Evaluation of polygenic determinants of non-alcoholic fatty liver disease (NAFLD) by a candidate genes resequencing strategy

NAFLD is a polygenic condition but the individual and cumulative contribution of identified genes remains to be established. To get additional insight into the genetic architecture of NAFLD, GWAS-identified GCKR, PPP1R3B, NCAN, LYPLAL1 and TM6SF2 genes were resequenced by next generation sequencing in a cohort of 218 NAFLD subjects and 227 controls, where PNPLA3 rs738409 and MBOAT7 rs641738 genotypes were also obtained. A total of 168 sequence variants were detected and 47 were annotated as functional. When all functional variants within each gene were considered, only those in TM6SF2 accumulate in NAFLD subjects compared to controls (P = 0.04). Among individual variants, rs1260326 in GCKR and rs641738 in MBOAT7 (recessive), rs58542926 in TM6SF2 and rs738409 in PNPLA3 (dominant) emerged as associated to NAFLD, with PNPLA3 rs738409 being the strongest predictor (OR 3.12, 95% CI, 1.8-5.5, P 0.28 was associated with a 3-fold increased risk of NAFLD. Interestingly, rs61756425 in PPP1R3B and rs641738 in MBOAT7 genes were predictors of NAFLD severity. Overall, TM6SF2, GCKR, PNPLA3 and MBOAT7 were confirmed to be associated with NAFLD and a score based on these genes was highly predictive of this condition. In addition, PPP1R3B and MBOAT7 might influence NAFLD severity

Regulating liminality: Making sense of the vegetative state and defining the limits of end-of-life action

Persistently alive but unaware, vegetative state patients are stuck in the transition between life and death – that is, in a liminal hotspot. This condition raises complex ethical and legal dilemmas concerning end-of-life action. Drawing on social representations (SRs) and the liminality framework, our research investigated how the vegetative state was constructed within the Italian parliamentary debates discussing end-of-life bills (2009–2017). We aimed to understand (1) how political groups represented the vegetative state, (2) how they legitimised different end-of-life bills and (3) came to terms with the issue of liminal hotspots. By dialogically analysing three debates (No. of interventions = 98), we identified six themes and discursive aims allowing parliamentarians to differently represent the vegetative state and support different courses of action. In turn, we identified new features of the psycho-social processes generating SRs: the dialogical tensions between anchoring and de-anchoring. Results corroborated the idea that de-paradoxifying liminality relies on group sense-making and, thus, different political leanings differently addressed the liminality of the vegetative state. We also reveal a novel feature of dealing with liminal hotspots informing the psycho-social literature that applies when a decision needs to be taken, such as in the case of crafting a law: moving from the paradox.info:eu-repo/semantics/publishedVersio

On Cascades of Reset Automata

The Krohn-Rhodes decomposition theorem is a pivotal result in automata theory. It introduces the concept of cascade product, where two semiautomata, that is, automata devoid of initial and final states, are combined in a feed-forward fashion. The theorem states that any semiautomaton can be decomposed into a sequence of permutation-reset semiautomata. For the counter-free case, this decomposition consists entirely of reset components with two states each. This decomposition has significantly impacted recent research in various areas of computer science, including the identification of a class of transformer encoders equivalent to star-free languages and the conversion of Linear Temporal Logic formulas into past-only expressions (pastification). The paper revisits the cascade product in the context of reset automata, thus considering each component of the cascade as a language acceptor. First, we give regular expression counterparts of cascades of reset automata. We then establish several expressiveness results, identifying hierarchies of languages based on the restriction of the height (number of components) of the cascade or of the number of states in each level. We also show that any cascade of reset automata can be transformed, with a quadratic increase in height, into a cascade that only includes two-state components. Finally, we show that some fundamental operations on cascades, like intersection, union, negation, and concatenation with a symbol to the left, can be directly and efficiently computed by adding a two-state component

Resilience Analysis of Service Oriented Collaboration Process Management systems

Collaborative business process management allows for the automated coordination of processes involving human and computer actors. In modern economies it is increasingly needed for this coordination to be not only within organizations but also to cross organizational boundaries. The dependence on the performance of other organizations should however be limited, and the control over the own processes is required from a competitiveness perspective. The main objective of this work is to propose an evaluation model for measuring a resilience of a Service Oriented Architecture (SOA) collaborative process management system. In this paper, we have proposed resilience analysis perspectives of SOA collaborative process systems, i.e. overall system perspective, individual process model perspective, individual process instance perspective, service perspective, and resource perspective. A collaborative incident and maintenance notification process system is reviewed for illustrating our resilience analysis. This research contributes to extend SOA collaborative business process management systems with resilience support, not only looking at quantification and identification of resilience factors, but also considering ways of improving the resilience of SOA collaborative process systems through measures at design and run-time

Insights Into the Immune Response of the Black Soldier Fly Larvae to Bacteria

In insects, a complex and effective immune system that can be rapidly activated by a plethora of stimuli has evolved. Although the main cellular and humoral mechanisms and their activation pathways are highly conserved across insects, the timing and the ef\ufb01cacy of triggered immune responses can differ among different species. In this scenario, an insect deserving particular attention is the black soldier \ufb02 y (BSF), Hermetia illucens (Diptera: Stratiomyidae). Indeed, BSF larvae can be reared on a wide range of decaying organic substrates and, thanks to their high protein and lipid content, they represent a valuable source of macromolecules useful for different applications (e.g., production of feedstuff, bioplastics, and biodiesel), thus contributing to the development of circular economy supply chains for waste valorization. However, decaying substrates bring the larvae into contact with different potential pathogens that can challenge their health status and growth. Although these life strategies have presumably contributed to shape the evolution of a sophisticated and ef \ufb01 cient immune system in this dipteran, knowledge about its functional features is still fragmentary. In the present study, we investigated the processes underpinning the immune response to bacteria in H. illucens larvae and characterized their reaction times. Our data demonstrate that the cellular and humoral responses in this insect show different kinetics: phagocytosis and encapsulation are rapidly triggered after the immune challenge, while the humoral components intervene later. Moreover, although both Gram-positive and Gram-negative bacteria are completely removed from the insect body within a few hours after injection, Gram-positive bacteria persist in the hemolymph longer than do Gram-negative bacteria. Finally, the activity of two key actors of the humoral response, i.e., lysozyme and phenoloxidase, show unusual dynamics as compared to other insects. This study represents the \ufb01 rst detailed characterization of the immune response to bacteria of H. illucens larvae, expanding knowledge on the defense mechanisms of this insect among Diptera. This information is a prerequisite to manipulating the larval immune response by nutritional and environmental factors to increase resistance to pathogens and optimize health status during mass rearing

Increased production of inflammatory cytokines by circulating monocytes in mesial temporal lobe epilepsy: A possible role in drug resistance

: We analyzed peripheral blood mononuclear cells (PBMCs) and serum inflammatory biomarkers in patients with mesial temporal lobe epilepsy (drug-resistant - DR, vs. drug-sensitive - DS). Patients with epilepsy showed higher levels of serum CCL2, CCL3, IL-8 and AOPP, and lower levels of FRAP and thiols compared to healthy controls (HC). Although none of the serum biomarkers distinguished DR from DS patients, when analysing intracellular cytokines after in vitro stimulation, DR patients presented higher percentages of IL-1β and IL-6 positive monocytes compared to DS patients and HC. Circulating innate immune cells might be implicated in DR epilepsy and constitute potential new targets for treatments

Handling Conflicts in Depth-First Search for LTL Tableau to Debug Compliance Based Languages

Providing adequate tools to tackle the problem of inconsistent compliance rules is a critical research topic. This problem is of paramount importance to achieve automatic support for early declarative design and to support evolution of rules in contract-based or service-based systems. In this paper we investigate the problem of extracting temporal unsatisfiable cores in order to detect the inconsistent part of a specification. We extend conflict-driven SAT-solver to provide a new conflict-driven depth-first-search solver for temporal logic. We use this solver to compute LTL unsatisfiable cores without re-exploring the history of the solver.Comment: In Proceedings FLACOS 2011, arXiv:1109.239

Phase 2 study of canfosfamide in combination with pegylated liposomal doxorubicin in platinum and paclitaxel refractory or resistant epithelial ovarian cancer

<p>Abstract</p> <p>Background</p> <p>Canfosfamide is a novel glutathione analog activated by glutathione S-transferase P1-1. This study evaluated the safety and efficacy of canfosfamide in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum resistant ovarian cancer. Patients with platinum resistant ovarian carcinoma and measurable disease received canfosfamide at 960 mg/m²in combination with PLD at 50 mg/m², intravenously day 1 in every 28 day cycles until tumor progression or unacceptable toxicities. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS).</p> <p>Results</p> <p>Canfosfamide plus PLD combination therapy was administered at 960/50 mg/m², respectively. Thirty-nine patients received a median number of 4 cycles (range 1.0-18.0). The ORR was 27.8% (95% CI, 14.2-45.2) with a disease stabilization rate of 80.6% (95% CI, 64.0-91.8) in the evaluable population. The CA-125 marker responses correlated with the radiological findings of complete response or partial response. The median PFS was 6.0 months (95% CI, 4.2-7.9) and median survival was 17.8 months. The combination was well tolerated. Myelosuppression was managed with dose reductions and growth factor support. Grade 3 febrile neutropenia was observed in 2 patients (5.1%). Non-hematologic adverse events occurred at the expected frequency and grade for each drug alone, with no unexpected or cumulative toxicities.</p> <p>Conclusions</p> <p>Canfosfamide in combination with PLD is well tolerated and active in platinum and paclitaxel refractory or resistant ovarian cancer. A randomized phase 3 study was conducted based on this supportive phase 2 study.</p> <p>Trial Registration</p> <p>This study was registered at www.clinicaltrials.gov: NCT00052065.</p