCA1 inhibits cell proliferation in transformed Saccharomyces cerevisiae cells and this effect is abolished by disease-associated mutations in the BRCT domain. Moreover, BRCA1 mutations located both inside and outside the BRCT domain may induce an increase in the homologous recombination frequency in yeast cells. Here we present a microarray analysis of gene expression induced in yeast cells transformed with five BRCA1 missense variants, in comparison with gene expression induced by wildtype BRCA1. Data analysis was performed by grouping the BRCA1 variants into three sets: Recombination (R)-set (Y179C and S1164I), Recombination and Proliferation (RP)-set(I1766S and M1775R) and Proliferation (P)-set (A1789T), according to their effects on yeast cell phenotype. We found 470, 740 and 1136 differentially expressed genes in R-, P- and RP-set, respectively. Our results point to some molecular mechanisms critical for the control of cell proliferation and of genome integrity providing support to a possible pathogenic role of the analysed mutations. They also confirm that yeast, despite the absence of a BRCA1 homologue, represents a valid model system to examine BRCA1 molecular functions, as the molecular pathways activated by BRCA1 variants are conserved in humans

Traumatic experiences, stressful events, and alexithymia in chronic migraine with medication overuse

Background: Many factors are involved in the prognosis and outcome of Chronic Migraine and Medication Overuse Headache (CM+MOH), and their understanding is a topic of interest. It is well known that CM+MOH patients experience increased psychiatric comorbidity, such as anxiety, depression, or personality disorders. Other psychological factors still need to be explored. The present study is aimed to evaluate whether early life traumatic experiences, stressful life events, and alexithymia can be associated with CM+MOH. Methods: Three hundred and thirty-one individuals were recruited for this study. They belonged to one of the two following groups: CM+MOH (N = 179; 79% females, Age: 45.2 \ub1 9.8) and episodic migraine (EM) (N = 152; 81% females; Age: 40.7 \ub1 11.0). Diagnosis was operationally defined according to the International Classification of Headache Disorders 3rd edition (ICHD-III\u3b2). Data on early life (physical and emotional) traumatic experiences, recent stressful events and alexithymia were collected by means of the Childhood Trauma Questionnaire, the Stressful life-events Questionnaire, and the Toronto Alexithymia Scale (TAS-20), respectively. Results: Data showed a higher prevalence of emotional (\u3c72= 6.99; d.f. = 1; p = 0.006) and physical (\u3c72= 6.18; d.f. = 1; p = 0.009) childhood trauma and of current stressful events of important impact (\u3c72= 4.42; d.f. = 1; p = 0.025) in CM+MOH patients than in EM ones. CM+MOH patients were characterized by higher difficulties in a specific alexithymic trait (Factor 1 subscale of TAS-20) [F(1, 326)= 6.76, p = 0.01, \u3b7p2= 0.02] when compared to the EM group. The role of these factors was confirmed in a multivariate analysis, which showed an association of CM+MOH with emotional (OR 2.655; 95% CI 1.153-6.115, p = 0.022) or physical trauma (OR 2.763; 95% CI 1.322-5.771, p = 0.007), and a high score at the Factor 1 (OR 1.039; 95% CI 1.002-1.078, p = 0.040). Conclusions: Our findings demonstrated a clear relationship between CM+MOH and life traumas, stressful events, and alexithymia. These observations have a relevant role in multiple fields of related to chronic headache: from the management to the nosographic framing